Cumulative Dosage of Intrathecal Chemotherapy Agents Predicts White Matter Integrity in Long-Term Survivors of Acute Lymphoblastic Leukemia: A PETALE Study.

Acute lymphoblastic leukemia (ALL) stands as the most prevalent form of pediatric cancer in North America, with a current five-year survival rate of 85%. While more children achieved ALL remission and transition into adulthood, the prevalence of long-term treatment-related effects, especially neurocognitive sequelae, remains significant. This study pursues two objectives. Firstly, it investigates if Magnetization Transfer Ratio (MTR), a method assessing myelin integrity, is sensitive to white matter (WM) microstructural changes in long-term ALL survivors and whether these relate to cognitive impairments. Secondly, it examines the dose-related effects of chemotherapy agents on the MTR and its relationship to other risk factors such as female sex, early age diagnosis, and cranial radiotherapy. Magnetization transfer imaging was utilized to assess WM integrity in 35 survivors at a mean of 18.9 years after the onset of ALL (range since diagnosis: 6.9-26.8). Additionally, 21 controls matched for age, sex, and education level, with no history of cancer, were included. MTR was extracted from both the entire brain's WM and the corpus callosum through semi-automated procedures. The results indicated lower MTR means in survivors, which is linked to cognitive function. Negative associations between MTR means and intrathecal agents' (MTX, cytarabine, and hydrocortisone) cumulative doses received were highlighted. This study offers valuable insights into the connections between myelin deterioration, cognitive impairment, and the implications of IT chemotherapy, enhancing our understanding of ALL survivorship dynamics. It underscores MTR's relevance in monitoring neurotoxicity during oncological drug follow-up examinations.

Public health investments: neglect or wilful omission? Historical trends in Quebec and implications for Canada.

This commentary explores public health (PH) investments in Quebec and underlines the challenge of tracking PH resources across Canada. We analyzed governmental data to compare investments across all health and social programs in Quebec from 2004-2005 to 2017-2018. The province's PH budgets suffered from disproportionately low investments and abrupt cuts. These cuts were the largest among all health programs in 2015-2016 (- 7.1%). PH budgets did not keep up with inflation and, in constant dollars, have declined over the last decade. Furthermore, their evolution over the span of 14 years significantly differed from other health programs. On average, programs providing direct services experienced overall budget increases of 81%, whereas PH budgets had the lowest increase of all such programs at only 46%. PH suffers from serious erosion of its capacity. Unfortunately, there is a dire lack of comparable data for provincial, national, and international PH budgets, which further complicates the monitoring of PH erosion. We contend that systematic tracking of PH budgets remains profoundly inadequate across Canada. We recommend (1) regular, comprehensive, and publicly reported analyses of PH budgets; (2) in-depth comparisons of PH investments across Canadian jurisdictions; and (3) a strong PH systems and services research agenda for Canada.

The Impact of Team-Based Primary Care on Guideline-Recommended Disease Screening.

INTRODUCTION: Family Medicine Groups, implemented in Quebec in 2002, are interprofessional primary care teams designed to improve timely access to high-quality primary care. This study investigates whether Family Medicine Groups increased rates of guideline-recommended screenings for 3 chronic diseases: colorectal cancer (colonoscopy/sigmoidoscopy), breast cancer (mammography), and osteoporosis (bone mineral density testing). METHODS: Using population-based administrative health data from the provincial insurer (2000-2010), the authors examined elderly and chronically ill patients who registered with a general practitioner in the first 15 months of the Family Medicine Group policy. Propensity score weighting and a difference-in-differences model estimated differential change in biennial screening rates among Family Medicine Group and non-Family Medicine Group patients over 5 years of follow-up (analysis, 2016-2018). RESULTS: Rates of mammography, colonoscopy/sigmoidoscopy, and bone mineral density testing increased after patient registration with a general practitioner, similarly for both Family Medicine Group and non-Family Medicine Group patients. Colonoscopy/sigmoidoscopy rates increased by 9.7% and 10.4% for Family Medicine Group and non-Family Medicine Group patients, mammography rates by 5.3% and 3.4%, and bone mineral density testing by 4.2% and 7.1%. Difference-in-differences estimates showed no detectable effect of Family Medicine Groups on disease screening rates: -0.06 percentage points (95% CI= -0.32, 0.20) for colonoscopy/sigmoidoscopy, 1.01 percentage points (95% CI= -0.25, 2.27) for mammography, and -0.32 (95% CI= -0.71, -0.07) for bone mineral density testing. CONCLUSIONS: This study found no evidence that Family Medicine Groups affected screening rates for these 3 chronic diseases. Limitations in the implementation of the Family Medicine Group policy in its early years may have contributed to this lack of impact. Interprofessional primary care teams may need to include elements other than organizational changes to increase disease prevention efforts.

Visual short-term memory activation patterns in adult survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Treatments against ALL might lead to later cognitive effects and alterations in brain structure in survivors but to the authors' knowledge the observed variability in the severity of neurocognitive deficits is not fully understood. The objective of the current study was to investigate abnormalities in visual short-term memory (VSTM) brain activation in survivors of childhood ALL using magnetoencephalography. METHODS: A VSTM task was completed by 40 survivors of ALL and 26 controls. VSTM capacity (Cowan K) and brain activation were assessed during the retention period of the task (400-1400 milliseconds) using a standard minimum norm source localization method. RESULTS: Performance (Cowan K) was found to be similar between survivors of ALL and controls. Atypical brain activation was found in survivors of ALL during the task, including overactivation of regions usually involved in VSTM (lateral occipital, precentral gyrus, and postcentral gyrus), recruitment of regions that typically are not involved in VSTM (superior/middle temporal gyrus and supramarginal gyrus), and lower activation of frontal brain regions (inferior frontal gyrus). These patterns of activation were modulated by the age at the time of cancer onset (P = .01) because activity was found to be reduced in participants who were younger at diagnosis. CONCLUSIONS: The results of the current study suggest a pattern of neural inefficiency and compensatory activity during VSTM in survivors of ALL.

Influence of genetic factors on long-term treatment related neurocognitive complications, and on anxiety and depression in survivors of childhood acute lymphoblastic leukemia: The Petale study.

BACKGROUND: A substantial number of survivors of childhood acute lymphoblastic leukemia suffer from treatment-related late adverse effects including neurocognitive impairment. While multiple studies have described neurocognitive outcomes in childhood acute lymphoblastic leukemia (ALL) survivors, relatively few have investigated their association with individual genetic constitution. METHODS: To further address this issue, genetic variants located in 99 genes relevant to the effects of anticancer drugs and in 360 genes implicated in nervous system function and predicted to affect protein function, were pooled from whole exome sequencing data of childhood ALL survivors (PETALE cohort) and analyzed for an association with neurocognitive complications, as well as with anxiety and depression. Variants that sustained correction for multiple testing were genotyped in entire cohort (n = 236) and analyzed with same outcomes. RESULTS: Common variants in MTR, PPARA, ABCC3, CALML5, CACNB2 and PCDHB10 genes were associated with deficits in neurocognitive tests performance, whereas a variant in SLCO1B1 and EPHA5 genes was associated with anxiety and depression. Majority of associations were modulated by intensity of treatment. Associated variants were further analyzed in an independent SJLIFE cohort of 545 ALL survivors. Two variants, rs1805087 in methionine synthase, MTR and rs58225473 in voltage-dependent calcium channel protein encoding gene, CACNB2 are of particular interest, since associations of borderline significance were found in replication cohort and remain significant in combined discovery and replication groups (OR = 1.5, 95% CI, 1-2.3; p = 0.04 and; OR = 3.7, 95% CI, 1.25-11; p = 0.01, respectively). Variant rs4149056 in SLCO1B1 gene also deserves further attention since previously shown to affect methotrexate clearance and short-term toxicity in ALL patients. CONCLUSIONS: Current findings can help understanding of the influence of genetic component on long-term neurocognitive impairment. Further studies are needed to confirm whether identified variants may be useful in identifying survivors at increased risk of these complications.

Comparative analysis of health system performance in Montreal and New York: the importance of context for interpreting indicators.

Although eliminating financial barriers to care is a necessary condition for improving access to health services, it is not sufficient. Given the contrasting health systems with regard to financing and organization of health insurance in the United States and Canada, there is a long history of comparing these countries. We extend the empirical studies on the Canadian and US health systems by comparing access to ambulatory care as measured by hospitalization rates for ambulatory care sensitive conditions (ACSC) in Montreal and New York City. We find that, in New York, ACSC rates were more than twice as high (12.6 per 1000 population) as in Montreal (4.8 per 1000 population). After controlling for age, sex, and number of diagnoses, significant differences in ACSC rates are present in both cities, but are more pronounced in New York. Our findings are consistent with the hypothesis that universal, first-dollar health insurance coverage has contributed to lower ACSC rates in Montreal than New York. However, Montreal's surprisingly low ACSC rate calls for further research.

DIVERGT screening procedure predicts general cognitive functioning in adult long-term survivors of pediatric acute lymphoblastic leukemia: A PETALE study.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Because of major improvements in treatment protocols, the survival rate now exceeds 80%. However, ALL treatments can cause long-term neurocognitive sequelae, which negatively impact academic achievement and quality of life. Therefore, cognitive sequelae need to be carefully evaluated. The DIVERGT is a battery of tests proposed as a screening tool, sensitive to executive function impairments in children and adolescent cancer survivors. Our study aimed at verifying the predictive value of the DIVERGT on general cognitive functioning in adult long-term survivors of ALL. METHODS: ALL survivors completed the DIVERGT 13.4 years, on average, after remission (N = 247). In addition, 49 of these survivors (equally selected amongst those with low, average, and high DIVERGT scores) as well as 29 controls completed a more comprehensive neuropsychological evaluation within a 3-year period from DIVERGT administration. Multivariate regression analysis was used to assess the predictive value of the DIVERGT on general intelligence, mathematics, verbal memory, and working memory. As a follow-up analysis, three performance groups were created based on the DIVERGT results. Multivariate analysis of variance (MANOVA) assessed neuropsychological differences between groups. RESULTS: The DIVERGT accurately predicted General Ability Index (GAI) (P < 0.0001), mathematics (P < 0.0001) and verbal memory (P = 0.045). Moreover, the low-performance group consistently had poorer performance than the high-performance and control groups on the neuropsychological tests. CONCLUSION: The DIVERGT is a useful, time-effective screening battery for broader neurocognitive impairments identification in long-term adult ALL survivors. It could be implemented as routine examination in cancer follow-up clinics.

The impact of team-based primary care on health care services utilization and costs: Quebec's family medicine groups.

We investigate the effects on health care costs and utilization of team-based primary care delivery: Quebec's Family Medicine Groups (FMGs). FMGs include extended hours, patient enrolment and multidisciplinary teams, but they maintain the same remuneration scheme (fee-for-service) as outside FMGs. In contrast to previous studies, we examine the impacts of organizational changes in primary care settings in the absence of changes to provider payment and outside integrated care systems. We built a panel of administrative data of the population of elderly and chronically ill patients, characterizing all individuals as FMG enrollees or not. Participation in FMGs is voluntary and we address potential selection bias by matching on GP propensity scores, using inverse probability of treatment weights at the patient level, and then estimating difference-in-differences models. We also use appropriate modelling strategies to account for the distributions of health care cost and utilization data. We find that FMGs significantly decrease patients' health care services utilization and costs in outpatient settings relative to patients not in FMGs. The number of primary care visits decreased by 11% per patient per year among FMG enrolees and specialist visits declined by 6%. The declines in costs were of roughly equal magnitude. We found no evidence of an effect on hospitalizations, their associated costs, or the costs of ED visits. These results provide support for the idea that primary care organizational reforms can have impacts on the health care system in the absence of changes to physician payment mechanisms. The extent to which the decline in GP visits represents substitution with other primary care providers warrants further investigation.

Does enrollment in multidisciplinary team-based primary care practice improve adherence to guideline-recommended processes of care? Quebec's Family Medicine Groups, 2002-2010.

BACKGROUND: We investigated whether multidisciplinary team-based primary care practice improves adherence to process of care guidelines, in the absence of financial incentives related to pay-for-performance. METHODS: We conducted a natural experiment including 135,119 patients, enrolled with a general practitioner (GP) in a multidisciplinary team Family Medicine Group (FMG) or non-FMG practice, using longitudinal data from Quebec's universal insurer over the relevant time period (2000-2010). All study subjects had diabetes, chronic obstructive pulmonary disease, or heart failure and were followed over a 7-year period, 2 years prior to enrollment and 5 years after. We constructed indicators on adherence to disease-specific guidelines and composite indicators across conditions. We evaluated the effect of FMGs using propensity score methods and Difference-in-Differences (DD) models. RESULTS: Rates of adherence to chronic disease guidelines increased for both FMG and non-FMG patients after enrollment, but not differentially so. Adherence to prescription-related guidelines improved less for FMG patients (DD [95% CI]=-2.83% [-4.08%, -1.58%]). We found no evidence of an FMG effect on adherence to consultation-related guidelines, (DD [95% CI]=-0.24% [-2.24%; 1.75%]). CONCLUSIONS: We found no evidence that FMGs increased adherence to the guidelines we evaluated. Future research is needed to assess why this reform did not improve performance on these quality-of-care indicators.

Characteristics of physicians and patients who join team-based primary care practices: evidence from Quebec's Family Medicine Groups.

PURPOSE: New models of delivering primary care are being implemented in various countries. In Quebec, Family Medicine Groups (FMGs) are a team-based approach to enhance access to, and coordination of, care. We examined whether physicians' and patients' characteristics predicted their participation in this new model of primary care. METHODS: Using provincial administrative data, we created a population cohort of Quebec's vulnerable patients. We collected data before the advent of FMGs on patients' demographic characteristics, chronic illnesses and health service use, and their physicians' demographics, and practice characteristics. Multivariate regression was used to identify key predictors of joining a FMG among both patients and physicians. RESULTS: Patients who eventually enrolled in a FMG were more likely to be female, reside outside of an urban region, have a lower SES status, have diabetes and congestive heart failure, visit the emergency department for ambulatory sensitive conditions and be hospitalized for any cause. They were also less likely to have hypertension, visit an ambulatory clinic and have a usual provider of care. Physicians who joined a FMG were less likely to be located in urban locations, had fewer years in medical practice, saw more patients in hospital, and had patients with lower morbidity. CONCLUSIONS: Physicians' practice characteristics and patients' health status and health care service use were important predictors of joining a FMG. To avoid basing policy decisions on tenuous evidence, policymakers and researchers should account for differential selection into team-based primary health care models.