Association Between Geriatric Assessment and Post-Chemotherapy Functional Status in Older Patients with Cancer.

BACKGROUND: Maintaining functional status is among the most important patient-centered outcomes for older adults with cancer. This study investigated the association between comprehensive geriatric assessment (CGA) and progressive disease or decline of IADL-independence 1 year after chemotherapy, overall survival (OS), and premature termination of chemotherapy. CGA-based functional status and quality of life (QOL) 1 year after chemotherapy are also described. METHODS: This prospective cohort study involved patients aged ≥65 years treated with chemotherapy for any cancer type. CGA and the G8-screening tool were performed before and after the completion of chemotherapy. Analyses were adjusted for tumor type and treatment intent: (a) indolent hematological malignancies, (b) aggressive hematological malignancies, c) solid malignancies treated with curative intent, and (d) solid malignancies treated with palliative intent. RESULTS: All 291 included patients lived in The Netherlands; 193 (67.4%) lived fully independent prior to chemotherapy. The median age was 72 years; 164 (56.4%) were male. IADL independence, CGA-based functional status, and QOL were maintained in half of the patients 1 year after chemotherapy. An abnormal G8-score before chemotherapy was a higher risk for progressive disease or a decline of IADL-independence (OR 3.60, 95% CI, 1.98-6.54, P < .0001), prematurely terminated chemotherapy (OR 2.12, 95% CI, 1.24-3.65, P = .006), and shorter median OS (HR 1.71, 95% CI, 1.16-2.52, P = .007). The impact of an abnormal G8-score differed across tumor type (oncological or hematological) and treatment indication (adjuvant or palliative). CONCLUSION: An abnormal G8 score before chemotherapy is associated with progressive disease and functional decline after chemotherapy and shorter median OS, especially in patients with solid malignancies.

Severe sarcopenia might be associated with a decline of physical independence in older patients undergoing chemotherapeutic treatment.

PURPOSE: Assessing physical reserve in older cancer patients before treatment decision-making remains challenging. The maintenance of physical independence during therapy is sometimes just as important for these patients as oncological outcomes. Recently, sarcopenia has been recognized as a possible important prognostic factor for outcome in cancer patients. We investigated the association between different levels of sarcopenia and the decline of physical independence during chemotherapy in older cancer patients (≥ 65 years). METHODS: Sarcopenia was divided into presarcopenia, sarcopenia, and severe sarcopenia according to an international consensus and was related to physical independence determined by measuring instrumental activities of daily living (IADL), using binary logistic regression models. CT-based muscle mass is necessary to diagnose sarcopenia and was related to five functional tests, in order to investigate whether these easy-to-perform tests could replace the more invasive CT-based muscle measurement. RESULTS: A total of 131 patients were included (median age 72 years). The prevalence of presarcopenia, sarcopenia, and severe sarcopenia was 47.7, 18.5, and 7.7%, respectively. Compared to no sarcopenia, only severe sarcopenia seemed associated with a decline of physical independence after chemotherapy (OR 5.95, 95% CI 0.76-46.48). Muscle mass was only significantly associated with muscle strength, but not with tests measuring physical function. CONCLUSION: The level of sarcopenia might be a useful tool in addition to routine oncological assessment to identify older cancer patients with increased risk of physical decline after chemotherapy.

The relationship between teachers' disciplinary practices and school bullying and students' satisfaction with school: The moderated mediation effects of sex and school belonging.

An authoritative school climate, along with greater teacher support and warm relations among peers are frequently connected with less school bullying. The main aim of this paper is to examine the direct link as perceived by students between teachers' disciplinary practices and bullying in school and students' satisfaction with school. The indirect relationships are explored via the mediation of school belonging and the moderation of sex. High school students (N = 860, 40.4% male students) completed the Delaware School Climate Survey, the Multidimensional Students' Life Satisfaction Scale, and the Psychological Sense of School Membership Scale at a single time point. In general, teachers' disciplinary practices have significant direct effects on perceptions of bullying and satisfaction with school. Positive disciplinary (direct effect = .28, SE = .04) and SEL techniques (direct effect = .22, SE = .04) are related to bullying only among males, while punitive techniques are directly linked to school bullying unrelated to sex (b = .03, SE = .05). Similarly, the effect of positive disciplinary (direct effect = .27, SE = .08) and SEL (direct effect = .21, SE = .08) techniques on satisfaction with school was significant only among males. A direct relationship between punitive disciplinary techniques and satisfaction with school was not recognized. The mediation analysis revealed the indirect effects of teachers' disciplinary practices on the dependent variables via school belonging to be stronger among females. Teachers' negative modeling through punitive disciplinary practices leads to more bullying. School belonging may serve as a protective factor related to the negative impact of teachers' disciplinary practices on school bullying as well as satisfaction with school, especially among females. Interventions should be focused on fostering school belonging along with the development of positive sex-specific disciplinary practices.

DPYD*7 as a Predictor of Severe Fluoropyrimidine-Related Adverse Events.

PURPOSE: Around 20%-30% of patients treated with fluoropyrimidines develop severe treatment-related adverse events (AEs). These are mainly caused by deficiency of dihydropyrimidine dehydrogenase, its main metabolizing enzyme. The DPYD*7 variant allele contains a frameshift mutation that leads to absence of dihydropyrimidine dehydrogenase. Clinical studies on this variant in patients treated with fluoropyrimidines are lacking because of its low minor allelic frequency. However, the DPYD*7 minor allelic frequency is 56-times higher in the Dutch compared with the global population. This allowed us to evaluate fluoropyrimidine tolerability in DPYD*7 variant allele carriers. MATERIALS AND METHODS: Patients treated with standard-of-care fluoropyrimidine who were pretreatment DPYD genotyped for DPYD*2A, *13, 2846A>T, and 1236G>A single-nucleotide polymorphisms were included for analyses. Patients were additionally screened for the DPYD*7 allele (rs72549309, 295-298delTCAT). AEs were graded if they worsened from baseline, according to Common Terminology Criteria for Adverse Events version 5.0. AEs ≥ grade 3 were considered severe. RESULTS: From 3,748 patients, we found 13 patients carrying heterozygous DPYD*7. Relevant clinical data were available for 11 patients. All patients developed fluoropyrimidine-related AEs, of which five patients developed severe AEs (46%). From these five patients, three patients were started with 65% or 50% of standard dose, but apparently still developed severe toxicity. Because of severe AEs, three patients discontinued treatment prematurely (one patient already started with 50% of standard dose) and one patient who started with 50% of standard dose was further reduced to 35% of standard dose. CONCLUSION: In this study, the clinical consequences of carrying the DPYD*7 variant allele were confirmed as 46% of the patients developed severe AEs, even in the presence of initial dose reductions. This underlines the need for prospective studies investigating the required fluoropyrimidine dose for DPYD*7 carriers.

Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8.

In humans, inactivating mutations in the gene of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8; SLC16A2) lead to severe forms of psychomotor retardation combined with imbalanced thyroid hormone serum levels. The MCT8-null mice described here, however, developed without overt deficits but also exhibited distorted 3,5,3'-triiodothyronine (T3) and thyroxine (T4) serum levels, resulting in increased hepatic activity of type 1 deiodinase (D1). In the mutants' brains, entry of T4 was not affected, but uptake of T3 was diminished. Moreover, the T4 and T3 content in the brain of MCT8-null mice was decreased, the activity of D2 was increased, and D3 activity was decreased, indicating the hypothyroid state of this tissue. In the CNS, analysis of T3 target genes revealed that in the mutants, the neuronal T3 uptake was impaired in an area-specific manner, with strongly elevated thyrotropin-releasing hormone transcript levels in the hypothalamic paraventricular nucleus and slightly decreased RC3 mRNA expression in striatal neurons; however, cerebellar Purkinje cells appeared unaffected, since they did not exhibit dendritic outgrowth defects and responded normally to T3 treatment in vitro. In conclusion, the circulating thyroid hormone levels of MCT8-null mice closely resemble those of humans with MCT8 mutations, yet in the mice, CNS development is only partially affected.

Mechanisms of disease: psychomotor retardation and high T3 levels caused by mutations in monocarboxylate transporter 8.

The actions and the metabolism of thyroid hormone are intracellular events that require the transport of iodothyronines across the plasma membrane. It is increasingly clear that this process does not occur by simple diffusion, but is facilitated by transport proteins. Only recently have iodothyronine transporters been identified at the molecular level, of which organic anion transporting polypeptide 1C1 and monocarboxylate transporter 8 (MCT8) deserve special mention, because of their high activity and specificity for iodothyronines. Organic anion transporting polypeptide 1C1 is almost exclusively expressed in brain capillaries, and may be crucial for the transport of the prohormone T4 across the blood-brain barrier. MCT8 is also expressed in the brain--in particular, in neurons--but also in other tissues. MCT8 seems to be especially important for the uptake of active hormone T3 into neurons, which is essential for optimal brain development. T3 is produced from T4 by type 2 deiodinase in neighboring astrocytes. Neurons express type 3 deiodinase, the enzyme that terminates T3 activity. The SLC16A2 (formerly MCT8) gene is located on chromosome Xq13.2 and has recently been associated with a syndrome combining severe, X-linked, psychomotor retardation and high serum T3 levels. In over 20 families, where affected males have developed this syndrome, several mutations in MCT8 have been identified. The disease mechanism is thought to involve a defect in the neuronal entry of T3 and, therefore, in the action and metabolism of T3 in these cells. This defect results in impaired neurological development and a decrease in T3 clearance.