Critical issue on the extinction and inattention subtest of NIHSS scale: an analysis on post-acute stroke patients attending inpatient rehabilitation.

OBJECTIVES: This study aims to evaluate the diagnostic performance of NIHSS extinction and inattention item, compared to the results of the Oxford Cognitive Screen (OCS) heart subtest. Additionally, the possible role of the NIHSS visual field subtest on the NIHSS extinction and inattention subtest performance is explored and discussed. METHODS: We analysed scores on NIHSS extinction and inattention subtest, NIHSS visual field subtest, and OCS heart subtest on a sample of 118 post-stroke patients. RESULTS: Compared to OCS heart subtest, the results on NIHSS extinction and inattention subtest showed an accuracy of 72.9% and a moderate agreement level (Cohen's kappa = 0.404). Furthermore, a decrease in NIHSS accuracy detecting neglect (61.1%) was observed in patients with pathological scores in NIHSS visual field item. CONCLUSIONS: Extreme caution is recommended for the diagnostic performance of extinction and inattention item of NIHSS. Signs of neglect may not be detected by NIHSS, and may be confused with visual field impairment. TRIAL REGISTRATION: This study refers to an observational study protocol submitted to ClinicalTrials.gov with identifier: NCT03968627 . The name of the registry is "Development of a National Protocol for Stroke Rehabilitation in a Multicenter Italian Institution" and the date of the registration is the 30th May 2019.

Diagnostic Validity of the Smart Aging Serious Game: An Innovative Tool for Digital Phenotyping of Mild Neurocognitive Disorder.

BACKGROUND: The Smart Aging Serious Game (SASG) is an ecologically-based digital platform used in mild neurocognitive disorders. Considering the higher risk of developing dementia for mild cognitive impairment (MCI) and vascular cognitive impairment (VCI), their digital phenotyping is crucial. A new understanding of MCI and VCI aided by digital phenotyping with SASG will challenge current differential diagnosis and open the perspective of tailoring more personalized interventions. OBJECTIVE: To confirm the validity of SASG in detecting MCI from healthy controls (HC) and to evaluate its diagnostic validity in differentiating between VCI and HC. METHODS: 161 subjects (74 HC: 37 males, 75.47±2.66 mean age; 60 MCI: 26 males, 74.20±5.02; 27 VCI: 13 males, 74.22±3.43) underwent a SASG session and a neuropsychological assessment (Montreal Cognitive Assessment (MoCA), Free and Cued Selective Reminding Test, Trail Making Test). A multi-modal statistical approach was used: receiver operating characteristic (ROC) curves comparison, random forest (RF), and logistic regression (LR) analysis. RESULTS: SASG well captured the specific cognitive profiles of MCI and VCI, in line with the standard neuropsychological measures. ROC analyses revealed high diagnostic sensitivity and specificity of SASG and MoCA (AUCs > 0.800) in detecting VCI versus HC and MCI versus HC conditions. An acceptable to excellent classification accuracy was found for MCI and VCI (HC versus VCI; RF: 90%, LR: 91%. HC versus MCI; RF: 75%; LR: 87%). CONCLUSION: SASG allows the early assessment of cognitive impairment through ecological tasks and potentially in a self-administered way. These features make this platform suitable for being considered a useful digital phenotyping tool, allowing a non-invasive and valid neuropsychological evaluation, with evident implications for future digital-health trails and rehabilitation.

Predictors of Function, Activity, and Participation of Stroke Patients Undergoing Intensive Rehabilitation: A Multicenter Prospective Observational Study Protocol.

Background: The complex nature of stroke sequelae, the heterogeneity in rehabilitation pathways, and the lack of validated prediction models of rehabilitation outcomes challenge stroke rehabilitation quality assessment and clinical research. An integrated care pathway (ICP), defining a reproducible rehabilitation assessment and process, may provide a structured frame within investigated outcomes and individual predictors of response to treatment, including neurophysiological and neurogenetic biomarkers. Predictors may differ for different interventions, suggesting clues to personalize and optimize rehabilitation. To date, a large representative Italian cohort study focusing on individual variability of response to an evidence-based ICP is lacking, and predictors of individual response to rehabilitation are largely unexplored. This paper describes a multicenter study protocol to prospectively investigate outcomes and predictors of response to an evidence-based ICP in a large Italian cohort of stroke survivors undergoing post-acute inpatient rehabilitation. Methods: All patients with diagnosis of ischemic or hemorrhagic stroke confirmed both by clinical and brain imaging evaluation, admitted to four intensive rehabilitation units (adopting the same stroke rehabilitation ICP) within 30 days from the acute event, aged 18+, and providing informed consent will be enrolled (expected sample: 270 patients). Measures will be taken at admission (T0), at discharge (T1), and at follow-up 6 months after a stroke (T2), including clinical data, nutritional, functional, neurological, and neuropsychological measures, electroencephalography and motor evoked potentials, and analysis of neurogenetic biomarkers. Statistics: In addition to classical multivariate logistic regression analysis, advanced machine learning algorithms will be cross-validated to achieve data-driven prognosis prediction models. Discussion: By identifying data-driven prognosis prediction models in stroke rehabilitation, this study might contribute to the development of patient-oriented therapy and to optimize rehabilitation outcomes. Clinical Trial Registration: ClinicalTrials.gov, NCT03968627. https://www.clinicaltrials.gov/ct2/show/NCT03968627?term=Cecchi&cond=Stroke&draw=2&rank=2.

Analysis of Feasibility, Adherence, and Appreciation of a Newly Developed Tele-Rehabilitation Program for People With MCI and VCI.

Background: Patients with Mild Cognitive Impairment (MCI) and Vascular Cognitive Impairment (VCI) are at a high risk of progressing to dementia. Recent guidelines indicate the importance of promoting multidimensional and multi-domain interventions to prevent further decline. Due to its growing effectiveness, comparable to conventional face-to-face interventions, the use of technology is gaining relevance. Tele-rehabilitation systems have the potential to engage patients in multi-dimensional activity programs and to guarantee a low-cost continuum of care through remote control. A possible limitation of such programs is represented by the lack of familiarization with technology and computers in elderly people. The purpose of this study is to describe the feasibility, adherence, and appreciation of the GOAL Tele-R system, administered by a web-application through remote control in patients with MCI/VCI. Methods: Feasibility of the Tele-R system was evaluated by means of distribution of patients' attrition along the study phases, controlling for potential systematic bias in drop-out rates due to the technological device. Adherence was evaluated analyzing drop-out rates and indexes of carried out activities. Patients' appreciation was analyzed through ad hoc satisfaction questionnaire items. Results: Out of 86 approached patients, 25 (29%) were not enrolled, 30 (35%) dropped-out after randomization, and 31 (36%) completed the study (standard care group n = 12, the tele-R group n = 19). Compared to the tele-R group, rates of drop-outs resulted significantly higher for the standard care group (34 vs. 62%, respectively, p = 0.029). Taking into account baseline characteristics, females resulted in a statistically significant higher rate of drop-outs compared to males (66 vs. 27%, respectively, p = 0.003). Overall adherence to the proposed activities was 84% (85% for cognitive module and 83% for physical activity module). Concerning satisfaction, participants provided a good mean level of appreciation (3.7 ± 0.8, range 1-5), a positive feedback for usability, and a subjective perception of cognitive, emotional, and physical benefits due to the training. Conclusion: The GOAL Tele-R system seems a feasible technological rehabilitation program, reaching an acceptable level of adherence and appreciation in patients with an MCI/VCI condition. Clinical Trial Registration: www.ClinicalTrials.gov, ID: NCT03383549 (registration date: 26/dec/2017).

The Visual Scanning Test: a newly developed neuropsychological tool to assess and target rehabilitation of extrapersonal visual unilateral spatial neglect.

PURPOSE: Visual unilateral spatial neglect (VUSN) is a neuropsychological condition commonly experienced after stroke whereby patients are unable to attend to stimuli on the controlesional side of their space. VUSN can occur in the personal, peripersonal, and/or extrapersonal portion of patient's space. Traditional paper-and-pencil neuropsychological tests are widely used to evaluate VUSN, but they assess peripersonal VUSN. Instead, personal and extrapersonal neglect are less easily evaluated. The aim of this study was to present normative values for the Visual Scanning Test (VST), a new neuropsychological tool to quantitatively assess the extrapersonal VUSN. METHODS: Eighty-six healthy subjects took part in the study (61 female), with a mean age of 52.8 years (SD = 17.0) and a mean of 14.0 years of education (SD = 5.2). The VST involved a visual search for a target between similar visual distractors, projected in the far space. The test was administered twice to each participant, with an interval of 2 weeks. From the recorded data, it was possible to obtain indexes related to the reaction times and to the accuracy of the performance on the VST. RESULTS: Multiple linear regression analysis revealed that age and education significantly influenced VST-derived indexes. From the regression analysis, a correction grid for raw scores was built. Adjusted scores were then ranked, and by means of a non-parametric procedure, tolerance limits (both outer and inner one-sided) were defined. CONCLUSIONS: The present study provided normative data for the VST in an Italian population useful for both clinical and research purposes. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03931798.

Development and implementation of a stroke rehabilitation integrated care pathway in an Italian no profit institution: an observational study.

BACKGROUND: To standardize assessment and coordinate processes in stroke rehabilitation, an integrated care pathway (ICP) was developed in an Italian Rehabilitation and Research Institution by a knowledge-translation interdisciplinary process, from evidence-based guidelines to rehabilitation practice. The ICP was implemented in two pilot Tuscan rehabilitation Centers. AIM: The purpose of this study was to describe ICP development and assess the ICP effects on postacute stroke inpatient rehabilitation outcomes. DESIGN: Prospective observational study, before and after comparison. SETTING: Two Tuscan inpatient rehabilitation centers. POPULATION: Patients accessing either centers for intensive rehabilitation after acute stroke. METHODS: Two cohorts were prospectively recruited before (2015-2017) and after (2018) implementation of the pathway. The primary outcome was change in activities of daily living disability, assessed by the modified Barthel Index (mBI) from admission to discharge. Secondary outcomes included length of stay (LOS), adverse outcomes, and changes in communication ability, trunk control, pain, ambulation, bladder catheter (Y/N), bedsores (Y/N). RESULTS: In 2015-2017, 443 postacute stroke patients (mean age 77±11 years, 47% women), while in 2018, 84 patients (mean age 76±13 years, 61% women) were admitted to the two facilities. Comparing the 2018 vs. the 2015-17 cohort, the mean mBI increase was not substantially different (26 vs. 24 points), nor were LOS (37±18 vs. 36±16 days), adverse outcomes, discharge destination, and improvement of ambulation, pain, and communication (P>0.05). Instead, a significantly higher improvement of trunk control (trunk control test: 69.6±33.2 vs. 79.0±31.3, P=0.019), and a higher percentage of bedsore resolution (13% vs. 5%, P=0.033), and bladder catheter removal (37% vs. 17% P<0.001) were observed in 2018 vs. 2015-2017. CONCLUSIONS: Compared to prior practice, ICP was associated to improvement of trunk control recovery, bladder catheter removal, and bedsores resolution. Further ICP implementation on a larger scale is needed to verify improvements of stroke inpatient rehabilitation outcomes. CLINICAL REHABILITATION IMPACT: An evidence-based stroke rehabilitation ICP was interdisciplinary developed and implemented in two rehabilitation centers of a multicenter Italian health group. ICP implementation as to inpatient intensive postacute stroke rehabilitation was associated to improved trunk control recovery, bladder catheter removal, and bedsore resolution. Further ICP implementation will allow multicenter studies and quality benchmarking.

Association between physical activity and functional and cognitive status in nonagenarians: results from the Mugello study.

This study aimed at assessing daily physical activity and its relationship with functional and cognitive status in nonagenarians. Cross-sectional study. 167 nonagenarians (124 women and 43 men, mean age 92 years ± 3) who participated in the Mugello study. Participants underwent daily step count through the SenseWear armband, which was considered as an indicator of physical activity. Other main variables were: handgrip strength, gait speed, depression, cognitive status and quality of life. The median value of steps per day was 883 and 658 in women and men, respectively, with a participant, in the women group, showing values up to 10,000. After adjusting for potential confounders, physical activity remained a significant positive correlate of handgrip strength (r = 0.4), gait speed (r = 0.8), and cognitive status (r = 0.6 and 0.8, respectively for raw scores and for scores adjusted for age and education). On the contrary, physical activity remained a significant negative correlate of depression (r = 0.5). Our results provide quantitative information on daily physical activity and show a significant relationship between daily physical activity and functional and cognitive status in nonagenarians.

Effect of Retirement on Cognition: Evidence From the Irish Marriage Bar.

This study empirically investigates the relationship between retirement duration and cognition among older Irish women using microdata collected in the third wave of The Irish Longitudinal Study on Ageing. Ordinary least squares (OLS) regression estimates indicate that the longer an individual has been retired, the lower the cognitive functioning, with other factors thought to affect cognition held constant (e.g., age, education, and early-life socioeconomic conditions). However, retirement is potentially endogenous with respect to cognition because cognition may affect decisions relating to retiring. If so, the OLS estimates will be biased. To test for this possibility, instrumental variable (IV) estimation is used. This method requires an IV that is highly correlated with retirement duration but not correlated with cognition. The instrument used in this study is based on the so-called marriage bar, the legal requirement that women leave paid employment upon getting married, which took effect in Ireland in the 1930s and was abolished only in the 1970s. The IV regression estimates, along with formal statistical tests, provide no evidence in support of the view that cognition affects retirement decisions. The finding of a small negative effect of retirement duration on cognition is robust to alternative empirical specifications. These findings are discussed in the wider context of the effects of work-like and work-related activities on cognition.

The Games for Older Adults Active Life (GOAL) Project for People With Mild Cognitive Impairment and Vascular Cognitive Impairment: A Study Protocol for a Randomized Controlled Trial.

Background: People living with Mild Cognitive Impairment (MCI) and Vascular Cognitive Impairment (VCI) are persons who do not fulfill a diagnosis of dementia, but who have a high risk of progressing to a dementia disorder. The most recent guidelines to counteract cognitive decline in MCI/VCI subjects suggest a multidimensional and multi-domain interventions combining cognitive, physical, and social activities. The purpose of this study is to test an innovative service that provides a multi-dimensional tele-rehabilitation program through a user-friendly web application. The latter has been developed through a participatory design involving MCI specialists, patients, and their caregivers. Particularly, the proposed tele-rehabilitation program includes cognitive, physical, and caregiver-supported social activities. The goal is to promote and preserve an active life style and counteract cognitive decline in people living with MCI/VCI. Methods:The study is a randomized controlled trial. Sixty subjects will be randomly assigned to the experimental group, who will receive the tele-rehabilitation program, or the control group, who will not receive any treatment. The trial protocol comprises three steps of assessment for the experimental group: at the baseline (T_0), after tele-rehabilitation program (T_1) and at follow-up after 12-months (T_2). Differently, the control group will be assessed twice: at the baseline and at 12-months follow-up. Both the experimental and the control group will be assessed with a multidimensional evaluation battery, including cognitive functioning, behavioral, functional, and quality of life measures. The tele-rehabilitation program lasts 8 weeks and includes cognitive exercises 3 days a week, physical activities 2 days a week, and social activities once a week. In addition, group will be given an actigraph (GENEActiv, Activisinghts Ltd., Cambridgshire, UK) to track physical and sleep activity. Discussion:Results of this study will inform on the efficacy of the proposed tele-rehabilitation to prevent or delay further cognitive decline in MCI/VCI subjects. The expected outcome is to counteract cognitive decline and improve both physical functioning and quality of life. Ethics and Dissemination:The study is approved by the Local Ethics Committee and registered in https://clinicaltrials.gov (NCT03383549). Dissemination will include submission to a peer-reviewed journal, patients, and healthcare magazines and congress presentations. Trial Registration: ClinicalTrials.gov ID: NCT03383549 (registration date: 26/dec/2017) Trial Funding: Bando FAS Salute 2014 Regione Toscana Version Identifier: ver 5-16/11/2018.

Factors Contributing to Unexpected Retirement and Unemployment in Adults Over 50 Years Old in Ireland.

Older adults are increasingly important to maintaining stable workforces. As such, factors contributing to early workforce exit must be identified. This study aimed to identify predictors of unexpected retirement and unemployment at older age, with respect to psychological constructs, resulting adverse behaviors, and health-related factors reflecting functional status. Data were extracted from The Irish Longitudinal Study on Ageing (TILDA) to predict unexpected retirement and unemployment in older adults in Ireland. Increasing age, increasing number of impairments in activities of daily living, and frailty status of "pre-frail/frail" (relative to non-frail) increased the likelihood of unexpected retirement; while greater numbers of physical limitations and "pre-frail/frail" status significantly predicted unemployment at older age. Pre-frail/frail status or reduced physical capability for everyday tasks may adversely affect older individuals' ability to obtain and/or maintain employment. These findings advance the current understanding of factors associated with unexpected retirement and unemployment at older ages. Findings may aid in identifying strategies to extend working life and to aid at-risk older adults, and may inform components of care on which to focus to minimize loss of function and mobility, and maintain independence, with aging.

The Impact of Voluntary and Involuntary Retirement on Mental Health: Evidence from Older Irish Adults.

BACKGROUND: The few studies that have attempted to identify the causal effects of retirement on mental health and well-being have provided conflicting evidence. Hence, whether retirement affects mental health positively or negatively is still unclear. AIMS OF THE STUDY: Our primary objective is to investigate the impact of retirement on mental health as measured by the 20-item Center for Epidemiological Studies Depression Scale (CES-D). METHODS: We use data from the first two waves of The Irish Longitudinal Study on Ageing (TILDA). This is a nationally representative sample of individuals aged 50 and over and living in Ireland. To deal with possible endogeneity problems, we use first-differenced estimation models and control for a broad range of life events occurring between the two waves. These include transition to retirement but also demographic, social, economic and physical health events. As part of the TILDA survey, reasons for retirement are asked. We exploit this information and distinguish between individuals who retired voluntarily, involuntarily or because of own ill health. RESULTS: We find that involuntary, or forced, retirement has a negative and statistically significant effect on mental health. In the case of voluntary retirement, negative mental health effects are also found but the magnitude is smaller and the effects are not statistically significant in all models. We also find that retirement due to poor ill health is negatively associated with mental health. These negative effects seem to diminish with time. DISCUSSION: The finding of differences in the extent of mental health impacts across the various reasons for retirement is an important addition to the literature. While our estimation approach reduces potential endogeneity problems, time-variant unobservables are not removed through our first differencing approach. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: Individuals who are retiring involuntarily are more likely than others to be suffering depressive symptoms. Hence, they are more likely to present at GPs with such symptoms. IMPLICATIONS FOR HEALTH POLICIES: It would be preferable if involuntary retirement can be avoided. Transitions paths from work to retirement could help protect people's mental health. IMPLICATIONS FOR FURTHER RESEARCH: Reasons for retirement should now feature in analyses of this type.

How Well-Informed Are Pension Scheme Members on Their Future Pension Benefits? Evidence from Ireland.

One part of the policy response in many countries to increasing pension coverage will be greater private provision on the part of individuals. This requires that individuals are well informed about pensions. In this article, we assess levels of knowledge of pensions using a representative sample of older Irish adults. We find that two-thirds of individuals enrolled in pension schemes do not know what amount will be paid out on retirement and/or whether the payments will be in the form of lump sums, monthly payments, or both. One policy implication is the need for increased information to be directed at certain groups, in particular, women and less educated people. More fundamentally, the results suggest that the mandatory elements in pension systems should be extended.

Exploring differences in prevalence of diagnosed, measured and undiagnosed hypertension: the case of Ireland and the United States of America.

OBJECTIVES: To: (1) compare prevalence of diagnosed, measured, total and undiagnosed hypertension among late middle-aged adults in the United States of America and Ireland; (2) identify the most important predictors of hypertension and compare them across the two countries; (3) investigate whether cross-national differences in prevalence rates are explained by country differences in behavioural risk factors. METHODS: We use data from the 2008 and 2010 waves of the Health and Retirement Study (n = 1,938) and the first wave (2009/2011) of The Irish Longitudinal Study on Ageing (n = 1,455). We employ probit models to determine whether individual attributes, socioeconomic characteristics and behavioural health factors, including smoking, alcohol consumption and obesity, are associated with hypertension. We do not consider whether respondents are on antihypertensive medication. RESULTS: Prevalence of diagnosed hypertension is higher in the United States of America (48.6 versus 32.4 %). Prevalence of undiagnosed hypertension is higher in Ireland (41.2 versus 19.7 %). Little of the difference in prevalence rates is explained by country differences in behavioural risk factors. CONCLUSIONS: A greater focus on prevention of high blood pressure is necessary in Ireland.

Explaining significant differences in subjective and objective measures of cardiovascular health: evidence for the socioeconomic gradient in a population-based study.

BACKGROUND: To assess prevalence rates of subjective and objective reports of two cardiovascular disorders (hypertension and hypercholesterolemia) for the same subset of respondents in a large-scale study. To determine whether and the extent to which the socioeconomic health gradient differed in the subjective and objective reports of the two cardiovascular disorders. METHODS: Data from the first wave (2009/2011) of The Irish Longitudinal Study on Ageing were used (n = 4,179). This is a nationally representative study of community-dwelling adults aged 50+ residing in Ireland. Subjective measures were derived from self-reports of doctor-diagnosed hypertension and high cholesterol. Objective measure of hypertension was defined as: systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg and/or on antihypertensive medication. Objective measure of hypercholesterolemia was defined as: total cholesterol ≥5.2 mmol/L and/or on cholesterol-lowering medication. Objective measures of low-density-lipoprotein cholesterol and high-density-lipoprotein cholesterol were also used. Two measures of socioeconomic gradient were employed: education and wealth. Binary and multinomial logistic and linear regression analyses were used. Analyses were adjusted for an extensive battery of covariates, including demographics and measures of physical/behavioural health and health care utilization. RESULTS: Prevalence of cardiovascular disorders: prevalence of hypertension and hypercholesterolemia was significantly higher when the cardiovascular disorders were measured objectively as compared to self-reports (64% and 72.1% versus 37% and 41.1%, respectively). Socioeconomic gradient in hypertension: the odds of being objectively hypertensive were significantly lower for individuals with tertiary/higher education (OR, 0.74; 95% CI, 0.60-0.92) and in the highest tertile of the wealth distribution (OR, 0.77; 95% CI, 0.62-0.95). In contrast, the associations between socioeconomic status and self-reported hypertension were not statistically significant. Socioeconomic gradient in hypercholesterolemia: wealthier individuals had higher odds of self-reporting elevated cholesterol (OR, 1.28; 95% CI, 1.03-1.58). Associations between socioeconomic status and objectively measured hypercholesterolemia and low-density-lipoprotein cholesterol were not significant. Higher education and, to a lesser extent, greater wealth were associated with higher levels of high-density-lipoprotein cholesterol. CONCLUSIONS: Clear discrepancies in prevalence rates and gradients by socioeconomic status were found between subjective and objective reports of both disorders. This emphasizes the importance of objective measures when collecting population data.

Body mass index, waist circumference and employment: evidence from older Irish adults.

Data from the first wave of the Irish Longitudinal Study on Ageing are used to examine the relationship between fatness and obesity and employment status among older Irish adults. Employment status is regressed on one of the following measures of fatness: BMI and waist circumference entered linearly as continuous variables and obesity as a categorical variable defined using both BMI and waist circumference. Controls for demographic and socioeconomic characteristics, socioeconomic characteristics in childhood and physical, mental and behavioural health are also included. The regression results for women indicate that all measures of fatness are negatively associated with the probability of being employed and that the employment elasticity associated with waist circumference is larger than the elasticity associated with BMI. The results for men indicate that employment is not significantly associated with BMI and waist circumference when these are entered linearly in the regression, but it is significantly and negatively associated with obesity defined either using BMI or waist circumference as categorical variables. The results also indicate that the negative association between obesity and employment status is larger among women. For example, the probability of being employed for the obese category defined using BMI is around 8 percentage points lower for women and 5 percentage points lower for men.

National and international graduate migration flows.

This article examines the nature of national and international graduate migration flows in the UK. Migration equations are estimated with microdata from a matched dataset of Students and Destinations of Leavers from Higher Education, information collected by the Higher Education Statistical Agency. The probability of migrating is related to a set of observable characteristics using multinomial logit regression. The analysis suggests that migration is a selective process with graduates with certain characteristics having considerably higher probabilities of migrating, both to other regions of the UK and abroad.

Vascular complications of pancreatectomy.

Despite decreased postoperative mortality, pancreatic resections continue to be associated with high morbidity rates. Vascular complications and, in particular, erosive bleeding from the large retroperitoneal vasculature are particularly difficult to treat and account for a large percentage of the residual postoperative mortality of pancreatic resections. We herein analyze the pathogenesis, diagnosis, preventive measures and possible remedies of either hemorrhagic or occlusive complications of pancreatic resections through a review of the literature and of our institutional experience consisting of 818 pancreatectomies.

Synergistic cytotoxicity and pharmacogenetics of gemcitabine and pemetrexed combination in pancreatic cancer cell lines.

PURPOSE: Gemcitabine is an inhibitor of ribonucleotide reductase (RR) and DNA synthesis and is an effective agent in the treatment of pancreas cancer. The present study investigates whether the multitargeted antifolate pemetrexed would be synergistic with gemcitabine against MIA PaCa-2, PANC-1, and Capan-1 pancreatic cancer cell lines. EXPERIMENTAL DESIGN: Cells were treated with gemcitabine and pemetrexed, and the type of drug interaction was assessed using the combination index. Cytotoxicity of gemcitabine was examined with inhibitors of (a) deoxycytidine kinase (dCK), which activates gemcitabine by phosphorylation, and (b) 5'-nucleotidase (drug dephosphorylation) and cytidine deaminase (drug deamination), the main inactivating enzymes. The effects of gemcitabine and pemetrexed on cell cycle were analyzed by flow cytometry, and apoptosis was examined by fluorescence microscopy. Finally, quantitative, real-time PCR was used to study the pharmacogenetics of the drug combination. RESULTS: Synergistic cytotoxicity and enhancement of apoptosis was demonstrated, mostly with the sequence pemetrexed-->gemcitabine. Pemetrexed increased cells in S phase, the most sensitive to gemcitabine, and a positive correlation was found between the expression ratio of dCK:RR and gemcitabine sensitivity. Indeed, pemetrexed significantly enhanced dCK gene expression (+227.9, +86.0, and +135.5% in MIA PaCa-2, PANC-1, and Capan-1 cells, respectively), and the crucial role of this enzyme was confirmed by impairment of gemcitabine cytotoxicity after dCK saturation with 2'-deoxycytidine. CONCLUSIONS: These data demonstrate that the gemcitabine and pemetrexed combination displays schedule-dependent synergistic cytotoxic activity, favorably modulates cell cycle, induces apoptosis, and enhances dCK expression in pancreatic cancer cells.