Intra-individual Dose Escalation of Abiraterone According to Its Plasma Exposure in Patients with Progressive Metastatic Castration-Resistant Prostate Cancer: Results of the OPTIMABI Trial.

BACKGROUND AND OBJECTIVE: Trough abiraterone concentration (ABI Cmin) of 8.4 ng/mL has been identified as an appropriate efficacy threshold in patients treated for metastatic castration-resistant prostate cancer (mCRPC). The aim of the phase II OPTIMABI study was to evaluate the efficacy of pharmacokinetics (PK)-guided dose escalation of abiraterone acetate (AA) in underexposed patients with mCRPC with early tumour progression. METHODS: This multicentre, non-randomised study consisted of two sequential steps. In step 1, all patients started treatment with 1000 mg of AA once daily. Abiraterone Cmin was measured 22-26 h after the last dose intake each month during the first 12 weeks of treatment. In step 2, underexposed patients (Cmin < 8.4 ng/mL) with tumour progression within the first 6 months of treatment were enrolled and received AA 1000 mg twice daily. The primary endpoint was the rate of non-progression at 12 weeks after the dose doubling. During step 1, adherence to ABI treatment was assessed using the Girerd self-reported questionnaire. A post-hoc analysis of pharmacokinetic (PK) data was conducted using Bayesian estimation of Cmin from samples collected outside the sampling guidelines (22-26 h). RESULTS: In the intention-to-treat analysis (ITT), 81 patients were included in step 1. In all, 21 (26%) patients were underexposed in step 1, and 8 of them (38%) experienced tumour progression within the first 6 months. A total of 71 patients (88%) completed the Girerd self-reported questionnaire. Of the patients, 62% had a score of 0, and 38% had a score of 1 or 2 (minimal compliance failure), without a significant difference in mean ABI Cmin in the two groups. Four patients were enrolled in step 2, and all reached the exposure target (Cmin > 8.4 ng/mL) after doubling the dose, but none met the primary endpoint. In the post-hoc analysis of PK data, 32 patients (39%) were underexposed, and ABI Cmin was independently associated with worse progression-free survival [hazard ratio (HR) 2.50, 95% confidence interval (CI) 1.07-5.81; p = 0.03], in contrast to the ITT analysis. CONCLUSION: The ITT and per-protocol analyses showed no statistical association between ABI underexposure and an increased risk of early tumour progression in patients with mCRPC, while the Bayesian estimator showed an association. However, other strategies than dose escalation at the time of progression need to be evaluated. Treatment adherence appeared to be uniformly good in the present study. Finally, the use of a Bayesian approach to recover samples collected outside the predefined blood collection time window could benefit the conduct of clinical trials based on drug monitoring. OPTIMABI trial is registered as National Clinical Trial number NCT03458247, with the EudraCT number 2017-000560-15).

Nonsteroidal anti-inflammatory drugs sensitize epithelial cells to Clostridioides difficile toxin-mediated mitochondrial damage.

Clostridioides difficile damages the colonic mucosa through the action of two potent exotoxins. Factors shaping C. difficile pathogenesis are incompletely understood but are likely due to the ecological factors in the gastrointestinal ecosystem, mucosal immune responses, and environmental factors. Little is known about the role of pharmaceutical drugs during C. difficile infection (CDI), but recent studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) worsen CDI. The mechanism underlying this phenomenon remains unclear. Here, we show that NSAIDs exacerbate CDI by disrupting colonic epithelial cells (CECs) and sensitizing cells to C. difficile toxin-mediated damage independent of their canonical role of inhibiting cyclooxygenase (COX) enzymes. Notably, we find that NSAIDs and C. difficile toxins target the mitochondria of CECs and enhance C. difficile toxin-mediated damage. Our results demonstrate that NSAIDs exacerbate CDI by synergizing with C. difficile toxins to damage host cell mitochondria. Together, this work highlights a role for NSAIDs in exacerbating microbial infection in the colon.

Social inequalities in treatment receipt for childhood cancers in Ireland: A population-based analysis.

Treatment advances over the past five decades have resulted in significant improvements in survival from childhood cancer. Although survival rates are relatively high, social disparities in outcomes have been sometimes observed. In a population-based study, we investigated social inequalities by sex and deprivation in treatment receipt in childhood cancer in Ireland. Cancers incident in people aged 0 to 19 during 1994 to 2012 and treatments received were abstracted from the National Cancer Registry Ireland. Multivariable modified Poisson regression with robust error variance (adjusting for age, and year) was used to assess associations between sex and deprivation category of area of residence at diagnosis and receipt of cancer-directed surgery, chemotherapy or radiotherapy. Three thousand seven hundred and four childhood cancers were included. Girls were significantly less likely than boys to receive radiotherapy for leukemia overall (relative risk [RR] = 0.70; 95% confidence interval [CI] = 0.50-0.98), and acute lymphoblastic leukemia specifically (RR = 0.54; 95% CI = 0.36-0.79), and surgery for central nervous system (CNS) overall (RR = 0.83; 95% CI = 0.74-0.93) and other CNS (RR = 0.76; 95% CI = 0.60-0.96). Girls were slightly less likely to receive chemotherapy for non-Hodgkin lymphoma and surgery for Hodgkin lymphoma (HL), but these results were not statistically significant. Children residing in more deprived areas were significantly less likely to receive chemotherapy for acute myeloid leukemia or surgery for lymphoma overall and HL, but more likely to receive chemotherapy for medulloblastoma. These results may suggest social inequalities in treatment receipt for childhood cancers. Further research is warranted to explore whether similar patterns are evident in other childhood cancer populations and to better understand the reasons for the findings.

Compared outcomes of femoral shaft fracture treatment in school-age children in Sub-Saharan Africa: Primary open reduction and intramedullary K-wire fixation versus traction followed by spica cast.

BACKGROUND: Elastic stable intramedullary nailing has become the treatment of choice for femur shaft fractures in school-age children in developed world. However, in the sub-Saharan Africa, this management is still challenging because of the lack of fluoroscopy in more hospitals. We performed either primary open reduction and intramedullary K-wire fixation (PORIKF) or conservative treatment. The aim of this study was to compare the clinical and functional outcomes of these two procedures employed. PATIENTS AND METHODS: This retrospective study included 62 children with 64 fractures (10 years on an average; range: 6-15 years) treating for femoral shaft fractures either by PORIKF (n = 21; 23 fractures) or skin traction followed by spica cast (n = 41) between 2008 and 2017. Outcomes were assessed using Flynn criteria. Comparisons were made by Fisher and Student's t-test with a significant P < 5%. RESULTS: Outcomes were satisfactory in 21 cases (91%) in the PORIKF group compared with 32 (78%) in the conservative group (P = 0.3012). The average hospital stay was 18.6 days in the PORIKF group, whereas it was 20 in the conservative group (P = 0.0601). The mean time for bone union was 13.9 weeks in the PORIKF group and 13.2 weeks in the conservative group, (P = 0.4346). There was a statistically significant difference between the two groups in terms of major complications (P = 0.0177). One patient had osteomyelitis in the PORIKF group. Unacceptable shortening >2 cm was observed only in the conservative group. The average time to return to daily activities was 30 days shorter in the PORIKF group when compared to conservative group (P < 0.05). CONCLUSION: PORIKF provides better results than conservative treatment. Open reduction did not increase the rate of infectious complication.

Educational attainment of childhood cancer survivors: A systematic review.

BACKGROUND: Advances in treatment mean that most children diagnosed with cancer during childhood survive. Therefore, it is increasingly important to examine the long-term consequences of childhood cancer, including educational attainment. This systematic review investigated whether the educational attainment of childhood cancer survivors differ from the cancer-free population. DESIGN/METHODS: We searched seven databases for articles published from January 2005 to August 2018. We identified full papers in English, reporting primary data on academic attainment of adult survivors of childhood cancer, compared to a control group. Quality appraisal was conducted using the Newcastle-Ottawa Scale. RESULTS: Fourteen studies met the inclusion criteria. Nine papers included patients with various types of cancers, four focused on a single type of cancer, and one on patients who underwent stem cell transplantation. Of the 14 papers, 2 studies were considered good quality, 10 were considered adequate quality, and 2 were considered poor quality. Four studies reported more favorable educational attainment among survivors while six did not report significant differences. Less favorable attainment was consistently reported for CNS survivors in four studies. CONCLUSION: The literature does not provide a clear pattern of the long-term consequences of childhood cancer on education attainment. While this may suggest that there is no consistent difference between the education attainment of cancer survivors and controls, it may also be the result of limitations in the existing research. To better assess the education attainment of survivors, there is a need for high-quality studies, with appropriate comparators, and standardized measures of education attainment across countries.

The NC domain of HIV-1 Gag contributes to the interaction of Gag with TSG101.

BACKGROUND: HIV-1 Gag polyprotein orchestrates the assembly of viral particles. Its C-terminus consists of the nucleocapsid (NC) domain that interacts with RNA, and the p6 domain containing the PTAP motif that binds the cellular ESCRT factor TSG101 and ALIX. Deletion of the NC domain of Gag (GagNC) results in defective Gag assembly, a decrease in virus production and, thus probably affects recruitment of the ESCRT machinery. To investigate the role of GagNC in this recruitment, we analysed its impact on TSG101 and ALIX localisations and interactions in cells expressing Gag. METHODS: Cells expressing mCherry-Gag or derivatives, alone or together with eGFP-TSG101 or eGFP-ALIX, were analysed by confocal microscopy and FLIM-FRET. Chemical shift mapping between TSG101-UEV motif and Gag C-terminus was performed by NMR. RESULTS: We show that deletion of NC or of its two zinc fingers decreases the amount of Gag-TSG101 interacting complexes in cells. These findings are supported by NMR data showing chemical shift perturbations in the NC domain in- and outside - of the zinc finger elements upon TSG101 binding. The NMR data further identify a large stretch of amino acids within the p6 domain directly interacting with TSG101. CONCLUSION: The NC zinc fingers and p6 domain of Gag participate in the formation of the Gag-TSG101 complex and in its cellular localisation. GENERAL SIGNIFICANCE: This study illustrates that the NC and p6 domains cooperate in the interaction with TSG101 during HIV-1 budding. In addition, details on the Gag-TSG101 complex were obtained by combining two high resolution biophysical techniques.

Urban-Rural Variations in Quality-of-Life in Breast Cancer Survivors Prescribed Endocrine Therapy.

The number of breast cancer survivors has increased as a result of rising incidence and increased survival. Research has revealed significant urban-rural variation in clinical aspects of breast cancer but evidence in the area of survivorship is limited. We aimed to investigate whether quality of life (QoL) and treatment-related symptoms vary between urban and rural breast cancer survivors prescribed endocrine therapy. Women with a diagnosis of stages I-III breast cancer prescribed endocrine therapy were identified from the National Cancer Registry Ireland and invited to complete a postal survey (N = 1606; response rate = 66%). A composite measure of urban-rural classification was created using settlement size, population density and proximity to treatment hospital. QoL was measured using the Functional Assessment of Cancer Therapy (FACT-G) and an endocrine subscale. The association between urban-rural residence/status and QoL and endocrine symptoms was assessed using linear regression with adjustment for socio-demographic and clinical covariates. In multivariable analysis, rural survivors had a statistically significant higher overall QoL (ß = 3.81, standard error (SE) 1.30, p < 0.01), emotional QoL (ß = 0.70, SE 0.21, p < 0.01) and experienced a lower symptom burden (ß = 1.76, SE 0.65, p < 0.01) than urban survivors. QoL in breast cancer survivors is not simply about proximity and access to healthcare services but may include individual and community level psychosocial factors.

Socioeconomic disadvantage but not remoteness affects short-term survival in prostate cancer: A population-based study using competing risks.

AIM: We examined how sociodemographic, clinical and area-level factors are related to short-term prostate cancer mortality versus mortality from other causes, a crucial distinction for this disease that disproportionately affects men older than 60 years. METHODS: We applied competing risk survival models to administrative data from the Queensland Cancer Registry (Australia) for men diagnosed with prostate cancer between January 2005 and July 2007, including stratification by Gleason score. RESULTS: The men (n = 7393) in the study cohort had a median follow-up of 5 years 3 months. After adjustment, remoteness and area-level disadvantage were not significantly associated with prostate cancer mortality. However, area-level disadvantage had a significant negative relationship with hazard of death from a cause other than prostate cancer within 7 years; compared with those living in the most advantaged areas, the likelihood of mortality was higher for those in the most disadvantaged (subhazard ratio [SHR] = 1.39; 95% CI, 1.01-1.90; P = 0.041), disadvantaged (SHR = 1.51; 95% CI, 1.14-2.00; P = 0.004), middle (SHR = 1.34; 95% CI, 1.02-1.75; P = 0.034) and advantaged areas (SHR = 1.44; 95% CI, 1.09-1.89; P = 0.009). Those with Gleason score of 7 and higher had a lower hazard of prostate cancer mortality if they were living with a partner, whereas those with lower Gleason scores and living a partner had lower hazards of other-cause mortality. CONCLUSIONS: Understanding why men living in more disadvantaged areas have higher risk of non-prostate cancer mortality should be a priority.

Urban-rural differences in cancer-directed surgery and survival of patients with non-small cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer death worldwide. Clinically appropriate cancer-directed surgery is an influential and significant prognostic factor. In a population-based study, we determined how urban/rural residence was related to surgery receipt for patients with non-small cell lung cancer. We assessed the relationship between relative survival and patients' area of residence, taking into account surgery receipt and area socioeconomic level. METHODS: We extracted data from the National Cancer Registry Ireland on patients with non-small cell lung cancer diagnosed during 1994-2011 and linked to area-level data on socioeconomic indicators and urban/rural categories. We calculated ORs for receipt of cancer-directed surgery using logistic regression with postestimation of adjusted proportions. Relative survival estimates with follow-up to 31 December 2012 were calculated for all cases and stratified by surgery receipt, adjusting for clinical variables, area socioeconomic level and other sociodemographic characteristics. RESULTS: 15 031 people diagnosed with non-small cell lung cancer were included in the analysis. On the basis of the multiple logistic regression model, a significantly larger proportion of urban patients (adjusted proportion 23%) as compared with rural patients (adjusted proportion 21%) received surgery (p<0.001). In multivariate analysis, rural residence was significantly related to a decrease in excess mortality for all cases (HR 0.90, 95% CI 0.87 to 0.94, p<0.001) and for non-surgical cases (HR 0.88, 95% CI 0.85 to 0.92, p<0.001). CONCLUSIONS: The findings point to the need for targeted policies addressing access to treatment for rural patients with non-small cell lung cancer.

Projecting productivity losses for cancer-related mortality 2011 - 2030.

BACKGROUND: When individuals stop working due to cancer this represents a loss to society - the loss of productivity. The aim of this analysis was to estimate productivity losses associated with premature mortality from all adult cancers and from the 20 highest mortality adult cancers in Ireland in 2011, and project these losses until 2030. METHODS: An incidence-based method was used to estimate the cost of cancer deaths between 2011 and 2030 using the Human Capital Approach. National data were used for cancer, population and economic inputs. Both paid work and unpaid household activities were included. Sensitivity analyses estimated the impact of assumptions around future cancer mortality rates, retirement ages, value of unpaid work, wage growth and discounting. RESULTS: The 233,000 projected deaths from all invasive cancers in Ireland between 2011 and 2030 will result in lost productivity valued at €73 billion; €13 billion in paid work and €60 billion in household activities. These losses represent approximately 1.4 % of Ireland's GDP annually. The most costly cancers are lung (€14.4 billion), colorectal and breast cancer (€8.3 billion each). However, when viewed as productivity losses per cancer death, testis (€364,000 per death), cervix (€155,000 per death) and brain cancer (€136,000 per death) are most costly because they affect working age individuals. An annual 1 % reduction in mortality reduces productivity losses due to all invasive cancers by €8.5 billion over 20 years. CONCLUSIONS: Society incurs substantial losses in productivity as a result of cancer-related mortality, particularly when household production is included. These estimates provide valuable evidence to inform resource allocation decisions in cancer prevention and control.

Comparing the costs of three prostate cancer follow-up strategies: a cost minimisation analysis.

PURPOSE: Prostate cancer follow-up is traditionally provided by clinicians in a hospital setting. Growing numbers of prostate cancer survivors mean that this model of care may not be economically sustainable, and a number of alternative approaches have been suggested. The aim of this study was to develop an economic model to compare the costs of three alternative strategies for prostate cancer follow-up in Ireland-the European Association of Urology (EAU) guidelines, the National Institute of Health Care Excellence (NICE) guidelines and current practice. METHODS: A cost minimisation analysis was performed using a Markov model with three arms (EAU guidelines, NICE guidelines and current practice) comparing follow-up for men with prostate cancer treated with curative intent. The model took a health care payer's perspective over a 10-year time horizon. RESULTS: Current practice was the least cost efficient arm of the model, the NICE guidelines were most cost efficient (74 % of current practice costs) and the EAU guidelines intermediate (92 % of current practice costs). For the 2562 new cases of prostate cancer diagnosed in 2009, the Irish health care system could have saved €760,000 over a 10-year period if the NICE guidelines were adopted. CONCLUSIONS: This is the first study investigating costs of prostate cancer follow-up in the Irish setting. While economic models are designed as a simplification of complex real-world situations, these results suggest potential for significant savings within the Irish health care system associated with implementation of alternative models of prostate cancer follow-up care.

Involvement of the Rac1-IRSp53-Wave2-Arp2/3 Signaling Pathway in HIV-1 Gag Particle Release in CD4 T Cells.

UNLABELLED: During HIV-1 assembly, the Gag viral proteins are targeted and assemble at the inner leaflet of the cell plasma membrane. This process could modulate the cortical actin cytoskeleton, located underneath the plasma membrane, since actin dynamics are able to promote localized membrane reorganization. In addition, activated small Rho GTPases are known for regulating actin dynamics and membrane remodeling. Therefore, the modulation of such Rho GTPase activity and of F-actin by the Gag protein during virus particle formation was considered. Here, we studied the implication of the main Rac1, Cdc42, and RhoA small GTPases, and some of their effectors, in this process. The effect of small interfering RNA (siRNA)-mediated Rho GTPases and silencing of their effectors on Gag localization, Gag membrane attachment, and virus-like particle production was analyzed by immunofluorescence coupled to confocal microscopy, membrane flotation assays, and immunoblot assays, respectively. In parallel, the effect of Gag expression on the Rac1 activation level was monitored by G-LISA, and the intracellular F-actin content in T cells was monitored by flow cytometry and fluorescence microscopy. Our results revealed the involvement of activated Rac1 and of the IRSp53-Wave2-Arp2/3 signaling pathway in HIV-1 Gag membrane localization and particle release in T cells as well as a role for actin branching and polymerization, and this was solely dependent on the Gag viral protein. In conclusion, our results highlight a new role for the Rac1-IRSp53-Wave2-Arp2/3 signaling pathway in the late steps of HIV-1 replication in CD4 T lymphocytes. IMPORTANCE: During HIV-1 assembly, the Gag proteins are targeted and assembled at the inner leaflet of the host cell plasma membrane. Gag interacts with specific membrane phospholipids that can also modulate the regulation of cortical actin cytoskeleton dynamics. Actin dynamics can promote localized membrane reorganization and thus can be involved in facilitating Gag assembly and particle formation. Activated small Rho GTPases and effectors are regulators of actin dynamics and membrane remodeling. We thus studied the effects of the Rac1, Cdc42, and RhoA GTPases and their specific effectors on HIV-1 Gag membrane localization and viral particle release in T cells. Our results show that activated Rac1 and the IRSp53-Wave2-Arp2/3 signaling pathway are involved in Gag plasma membrane localization and viral particle production. This work uncovers a role for cortical actin through the activation of Rac1 and the IRSp53/Wave2 signaling pathway in HIV-1 particle formation in CD4 T lymphocytes.

Productivity Losses Associated with Head and Neck Cancer Using the Human Capital and Friction Cost Approaches.

OBJECTIVES: Previous studies suggest that productivity losses associated with head and neck cancer (HNC) are higher than in other cancers. These studies have only assessed a single aspect of productivity loss, such as temporary absenteeism or premature mortality, and have only used the Human Capital Approach (HCA). The Friction Cost Approach (FCA) is increasingly recommended, although has not previously been used to assess lost production from HNC. The aim of this study was to estimate the lost productivity associated with HNC due to different types of absenteeism and premature mortality, using both the HCA and FCA. METHODS: Survey data on employment status were collected from 251 HNC survivors in Ireland and combined with population-level survival estimates and national wage data. The cost of temporary and permanent time off work, reduced working hours and premature mortality using both the HCA and FCA were calculated. RESULTS: Estimated total productivity losses per employed person of working age were EUR253,800 using HCA and EUR6800 using FCA. The main driver of HCA costs was premature mortality (38% of total) while for FCA it was temporary time off (73% of total). CONCLUSIONS: The productivity losses associated with head and neck cancer are substantial, and return to work assistance could form an important part of rehabilitation. Use of both the HCA and FCA approaches allowed different drivers of productivity losses to be identified, due to the different assumptions of the two methods. For future estimates of productivity losses, the use of both approaches may be pragmatic.

Distance from treating hospital and colorectal cancer survivors' quality of life: a gendered analysis.

PURPOSE: Distance from residence to hospital has been associated with clinical outcomes for colorectal cancer patients. However, little is known about the association of remoteness with quality of life (QoL) for colorectal cancer survivors. We examined the relationship between distance from hospital and colorectal cancer survivors' QoL, with a specific focus on gender. METHODS: Colorectal cancer survivors in Ireland who were more than 6-months postdiagnosis completed the European Organization for Research and Treatment of Cancer QLQ-C30, measuring global health status (GHS) and physical, role, cognitive, social, and emotional functioning. Bootstrap linear regression was used to evaluate the association between remoteness and QoL scales, controlling for demographic and clinical variables. Separate models were generated for the full sample, for women, and for men. RESULTS: The final analytical sample was 496 colorectal cancer survivors; 186 women and 310 men. Living remote from the treating hospital was associated with lower physical functioning (coefficient -4.38 [95 % confidence interval -8.13, -0.91]) and role functioning (coeff. -7.78 [-12.64, -2.66]) among all colorectal cancer survivors. In the separate gender models, remoteness was significantly associated with lower physical (coeff. -7.00 [-13.47, -1.49]) and role functioning (coeff. -11.50 [-19.66, -2.65]) for women, but not for men. Remoteness had a significant negative relationship to GHS (coeff. -4.31 [-8.46, -0.27]) for men. CONCLUSIONS: Aspects of QoL are lower among colorectal cancer survivors who live far from their treating hospital. There are gender differences in how remoteness is related to QoL domains. The results of this study suggest that policy makers, service providers, and health care professionals should consider the specific QoL needs of remote colorectal cancer survivors, and be attuned to and prepared to address the differing needs of men and women.

Long-term workforce participation patterns following head and neck cancer.

PURPOSE: This analysis describes the long-term workforce participation patterns of individuals diagnosed with head and neck cancer (HNC). METHODS: Survivors of HNC (ICD10 C00-C14, C32) diagnosed at least 8 months previously were identified from the National Cancer Registry Ireland and sent a survey including questions about working arrangements before and since diagnosis. Descriptive statistics and multivariate logistic regression were used to examine the factors that influence workforce participation at 0, 1 and 5 years after diagnosis. RESULTS: Two hundred sixty-four individuals employed at the time of diagnosis responded to the survey, an average 6 years post-diagnosis. Seventy-seven percent took time off work after diagnosis, with a mean work absence of 9 months (range 0-65 months). Fifty-two percent of participants reduced their working hours (mean reduction 15 h/week). The odds of workforce participation following HNC were increased by not being eligible for free medical care (OR 2.61, 95% CI 1.15-5.94), having lip, mouth or salivary gland cancer (compared to cancer of the pharynx or cancer of the larynx, OR 2.79, 1.20-6.46), being self-employed (OR 2.01, 1.07-3.80), having private health insurance (OR 2.06, 1.11-3.85) and not receiving chemotherapy (OR 2.82, 1.31-6.06). After 5 years, only the effect of medical card remained (i.e., medical insurance) (OR 4.03, 1.69-9.62). CONCLUSIONS: Workforce participation patterns after HNC are complex and are influenced by cancer, treatment and employment factors. IMPLICATIONS FOR CANCER SURVIVORS: Patients should be informed of the potential impacts of HNC on workforce participation, and clinicians, policy makers and employers should be aware of these potential longer-term effects and related variables.

The magnitude and characteristics of the population of cancer survivors: using population-based estimates of cancer prevalence to inform service planning for survivorship care.

BACKGROUND: Rising cancer incidence and survival mean that the number of cancer survivors is growing. Accumulating evidence suggests many survivors have long-term medical and supportive care needs, and that these needs vary by survivors' socio-demographic and clinical characteristics. To illustrate how cancer registry data may be useful in survivorship care service planning, we generated population-based estimates of cancer prevalence in Ireland and described socio-demographic and clinical characteristics of the survivor population. METHODS: Details of people diagnosed with invasive cancer (ICD10 C00-C96) during 1994-2011, and who were still alive on 31/12/2011, were abstracted from the National Cancer Registry, and tabulated by cancer site, sex, current age, marital status, initial treatment, and time since diagnosis. Associations were investigated using chi-square tests. RESULTS: After excluding non-melanoma skin cancers, 17-year cancer prevalence in Ireland was 112,610 (females: 58,054 (52%) males: 54,556 (48%)). The four most prevalent cancers among females were breast (26,066), colorectum (6,598), melanoma (4,593) and uterus (3,505) and among males were prostate (23,966), colorectum (8,207), lymphoma (3,236) and melanoma (2,774). At the end of 2011, 39% of female survivors were aged <60 and 35% were ≥70 compared to 25% and 46% of males (p < 0.001). More than half of survivors of bladder, colorectal and prostate cancer were ≥70. Cancers with the highest percentages of younger (<40) survivors were: testis (50%); leukaemia (females: 28%; males: 22%); cervix (20%); and lymphoma (females: 19%; males: 20%). Fewer female (57%) than male (64%) survivors were married but the percentage single was similar (17-18%). More female (25%) than male survivors (18%; p < 0.001) were ≥10 years from diagnosis. Overall, 69% of survivors had undergone cancer-directed surgery, and 39%, 32% and 18% had received radiotherapy, chemotherapy and hormone therapy, respectively. These frequencies were higher among females than males (surgery: 82%, 54%; radiotherapy: 42%, 35%; chemotherapy: 40%, 22%; hormone therapy: 23%, 13%). CONCLUSIONS: These results reveal the socio-demographic and clinical heterogeneity of the survivor population, and highlight groups which may have specific medical and supportive care needs. These types of population-based estimates may help decision-makers, planners and service providers to develop follow-up and after-care services to effectively meet survivors' needs.

Quality of life in urban and rural settings: a study of head and neck cancer survivors.

OBJECTIVE: Urban-rural variation in cancer incidence, treatment, and clinical outcomes has been well researched. With the growing numbers and longer lifespan of cancer survivors, quality of life (QOL) is now a critical issue. The present study investigates the QOL of head and neck cancer (HNC) survivors in Ireland, paying special attention to urban and rural variation. METHODS: From the population-based National Cancer Registry Ireland, we identified 991 survivors of HNC (ICD10 C00-C14, C32), who were at least eight months post-diagnosis, and invited them to complete a postal survey. We used self-reported data and information from the Registry to create a composite variable classifying respondents' current area of residence as "urban" or "rural." Respondents self-reported QOL using the Functional Assessment for Cancer Therapy with Head and Neck module (FACT-HN). We used bootstrap linear regression to control for confounding variables, while estimating the association of urban and rural residence to FACT-HN domain scores. RESULTS: We obtained survey and Registry data from 583 HNC survivors. Controlling for demographic and clinical variables, rural survivors reported higher physical (coefficient 1.27, bias-corrected and accelerated 95% confidence interval 0.54, 2.43), emotional (coef. 0.99, 95% CI 0.21, 2.02), and HNC-specific (coef. 1.55, 95% CI 0.32, 3.54) QOL than their urban counterparts. Social and functional QOL did not differ significantly. CONCLUSIONS: These findings add to growing evidence of important differences in life experiences of cancers survivors in urban and rural settings. Results such as these will allow health professionals, policy makers and service providers to better serve these populations.

A simple HPLC-UV method for the simultaneous quantification of gefitinib and erlotinib in human plasma.

Gefitinib and erlotinib are two oral tyrosine kinase inhibitors (TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Published methods for simultaneous analysis of erlotinib and gefitinib in plasma are exclusively based on mass spectrometry. The purpose of this study was to develop a simple and sensitive HPLC-UV method to simultaneously quantify these two TKI in plasma. Following liquid-liquid extraction, gefitinib, erlotinib and sorafenib (internal standard), were separated with gradient elution (on a C8+ Satisfaction(®) using a mobile phase of acetonitrile/20mM ammonium acetate pH 4.5). Samples were eluted at a flow rate of 0.4 ml/min throughout the 15-min run. Dual UV wavelength mode was used, with gefitinib and erlotinib monitored at 331 nm, and sorafenib at 249 nm. The calibration was linear in the range 20-1000 ng/ml and 80-4000 ng/ml for gefitinib and erlotinib, respectively. Inter- and intra-day imprecision were less than 7.2% and 7.6% for gefitinib and erlotinib, respectively. This analytical method was successfully applied to assess the steady state plasma exposure to these TKI in NSCLC patients. This simple, sensitive, accurate and cost-effective method can be used in routine clinical practice to monitor gefitinib or erlotinib concentrations in plasma from NSCLC patients.

Nanoparticle-based bio-barcode assay redefines "undetectable" PSA and biochemical recurrence after radical prostatectomy.

We report the development of a previously undescribed gold nanoparticle bio-barcode assay probe for the detection of prostate specific antigen (PSA) at 330 fg/mL, automation of the assay, and the results of a clinical pilot study designed to assess the ability of the assay to detect PSA in the serum of 18 men who have undergone radical prostatectomy for prostate cancer. Due to a lack of sensitivity, available PSA immunoassays are often not capable of detecting PSA in the serum of men after radical prostatectomy. This new bio-barcode PSA assay is approximately 300 times more sensitive than commercial immunoassays. Significantly, with the barcode assay, every patient in this cohort had a measurable serum PSA level after radical prostatectomy. Patients were separated into categories based on PSA levels as a function of time. One group of patients showed low levels of PSA with no significant increase with time and did not recur. Others showed, at some point postprostatectomy, rising PSA levels. The majority recurred. Therefore, this new ultrasensitive assay points to significant possible outcomes: (i) The ability to tell patients, who have undetectable PSA levels with conventional assays, but detectable and nonrising levels with the barcode assay, that their cancer will not recur. (ii) The ability to assign recurrence earlier because of the ability to measure increasing levels of PSA before conventional tools can make such assignments. (iii) The ability to use PSA levels that are not detectable with conventional assays to follow the response of patients to adjuvant or salvage therapies.