The importance of correctly timing cancer immunotherapy

Introduction: The treatment options for cancer—surgery, radiotherapy and chemotherapy—are now supplemented with immunotherapy. Previously underappreciated but now gaining strong interest are the immune modulatory properties of the three conventional modalities. Moreover, there is a better understanding of the needs and potential of the different immune therapeutic platforms. Key to improved treatment will be the combinations of modalities that complete each other’s shortcomings.

Area covered: Tumor-specific T-cells are required for optimal immunotherapy. In this review, the authors focus on the correct timing of different types of chemotherapeutic agents or immune modulators and immunotherapeutic drugs, not only for the activation and expansion of tumor-specific T-cells but also to support and enhance their anti-tumor efficacy.

Expert opinion: At an early phase of disease, clinical success can be obtained using single treatment modalities but at later disease stages, combinations of several modalities are required. The gain in success is determined by a thorough understanding of the direct and indirect immune effects of the modalities used. Profound knowledge of these effects requires optimal tuning of immunomonitoring. This will guide the appropriate combination of treatments and allow for correct sequencing the order and interval of the different therapeutic modalities.     

Measuring activity limitations in walking: development of a hierarchical scale for patients with lower-extremity disorders who live at home

OBJECTIVE: To develop a hierarchical scale that measures activity limitations in walking in patients with lower-extremity disorders who live at home. DESIGN: Cross-sectional study. SETTING: Orthopedic workshops and outpatient clinics of secondary and tertiary care centers. PARTICIPANTS: Patients (N=981; mean age +/- standard deviation, 58.6+/-15.4 y; 46% men) living at home, with different lower-extremity disorders: stroke, poliomyelitis, osteoarthritis, amputation, complex regional pain syndrome type I, and diabetic and degenerative foot disorders. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: (1) Fit of the monotone homogeneity model, indicating whether items can be used for measuring patients; (2) fit of the double monotonicity model, indicating invariant (hierarchical) item ordering; (3) intratest reliability, indicating repeatability of the sum score; (4) robustness, addressing the clinimetric properties within subgroups of patients; and (5) differential item functioning, addressing the validity of comparisons between subgroups of patients. RESULTS: Thirty-five of 41 dichotomous items had (1) good fit of the monotone homogeneity model (coefficient H=.50), (2) good fit of the double monotonicity model (coefficient H(T)=.33), (3) good intratest reliability (coefficient rho=.95), (4) satisfactory robustness (within subgroups of patients defined by age, sex, and diagnosis), and (5) some differential item functioning (6 items in amputees compared with nonamputees). CONCLUSIONS: A hierarchical scale, with excellent scaling characteristics, was developed to measure activity limitations in walking in patients with lower-extremity disorders who live at home. The measurements should be interpreted cautiously when making comparisons between amputees and nonamputees.     

Determinants of functioning of adolescents and young adults with cerebral palsy

Purpose. To describe the level of functioning of adolescents and young adults with cerebral palsy (CP) and study determinants of their level of functioning.

Method. In the CP Transition study, adolescents and young adults aged 16 - 20 years, diagnosed with CP without severe learning disabilities (n = 103) participated. In this group we assessed subject characteristics, i.e., age, type of CP, gross motor function (GMFCS), level of education as well as outcome measures on functioning in daily activities and social participation (Life Habits questionnaire, Vineland Adaptive Behavior Scale, Functional Independence Measure). Multivariate regression analyses were performed.

Results. About 20 - 30% of the participants encountered restrictions in daily activities (mobility, self-care, nutrition) and social participation (taking responsibility, community living, leisure activities and employment). The GMFCS level, level of education, and age proved to be important determinants of functioning in daily activities and social participation, explaining 70% and 66% of the variance in outcome respectively.

Conclusion. A significant number of adolescents and young adults with CP without severe learning disabilities are restricted in daily activities and social participation. These problems are mainly attributable to restricted gross motor functioning, a low level of education and younger age.     

Mapping the information flow from one brain to another during gestural communication

Both the putative mirror neuron system (pMNS) and the ventral medial prefrontal cortex (vmPFC) are deemed important for social interaction: the pMNS because it supposedly “resonates” with the actions of others, the vmPFC because it is involved in mentalizing. Strictly speaking, the resonance property of the pMNS has never been investigated. Classical functional MRI experiments have only investigated whether pMNS regions augment their activity when an action is seen or executed. Resonance, however, entails more than only “going on and off together”. Activity in the pMNS of an observer should continuously follow the more subtle changes over time in activity of the pMNS of the actor. Here we directly explore whether such resonance indeed occurs during continuous streams of actions. We let participants play the game of charades while we measured brain activity of both gesturer and guesser. We then applied a method to localize directed influences between the brains of the participants: between-brain Granger-causality mapping. Results show that a guesser''s brain activity in regions involved in mentalizing and mirroring echoes the temporal structure of a gesturer''s brain activity. This provides evidence for resonance theories and indicates a fine-grained temporal interplay between regions involved in motor planning and regions involved in thinking about the mental states of others. Furthermore, this method enables experiments to be more ecologically valid by providing the opportunity to leave social interaction unconstrained. This, in turn, would allow us to tap into the neural substrates of social deficits such as autism spectrum disorder.     

Cardiovascular disease risk factors and the relationships with physical activity, aerobic fitness, and body fat in adolescents and young adults with myelomeningocele

Buffart LM, van den Berg-Emons RJ, Burdorf A, Janssen WG, Stam HJ, Roebroeck ME. Cardiovascular disease risk factors and the relationships with physical activity, aerobic fitness, and body fat in adolescents and young adults with myelomeningocele.

Objectives

To describe cardiovascular disease (CVD) risk factors in adolescents and young adults with myelomeningocele (MMC) and to explore relationships with physical activity, aerobic fitness, and body fat.

Design

Cross-sectional study.

Setting

Outpatient clinic.

Participants

Adolescents and young adults (N=31) with MMC (58% men) age 16 through 30 years; 13 were ambulatory and 18 were nonambulatory.

Interventions

Not applicable.

Main Outcome Measures

We studied biologic and lifestyle-related CVD risk factors, including lipid and lipoprotein profiles, blood pressure, aerobic fitness (Vo₂peak), body fat, daily physical activity, and smoking behavior. We considered subjects at increased CVD risk when 2 or more of the following risk factors clustered: systolic blood pressure, total serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and cigarette smoking. Relationships were studied using regression analyses.

Results

Levels of TC, low-density lipoprotein cholesterol, and triglycerides were elevated in 29%, 38%, and 3% of the participants, respectively. HDL-C was reduced in 19%. Hypertension was found in 20%, and 19% were current cigarette smokers. Based on the clustering of risk factors, 42% of the participants were at increased CVD risk: 15% of ambulatory participants and 61% of nonambulatory participants (P=.03). Adjusted for sex and ambulatory status, participants with higher aerobic fitness tended to be more likely to have no CVD risk (odds ratio=13.0; P=.07). CVD risk was not associated to physical activity and body fat.

Conclusions

A large proportion of the study sample was at CVD risk, indicated by clustering of risk factors. Improving aerobic fitness in young adults with MMC may contribute in reducing CVD risk; this needs to be confirmed in future studies.