Radiosensitivity Index is Not Fit to be Used for Dose Adjustments: A Pan-Cancer Analysis.

AIMS: To explore the preclinical and latest clinical evidence of the radiation sensitivity signature termed 'radiosensitivity index' (RSI), to assess its suitability as an input into dose-adjustment algorithms. MATERIALS AND METHODS: The original preclinical test-set data from the publication where RSI was derived were collected and reanalysed by comparing the observed versus predicted survival fraction at 2 Gy (SF2). In addition, the predictive capability of RSI was also compared to random guessing. Clinical data were collected from a recently published dataset that included RSI values, overall survival outcomes, radiotherapy dose and tumour site for six cancers (glioma, triple-negative breast, endometrial, melanoma, pancreatic and lung cancer). Cox proportional hazards models were used to assess: (i) does adjusting for RSI elucidate a dose response and (ii) does an interaction between RSI and dose exist with good precision. RESULTS: Preclinically, RSI showed a negative correlation (Spearman's rho = -0.61) between observed and predicted SF2, which remained negative after removing leukaemia cell lines. Furthermore, random guesses showed better correlation to SF2 than RSI, 98% of the time on the full dataset and 80% after removing leukaemia cell lines. The preclinical data show that RSI does not explain the variance in SF2 better than random guessing. Clinically, a dose response was not seen after adjusting for RSI (hazard ratio = 1.00, 95% confidence interval 0.97-1.04; P = 0.876) and no evidence of an interaction between RSI and dose was found (P = 0.844). CONCLUSIONS: These results suggest that RSI does not explain a sufficient amount of the outcome variance to be used within dose-adjustment algorithms.

Clinico-pathological predictors of clinical complete response in rectal cancer.

PURPOSE: Prediction of clinical complete response in rectal cancer before neoadjuvant chemo-radiotherapy treatment enables treatment selection. Patients predicted to have complete response could have chemo-radiotherapy, and others could have additional doublet chemotherapy at this stage of their treatment to improve their overall outcome. This work investigates the role of clinical variables in predicting clinical complete response. METHOD: Using the UK-based OnCoRe database (2008 to 2019), we performed a propensity-score matched study of 322 patients who received neoadjuvant chemoradiotherapy. We collected pre-treatment clinic-pathological, inflammatory and radiotherapy-related characteristics. We determined the odds for the occurrence of cCR using conditional logistic regression models. We derived the post-model Area under the Curve (AUC) as an indicator of discrimination performance and stated a priori that an AUC of 0.75 or greater was required for potential clinical utility. RESULTS: Pre-treatment tumour diameter, mrT-stage, haemoglobin, alkaline phosphate and total radiotherapy depths were associated with cCR on univariable and multivariable analysis. Additionally, neutrophil to lymphocyte ratio (NLR), neutrophil-monocyte to lymphocyte ratio (NMLR), lymphocyte count and albumin were all significantly associated with cCR on multivariable analysis. A nomogram using the above parameters was developed with a resulting ROC AUC of 0.75. CONCLUSION: We identified routine clinic-pathological, inflammatory and radiotherapy-related variables which are independently associated with cCR. A nomogram was developed to predict cCR. The performance characteristics from this model were on the prior clinical utility threshold. Additional research is required to develop more associated variables to better select patients with rectal cancer undergoing chemoradiotherapy who may benefit from pursuing a W&W strategy.

Translation of Prognostic and Pharmacodynamic Biomarkers from Trial to Non-trial Patients with Metastatic Castration-resistant Prostate Cancer Treated with Docetaxel.

AIMS: We conducted a pooled analysis of four randomised controlled trials and a non-trial retrospective dataset to study the changes in serum prostate-specific antigen (PSA) concentrations during treatment and its impact on survival in men treated with docetaxel for metastatic castration-resistant prostate cancer. We also compared the outcomes and pre-treatment prognostic factors between trial and non-trial patients. MATERIALS AND METHODS: Data were obtained from four randomised controlled trials and a non-trial cohort from a tertiary cancer centre. The PSA kinetics covariates chosen were absolute value (PSAT), best percentage change (BPCH) and tumour growth rate (K). The association between the covariates collected and overall survival was assessed within a Cox proportional hazards model. How well a covariate captured the difference between trial and non-trial patients was assessed by reporting on models with or without trial status as a covariate. RESULTS: We reviewed individual datasets of 2282 patients. The median overall survival for trial patients was 20.4 (95% confidence interval 19.6-22.2) months and for the non-trial cohort was 12.4 (10.7-14.7) months (P < 0.001). Of the pre-treatment factors, we found that only lactate dehydrogenase fully captured the difference in prognosis between the trial and non-trial cohorts. All PSA kinetic metrics appeared to be prognostic in both the trial and non-trial patients. However, the effect size was reduced in non-trial versus trial patients (interaction P < 0.001). Of the time-dependent covariates, we found that BPCH best captured the difference between trial and non-trial patient prognosis. CONCLUSIONS: The analysis presented here highlights how data from open-source trial databases can be combined with emerging clinical practice databases to assess differences between trial versus non-trial patients for particular treatments. These results highlight the importance of developing prognostic models using both pre-treatment and time-dependent biomarkers of new treatments.

Using Real-world Data to Define a Validated Nomogram for Advanced Bladder Cancer Patients Who Respond to Immunotherapy.

AIMS: Immune checkpoint inhibitors (ICIs) are used in incurable urothelial cancers, both in chemo-naïve and platinum-refractory patients. Efficacy and toxicity data published outside controlled clinical trials are limited. We report overall survival, progression-free survival and toxicities of ICIs in locally advanced (LABC) or metastatic bladder cancer (MBC). We aimed to develop and validate a prognostic model for these patients. MATERIALS AND METHODS: A multicentre real-world individual patient-level data study (n = 272) evaluating ICIs in the first-line platinum-ineligible or platinum-refractory setting for LABC/MBC between March 2017 and February 2020 was undertaken. Cox regression analyses evaluated the association of prognostic factors with overall survival. Data were split to create a training (n = 208) and validation (n = 64) cohort. The backward elimination method with a P-value cut-off of 0.05 was used to develop a reduced prognostic model using the training data set. The concordance index and assessment of observed versus predicted survival probabilities were used to evaluate the final model. RESULTS: The median follow-up was 18.9 (15.8-21.5) months. The median overall survival and progression-free survival in the training cohort were 9.2 (95% confidence interval 7.4-10.5) and 4.5 months (3.5-5.7), respectively. The most common grade 1/2 adverse events recorded were fatigue (47.8%) and infection (19.9%). Five key prognostic factors found in the training set were low haemoglobin, high neutrophil count, choice of immunotherapy favouring pembrolizumab, presence of liver metastasis and steroid use within 30 days of treatment. The concordance index for the training and validation cohorts was 0.66 (standard error = 0.05) and 0.64 (standard error = 0.04), respectively, for the final model. A nomogram was developed to calculate the expected survival probabilities based on risk factors. CONCLUSIONS: Real-world data were used to produce a validated prognostic model for overall survival in LABC/MBC treated with ICIs. This model could assist in patient stratification, interpreting and framing future trials incorporating PD-1/PD-L1 inhibitors in LABC/MBC.

A Multicentre UK Study of Outcomes for Locally Advanced Sinonasal Squamous Cell Carcinoma Treated with Adjuvant or Definitive Intensity-modulated Radiotherapy.

AIMS: Sinonasal malignancies are rare; the most common histological subtype is squamous cell carcinoma (SCC). No randomised trial data exist to guide treatment decisions, with options including surgery, radiotherapy and chemotherapy. The role and sequence of a primary non-surgical approach in this disease remains uncertain. The aim of this study was to present treatment outcomes for a multicentre population of patients with locally advanced, stage IVa/b sinonasal SCC treated with radical-intent intensity-modulated radiotherapy, either definitively or postoperatively. MATERIALS AND METHODS: Consecutively treated patients with locally advanced, stage IVa/b sinonasal SCC at four UK oncology centres between January 2012 and December 2017 were retrospectively identified. Descriptive statistics and survival analyses were carried out. Univariable Cox regression analysis was carried out to evaluate the relationship between patient, disease and treatment factors and survival outcomes. RESULTS: In total, 56 patients with sinonasal SCC were included (70% maxillary sinus, 21% nasal cavity, 9% ethmoid/frontal sinus). Forty-one patients (73%) were treated by surgery/adjuvant (chemo)radiotherapy and 15 (27%) by definitive (chemo)radiotherapy. The median duration of follow-up was 3.8 years (interquartile range 2.0-4.7 years). Estimates for 5-year overall survival and progression-free survival were 30.2% and 24.2%, respectively. Local, regional and distant treatment failures were seen in 33%, 33% and 16% of patients, respectively. Univariable analysis revealed inferior progression-free survival for patients treated with neck dissection (hazard ratio 2.6, 95% confidence interval 1.2-6.1, P = 0.022) but no other significant association between the studied factors and survival outcomes. CONCLUSION: We show poor survival outcomes and high rates of locoregional treatment failure for patients with locally advanced stage IVa/b sinonasal SCC. There is a need to investigate improved treatments for this group of patients.

A case of Infective Native (Abdominal) Aortic Aneurysm Caused by Streptococcus Agalactiae: An Updated Literature Review Based on New Nomenclature.

The management of abdominal aortic aneurysms (AAA) has evolved significantly with the advent of endovascular strategies. Thus, there has been a decline in the number of open AAA repairs once an endovascular option is available. There have also been reports of successful endovascular management of infective native aortic aneurysms (INAA)1, previously called mycotic aneurysms2. The rarity of this condition makes its management a challenging one as there are no standard guidelines. The European Society of Vascular Surgery has suggested that the nomenclature be changed from mycotic aneurysms as this can be misleading to standardise reporting1. The authors' present a case of a 67-year old male who presented during the peak of the Corona Virus pandemic with constitutional gastrointestinal symptoms. He was subsequently diagnosed with an INAA and successfully managed with open Neo-Aorto Iliac System reconstruction with a homograft3. The report highlights various strategies used in the surgical approach and their benefits in the management of INAA. Furthermore, a literature review of Streptococcus (Streptococcus agalactiae) species as a rare cause of INAA and how these cases were managed are also highlighted.

Improved survival prediction for oropharyngeal cancer beyond TNMv8.

PURPOSE: For oropharynx squamous cell carcinoma (OPSCC) this study aimed to: (i) compare 5-year overall survival (OS) stratification by AJCC/UICC TNM versions 7 (TNMv7) and 8 (TNMv8), (ii) determine whether changes to T and N stage groupings improve prognostication and (iii) develop and validate a model incorporating additional clinical characteristics to improve 5-year OS prediction. MATERIAL AND METHODS: All OPSCC treated with curative-intent at our institution between 2011 and 2017 were included. The primary endpoint was 5-year OS. Survival curves were produced for TNMv7 and TNMv8. A three-way interaction between T, N stage and p16 status was evaluated for improved prognostication. Cox proportional hazards modelling was used to derive a new predictive model. RESULTS: Of 750 OPSCC cases, 574 (77%) were p16-positive. TNMv8 was more prognostic than TNMv7 (concordance probability estimate [CPE] ±â€¯SE = 0.72 ±â€¯0.02 vs 0.53 ±â€¯0.02). For p16-positive disease, TNMv8 discriminated stages II vs I (HR 2.32, 95% CI 1.47-3.67) and III vs II (HR 1.75, 95% CI 1.13-2.72). For p16-negative disease, TNMv7 and TNMv8 demonstrated poor hazard discrimination. Different T, N stage and p16-status combinations did not improve prognostication after adjusting for other factors (CPE = 0.79 vs 0.79, p = 0.998). A model for p16-positive and p16-negative OPSCC including additional clinical characteristics improved 5-year OS prediction beyond TNMv8 (c-index 0.76 ±â€¯0.02). CONCLUSIONS: TNMv8 is superior to TNMv7 for p16-positive OPSCC, but both performed poorly for p16-negative disease. A novel model incorporating additional clinical characteristics improved 5-year OS prediction for both p16-positive and p16-negative disease.

Sacral Insufficiency Fracture Following Pelvic Radiotherapy in Gynaecological Malignancies: Development of a Predictive Model.

AIMS: To investigate the time-to-event and the evolution of sacral insufficiency fractures in gynaecological patients receiving pelvic external beam radiotherapy (EBRT) in relation to dosimetric and imaging parameters across a spectrum of radiotherapy delivery techniques, and to develop a predictive model with a clinical nomogram to identify those at risk of sacral insufficiency fracture. MATERIALS AND METHODS: Patients who received radical or adjuvant pelvic EBRT for gynaecological malignancy between 2014 and 2019 were identified. The data collected were: demographics and clinical details; radiotherapy planning data: dose, fractionation, technique (fixed-field intensity-modulated radiotherapy, adaptive arc, and non-adaptive arc), 60 Gy simultaneous integrated boost. Each plan was examined to determine the sacral dose in 5%/Gy3 increments. Follow-up magnetic resonance scans were reviewed for insufficiency fractures, defined as linear low T1-weighted signal intensity with a high short-T1 inversion recovery (STIR) signal. The site of insufficiency fracture was recreated on the planning computed tomography, the dose to insufficiency fracture contours was recorded and insufficiency fractures were determined as healed with resolution of high STIR signal. Univariable analysis was conducted of the clinical variables. The area under the receiver operator characteristic curve and odds ratio of the risk prediction model with 95% confidence interval are reported with a nomogram for use in clinical practice. RESULTS: 115 patients were identified; the median imaging follow-up was 12 months (2-47). 37.4% developed sacral insufficiency fractures; 93.0% were detected within 12 months of EBRT. At the final radiological follow-up, 83.7% of insufficiency fractures remained active. The radiotherapy delivery technique was not associated with insufficiency fracture after adjusting for patient age (P = 0.115). The location of the 60 Gy simultaneous integrated boost planning target volume did not impact upon the site of insufficiency fracture or the dose received by the insufficiency fracture sites. Age and V40Gy3 are predictors for insufficiency fracture and form the clinical risk model (receiver operator characteristic 0.72). CONCLUSIONS: Age and V40Gy3 predict sacral insufficiency fractures; future work should focus on optimising radiotherapy planning with adoption of a bone-sparing planning approach for those patients at high risk of insufficiency fracture.

Palliative Lung Radiotherapy: Higher Dose Leads to Improved Survival?

AIMS: Choosing the optimal palliative lung radiotherapy regimen is challenging. Guidance from The Royal College of Radiologists recommends treatment stratification based on performance status, but evidence suggests that higher radiotherapy doses may be associated with survival benefits. The aim of this study was to investigate the effects of fractionation regimen and additional factors on the survival of palliative lung cancer radiotherapy patients. MATERIALS AND METHODS: A retrospective univariable (n = 925) and multivariable (n = 422) survival analysis of the prognostic significance of baseline patient characteristics and treatment prescription was carried out on patients with non-small cell and small cell lung cancer treated with palliative lung radiotherapy. The covariates investigated included: gender, age, performance status, histology, comorbidities, stage, tumour location, tumour side, smoking status, pack year history, primary radiotherapy technique and fractionation scheme. The overall mortality rate at 30 and 90 days of treatment was calculated. RESULTS: Univariable analysis revealed that performance status (P < 0.001), fractionation scheme (P < 0.001), comorbidities (P = 0.02), small cell histology (P = 0.02), 'lifelong never' smoking status (P = 0.01) and gender (P = 0.06) were associated with survival. Upon multivariable analysis, only better performance status (P = 0.01) and increased dose/fractionation regimens of up to 30 Gy/10 fractions (P < 0.001) were associated with increased survival. Eighty-five (9.2%) and 316 patients (34%) died within 30 and 90 days of treatment, respectively. CONCLUSION: In this retrospective single-centre analysis of palliative lung radiotherapy, increased total dose (up to and including 30 Gy/10 fractions) was associated with better survival regardless of performance status.

Variables associated with survival in patients with invasive bladder cancer with and without surgery.

We recorded the survival of 141 patients assessed for radical cystectomy, which included cardiopulmonary exercise testing. The median Kaplan-Meier survival estimates were: 1540 days for the whole cohort; 2200 days after cystectomy scheduled (n = 108); and 843 days without surgery. The mortality hazard remained double that expected for a matched general population, but survival was better in patients scheduled for surgery than those who were not: the mortality hazard ratio (95%CI) after cystectomy was 0.43 (0.26-0.73) the mortality hazard without surgery, p = 0.001. The mortality hazard ratios for the three-variable Bayesian Model Averaging survival model for all 141 patients were: referral for surgery (0.5); haemoglobin concentration (0.98); and efficiency of carbon dioxide output (1.05). Efficiency of carbon dioxide output was the single variable in the postoperative model (n = 108), mortality hazard 1.08 (per unit increase). The ratio of observed to expected peak oxygen consumption associated best with mortality in 33 patients not referred for surgery, hazard ratio 0.001. Our results can inform consultations with patients with invasive bladder cancer and suggest that interventions to increase fitness and haemoglobin may improve survival in patients who do and who do not undergo radical cystectomy.

A Multicentre UK Study of Outcomes of Nasopharyngeal Carcinoma Treated With Intensity-Modulated Radiotherapy ± Chemotherapy.

AIMS: To report the outcomes of nasopharyngeal carcinoma in adults across three large centres in a non-endemic region in the era of intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Adult patients with nasopharyngeal carcinoma treated in three large cancer centres with IMRT ± chemotherapy with curative intent between 2009 and 2016 were identified from institutional databases. Radiotherapy was delivered with 70 Gy in 33-35 daily fractions. A univariable analysis was carried out to evaluate the relationship of patient, tumour and treatment factors with progression-free survival (PFS) and overall survival. RESULTS: In total, 151 patients were identified with a median follow-up of 5.2 years. The median age was 52 years (range 18-85). Seventy-five per cent were of Caucasian origin; 75% had non-keratinising tumours; Epstein Barr virus status was only available in 23% of patients; 74% of patients had stage III or IV disease; 54% of patients received induction chemotherapy; 86% of patients received concurrent chemotherapy. Five-year overall survival, PFS, local disease-free survival, regional disease-free survival and distant disease-free survival were 70%, 65%, 91%, 94% and 82%, respectively. Keratinising squamous cell carcinoma, older age, worse performance status, smoking and alcohol intake were associated with inferior overall survival and PFS. CONCLUSIONS: Local, regional and distant disease control are relatively high following IMRT ± chemotherapy in a non-endemic population. There was considerable heterogeneity in terms of radiotherapy treatment and the use of chemotherapy, encouraging the development of treatment protocols and expert peer review in non-endemic regions.

Novel phase I trial design to evaluate the addition of cediranib or selumetinib to preoperative chemoradiotherapy for locally advanced rectal cancer: the DREAMtherapy trial.

BACKGROUND: The DREAMtherapy (Dual REctal Angiogenesis MEK inhibition radiotherapy) trial is a novel intertwined design whereby two tyrosine kinase inhibitors (cediranib and selumetinib) were independently evaluated with rectal chemoradiotherapy (CRT) in an efficient manner to limit the extended follow-up period often required for radiotherapy studies. PATIENTS AND METHODS: Cediranib or selumetinib was commenced 10 days before and then continued with RT (45 Gy/25#/5 wks) and capecitabine (825 mg/m2 twice a day (BID)). When three patients in the cediranib 15-mg once daily (OD) cohort were in the surveillance period, recruitment to the selumetinib cohort commenced. This alternating schedule was followed throughout. Three cediranib (15, 20 and 30 mg OD) and two selumetinib cohorts (50 and 75 mg BID) were planned. Circulating and imaging biomarkers of inflammation/angiogenesis were evaluated. RESULTS: In case of cediranib, dose-limiting diarrhoea, fatigue and skin reactions were seen in the 30-mg OD cohort, and therefore, 20 mg OD was defined as the maximum tolerated dose. Forty-one percent patients achieved a clinical or pathological complete response (7/17), and 53% (9/17) had an excellent clinical or pathological response (ECPR). Significantly lower level of pre-treatment plasma tumour necrosis factor alpha (TNFα) was found in patients who had an ECPR. In case of selumetinib, the 50-mg BID cohort was poorly tolerated (fatigue and diarrhoea); a reduced dose cohort of 75-mg OD was opened which was also poorly tolerated, and further recruitment was abandoned. Of the 12 patients treated, two attained an ECPR (17%). CONCLUSIONS: This novel intertwined trial design is an effective way to independently investigate multiple agents with radiotherapy. The combination of cediranib with CRT was well tolerated with encouraging efficacy. TNFα emerged as a potential predictive biomarker of response and warrants further evaluation.

Systems Pharmacology Modeling of Prostate-Specific Antigen in Patients With Prostate Cancer Treated With an Androgen Receptor Antagonist and Down-Regulator.

First-in-human (FIH) studies with AZD3514, a selective androgen receptor (AR) down-regulator, showed decreases of >30% in the prostate-specific antigen (PSA) in some patients. A modeling approach was adopted to understand these observations and define the optimum clinical use hypothesis for AZD3514 for clinical testing. Initial empirical modeling showed that only baseline PSA correlated significantly with this biological response, whereas drug concentration did not. To identify the mechanistic cause of this observation, a mechanism-based model was first developed, which described the effects of AZD3514 on AR protein and PSA mRNA levels in LNCaP cells with and without dihydrotestosterone (DHT). Second, the mechanism-based model was linked to a population pharmacokinetic (PK) model; PSA effects of clinical doses were subsequently simulated under different clinical conditions. This model was used to adjust the design of the ongoing clinical FIH study and direct the backup program.

Placental expression of adenosine A(2A) receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies: interactions with placental renin-angiotensin system.

Hypoxia-inducible factors (HIFs), adenosine and tissue renin-angiotensin-system (RAS) promote angiogenesis and vascularisation. We investigated the temporal expression placental adenosine A2AR receptor and HIF-1α in early pregnancy and at delivery in normotensive (NT) and pre-eclamptic (PE) women. Results were compared to our previously reported angiotensin receptor data. Expression of A2AR and HIF-1α was highest at ≤10 weeks, positively correlated through pregnancy and was higher in PE than NT at delivery. The A2AR associated with the AT4R only in early pregnancy. We suggest adenosine and RAS may interact to promote placentation with a potential adaptation to poor placental perfusion in PE.

An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment.

Cell lines expressing ion channels (IC) and the advent of plate-based electrophysiology device have enabled a molecular understanding of the action potential (AP) as a means of early QT assessment. We sought to develop an in silico AP (isAP) model that provides an assessment of the effect of a compound on the myocyte AP duration (APD) using concentration-effect curve data from a panel of five ICs (hNav1.5, hCav1.2, hKv4.3/hKChIP2.2, hKv7.1/hminK, hKv11.1). A test set of 53 compounds was selected to cover a range of selective and mixed IC modulators that were tested for their effects on optically measured APD. A threshold of >10% change in APD at 90% repolarization (APD(90)) was used to signify an effect at the top test concentration. To capture the variations observed in left ventricular midmyocardial myocyte APD data from 19 different dogs, the isAP model was calibrated to produce an ensemble of 19 model variants that could capture the shape and form of the APs and also quantitatively replicate dofetilide- and diltiazem-induced APD(90) changes. Provided with IC panel data only, the isAP model was then used, blinded, to predict APD(90) changes greater than 10%. At a simulated concentration of 30 µM and based on a criterion that six of the variants had to agree, isAP prediction was scored as showing greater than 80% predictivity of compound activity. Thus, early in drug discovery, the isAP model allows integrating separate IC data and is amenable to the throughput required for use as a virtual screen.

Autogenous brachial-brachial fistula for vein access. Haemodynamic factors predicting outcome and 1 year clinical data.

UNLABELLED: Two-stage autogenous brachial vein-brachial artery access (ABBA) has been proposed as an option where adequate superficial vein is not available for the creation of conventional haemodialysis fistulae. METHODS: This report depicts the clinical outcome of a series of 17 consecutive patients who underwent ABBA in a single centre. Of the 17 patients, nine had had at least one previous arterioventricular (AV) fistula or graft, and eight were new to haemodialysis. Patencies were assessed using the Kaplan-Meier survival analysis. RESULTS: In 14 patients, the brachial vein was transposed (82%) and the time to transposition ranged from 4 to 26 weeks (median time: 6 weeks). The functional patency rate was 45.75% at 12 months. After stage one, all fistulas that went on to develop well had a brachial vein flow of at least 900 ml min(-1), and this was significantly higher than in fistulas that failed to develop (p=0.005). The maturation rate in our study was 65% and the median time to cannulation of the fistula was 8 weeks from the stage 1. Of the 17 patients, 12 (71%) experienced at least one complication. Ten (59%) demonstrated moderate-to-severe stenoses; eight of which necessitated angioplasty and/or percutaneous mechanical thrombolysis. CONCLUSIONS: ABBA was characterised by a high incidence of complications and a long period to achieve maturation. Despite close monitoring and a high rate of secondary interventions, the patency rate was low. With this experience, we now only consider it an alternative in patients without adequate superficial veins, who have had failed grafts or where there is a very high risk of infection.

The non-invasive biopsy--will urinary proteomics make the renal tissue biopsy redundant?

Proteomics is a rapidly advancing technique which gives functional insight into gene expression in living organisms. Urine is an ideal medium for study as it is readily available, easily obtained and less complex than other bodily fluids. Considerable progress has been made over the last 5 years in the study of urinary proteomics as a diagnostic tool for renal disease. Advantages over the traditional renal biopsy include accessibility, safety, the possibility of serial sampling and the potential for non-invasive prognostic and diagnostic monitoring of disease and an individual's response to treatment. Urinary proteomics is now moving from a discovery phase in small studies to a validation phase in much larger numbers of patients with renal disease. Whilst there are still some limitations in methodology, which are assessed in this review, the possibility of urinary proteomics replacing the invasive tissue biopsy for diagnosis of renal disease is becoming an increasingly realistic option.

Nonatopic allergen-independent mast cell activation in parasitized eosinophilic athymic rats.

It is possible to induce eosinophilia in congenitally athymic rats by infection with the parasite Ascaris suum. Athymic bronchial eosinophilia is associated with increased expression of IL-5 and eotaxin mRNA, and with the presence of residual T cells and mast cells. Anamnestic mastocytosis is particularly pronounced and in this study we examine the relationship between mast cell degranulation and IgE production in athymic rats following infection. Incubation of peritoneal mast cells from athymic rats with anti-IgE induced dose-dependent degranulation, as measured by histamine release. However, the failure of mast cells from infected athymic rats to degranulate following incubation with all but one of the parasite antigens selected confirms the absence of a specific IgE response. In contrast, all agonists induced degranulation in euthymic rats. The only parasite-derived factor to induce histamine release in all mast cells was Ascaris body fluid, which contains an element capable of inducing IgE-independent degranulation. Furthermore, increased levels of rat mast cell protease II in athymic bronchoalveolar lavage fluid suggest degranulation of mast cells by IgE and allergen independent means in vivo. We believe that the development of eosinophilic lung inflammation in the absence of specific IgE makes this a prototype for investigating the immunological mechanisms underlying nonatopic asthma.