Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS).

BACKGROUND: ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). METHODS: Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. RESULTS: Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6-1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1-10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. CONCLUSIONS: Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017-004166-10).

Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) can be cured by radical radiotherapy (RT). We previously found tumour MRE11 expression to be predictive of survival following RT in MIBC, and this was independently validated in a separate institute. Here, we investigated germline MRE11A variants as possible predictors of RT outcomes in MIBC, using next-generation sequencing (NGS). PATIENTS AND METHODS: The MRE11A gene was amplified in germline DNA from 186 prospectively recruited MIBC patients treated with RT and sequenced using bar-coded multiplexed NGS. Germline variants were analysed for associations with cancer-specific survival (CSS). For validation as a prognostic or predictive marker, rs1805363 was then genotyped in a cystectomy-treated MIBC cohort of 256 individuals. MRE11A mRNA isoform expression was measured in bladder cancer cell lines and primary tumour samples. RESULTS: Carriage of at least one of six (five novel) rare variants was associated with the worse RT outcome (hazard ratio [HR] 4.04, 95% confidence interval [95% CI] 1.42-11.51, P = 0.009). The single-nucleotide polymorphism (SNP), rs1805363 (minor allele frequency 11%), was also associated with worse CSS (per-allele HR 2.10, 95% CI 1.34-3.28, Ptrend = 0.001) following RT in MIBC, with a gene-dosage effect observed, but no effect seen on CSS in the cystectomy cohort (Ptrend = 0.89). Furthermore, rs1805363 influenced relative MRE11A isoform expression, with increased isoform 2 expression with carriage of the rs1805363 minor A allele. CONCLUSIONS: Germline MRE11A SNP rs1805363 was predictive of RT, but not of cystectomy outcome in MIBC. If successfully validated in an independent RT-treated cohort, this SNP could be a useful clinical tool for selecting patients for bladder-conserving treatment.

The association of pre-treatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme.

Neutrophil-lymphocyte ratio (NLR) is a marker of systemic inflammatory response and its elevation has recently been shown to be a poor prognostic factor in many malignancies including colon, prostate and bladder cancer. The primary aim of this study was to assess the prognostic impact of NLR in a clinically annotated cohort of patients with glioblastoma multiforme (GBM). We hypothesised that elevated NLR would be associated with worse prognosis. Between 2004 and 2009, 137 patients had surgery for GBM and were assessed for consideration of adjuvant therapy at our institution. Of these, 84 patients with an evaluable pre-corticosteroid full blood count result were identified and included in the final analysis. Median overall survival was 9.3 months (range 0.7-82.1). On univariate analysis, age >65 years, gender, ECOG performance status ≥2, frontal tumour, extent of surgical resection, completion of adjuvant chemoradiation protocol and NLR > 4 were significantly correlated with overall survival. Patients with NLR > 4, had a worse median overall survival at 7.5 months versus 11.2 months in patients with NLR ≤ 4 (hazard ratio 1.6, 95 % CI 1.00-2.52, p = 0.048). On multivariate analysis NLR > 4 remained an independent prognostic indicator for poor outcome. These data are an important reminder of the potential relevance of host immunity in GBM. In our cohort, NLR > 4 conferred a worse prognosis independent of other well established prognostic factors. If validated in other cohorts NLR may prove to be a useful addition in predicting prognosis in GBM patients. The demonstration that host immunity plays a role in GBM biology suggests that investigation of emerging therapies which modulate host immune response are warranted in this disease.

An Irish breast cancer survivorship study: are we meeting our patients' needs?

UNLABELLED: Irish breast cancer survivor's needs have not been studied. Physical, psychological, social and spiritual concerns were investigated. Patient satisfaction with hospital discharge, GP follow-up, and the benefit of a discharge pack was investigated. A cohort of patients from the South East Cancer Centre was identified. INCLUSION CRITERIA: localized breast cancer, completion of adjuvant therapy, GP-led follow-up in the last 5 years. An anonymous questionnaire was developed, and ethical approval obtained. Subgroup analyses for age and time since diagnosis and discharge were completed. 80 patients were identified. 44 patients (55%) completed the questionnaire, 5 (6%) were excluded. Commonest concerns included: fatigue (51%), fear of recurrence (69%) and second cancers concerns (69%) 23 (59%) and 25 patients (64%) were satisfied with discharge and GP follow-up respectively. 27 patients (67%) reported benefit from a discharge pack. Irish breast cancer survivors had concerns, and were satisfied with GP follow-up.

A phase II study evaluating the safety and efficacy of an adenovirus-ΔLMP1-LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma.

BACKGROUND: Individuals with metastatic Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) continue to have poor outcomes. To evaluate the ability of a dendritic cell (DC) vaccine to target subdominant EBV antigens LMP1 and LMP2 expressed by NPC cells, we vaccinated patients using autologous DCs transduced with an adenovirus encoding a truncated LMP1 (ΔLMP1) and full-length LMP2 (Ad-ΔLMP1-LMP2). MATERIALS AND METHODS: Sixteen subjects with metastatic NPC received Ad-ΔLMP1-LMP2 DC vaccines i.d. biweekly for up to five doses. Toxicity, immune responses and clinical responses were determined. RESULTS: Most patients had extensive disease, with a median of three visceral sites of involvement (range 1-7). No significant toxicity was observed. Ad-ΔLMP1-LMP2 DCs induced delayed type hypersensitivity responses in 9 out of 12 patients, but although these DCs activated LMP1/2-specific T cells in vitro, no such increase in the frequency of peripheral LMP1/2-specific T cells was detected. Three patients had clinical responses including one with partial response (for 7½ months) and two with stable disease (for 6½ and 7½ months). CONCLUSIONS: Ad-ΔLMP1-LMP2 transduced DCs can be successfully generated and safely administered to patients with advanced NPC. Since efficacy was limited, future studies should focus on DC vaccines with greater potency administered to subjects with less tumor burden.

Intensity-modulated Radiotherapy for Rectal Cancer in the UK in 2020.

AIMS: Preoperative (chemo)radiotherapy followed by total mesorectal excision is the current standard of care for patients with locally advanced rectal cancer. The use of intensity-modulated radiotherapy (IMRT) for rectal cancer is increasing in the UK. However, the extent of IMRT implementation and current practice was not previously known. A national survey was commissioned to investigate the landscape of IMRT use for rectal cancer and to inform the development of national rectal cancer IMRT guidance. MATERIALS AND METHODS: A web-based survey was developed by the National Rectal Cancer IMRT Guidance working group in collaboration with the Royal College of Radiologists and disseminated to all UK radiotherapy centres. The survey enquired about the implementation of IMRT with a focus on the following aspects of the workflow: dose fractionation schedules and use of a boost; pre-treatment preparation and simulation; target volume/organ at risk definition; treatment planning and treatment verification. A descriptive statistical analysis was carried out. RESULTS: In total, 44 of 63 centres (70%) responded to the survey; 30/44 (68%) and 36/44 (82%) centres currently use IMRT to treat all patients and selected patients with rectal cancer, respectively. There was general agreement concerning several aspects of the IMRT workflow, including patient positioning, use of intravenous contrast and bladder protocols. Greater variation in practice was identified regarding rectal protocols; use of a boost to primary/nodal disease; target volume delineation; organ at risk delineation and dose constraints and treatment verification. Delineation of individual small bowel loops and daily volumetric treatment verification were considered potentially feasible by most centres. CONCLUSION: This survey identified that IMRT is already used to treat rectal cancer in many UK radiotherapy centres, but there is heterogeneity between centres in its implementation and practice. These results have been a valuable aid in framing the recommendations within the new National Rectal Cancer IMRT Guidance.

Photoinduced structural conversions of transition metal chalcogenide materials.

The conversions of NiAs-type structures of transition metal chalcogenides (FeS and CoSe) to pyrite-type structures of dichalcogenides (FeS(2) and CoSe(2), respectively) under irradiation by HeNe laser (wavelength, 632.8 nm; intensity, 6 x 10(4) W/cm(2)) have been investigated using Raman spectroscopy. The laser-induced conversions give rise to Raman peaks corresponding to vibrations of S-S or Se-Se bonds of respective pyrite structures. The results are of interest for the characterization and fabrication of pyrite-like structures necessary for applications as oxygen reduction reaction catalysts. Material modifications at the micrometer and submicrometer levels are attainable. The structural conversions are accompanied by self-polymerization of excess chalcogen. Extended laser irradiation (>500 s) in air induces the substitution of chalcogen (S or Se) by oxygen in the chalcogenide materials and the subsequent formation of transition metal (Fe or Co) oxides. Excess chalcogen appears to prevent further oxidation. The article also presents conditions necessary to avoid laser-induced structural changes and oxidation of metal chalcogenide materials during Raman measurements.

Comparison of the LMA Supreme vs the i-gel in paralysed patients undergoing gynaecological laparoscopic surgery with controlled ventilation.

We compared the efficacy of the inflatable cuff of the LMA Supreme against the non-inflatable i-gel cuff in providing an adequate seal for laparoscopic surgery in the Trendelenburg position in 100 female patients. There was no difference in our primary outcome, oropharyngeal leak pressure, between the LMA Supreme and the i-gel (mean (SD) 26.4 (5.1) vs 25.0 (5.7) cmH(2) O, respectively; p = 0.18). Forty-seven (94%) LMA Supremes and 48 (96%) i-gels were successfully inserted on the first attempt, with similar ease, and comparable times to the first capnograph trace (mean (SD) 14.3 (4.7) s for the LMA Supreme vs 15.4 (8.2) s for the i-gel; p = 0.4). Gastric tube insertion was easier and achieved more quickly with the LMA Supreme vs the i-gel (9.0 (2.5) s vs 15.1 (7.3) s, respectively; p < 0.001). After creation of the pneumoperitoneum, there was a smaller difference between expired and inspired tidal volumes with the LMA Supreme (21.5 (15.2) ml) than with the i-gel (31.2 (23.5) ml; p = 0.009). There was blood on removal of two LMA Supremes and one i-gel. Four patients in the LMA Supreme group and one patient in the i-gel group experienced mild postoperative sore throat.

High flow extra-cranial to intra-cranial bypass for complex internal carotid aneurysms.

Cerebral revascularisation with extracranial - intracranial (EC-IC) bypass is generally indicated in patients with complex anterior circulation aneurysms who have failed parent artery occlusion. We report on the process and outcome of our early experience of performing high flow bypass in patients with complex anterior circulation aneurysms. We have reviewed patients who have undergone an EC-IC bypass for treatment of complex anterior circulation aneurysms, and report our outcome on graft patency, surgical complications, discharge destination, and obliteration rates. Nine patients that underwent 11 bypasses are described. Seven patients had a giant saccular aneurysm of the carotid, and these were all obliterated on post-operative imaging. Two patients presenting with an intracranial carotid dissection required trapping of the diseased segment following the bypass. The overall graft patency rate was 88%. One patient developed a post operative subdural collection (managed conservatively), and one patient required early graft revision. Discharge destination was home in 8/9 patients. There was no mortality. Although EC-IC bypass is a technically challenging procedure, it provides a valuable treatment option for patients with complex anterior circulation aneurysms. Good graft patency rates can be achieved with low surgical morbidity in patients with a disease process that otherwise attracts a highly unfavourable natural history.

Identification and separation of rigid image registration error sources, demonstrated for MRI-only image guided radiotherapy.

PURPOSE: Rigid image registration (RIR) accuracy is crucial for image guided radiotherapy (IGRT). However, existing clinical image registration assessment methods cannot separate and quantify RIR error sources. Herein, we develop an extension of the 'full circle method' for RIR consistency. Paired registration circuits are used to isolate sources of RIR error caused by reference dataset substitution, from those inherent to the underlying RIR. This approach was demonstrated in the context of MRI-only IGRT, assessing substitution of MRI-derived synthetic-CT (sCT) for conventional CT, in a cohort of rectal cancer patients. MATERIALS AND METHODS: Planning CT, MRI-derived sCT, and two CBCTs from seven rectal cancer patients were retrospectively registered with global and soft tissue clipbox based RIR. Paired registration circuits were constructed using two moving (cone beam CT) images and two reference images (CT and sCT), per patient. Differences between inconsistencies in registration circuits containing CT and sCT were used to determine changes in registration accuracy due to substitution of sCT for CT. RESULTS: sCT was found to be equivalent to CT under global RIR, with median differences of 0.05 mm and 0.01°. Soft tissue clipbox based RIR with sCT exhibited gross misregistration (>5 mm or 3°) for 3 patients. Registration consistency was degraded compared to CT across the cohort, with median differences of 0.54 mm and 0.15°. CONCLUSION: A paired registration circuit methodology for assessing RIR accuracy without ground truth information was developed and demonstrated for MRI-only IGRT in rectal cancer. This highlighted a reduction in clipbox based RIR consistency when sCT was substituted for conventional CT. The developed method enabled separation of degraded registration accuracy, from other error sources within the overall registration inconsistency. This novel methodology is applicable to any RIR scenario and enables analysis of the change in RIR performance on modification of image data or process.

The current practice of cytoreductive surgery and HIPEC for colorectal peritoneal metastases: Results of a worldwide web-based survey of the Peritoneal Surface Oncology Group International (PSOGI).

BACKGROUND: At present, selected patients with resectable colorectal peritoneal metastases (CRC-PM) are increasingly treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study was to investigate the current worldwide practice. METHODS: HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning their personal expertise and current hospital and countrywide practice. RESULTS: It is estimated that currently more than 3800 patients with CRC-PM (synchronous and metachronous) are annually treated with CRS and HIPEC in 430 centers. Integration of CRS and HIPEC in national guidelines varies, resulting in large treatment disparities between countries. Amongst the experts, there was general agreement on issues related to indication, surgical technique and follow up but less on systemic chemotherapy or proactive strategies. CONCLUSION: This international survey demonstrates that CRS and HIPEC is now performed on a large scale for CRC-PM patients. Variation in treatment may result in heterogeneity in surgical and oncological outcomes, emphasising the necessity to reach consensus on several issues of this comprehensive procedure. Future initiatives directed at achieving an international consensus statement are needed.

Commentary on "DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma."

PURPOSE: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy. EXPERIMENTAL DESIGN: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features. RESULTS: One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log-rank P = 0.007) and overall survival (23.7 vs. 13.0 months, log-rank P = 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable effect on clinical outcomes. CONCLUSIONS: Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment.

Alpha 2-chimerin, an SH2-containing GTPase-activating protein for the ras-related protein p21rac derived by alternate splicing of the human n-chimerin gene, is selectively expressed in brain regions and testes.

n-Chimerin (alpha 1-chimerin) is a brain GTPase-activating protein (GAP) for the ras-related p21rac. We now report the occurrence of another form of chimerin, termed alpha 2-chimerin. This is the product of an alternately spliced transcript of the human n-chimerin gene encoding an N-terminal SH2 (src homology 2) domain in addition to the phorbol ester receptor and GAP domains. alpha 1- and alpha 2-chimerin mRNAs were expressed differently. In the rat brain, only alpha 1-chimerin mRNA was expressed in cerebellar Purkinje cells, although both alpha 1- and alpha 2-chimerin mRNAs occurred in neurons in the cerebral cortex, hippocampus, and thalamus. Only alpha 2-chimerin RNA was expressed in rat testes, in early pachytene spermatocytes. A 45-kDa SH2-containing chimerin corresponding to the alpha 2 form was purified from rat brain. As with Escherichia coli 45-kDa recombinant alpha 2-chimerin, purified brain alpha 2-chimerin exhibited racGAP activity which was stimulated by phosphatidylserine. The recombinant SH2 domain bound several 32P-labelled phosphoproteins of PC12 cells, whose phosphorylation increased in response to trophic factors, including nerve growth factor. To examine the relationships of alpha 1- and alpha 2-chimerin transcripts, human genomic DNA clones were characterized. In alpha 2-chimerin mRNA, a 3' splice acceptor site within exon 1 of alpha 1-chimerin mRNA was used, replacing its 5' untranslated region and N-terminal coding sequence. The single human n-chimerin gene was mapped to chromosome 2q31-q32.1, colocalizing with the CRE-BP1 transcription factor gene (2q32). It contained several splice junctions conserved with the sequence-related protein kinase C and bcr genes. alpha 2-Chimerin is only the second SH2-containing GAP and the first example of an SH2 domain generated by alternate splicing.

A methodology for investigating new nonprecious metal catalysts for PEM fuel cells.

This paper reports an approach to investigate metal-chalcogen materials as catalysts for the oxygen reduction reaction (ORR) in proton exchange membrane (PEM) fuel cells. The methodology is illustrated with reference to Co-Se thin films prepared by magnetron sputtering onto a glassy-carbon substrate. Scanning Auger microscopy (SAM), X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectroscopy (EDX), and X-ray diffraction (XRD) have been used, in parallel with electrochemical activity and stability measurements, to assess how the electrochemical performance relates to chemical composition. It is shown that Co-Se thin films with varying Se are active for oxygen reduction, although the open circuit potential (OCP) is lower than for Pt. A kinetically controlled process is observed in the potential range 0.5-0.7 V (vs reversible hydrogen electrode) for the thin-film catalysts studied. An initial exposure of the thin-film samples to an acid environment served as a pretreatment, which modified surface composition prior to activity measurements with the rotating disk electrode (RDE) method. Based on the SAM characterization before and after electrochemical tests, all surfaces demonstrating activity are dominated by chalcogen. XRD shows that the thin films have nanocrystalline character that is based on a Co(1-x)Se phase. Parallel studies on Co-Se powder supported on XC72R carbon show comparable OCP, Tafel region, and structural phase as for the thin-film model catalysts. A comparison for ORR activity has also been made between this Co-Se powder and a commercial Pt catalyst.

Management of para-aortic lymph node metastasis in colorectal patients: A systemic review.

INTRODUCTION: Para-aortic lymph node (PALN) involvement occurs in up to 2% of colorectal cancer (CRC) patients. While resection for isolated hepatic and pulmonary metastases in colorectal cancer is standard practice, the role of PALN dissection (PALND) in CRC has not been established and remains a controversy. We aim to perform a systematic review of the literature to determine if extensive lymphadenectomy improves survival, and is an acceptable strategy for PALN metastasis (PALNM). MATERIALS AND METHODS: A systematic search of PubMed and Embase databases for studies reporting on patients with isolated PALNM in CRC was performed. Studies including patients with synchronous and metachronous PALN were included, and studies including patients with other metastases were excluded. RESULTS: Eighteen retrospective, single-centre studies were included in the final analysis. The reported incidence of isolated PALNM ranged from 1.3 to 1.7%. A total of 370 patients with PALNM were evaluated, of which 145 had synchronous, and 225 had metachronous PALNM. For synchronous PALNM, the 5-year overall survival (OS) after metastatectomy, ranged from 22.7% to 33.9%. For metachronous PALNM, the 5-year OS ranged from 15 to 60%; median OS was 34-40 months in the PALND versus 3-14 months for patients who did not undergo PALND. There were no reported surgery related mortalities, and overall surgical morbidity was 7.8-33%. CONCLUSION: PALND for isolated PALNM from colorectal cancer can be performed with minimal morbidity and confers a survival advantage, in comparison with conventional palliative chemotherapy or chemoradiation therapy.

alpha2-chimaerin, a Cdc42/Rac1 regulator, is selectively expressed in the rat embryonic nervous system and is involved in neuritogenesis in N1E-115 neuroblastoma cells.

Neuronal differentiation involves Rac and Cdc42 GTPases. alpha-Chimaerin, a Rac/Cdc42 regulator, occurs as alpha1- and alternatively spliced Src homology 2 (SH2) domain-containing alpha2-isoforms. alpha2-chimaerin mRNA was highly expressed in the rat embryonic nervous system, especially in early postmitotic neurons. alpha1-chimaerin mRNA was undetectable before embryonic day 16.5. Adult alpha2-chimaerin mRNA was restricted to neurons within specific brain regions, with highest expression in the entorhinal cortex. alpha2-chimaerin protein localized to neuronal perikarya, dendrites, and axons. The overall pattern of alpha2-chimaerin mRNA expression resembles that of cyclin-dependent kinase regulator p35 (CDK5/p35) which participates in neuronal differentiation and with which chimaerin interacts. To determine whether alpha2-chimaerin may have a role in neuronal differentiation and the relevance of the SH2 domain, the morphological effects of both chimaerin isoforms were investigated in N1E-115 neuroblastoma cells. When plated on poly-lysine, transient alpha2-chimaerin but not alpha1-chimaerin transfectants formed neurites. Permanent alpha2-chimaerin transfectants generated neurites whether or not they were stimulated by serum starvation, and many cells were enlarged. Permanent alpha1-chimaerin transfectants displayed numerous microspikes and contained F-actin clusters, a Cdc42-phenotype, but generated few neurites. In neuroblastoma cells, alpha2-chimaerin was predominantly soluble with some being membrane-associated, whereas alpha1-chimaerin was absent from the cytosol, being membrane- and cytoskeleton-associated, paralleling their subcellular distribution in brain. Transient transfection with alpha2-chimaerin mutated in the SH2 domain (N94H) generated an alpha1-chimaerin-like phenotype, protein partitioned in the particulate fraction, and in NGF-stimulated pheochromocytoma cell line 12 (PC12) cells, neurite formation was inhibited. These results indicate a role for alpha2-chimaerin in morphological differentiation for which its SH2 domain is vital.

Cloning and characterization of vascular endothelial growth factor (VEGF) from zebrafish, Danio rerio.

We have cloned and sequenced a zebrafish (Danio rerio) Vascular Endothelial Growth Factor (vegf) cDNA. It encodes a precursor protein of 188 amino acids with a putative 23 amino acids signal peptide. Sequence comparison analysis indicates that the zebrafish vegf cDNA corresponds to the human VEGF165 isoform and shows about 52% identity to human VEGF165 at the amino acid level. A 2.8 kb vegf message RNA was detected in adult zebrafish by Northern blot analysis. Expression of vegf165 is also detected by RT-PCR in adult fish and throughout the zebrafish embryonic development. Whole mount in situ hybridization of zebrafish embryos indicates strong expression in four areas of the 18-19 h post-fertilization (hpf) embryo: within the anterior central nervous system in the prospective optic stalk, in mesoderm overlapping the bilaterally located merging heart fields, in mesoderm underlying and flanking the hindbrain posterior to rhombomere 4, and in medial regions of the somites. The study of vegf function in zebrafish embryonic vascular development will contribute to our understanding of the mechanisms of vertebrate endothelial cell differentiation and vasculature formation.

Prevention and Management of Radiation-induced Late Gastrointestinal Toxicity.

In the UK, about 90,000 cancer survivors will suffer from pelvic radiation disease (PRD) due to their curative treatment including radiotherapy. The National Cancer Survivorship Initiative aims to improve the understanding and management of PRD by the oncology community. This overview covers the prevention, investigation and treatment for late radiation-induced gastrointestinal symptoms in PRD. Multiple pharmacological and nutritional interventions have been studied, as prophylaxis for acute gastrointestinal toxicity (aiming to prevent late consequential effects), although predominantly only small randomised controlled trials have been conducted. These have produced mixed results, although promising signals for some agents have been observed. Evidence for the pharmacological prevention of late gastrointestinal toxicity is scarce. Even fewer randomised controlled trials have investigated the late gastrointestinal toxicity profile of advanced radiotherapy technologies. There are nationally agreed algorithms for the investigation and management of PRD, but a lack of awareness means patients still do not get referred appropriately. This overview outlines the management of radiation proctopathy and diarrhoea, and signposts other accessible resources. Finally, we provide recommendations for the management of late gastrointestinal symptoms in PRD and research in this field, especially the need for high-quality clinical trials.