Targeted therapies in the treatment of advanced/metastatic NSCLC

The treatment of advanced non-small cell lung cancer (NSCLC) has evolved substantially during the last years. Chemotherapy remains the cornerstone of treatment and prolongs survival with a positive impact on quality of life. However, we seem to have reached a plateau of activity in the treatment of NSCLC. Recently, the addition of bevacizumab or cetuximab to chemotherapy doublets has improved the outcome in selected patients with advanced NSCLC. Furthermore, the use of erlotinib and gefitinib is an alternative for second line treatment. Advances in our understanding of molecular biology of cancer and mechanisms of tumourigenesis have further enabled the discovery of several potential molecular targets and development of novel 'targeted therapies'. The purpose of this study is to review current data on the role of targeted therapies in the treatment of advanced NSCLC. (C) 2009 Elsevier Ltd. All rights reserved.

Use of culture and molecular analysis to determine the effect of antibiotic treatment on microbial community diversity and abundance during exacerbation in patients with cystic fibrosis

Background: Anaerobic bacteria are increasingly regarded as important in cystic fibrosis (CF) pulmonary infection. The aim of this study was to determine the effect of antibiotic treatment on aerobic and anaerobic microbial community diversity and abundance during exacerbations in patients with CF.

Methods: Sputum was collected at the start and completion of antibiotic treatment of exacerbations and when clinically stable. Bacteria were quantified and identified following culture, and community composition was also examined using culture-independent methods.

Results: Pseudomonas aeruginosa or Burkholderia cepacia complex were detected by culture in 24/26 samples at the start of treatment, 22/26 samples at completion of treatment and 11/13 stable samples. Anaerobic bacteria were detected in all start of treatment and stable samples and in 23/26 completion of treatment samples. Molecular analysis showed greater bacterial diversity within sputum samples than was detected by culture; there was reasonably good agreement between the methods for the presence or absence of aerobic bacteria such as P aeruginosa (kappa=0.74) and B cepacia complex (kappa=0.92), but agreement was poorer for anaerobes. Both methods showed that the composition of the bacterial community varied between patients but remained relatively stable in most individuals despite treatment. Bacterial abundance decreased transiently following treatment, with this effect more evident for aerobes (median decrease in total viable count 2.3 x 10(7) cfu/g, p=0.005) than for anaerobes (median decrease in total viable count 3 x 10(6) cfu/g, p=0.046).

Conclusion: Antibiotic treatment targeted against aerobes had a minimal effect on abundance of anaerobes and community composition, with both culture and molecular detection methods required for comprehensive characterisation of the microbial community in the CF lung. Further studies are required to determine the clinical significance of and optimal treatment for these newly identified bacteria.

Treatment of estrogens and androgens in dairy wastewater by a constructed wetland system.

Constructed wetland systems (CWS) have been used as a low cost bio-filtration system to treat farm wastewater. While studies have shown that CWS are efficient in removing organic compounds and pathogens, there is limited data on the presence of hormones in this type of treatment system. The objective of this study was to evaluate the ability of the CWS to reduce estrogenic and androgenic hormone concentration in dairy wastewater. This was achieved through a year long study on dairy wastewater samples obtained froma surface flow CWS. Analysis of hormonal levels was performed using a solid phase extraction (SPE) sample clean-up method, combined with reporter gene assays (RGAs) which incorporate relevant receptors capable of measuring total estrogenic or androgenic concentrations as low as 0.24 ng L1 and 6.9 ng L1 respectively. Monthly analysis showed a mean removal efficiency for estrogens of 95.2%, corresponding to an average residual concentration of 3.2 ng L1 17b-estradiol equivalent (EEQ), below the proposed lowest observable effect concentration (LOEC) of 10 ng L1. However, for one month a peak EEQ concentration of 115 ng L1 was only reduced to 18.8 ng L1. The mean androgenic activity peaked at 360 ng L1 and a removal efficiency of 92.1% left an average residual concentration of 32.3 ng L1 testosterone equivalent (TEQ). The results obtained demonstrate that this type of CWS is an efficient system for the treatment of hormones in dairy wastewater. However, additional design improvements may be required to further enhance removal efficiency of peak hormone concentrations.

Constitutive and Treatment-Induced CXCL8-Signalling Selectively Modulates the Efficacy of Anti-Metabolite Therapeutics in Metastatic Prostate Cancer

Background: The current study was undertaken to characterize the effect of anti-metabolites on inducing CXCL8 signaling and determining whether the constitutive and/or drug-induced CXCL8 signaling in metastatic prostate cancer (CaP) cells modulates their sensitivity to this class of agent.

Methods: The response of metastatic CaP cells to 5-Fluorouracil (5-FU), Pemetrexed or Tomudex was determined using cell count assays, flow cytometry and PARP cleavage analysis. Quantitative-PCR, ELISA and immunoblots were employed to determine effects of drugs or CXCL8 administration on target gene/protein expression.

Results: Administration of 5-FU but not pemetrexed potentiated CXCL8 secretion and increased CXCR1 and CXCR2 gene expression in metastatic PC3 cells. Consistent with this, the inhibition of CXCL8 signaling using a CXCR2 antagonist, AZ10397767, increased the cytotoxicity of 5-FU by 4-fold (P,0.001), and increased 5-FU-induced apoptosis in PC3 cells (P,0.01). In contrast, while administration of AZ10397767 had no effect on the sensitivity of pemetrexed, the CXCR2 antagonist exerted the greatest effect in increasing the sensitivity of PC3 cells to Tomudex, a directed thymidylate synthase (TS) inhibitor. Subsequent experiments confirmed that administration of recombinant human CXCL8 increased TS expression, a response mediated in part by the CXCR2 receptor. Moreover, siRNA-mediated knockdown of the CXCL8-target gene Bcl-2 increased the sensitivity of PC3 cells to 5-FU.

Conclusions: CXCL8 signaling provides a selective resistance of metastatic prostate cancer cells to specific anti-metabolites by promoting a target-associated resistance, in addition to underpinning an evasion of treatment-induced apoptosis. © 2012 Wilson et al.

Availability of stage at diagnosis, cancer treatment delay and compliance with cancer guidelines as cancer registry indicators for cancer care in Europe:Results of EUROCHIP-3 survey

EUROCHIP (European Cancer Health Indicators Project) focuses on understanding inequalities in the cancer burden, care and survival by the indicators "stage at diagnosis," "cancer treatment delay" and "compliance with cancer guidelines" as the most important indicators. Our study aims at providing insight in whether cancer registries collect well-defined variables to determine these indicators in a comparative way. Eighty-six general European population-based cancer registries (PBCR) from 32 countries responded to the questionnaire, which was developed by EUROCHIP in collaboration with ENCR (European Network of Cancer Registries) and EUROCOURSE. Only 15% of all the PBCR in EU had all three indicators available. The indicator "stage at diagnosis" was gathered for at least one cancer site by 81% (using TNM in 39%). Variables for the indicator "cancer treatment delay" were collected by 37%. Availability of type of treatment (30%), surgery date (36%), starting date of radiotherapy (26%) and starting date of chemotherapy (23%) resulted in 15% of the PBCRs to be able to gather the indicator "compliance to guidelines". Lack of data source access and qualified staff were the major reasons for not collecting all the variables. In conclusion, based on self-reporting, a few of the participating PBCRs had data available which could be used for clinical audits, evaluation of cancer care projects, survival and for monitoring national cancer control strategies. Extra efforts should be made to improve this very efficient tool to compare cancer burden and the effects of the national cancer plans over Europe and to learn from each other. © 2012 UICC.

The accuracy of accredited glaucoma optometrists in the diagnosis and treatment recommendation for glaucoma

Aim: To compare the diagnostic performance of accredited glaucoma optometrists (AGO) for both the diagnosis of glaucoma and the decision to treat with that of routine hospital eye care, against a reference standard of expert opinion (a consultant ophthalmologist with a special interest in glaucoma). Methods: A directly comparative, masked, performance study was undertaken in Grampian, Scotland. Of 165 people invited to participate, 100 (61%) were examined. People suspected of having glaucoma underwent, within one month, a full ophthalmic assessment in both a newly established community optometry led glaucoma management scheme and a consultant led hospital eye service. Results: Agreement between the AGO and the consultant ophthalmologist in diagnosing glaucoma was substantial (89%; ? = 0.703, SE = 0.083). Agreement over the need for treatment was also substantial (88%; ? = 0.716, SE = 0.076). The agreement between the trainee ophthalmologists and the consultant ophthalmologist in the diagnosis of glaucoma and treatment recommendation was moderate (83%, ? = 0.541, SE = 0.098, SE = 0.98; and 81%, ? = 0.553, SE = 0.90, respectively). The diagnostic accuracy of the optometrists in detecting glaucoma in this population was high for specificity (0.93 (95% confidence interval, 0.85 to 0.97)) but lower for sensitivity (0.76 (0.57 to 0.89)). Performance was similar when accuracy was assessed for treatment recommendation (sensitivity 0.73 (0.57 to 0.85); specificity 0.96 (0.88 to 0.99)). The differences in sensitivity and specificity between AGO and junior ophthalmologist were not statistically significant. Conclusions: Community optometrists trained in glaucoma provided satisfactory decisions regarding diagnosis and initiation of treatment for glaucoma. With such additional training in glaucoma, optometrists are at least as accurate as junior ophthalmologists but some cases of glaucoma are missed.

'Grooming' and the Sexual Abuse of Children: Implications for Sex Offender Assessment, Treatment and Management

'Grooming' has been termed 'a ubiquitous feature of the sexual abuse of children' (Thornton, 2003: 144). Despite the prominence of the term in contemporary discourses on sexual offending against children, it is a term that is insufficiently understood in the psychological, sociological, criminological or legal literature. Most recently, the term has been used in two primary offending contexts - on-line grooming and abuse by strangers, and institutional grooming and abuse by those in positions of trust. This article argues, however, that grooming and its role in child sexual abuse is a multi-faceted phenomenon and much more complex than has been highlighted previously. While there are a number of typologies of grooming, this article concentrates on those which may be most relevant for treatment and management contexts - 'peer-to-peer grooming' and 'institutional grooming.' Drawing on extensive fieldwork with professionals who work in the fields of child protection or victim support, and sex offender assessment, treatment or management across the United Kingdom and the Republic of Ireland, the aim of this article is two-fold: (i) to deconstruct the term grooming and examine its actual role in the onset of sexual offending against children; and (ii) to draw out the implications of these complexities for policy and practice, chiefly in terms of treatment and prevention.

Investigation into the radiobiological consequences of pre-treatment verification imaging with megavoltage X-rays in radiotherapy

Objective: The aim of this study was to investigate the effect of pre-treatment verification imaging with megavoltage (MV) X-rays on cancer and normal cell survival in vitro and to compare the findings with theoretically modelled data. Since the dose received from pre-treatment imaging can be significant, incorporation of this dose at the planning stage of treatment has been suggested.

Methods: The impact of imaging dose incorporation on cell survival was investigated by clonogenic assay, irradiating DU-145 prostate cancer, H460 non-small cell lung cancer and AGO-1522b normal tissue fibroblast cells. Clinically relevant imaging-to-treatment times of 7.5 minutes and 15 minutes were chosen for this study. The theoretical magnitude of the loss of radiobiological efficacy due to sublethal damage repair was investigated using the Lea-Catcheside dose protraction factor model.

Results: For the cell lines investigated, the experimental data showed that imaging dose incorporation had no significant impact upon cell survival. These findings were in close agreement with the theoretical results.

Conclusions: For the conditions investigated, the results suggest that allowance for the imaging dose at the planning stage of treatment should not adversely affect treatment efficacy.

Advances in Knowledge: There is a paucity of data in the literature on imaging effects in radiotherapy. This paper presents a systematic study of imaging dose effects on cancer and normal cell survival, providing both theoretical and experimental evidence for clinically relevant imaging doses and imaging-to-treatment times. The data provide a firm foundation for further study into this highly relevant area of research.

The role of private care in the interval between diagnosis and treatment of breast cancer in Northern Ireland: an analysis of Registry data

Objective: To examine the differences in the interval between diagnosis and initiation of treatment among women with breast cancer in Northern Ireland.

Design: A cross-sectional observational study.
Setting: All breast cancer care patients in the Northern Ireland Cancer Registry in 2006.
Participants: All women diagnosed and treated for breast cancer in Northern Ireland in 2006.
Main outcome measure: The number of days between diagnosis and initiation of treatment for breast cancer.

Results: The mean (median) interval between diagnosis and initiation of treatment among public patients was 19 (15) compared with 14 (12) among those whose care involved private providers. The differences between individual public providers were as marked as those between the public and private sector - the mean (median) ranging between 14 (12) and 25 (22) days. Multivariate models revealed that the differences were evident when a range of patient characteristics were controlled for including cancer stage.

Conclusions: A relatively small number of women received care privately in Northern Ireland but experienced shorter intervals between diagnosis and initiation of treatment than those who received care wholly in the public system. The variation among public providers was as great as that between the public and private providers. The impact of such differences on survival and in light of waiting time targets introduced in Northern Ireland warrants investigation.

The impact of peer review on the radiotherapy treatment planning process in the treatment of lung cancer

Background:
Advanced radiotherapy techniques permit accurate delivery of radiotherapy to lung tumours. Improved accuracy increases the possibility of radiotherapy field geographic miss of the tumour. One source of error is the accuracy of target volume (TV) delineation by the clinical oncologist. Colleague peer review of all curative intent lung cancer plans has been mandatory in our institution since May 2013. At least 2 clinical oncologists review plans checking treatment paradigm, TV delineated, dose to tumour and dose to critical organs. We report the impact of peer review on the radiotherapy planning process for lung cancer.

Methods:
The radiotherapy treatment plans of all patients receiving radical radiotherapy were presented at weekly peer review meetings after their TVs volumes were provisionally signed off by the treating consultant or post-fellowship registrar. All cases and any resultant change to the treatment plan were recorded in our prospective peer review database. We present the summary of changes agreed following the peer review process for a 6 month period.

Results:
Fifteen peer review sessions, including 46 patients (36 NSCLC, 10 SCLC) were analysed. An average of 3 cases were discussed per meeting (range 1 5). 24% of treatment courses were changed. In 4% there was a complete change in paradigm
of treatment (1 patient proceeded to induction chemotherapy, 1 patient had high dose palliative radiotherapy). In 16% there was a change in TV delineated and in 9% a change in dose (2 dose reductions and 2 alterations to post-operative dose fractionations).

Conclusions:
Consultant led peer review resulted in a change in a component of the treatment plan for 28% of patients that would not otherwise have taken place. Given this impact, consultant led peer review should be considered as an essential component in the radiotherapy planning process for all patients treated with curative radiotherapy.

Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial

Background: Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.

Methods: COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.

Findings: We registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).

Interpretation: Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.

The late effects of cancer and cancer treatment:a rapid review

This paper aims to synthesize literature about the definition, prevalence, onset and treatments associated with late effects. A rapid review was conducted using Google Scholar to identify reviews related to the late effects of adult-onset cancers. Papers were included if they provided a definition of late effects and/or presented a review of late effects as a result of adult-onset cancers in patients aged 18 years or older. Reviews related to nonmelanoma skin cancer were excluded. Reviews focusing on late effects in survivors of childhood-onset cancers (younger than 18 years) were ineligible for inclusion in the review. A total of 16 reviews were identified. Between 0% and 100% of survivors experienced a range of physical, psychological and social late effects. The onset of physical late effects was defined broadly as 'months or years' after treatment, whereas psychological late effects were defined as occurring at the end of treatment or similarly to physical late effects as 'months or years' after treatment. Few reviews provided an operational definition of late effects, and the onset of late effects was not often reported. Thus, reviews may have included the acute and long-term effects of cancer treatment. Evidence regarding causes, prevalence, and onset was incomplete for many late effects. Understanding the cause and onset of late effects is important in order to provide timely interventions to reduce the risk of late effect development in cancer patients.

A critical ethnography of communication processes involving the management of oral chemotherapeutic agents by patients with a primary diagnosis of colorectal cancer: study protocol

Aim
To describe the protocol used to examine the processes of communication between health professionals, patients and informal carers during the management of oral chemotherapeutic medicines to identify factors that promote or inhibit medicine concordance.

Background
Ideally communication practices about oral medicines should incorporate shared decision-making, two-way dialogue and an equality of role between practitioner and patient. While there is evidence that healthcare professionals are adopting these concordant elements in general practice there are still some patients who have a passive role during consultations. Considering oral chemotherapeutic medications, there is a paucity of research about communication practices which is surprising given the high risk of toxicity associated with chemotherapy.

Design
A critical ethnographic design will be used, incorporating non-participant observations, individual semi-structured and focus-group interviews as several collecting methods.

Methods
Observations will be carried out on the interactions between healthcare professionals (physicians, nurses and pharmacists) and patients in the outpatient departments where prescriptions are explained and supplied and on follow-up consultations where treatment regimens are monitored. Interviews will be conducted with patients and their informal carers. Focus-groups will be carried out with healthcare professionals at the conclusion of the study. These several will be analysed using thematic analysis. This research is funded by the Department for Employment and Learning in Northern Ireland (Awarded February 2012).

Discussion
Dissemination of these findings will contribute to the understanding of issues involved when communicating with people about oral chemotherapy. It is anticipated that findings will inform education, practice and policy.

‘All illness is personal to that individual’: a qualitative study of patients’ perspectives on treatment adherence in bronchiectasis

Background: Adherence to treatment is low in bronchiectasis and is associated with poorer health outcomes. Factors affecting adherence decisions have not been explored in patients with bronchiectasis. 

Objective: We aimed to explore patients' perspectives on adherence, factors affecting adherence decision making and to develop a conceptual model explaining this decision-making process in adults with bronchiectasis. 

Methods: Adults with bronchiectasis participated in one-to-one semi-structured interviews. Interviews were audio-recorded, transcribed verbatim and analysed independently by two researchers using thematic analysis. Data from core themes were extracted, categorized into factors affecting adherence decision making and used to develop the conceptual model. 

Results: Participants' beliefs about treatment, the practical aspects of managing treatment, their trust in health-care professionals and acceptance of disease and treatment were important aspects of treatment adherence. The conceptual model demonstrated that adherence decisions were influenced by participants' individual balance of barriers and motivating factors (treatment-related, disease-related, health-care-related, personal and social factors). 

Conclusion: Adherence decision-making in bronchiectasis is complex, but there is the potential to enhance adherence by understanding patients' specific barriers and motivators to adherence and using this to tailor adherence strategies to individual patients and treatments. © 2014 John Wiley & Sons Ltd.

Late effects of cancer and cancer treatment-the perspective of the patient

PURPOSE: Understanding the experience of late effects from the perspective of cancer survivors is essential to inform patient-centred care. This study investigated the nature and onset of late effects experienced by survivors and the manner in which late effects have affected their lives.

METHODS: Sixteen purposively selected cancer survivors participated in a qualitative interview study. The data were analysed inductively using a narrative schema in order to derive the main themes that characterised patients' accounts of late effects.

RESULTS: Individual survivors tended to experience more than one late effect spanning a range of physical and psychological effects. Late effects impacted on relationships, working life, finances and the ability to undertake daily activities. Survivors reported experiencing psychological late effects from around the end of treatment whereas the onset of physical effects occurred later during the post-treatment period. Late effects were managed using formal health services, informal social support and use of 'wellbeing strategies'. Survivors engaged in a process of searching for reasons for experiencing late effects and struggled to make sense of their situation. In particular, a process of 'peer-patient comparison' was used by survivors to help them make sense of, or cope with, their late effects. There appeared to be an association between personal disposition and adaptation and adjustment to the impact of late effects.

CONCLUSIONS: Cancer survivors identified potential components for supported self-management or intervention programmes, as well as important considerations in terms of peer comparisons, personal disposition and making sense of experienced late effects.