Short course radiotherapy versus radiochemotherapy for locally advanced rectal cancers in the elderly (UNICANCER PRODIGE 42/GERICO 12 study): Quality of life and comprehensive geriatric assessment.

BACKGROUND: The results of the PRODIGE 42/GERICO 12 study showed that short course radiotherapy had a better tolerance profile than radiochemotherapy, with comparable oncological results. We have included Quality of Life analyses and oncogeriatric evaluations in this study. PATIENTS AND METHODS: In all, 101 patients ≥75 years of age with resectable T3-T4 rectal adenocarcinoma less than 12 cm from the anal margin received short course radiotherapy (5X5 Gy in one week) or radiochemotherapy (50 Gy, 2 y/f and capecitabine 800 mg/m2, 5 days/week) with delayed surgery (7 weeks ± 1) in both groups. The Quality of Life analyses (EORTC QLQ C-30 et ELD14) were conducted upon inclusion, pre-operatively, at 3, 6 and 12 months post-op, together with the oncogeriatric evaluations, including an evaluation of the IADL and ADL scores, walking speed, GDS15, MMSE, MNA. RESULTS: We did not highlight any statistical difference for the global EORTC QLQ-C30 score; several factors are statistically in favor of the short course radiotherapy group at 3 months post-op (cognitive functions, fatigue, appetite). In the case of the ELD14 score, the disease burden is perceived as more negative at 3, 6 and 12 months postop in the radiochemotherapy group. The IADL score deteriorated in 44.8 % of the radiochemotherapy group and 14.8 % of the radiotherapy group (p = 0.032); similarly, the GDS15 depression score was better preserved in the short course radiotherapy group (p = 0.05). An analysis of the other scores: ADL, walking speed, MNA, MMSE did not highlight any statistical difference. CONCLUSION: Short course radiotherapy achieves better results in terms of Quality of Life and preservation of autonomy in patients aged ≥75 treated for locally advanced rectal cancer.

Quality of life and Comprehensive Geriatric Assessment (CGA) in older adults receiving Accelerated Partial Breast Irradiation (APBI) using a single fraction of Multi-Catheter Interstitial High-Dose Rate Brachytherapy (MIB). The SiFEBI phase I/II trial.

OBJECTIVES: The SiFEBI trial demonstrated that a post-operative Multicatheter Interstitial Brachytherapy (MIB) appears feasible and with acceptable toxicity in older adults aged 70 years and older presenting with low-risk breast cancer. The aim of the present ancillary study was to analyze the quality of life and Comprehensive Geriatric Assessment (CGA) domains within 6 months in older adults receiving Accelerated Partial Breast Irradiation (APBI) using a single fraction of MIB. MATERIALS AND METHODS: From 11/2012 to 09/2014, 37 patients were included and 26 were evaluable. Patients (pts) aged 70 years and older with a Balducci score of 1 or 2 and presenting with low-risk breast cancer were prospectively enrolled in this phase I/II trial (NCT01727011). After lumpectomy, intra-operative catheter implantation was performed for post-operative APBI after pathological findings. Quality of life (QoL) evaluation and CGA were scheduled at baseline and 1, 3, and 6 months after APBI. Autonomy decline was defined as a 1-point decrease in Activities of Daily Living (ADL). RESULTS: Mean age was 77 years. Within the first 6 months of follow-up, no autonomy decline was observed in ADL, 3 patients had an autonomy decline in Instrumental Activities of Daily Living (IADL) and 2 patients had a slower gait speed but no changes in cognitive function, nutritional status, and depression screening. Global QoL was quite similar at baseline compared to 1, 3, and 6 months. No differences were observed for functional items. CONCLUSION: APBI based on a single fraction of MIB in older adults with low-risk breast cancer appears to be feasible with a minimal loss of autonomy regarding IADL, no loss of autonomy in ADL, an acceptable decrease in other CGA domains, and with no impact on global quality of life.

Accurate assessment of nonalcoholic fatty liver disease lesions in liver allograft biopsies by a smartphone platform: A proof of concept.

Macrovesicular steatosis (MS) is a major risk factor for liver graft failure after transplantation and pathological microscopic examination of a frozen tissue section remains the gold standard for its assessment. However, the latter requires an experienced in-house pathologist for correct and rapid diagnosis as well as specific equipment that is not always available. Smartphones, which are must-have tools for everyone, are very suitable for incorporation into promising technology to generate moveable diagnostic tools as for telepathology. The study aims to compare the microscopic assessment of nonalcoholic fatty liver disease (NAFLD) spectrum in liver allograft biopsies by a smartphone microscopy platform (DIPLE device) to standard light microscopy. Forty-two liver graft biopsies were evaluated in transmitted light, using an iPhone X and the microscopy platform. A significant correlation was reported between the two different approaches for graft MS assessment (Spearman's correlation coefficient: r = .93; p < .001) and for steatohepatitis feature (r = .56; p < .001; r = .45; p < .001). Based on these findings, a smartphone integrated with a cheap microscopy platform can achieve adequate accuracy in the assessment of NAFLD in liver graft and could be used as an alternative to standard light microscopy when the latter is unavailable.

"As du Coeur" study: a randomized controlled trial on quality of life impact and cost effectiveness of a physical activity program in patients with cardiovascular disease.

BACKGROUND: Physical activity programs (PAP) in patients with cardiovascular disease require evidence of cost-utility. To assess improvement in health-related quality of life (QoL) and reduction of health care consumption of patients following PAP, a randomized trial was used. METHODS: Patients from a health insurance company who had experienced coronary artery disease or moderate heart failure were invited to participate (N = 1891). Positive responders (N = 50) were randomly assigned to a progressively autonomous physical activity (PAPA) program or to a standard supervised physical activity (SPA) program. The SPA group had two supervised sessions per week over 5 months. PAPA group had one session per week and support to aid habit formation (written tips, exercise program, phone call). To measure health-related quality of life EQ-5D utility score were used, before intervention, 6 months (T6) and 1 year later. Health care costs were provided from reimbursement databases. RESULTS: Mobility, usual activities and discomfort improved significantly in both group (T6). One year later, EQ-5D utility score was improved in the PAPA group only. Total health care consumption in the intervention group decreased, from a mean of 4097 euros per year before intervention to 2877 euros per year after (p = 0.05), compared to a health care consumption of 4087 euros and 4180 euros per year, in the total population of patients (N = 1891) from the health insurance company. The incremental cost effectiveness ratio was 10,928 euros per QALYs. CONCLUSION: A physical activity program is cost-effective in providing a better quality of life and reducing health care consumption in cardiovascular patients. TRIAL REGISTRATION: ISRCTN77313697 , retrospectively registered on 20 November 2015.

Optimizing drug development in oncology by clinical trial simulation: Why and how?

In therapeutic research, the safety and efficacy of pharmaceutical products are necessarily tested on humans via clinical trials after an extensive and expensive preclinical development period. Methodologies such as computer modeling and clinical trial simulation (CTS) might represent a valuable option to reduce animal and human assays. The relevance of these methods is well recognized in pharmacokinetics and pharmacodynamics from the preclinical phase to postmarketing. However, they are barely used and are poorly regarded for drug approval, despite Food and Drug Administration and European Medicines Agency recommendations. The generalization of CTS could be greatly facilitated by the availability of software for modeling biological systems, by clinical trial studies and hospital databases. Data sharing and data merging raise legal, policy and technical issues that will need to be addressed. Development of future molecules will have to use CTS for faster development and thus enable better patient management. Drug activity modeling coupled with disease modeling, optimal use of medical data and increased computing speed should allow this leap forward. The realization of CTS requires not only bioinformatics tools to allow interconnection and global integration of all clinical data but also a universal legal framework to protect the privacy of every patient. While recognizing that CTS can never replace 'real-life' trials, they should be implemented in future drug development schemes to provide quantitative support for decision-making. This in silico medicine opens the way to the P4 medicine: predictive, preventive, personalized and participatory.

Multicenter prospective micro-costing study evaluating mandibular free-flap reconstruction.

Free-flap mandibular reconstruction is a highly specialized procedure associated with severe complications necessitating re-interventions and re-hospitalizations. This surgery is expensive in terms of health workers' time, equipment, medical devices and drugs. Our main objective was to assess the direct hospital cost generated by osseocutaneous free-flap surgery in a multicentric prospective micro-costing study. Direct medical costs evaluated from a hospital perspective were assessed using a micro-costing method from the first consultation with the surgeon until the patient returns home, thus confirming the success or failure of the free-flap procedure. The mean total cost for free-flap intervention was 34,009€ (5151-119,604€), the most expensive item being the duration of hospital bed occupation, representing 30-90% of the total cost. In the event of complications, the mean cost increased by 77.3%, due primarily to hospitalization in ICU and the conventional unit. This surgery is effective and provides good results but remains highly complex and costly.

Protocol of the "As du Coeur" study: a randomized controlled trial on physical activity maintenance in cardiovascular patients.

BACKGROUND: Although the benefits of supervised physical activity programs in cardiac rehabilitation have been well documented, the amount of physical activity often drops quickly after the end of the supervised period. This trial (registered as ISRCTN77313697 ) will evaluate the effectiveness of an experimental intervention based on habit formation theory applied to physical activity maintenance. METHODS/DESIGN: Cardiovascular patients (N = 56) will be individually randomized into two groups. Two supervised physical activity (SPA) sessions per week will be offered to the first group for 20 weeks. Progressively autonomous physical activity (PAPA) will be offered to the second group as follows: 10 weeks of the same supervised program as the SPA group followed by 10 more weeks in which one supervised session will be replaced by a strategy to build and sustain the habit of autonomous practice of physical activity. The primary outcome is the amount of physical activity measured by the International Physical Activity Questionnaire (IPAQ; Craig et al., Med Sci Sport Exercises 35(8):1381-95, 2003). To compensate for the limited capacity to recruit subjects, multiple IPAQ measurements will be made (at T0, T5, T7, T9 and T12 months after the start of the intervention) and analyzed using the mixed model approach. We will also assess changes in physical and physiological indicators, automaticity of the physical activity behavior, motivation and quality of life. Last, we will assess the cost-effectiveness for each type of program. DISCUSSION: If proven to be effective, the PAPA intervention, which requires fewer supervised sessions, should provide a cost-effective solution to the problem of physical activity maintenance in cardiac rehabilitation.

Neurotoxicant exposure during pregnancy is a confounder for assessment of iodine supplementation on neurodevelopment outcome.

CONTEXT: The developing brain is vulnerable to iodine deficiency (ID) and environmental neuro-toxicants. OBJECTIVES: To assess neurocognitive development of children whose mothers have received (or not) iodine supplementation during pregnancy, in an area of borderline ID, while assessing in utero exposure to environmental neuro-toxicants. DESIGN/PATIENTS: Among 86 children born from normal euthyroid women who participated in our prospective interventional study on iodine supplementation (150 µg/day) started early in pregnancy, 44 (19 with iodine supplementation, 25 controls) were assessed at two years using the Bayley test. Information on parents' education and habits (smoking), and on child development was recorded. Thyroid tests at each trimester of pregnancy and on cord blood (CB) were available, as well as milk concentrations of selected environmental compounds known for their neurotoxicity, including heavy metals and PCBs. RESULTS: There was no difference in Bayley tests for children born to mothers with and without iodine supplementation, but sample size was small. Language and Social-Emotional Scales were negatively correlated with TBG at all times tested, while PCB 118 correlated negatively with all Language scales. Among maternal and CB thyroid tests, only CB thyroglobulin, the best marker of iodine status, correlated (negatively) with neurodevelopment scales (Motor and Expressive Language). CONCLUSIONS: This pilot study suggests that PCB118 has a negative impact on neurocognitive development, possibly mitigating the benefit of iodine supplementation in an area of borderline ID. We propose that exposure to environmental neurotoxicants should be taken into account when designing studies on the benefit of iodine supplementation in pregnancy. The potential interactions between TBG, environmental neurotoxicants and brain development warrant further studies.

Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials).

BACKGROUND: Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer. METHODS: Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9). RESULTS: For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items. CONCLUSION: The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer.