Radiopharmaceuticals in the elderly cancer patient: Practical considerations, with a focus on prostate cancer therapy: A position paper from the International Society of Geriatric Oncology Task Force.

Molecular imaging using radiopharmaceuticals has a clear role in visualising the presence and extent of tumour at diagnosis and monitoring response to therapy. Such imaging provides prognostic and predictive information relevant to management, e.g. by quantifying active tumour mass using positron emission tomography/computed tomography (PET/CT). As these techniques require only pharmacologically inactive doses, age and potential frailty are generally not important. However, this may be different for therapy involving radionuclides because the radiation can impact normal bodily function (e.g. myelosuppression). Since the introduction of Iodine-131 as a targeted therapy in thyroid cancer, several radiopharmaceuticals have been widely used. These include antibodies and peptides targeting specific epitopes on cancer cells. Among therapeutic bone seeking agents, radium-223 ((223)Ra) stands out as it results in survival gains in patients with castration-resistant prostate cancer and symptomatic bone metastases. The therapeutic use of radiopharmaceuticals in elderly cancer patients specifically has received little attention. In elderly prostate cancer patients, there may be advantages in radionuclides' ease of use and relative lack of toxicity compared with cytotoxic and cytostatic drugs. When using radionuclide therapies, close coordination between oncology and nuclear medicine is needed to ensure safe and effective use. Bone marrow reserve has to be considered. As most radiopharmaceuticals are cleared renally, dose adjustment may be required in the elderly. However, compared with younger patients there is less, if any, concern about adverse long-term radiation effects such as radiation-induced second cancers. Issues regarding the safety of medical staff, care givers and the wider environment can be managed by current precautions

Varietal differences in protein polymer built-up of wheat at different temperature and nitrogen regimes during grain filling

Both radionuclide imaging and near-infrared fluorescent (NIRF) imaging have a high sensitivity to detect tumors in vivo. The combination of these modalities using dual-labeled antibodies may allow both preoperative and intraoperative tumor localization and may be used in image-guided surgery to ensure complete resection of tumor tissue. Here, we evaluated the potential of dual-modality imaging of prostate cancer with the monoclonal antibody D2B, directed against an extracellular domain of prostate-specific membrane antigen (PSMA). For these studies, D2B was labeled both with (111)In and with the NIRF dye IRDye800CW.D2B was conjugated with N-hydroxysuccinimide-IRDye800CW and p-isothiocyanatobenzyl-diethylenetriaminepentaacetic acid (ITC-DTPA) and subsequently radiolabeled with (111)In. For biodistribution and NIRF imaging, (111)In-DTPA-D2B-IRDye800CW (2 μg, 0.55 MBq/mouse) was injected intravenously into BALB/c nude mice with subcutaneous PSMA-expressing LNCaP tumors (right flank) and PSMA-negative PC3 tumors (left flank). The biodistribution was determined at 1, 2, 3, and 7 d after injection. In addition, micro-SPECT/CT and NIRF imaging with (111)In-DTPA-D2B-IRDye800CW (3 μg, 8.5 MBq/mouse) was performed on mice with intraperitoneally growing LS174T-PSMA tumors.(111)In-DTPA-D2B-IRDye800CW specifically accumulated in subcutaneous PSMA-positive LNCaP tumors (45.8 ± 8.0 percentage injected dose per gram at 168 h after injection), whereas uptake in subcutaneous PSMA-negative PC3 tumors was significantly lower (6.6 ± 1.3 percentage injected dose per gram at 168 h after injection). Intraperitoneal LS174T-PSMA tumors could be visualized specifically with both micro-SPECT/CT and NIRF imaging at 2 d after injection, and the feasibility of image-guided resection of intraperitoneal tumors was demonstrated in this model.Dual-labeled (111)In-DTPA-D2B-IRDye800CW enables specific and sensitive detection of prostate cancer lesions in vivo with micro-SPECT/CT and NIRF imaging. In addition to preoperative micro-SPECT/CT imaging to detect tumors, NIRF imaging enables image-guided surgical resection. These preclinical findings warrant clinical studies with (111)In-DTPA-D2B-IRDye800CW to improve tumor detection and resection in prostate cancer patients

Relationship of promising methods in the detection of anthracycline-induced cardiotoxicity in breast cancer patients

Purpose\ud It remains challenging to identify patients at risk of anthracycline-induced cardiotoxicity. To better understand the different risk-stratifying approaches, we evaluated 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy and its interrelationship with conventional echocardiography, 2D strain imaging and several biomarkers.\ud \ud Methods\ud We performed 123I-mIBG scintigraphy, conventional and strain echocardiography and biomarker (NT-proBNP, TNF-α, galectin-3, IL-6, troponin I, ST-2 and sFlt-1) assessment in 59 breast cancer survivors 1 year after anthracycline treatment. Interobserver and intermethod variability was calculated on planar and SPECT 123I-mIBG scintigraphy, using the heart/mediastinum (H/M) ratio and washout (WO). Pearson’s r and multivariate analyses were performed to identify correlations and independent predictors of 123I-mIBG scintigraphy results.\ud \ud Results\ud Delayed planar anterior whole-heart ROI (WH) H/M ratios and WO were the most robust 123I-mIBG parameters. Significant correlations were observed between 123I-mIBG parameters and several conventional echo parameters, global longitudinal and radial strain (GLS and GRS) and galectin-3. The highest Pearson’s r was observed between delayed H/M ratio and GRS (Pearson’s r 0.36, p = 0.01). Multivariate analysis showed that GRS was the only independent predictor of the delayed WH H/M ratio (p = 0.023).\ud \ud Conclusion\ud The delayed planar H/M ratio is the most robust 123I-mIBG parameter. It correlates with several conventional echocardiographic parameters, GLS, GRS and galectin-3. Of these, only GRS predicts the H/M ratio

Contribution of chronic diseases to the mild and severe disability burden in Belgium

Background: Population aging accompanied by an increased longevity with disability has raised international concern, especially due to its costs to the health care systems. Chronic diseases are the main causes of physical disability and their simultaneous occurrence in the population can impact the disablement process, resulting in different severity levels. In this study, the contribution of chronic diseases to both mild and severe disability burden in Belgium was investigated. Methods: Data on 21 chronic diseases and disability from 35,799 individuals aged 15years or older who participated in the 1997, 2001, 2004, or 2008 Belgian Health Interview Surveys were analysed. Mild and severe disability were defined based on questions related to six activities of daily living and/or mobility limitations. To attribute disability by severity level to selected chronic diseases, multiple additive hazard models were fitted to each disability outcome, separately for men and women. Results: A stable prevalence of mild (5%) and severe (2-3%) disability was observed for the Belgian population aged 15years or older between 1997 and 2008. Arthritis was the most important contributor in women with mild and severe disability. In men, low back pain and chronic respiratory diseases contributed most to the mild and severe disability burden, respectively. The contribution also differed by age: for mild disability, depression and chronic respiratory diseases were important contributors among young individuals, while heart attack had a large contribution for older individuals. For severe disability, neurological diseases and stroke presented a large contribution in young and elderly individuals, respectively. Conclusions: Our results indicate that the assessment of the contribution of chronic diseases on disability is more informative if different levels of disability are taken into consideration. The identification of diseases which are related to different levels of disability - mild and severe - can assist policymakers in the definition and prioritisation of strategies to tackle disability, involving prevention, rehabilitation programs, support services, and training for disabled individuals

FROM MOUSTACHES TO MY SPACES

Radical removal of malignant lesions may be improved using tumor-targeted dual-modality probes that contain both a radiotracer and a fluorescent label to allow for enhanced intraoperative delineation of tumor resection margins. Because pretargeting strategies yield high signal-to-background ratios, we evaluated the feasibility of a pretargeting strategy for intraoperative imaging in prostate cancer using an anti-TROP-2 x anti-HSG bispecific antibody (TF12) in conjunction with the dual-labeled diHSG peptide (RDC018) equipped with both a DOTA chelate for radiolabeling purposes and a fluorophore (IRdye800CW) to allow near-infrared optical imaging. Nude mice implanted s.c. with TROP-2-expressing PC3 human prostate tumor cells or with PC3 metastases in the scapular and suprarenal region were injected i.v. with 1 mg of TF12 and, after 16 hours of tumor accumulation and blood clearance, were subsequently injected with 10 MBq, 0.2 nmol/mouse of either (111)In-RDC018 or (111)In-IMP288 as a control. Two hours after injection, both microSPECT/CT and fluorescence images were acquired, both before and after resection of the tumor nodules. After image acquisition, the biodistribution of (111)In-RDC018 and (111)In-IMP288 was determined and tumors were analyzed immunohistochemically. The biodistribution of the dual-label RDC018 showed specific accumulation in the TROP-2-expressing PC3 tumors (12.4 +/- 3.7% ID/g at 2 hours postinjection), comparable with (111)In-IMP288 (9.1 +/- 2.8% ID/g at 2 hours postinjection). MicroSPECT/CT and near-infrared fluorescence (NIRF) imaging confirmed this TROP-2-specific uptake of the dual-label (111)In-RDC018 in both the s.c. and metastatic growing tumor model. In addition, PC3 metastases could be visualized preoperatively with SPECT/CT and could subsequently be resected by image-guided surgery using intraoperative NIRF imaging, showing the preclinical feasibility of pretargeted dual-modality imaging approach in prostate cancer

Contribution of chronic diseases to the disability burden in a population 15 years and older, Belgium, 1997-2008

Background: Age-associated disability reduces quality of life in older populations and leads to wide-range implications for social and health policy. The identification of diseases that contribute to the disability burden is crucial to the development of prevention and intervention strategies to reduce disability. In this study, we assessed the contribution of chronic diseases to the prevalence of disability in Belgium. Methods: Data from 35,837 individuals aged 15 years or older who participated in the 1997, 2001, 2004, or 2008 Belgian Health Interview Surveys were used. Disability was defined as difficulties in doing at least one of six activities of daily living (transfer in and out of bed, transfer in and out of chair, dressing, washing hands and face, feeding, and going to the toilet) and/or mobility limitations (ability to walk without stopping less than 200 m). Multiple additive regression models were fitted separately for men and women to estimate the age-specific background disability rate (experienced by everyone, independent of the presence of specific diseases) and disease-specific disability rates (disability rate in subjects who reported selected chronic diseases). Results: Musculoskeletal, cardiovascular, and respiratory diseases were the main contributors to the disability burden in Belgium. Musculoskeletal diseases were the most prevalent diseases in men and women in all age groups. Neurological diseases and stroke were the most disabling diseases, i.e. caused the highest level of disability among the diseased individuals, in all age groups for men and women, respectively. Back pain was the main cause of disability in men aged 15 to 64 years, while heart attack was the major contributor to the disability prevalence in men aged 65 or older. Likewise, arthritis was the main cause of disability among women across all age groups. Depression was also an important contributor in young subjects (15-54 years). Cancer was not an important contributor to the disability prevalence in Belgium. Conclusions: To reduce the burden of disability in Belgium, interventions should target musculoskeletal, cardiovascular and respiratory diseases especially among elderly. Furthermore, attention should also be given to depression in young individuals

The effect of smoking on the duration of life with and without disability, Belgium 1997-2011

Background: Smoking is the single most important health threat yet there is no consistency as to whether non-smokers experience a compression of years lived with disability compared to (ex-)smokers. The objectives of the manuscript are (1) to assess the effect of smoking on the average years lived without disability (Disability Free Life Expectancy (DFLE)) and with disability (Disability Life Expectancy (DLE)) and (2) to estimate the extent to which these effects are due to better survival or reduced disability in never smokers. Methods. Data on disability and mortality were provided by the Belgian Health Interview Survey 1997 and 2001 and a 10 years mortality follow-up of the survey participants. Disability was defined as difficulties in activities of daily living (ADL), in mobility, in continence or in sensory (vision, hearing) functions. Poisson and multinomial logistic regression models were fitted to estimate the probabilities of death and the prevalence of disability by age, gender and smoking status adjusted for socioeconomic position. The Sullivan method was used to estimate DFLE and DLE at age 30. The contribution of mortality and of disability to smoking related differences in DFLE and DLE was assessed using decomposition methods. Results: Compared to never smokers, ex-smokers have a shorter life expectancy (LE) and DFLE but the number of years lived with disability is somewhat larger. For both sexes, the higher disability prevalence is the main contributing factor to the difference in DFLE and DLE. Smokers have a shorter LE, DFLE and DLE compared to never smokers. Both higher mortality and higher disability prevalence contribute to the difference in DFLE, but mortality is more important among males. Although both male and female smokers experience higher disability prevalence, their higher mortality outweighs their disability disadvantage resulting in a shorter DLE. Conclusion: Smoking kills and shortens both life without and life with disability. Smoking related disability can however not be ignored, given its contribution to the excess years with disability especially in younger age groups

Addhaz: Contribution of chronic diseases to the disability burden using R

The increase in life expectancy followed by the burden of chronic diseases contributes to disability at older ages. The estimation of how much chronic conditions contribute to disability can be useful to develop public health strategies to reduce the burden. This paper introduces the R package addhaz, which is based on the attribution method (Nusselder and Looman, 2004) to partition disability into the additive contributions of diseases using cross-sectional data. The R package includes tools to fit the additive hazard model, the core of the attribution method, to binary and multinomial outcomes. The models are fitted by maximizing the binomial and multinomial log-likelihood functions using constrained optimization. Wald and bootstrap confidence intervals can be obtained for the parameter estimates. Also, the contribution of diseases to the disability prevalence and their bootstrap confidence intervals can be estimated. An additional feature is the possibility to use parallel computing to obtain the bootstrap confidence intervals. In this manuscript, we illustrate the use of addhaz with several examples for the binomial and multinomial models, using the data from the Brazilian National Health Survey, 2013

Assessing the validity of the global activity limitation indicator in fourteen European countries

Background: The Global Activity Limitation Indicator (GALI), the measure underlying the European indicator Healthy Life Years (HLY), is widely used to compare population health across countries. However, the comparability of the item has been questioned. This study aims to further validate the GALI in the adult European population. Methods: Data from the European Health Interview Survey (EHIS), covering 14 European countries and 152,787 individuals, were used to explore how the GALI was associated with other measures of disability and whether the GALI was consistent or reflected different disability situations in different countries. Results: When considering each country separately or all combined, we found that the GALI was significantly associated with measures of activities of daily living, instrumental activity of daily living, and functional limitations (P < 0.001 in all cases). Associations were largest for activity of daily living and lowest though still high for functional limitations. For each measure, the magnitude of the association was similar across most countries. Overall, however, the GALI differed significantly between countries in terms of how it reflected each of the three disability measures (P < 0.001 in all cases). We suspect cross-country differences in the results may be due to variations in: the implementation of the EHIS, the perception of functioning and limitations, and the understanding of the GALI question. Conclusion: The study both confirms the relevance of this indicator to measure general activity limitations in the European population and the need for caution when comparing the level of the GALI from one country to another

Potential impact of reduced tobacco use on life and health expectancies in Belgium

Objectives: We investigated the potential impact of reduced tobacco use scenarios on total life expectancy and health expectancies, i.e., healthy life years and unhealthy life years. Methods: Data from the Belgian Health Interview Survey 2013 were used to estimate smoking and disability prevalence. Disability was based on the Global Activity Limitation Indicator. We used DYNAMO-HIA to quantify the impacts of risk factor changes and to compare the “business-as-usual” with alternative scenarios. Results: The “business-as-usual” scenario estimated that in 2028 the 15-year-old men/women would live additional 50/52 years without disability and 14/17 years with disability. The “smoking-free population” scenario added 3.4/2.8 healthy life years and reduced unhealthy life years by 0.79/1.9. Scenarios combining the prevention of smoking initiation with smoking cessation programs are the most effective, yielding the largest increase in healthy life years (1.9/1.7) and the largest decrease in unhealthy life years (− 0.80/− 1.47). Conclusions: Health impact assessment tools provide different scenarios for