Outcome of Weekly Carboplatin-Paclitaxel-based Definitive Chemoradiation in Oesophageal Cancer in Patients Not Considered to be Suitable for Platinum-Fluoropyrimidine-based Treatment: A Multicentre, Retrospective Review.

AIMS: Although cisplatin-fluoropyrimidine-based definitive chemoradiotherapy (dCRT) is a standard of care for oesophageal cancer, toxicity is significant and limits its use in elderly and frail patients. Weekly carboplatin-paclitaxel-based dCRT provides a viable alternative, although prospective data are lacking in the dCRT setting. Here we report the results of a national, multicentre retrospective review of outcome in patients treated with weekly carboplatin-paclitaxel-based dCRT. MATERIALS AND METHODS: In this multicentre retrospective study of nine radiotherapy centres across the UK we evaluated the outcome of patients who had non-metastatic, histologically confirmed carcinoma of the oesophagus (adenocarcinoma, squamous cell or undifferentiated; World Health Organization performance status 0-2; stage I-III disease) and had been selected to receive weekly carboplatin-paclitaxel-based dCRT as they were considered not suitable for cisplatin-fluoropyrimidine-based dCRT. dCRT consisted of carboplatin AUC 2 and paclitaxel 50 mg/m2 (days 1, 8, 15, 22, 29) and the recommended radiation dose was 50 Gy in 25 daily fractions. We assessed overall survival, progression-free survival (PFS; overall, local and distant), proportion of patients who were failure free at the response assessment (12 weeks after dCRT), treatment compliance and toxicity. RESULTS: In total, 214 patients from nine UK centres were treated between 15 February 2013 and 19 March 2019: 39.7% of patients were ≥75 years; 18.7% ≥ 80 years. Indications for weekly carboplatin-paclitaxel-based dCRT were comorbidities (47.2%), clinician choice (36.4%) and poor tolerance/progression on cisplatin-fluoropyrimidine induction chemotherapy (15.8%). The median overall survival was 24.28 months (95% confidence interval 20.07-30.09) and the median PFS was 16.33 months (95% confidence interval 14.29-20.96). Following treatment, 69.1% (96/139) had a combined complete response on endoscopy with non-progression (complete response/partial response/stable disease) on imaging. The 1- and 2-year overall survival rates for this patient group were 81.9% (95% confidence interval 75.6-86.8%) and 50.6% (95% confidence interval 40.5-60.0%), respectively. Thirty-three per cent (n = 70) of patients experienced at least one grade 3 + acute toxicity (grade 3/4 haematological: 10%; grade 3/4 non-haematological: 32%) and there were no treatment-related deaths. 86.9% of patients completed at least four cycles of concomitant weekly carboplatin-paclitaxel-based chemotherapy and planned radiotherapy was completed in 97.7% (209/214). CONCLUSION: Weekly carboplatin-paclitaxel-based CRT seems to be well tolerated in elderly patients and in those with comorbidities, where cisplatin-fluoropyrimidine-based dCRT is contraindicated. Survival outcomes are comparable with cisplatin-fluoropyrimidine-based dCRT.

A review of 145 234 ophthalmic patient episodes lost to follow-up.

PurposeLost to follow-up and delays in follow-up care are a major problem in chronic diseases, particularly when irreversible progression precedes symptoms. The NPSA Glaucoma Safety Alert in 2009 highlighted the risk and requirements for consistent robust review systems in ophthalmology. In response, Moorfields Eye Hospital reviewed the records of all patients in all subspecialties without review appointments booked. The purpose of this study was to determine whether ophthalmic patients lost to follow-up had come to harm and develop investigation techniques to optimise safety, which do not put excessive demands on clinical staff time.MethodsThe health records of all patients lost to follow-up (LTFU) between July 2007 and November 2012 were reviewed for evidence of clinical harm using a risk-based strategy involving an initial administrative review, then a clinician led electronic patient record review, followed by a review of paper records by clinicians. The final stage was a clinical outpatient review where required determined by clinical risk.ResultsPatients identified as lost to follow-up were 145 234; 79 562 episodes were closed following administrative review; 50 519 were discharged following clinician examination of paper records; 12 316 patients required clinical review; and 16 serious incidents were identified, of which 14 patients had glaucoma, 1 a medical retinal condition with secondary glaucoma, and 1 an oculoplastic condition. A number of actions implemented hospital wide are described which minimise future risk.ConclusionRisk from delays or lost to follow-up care continue and require better capacity and more accurate data nationally.

Single-Molecule FRET to Measure Conformational Dynamics of DNA Mismatch Repair Proteins.

Single-molecule FRET measurements have a unique sensitivity to protein conformational dynamics. The FRET signals can either be interpreted quantitatively to provide estimates of absolute distance in a molecule configuration or can be qualitatively interpreted as distinct states, from which quantitative kinetic schemes for conformational transitions can be deduced. Here we describe methods utilizing single-molecule FRET to reveal the conformational dynamics of the proteins responsible for DNA mismatch repair. Experimental details about the proteins, DNA substrates, fluorescent labeling, and data analysis are included. The complementarity of single molecule and ensemble kinetic methods is discussed as well.

Wrong intraocular lens events-what lessons have we learned? A review of incidents reported to the National Reporting and Learning System: 2010-2014 versus 2003-2010.

PurposeTo identify the causal factors in wrong intraocular lens (IOL) events from a national data set and to compare with similar historical data (2003-2010) prior to mandatory checklist use, for the purpose of developing strategies to prevent never events.MethodsData from wrong IOL patient safety incidents (PSIs) submitted to the National Reporting and Learning System (2010-2014) were reviewed by thematic analysis and compared with the data previously collected by the group using the same methodology.ResultsOne hundred and seventy eight wrong IOL PSIs were identified. The contributory factors included: transcription errors (n=26); wrong patient biometry (n=21); wrong IOL selection (n=16); changes in planned procedure (n=16); incorrect IOL brought into theatre (n=11); left/right eye selection errors (n=9); communication errors (n=9); and positive/negative IOL power errors (n=9). In 44 PSIs, no causal factor was reported, limiting the learning value of such reports. Compared with the data from previous years, biometry errors were much reduced but IOL transcription and documentation errors were greater, particularly if further checks did not refer to the original source documentation. IOL exchange surgery was reported in 45 cases.ConclusionsThe selection and implantation of the correct IOL is a complex process which is not adequately addressed by existing checking procedures. Despite the introduction of surgical checklists, wrong IOL incidents continue to occur and are probably under-reported. Human or behavioural factors are heavily implicated in these errors and need to be addressed by novel approaches, including simulation training. There is also scope to further improve the quality and detail of incident reporting and analysis to enhance patient safety.

Hypofractionated radiotherapy for glioblastoma: strategy for poor-risk patients or hope for the future?

The prognosis of patients with glioblastoma (GBM) remains poor, and the use of hyperfractionation or dose escalation beyond 60 Gy has not conferred any survival benefit. More recently, hypofractionated radiotherapy (HFRT) has been employed as a novel approach for achieving dose escalation, with interesting results. We present here a systematic overview of the role and development of HFRT as a possible therapeutic strategy in patients with GBM. We searched the PubMed database for studies published since 1990 that reported on the tolerance, safety and survival outcomes after HFRT. These studies reported on the paradox of improved survival in patients developing central radionecrosis within the high-dose volume. Most series reported no significant increase in early or late toxicity, except for one study that reported visual loss in one patient at 7 months after treatment. More recently, studies of HFRT combined with concurrent temozolomide (TMZ) reported a trend towards improved survival compared with historical controls, with a few studies reporting a median survival of approximately 20 months. The interpretation of data from the above studies is limited by the heterogeneities of patient population and the significant variation in the range of employed dose schedules. However, high-dose HFRT using intensity-modulated radiotherapy appears to be a safe and feasible therapeutic option. There is a suggestion of improved outcomes on combining HFRT with TMZ, which warrants further investigation in a randomised trial.

Neoadjuvant chemoradiotherapy for resectable oesophageal and gastro-oesophageal junction cancer--do we need another randomised trial?

AIMS: The optimal neoadjuvant therapy option for locally advanced oesophageal cancer remains elusive. Neoadjuvant chemoradiotherapy (CRT) is the preferred modality of choice in the USA. In contrast, neoadjuvant chemotherapy is commonly used in the UK. We provide a comprehensive overview of the available evidence for defining the ideal neoadjuvant treatment algorithm. MATERIALS AND METHODS: The PubMed database combined with American Society of Clinical Oncology and American Society for Therapeutic Radiology and Oncology websites were searched online to identify randomised studies and published meta-analyses that have compared these modalities compared with surgery alone. In particular, we searched for randomised trials that may have directly compared outcomes after neoadjuvant CRT or chemotherapy. RESULTS: We identified 17 published randomised studies of neoadjuvant CRT (n = 9) and chemotherapy (n = 8) compared with surgery alone and one prospective series that compared the above modalities against each other. Studies evaluating CRT have reported pathological complete response rates of 15-40% and no increase in postoperative mortality was observed, except in one study that used a hypofractionated radiation schedule. Two randomised studies showed significant survival benefit and the remaining (n = 7) were negative, but showed a trend towards improved survival. Furthermore, at least four meta-analyses have shown improved survival in favour of CRT extending up to an absolute benefit of 13% at 2 years. In comparison, five studies of neoadjuvant chemotherapy showed no survival difference and two of the remaining studies that showed significant benefit included gastric adenocarcinomas and used peri-operative chemotherapy. All the above studies have shown uniformly poor pathological complete response rates of less than 10 percent. Moreover, three meta-analyses were negative, but two showed up to 7% absolute survival benefit at 2 years in favour of chemotherapy. The trial comparing the above modalities showed a trend towards improved survival in favour of CRT, but closed early due to poor recruitment. CONCLUSION: Data from the above studies are potentially conflicting and inconclusive for defining the optimal neoadjuvant treatment schedule. In our opinion, the above question can only be answered within the context of a randomised control trial. We have included a proposal for a trial design for direct comparison of these modalities.

Can a community optometrist-based referral refinement scheme reduce false-positive glaucoma hospital referrals without compromising quality of care? The community and hospital allied network glaucoma evaluation scheme (CHANGES).

BACKGROUND/AIMS: To describe the design, activity, and quality of the referral refinement phase of a novel glaucoma shared-care scheme. METHODS: Eight Optometrists with a Specialist Interest in glaucoma (OSI) were trained to perform a community-based comprehensive glaucoma evaluation of low-risk glaucoma hospital referrals (only one/none of the following factors noted for either eye: abnormal optic disc, abnormal visual field, abnormal intraocular pressure (IOP; 22-28 mmHg or IOP asymmetry)) using equipment standardized to that of the hospital glaucoma service. RESULTS: One hundred and thirty-eight (27%) of a total of 512 glaucoma-related referrals were deemed 'low risk'. Their choice of OSI discharged 40 (35%). The consultant agreed (virtually) with the decision to discharge with 28 (70%) and disagreed with 12 (30%). Comparing findings between OSI and consultant for 99 referred patients, sensitivity, specificity, and negative predictive values for a suspicious optic disc were 78, 61, and 79%, respectively. For an IOP of >21 mmHg, they were 74, 85, and 90%, respectively. For an occludable anterior chamber angle (Van Herick's versus gonioscopy), they were 69, 88, and 94%, respectively. CONCLUSION: This referral refinement process can reduce numbers of false-positive referrals attending the hospital glaucoma service while retaining a relatively high level of examination quality.

Provision and cost of children's and young people's eye services in the UK: findings from a single primary care trust.

AIMS/BACKGROUND: Population-based information is useful for future strategic planning of healthcare resources. We wished to describe and cost the provision of eye services, beyond those of basic primary and emergency care, for the paediatric population of a single primary care trust. METHODS: Data from healthcare purchaser and provider records were collected for the year 2004/5 on provision and costing of hospital eye services, provision of spectacle vouchers, orthoptic screening, social services and visual-impairment team services to children in the Huntingdonshire Primary Care Trust population. RESULTS: In the year of study, in a population of 33,564 aged under 18 years, 1870 (5.6%) children underwent screening by an orthoptist. 1970 (5.9%) children required outpatient appointments, 445 (1.3%) were prescribed spectacles, and 87 (0.3%) children needed surgical procedures. A small proportion (69, 0.2%) of children were visually impaired. The total cost of providing comprehensive eye services to children within Hunts PCT was pound 366,727. CONCLUSION: Although the prevalence of significant visual impairment is low in childhood, overall, eye conditions are common in children and may have lifelong implications. The resources required to provide a comprehensive paediatric eye service, to screen for and manage common eye conditions, and support those with serious eye conditions or visual impairment, are significant. This study aids quantified prediction of future service usage, and facilitates decision-making on resource allocation and workforce organisation for children's eye care in the UK.

Microvascular free tissue transfer for gene delivery: in vivo evaluation of different routes of plasmid and adenoviral delivery.

Transfer of healthy autologous tissue as a microvascular free flap facilitates reconstruction during ablative cancer surgery. In addition to filling surgical defects, free flaps might concentrate viral vectors at the tumour bed and mediate local therapeutic effects. We evaluated the magnitude, topography and duration of luciferase gene expression after plasmid and adenoviral delivery in rat superficial inferior epigastric (SIE) flaps. For plasmid delivery, luciferase expression was significantly increased by all transduction routes (topical, intraflap injection, intravascular) (P<0.01) at day 1, but not at day 7. The spread of luciferase expression was significantly different between the 4 groups at 1 day (P=0.026) and was greatest for flaps transduced by intravascular injection. For adenoviral transduction, total radiance was significantly different between the transduced groups at 1, 14 and 28 days (P<0.05 for all comparisons). The highest levels of radiance were seen in the intravascular group. There was a statistically significant difference in the spread of light emission between the 3 groups at 1 (P=0.009) and 14 (P=0.013) days, but this was no longer evident at 28 days. Intravascular adenoviral delivery yields high-level, diffuse and durable gene expression in rat SIE flaps and is suitable for examination in therapeutic models.

Bilateral simultaneous central retinal vein occlusion secondary to hyperviscosity in Waldenstrom's macroglobulinaemia.

PURPOSE: Central retinal vein occlusions (CRVOs) are rarely treatable; most therapy is directed towards prevention or treatment of complications. Bilateral CRVO can be due to serum hyperviscosity, which affects 15% of all patients with Waldenstrom's macroglobulinaemia (WM). Although previously reported in a handful of cases, bilateral CRVO is a rare presenting feature. PATIENTS AND METHODS: Illustrated case reports of three patients presenting with bilateral CRVO due to undiagnosed WM. RESULTS: Plasma exchange, which successfully restored vision in two patients, was followed by long-term cytotoxic therapy. CONCLUSIONS: Plasma electrophoresis should be performed in all patients with retinal vein occlusions to exclude a paraproteinaemia. In patients with bilateral venous changes, there should be a very high level of suspicion of hyperviscosity, with the possibility of effective early therapy.

A survey of measures used for the prevention of postoperative endophthalmitis after cataract surgery in the United Kingdom.

PURPOSE: This study investigates the current practice of United Kingdom (UK) ophthalmologists in perioperative antibiotic and antiseptic use in cataract surgery. MATERIALS AND METHODS: A telephone interview survey was conducted with ophthalmic staff at all ophthalmic training units in the UK in October and November 2005. RESULTS: The practices of a total of 800 consultants were ascertained. Preoperatively, 795 (99.4%) surgeons used povidone-iodine to prepare the skin. In all, 558 (69.8%) instilled 5 or 10% povidone-iodine in the conjunctival sac; 47 (5.9%) gave preoperative antibiotic eyedrops. Intraoperatively, intracameral antibiotics were given either as a bolus [80 (10.0%) intracameral cefuroxime, 29 (3.6%) intracameral vancomycin] or in the irrigating fluid [33 (4.1%) vancomycin]. 48 (6.0%) gave subconjunctival gentamycin only routinely, 531 (66.4%) gave subconjunctival cefuroxime, and 39 (4.9%) gave other subconjunctival antibiotics. A single dose of topical antibiotics was given by 134 (16.8%) surgeons. Postoperatively, 515 (64.4%) used a combination steroid and neomycin eyedrop, and 213 (26.6%) gave a separate steroid and chloramphenicol eyedrop. CONCLUSIONS: This study reveals wide variations in the choice and duration of antibiotics used by UK ophthalmologists. The predominant methods of intraoperative prophylaxis are subconjunctival cefuroxime and intracameral cefuroxime. Most surgeons used a neomycin eyedrop for postoperative prophylaxis.

Combining radiation and cancer gene therapy: a potential marriage of physical and biological targeting?

The development and progression of cancer is marked by the acquisition of specific genetic hallmarks that endow tumour cells with a survival advantage over their normal tissue counterparts. In the process, tumours frequently develop resistance to radiotherapy and chemotherapy, and acquire the ability to evade the host immune response. Cancer gene therapy (CGT) represents an ideal therapeutic tool to target one or more of these underlying genetic abnormalities, and restore some form of order, to the otherwise autonomous and discordant microenvironment of the tumour. Most of the current research in CGT is aimed at its development as a novel form of targeted therapy that can be combined with other treatment modalities such as radiotherapy and chemotherapy. CGT may be integrated into radical chemoradiotherapy regimens, with the rationale of optimising the therapeutic index, through selective enhancement of radiosensitivity and cytotoxicity in tumour compared to normal tissues. CGT strategies have been developed that are aimed at enhancing the radiosensitivity of tissues by targeting angiogenesis, silencing abnormal cellular signalling, restoration of apoptosis, and promotion of immune detection and destruction of tumour cells. In addition, cytotoxic approaches such as virus directed enzyme prodrug therapy (VDEPT), genetic radionuclide therapy (GRANT) and oncolytic viral therapy have been combined with radiation to augment the cumulative tumour cell kill and overall therapeutic effect. In this article, we discuss various CGT strategies that have been investigated in combination with radiation. All the available preclinical and clinical evidence is reviewed with special emphasis on strategies that have already found their way into the clinic, or those with significant translational potential for the future.

SPECT/CT imaging of oncolytic adenovirus propagation in tumours in vivo using the Na/I symporter as a reporter gene.

Oncolytic adenoviruses have shown some promise in cancer gene therapy. However, their efficacy in clinical trials is often limited, and additional therapeutic interventions have been proposed to increase their efficacies. In this context, molecular imaging of viral spread in tumours could provide unique information to rationalize the timing of these combinations. Here, we use the human sodium iodide symporter (hNIS) as a reporter gene in wild-type and replication-selective adenoviruses. By design, hNIS cDNA is positioned in the E3 region in a wild-type adenovirus type 5 (AdIP1) and in an adenovirus in which a promoter from the human telomerase gene (RNA component) drives E1 expression (AdAM6). Viruses show functional hNIS expression and replication in vitro and kinetics of spread of the different viruses in tumour xenografts are visualized in vivo using a small animal nano-SPECT/CT camera. The time required to reach maximal spread is 48 h for AdIP1 and 72 h for AdAM6 suggesting that genetic engineering of adenoviruses can affect their kinetics of spread in tumours. Considering that this methodology is potentially clinically applicable, we conclude that hNIS-mediated imaging of viral spread in tumours may be an important tool for combined anticancer therapies involving replicating adenoviruses

Molecular biology for the radiation oncologist: the 5Rs of radiobiology meet the hallmarks of cancer.

Recent advances in our understanding of the biology of cancer have provided enormous opportunities for the development of novel therapies against specific molecular targets. It is likely that most of these targeted therapies will have only modest single agent activities but may have the potential to accentuate the therapeutic effects of ionising radiation. In this introductory review, the 5Rs of classical radiobiology are interpreted in terms of their relationship to the hallmarks of cancer. Future articles will focus on the specific hallmarks of cancer and will highlight the opportunities that exist for designing new combination treatment regimens.

Mechanism of processivity clamp opening by the delta subunit wrench of the clamp loader complex of E. coli DNA polymerase III.

The dimeric ring-shaped sliding clamp of E. coli DNA polymerase III (beta subunit, homolog of eukaryotic PCNA) is loaded onto DNA by the clamp loader gamma complex (homolog of eukaryotic Replication Factor C, RFC). The delta subunit of the gamma complex binds to the beta ring and opens it. The crystal structure of a beta:delta complex shows that delta, which is structurally related to the delta' and gamma subunits of the gamma complex, is a molecular wrench that induces or traps a conformational change in beta such that one of its dimer interfaces is destabilized. Structural comparisons and molecular dynamics simulations suggest a spring-loaded mechanism in which the beta ring opens spontaneously once a dimer interface is perturbed by the delta wrench.