Impact of vincristine-steroid pulses during maintenance for B-cell pediatric ALL: a systematic review and meta-analysis.

The benefit associated with the incorporation of vincristine-corticosteroid pulses in maintenance therapy for pediatric acute lymphoblastic leukemia (ALL) is unclear, particularly in the context of modern intensive therapy. This systematic review and meta-analysis examined the impact of reducing the frequency of vincristine-steroid pulses during maintenance for pediatric patients newly diagnosed with B-cell ALL. Two authors reviewed all eligible studies identified through a comprehensive search, extracted data from 25 publications (12 513 patients), and assessed the risk of bias. We created historical and contemporary subgroups; the latter included trials providing both a version of Protocol III from the early Berlin-Frankfurt-Munster trials and eliminating routine prophylactic cranial radiation. Meta-analysis of event-free survival data suggested no benefit between more frequent or less frequent pulses in contemporary trials (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.85-1.09), which differed significantly from historical trials (HR, 0.79; 95% CI, 0.68-0.91; P = .04). We found no significant impact of reduced pulse frequency on overall survival or relapse risk. There was however increased odds of grade 3+ nonhepatic toxicity in the high-pulse frequency group (odds ratio, 1.31; 95% CI, 1.12-1.52). This systematic review suggests that the previous benefit conferred by frequent pulses of vincristine-steroids in maintenance therapy for pediatric B-cell ALL in historical trials no longer applies in contemporary trials but is associated with toxicity. These results will help guide the development of the next phase of clinical trials in the field of pediatric ALL and question the continued use of pulses in maintenance among patients not in clinical trials, particularly those experiencing toxicity.

Detecting Sarcopenic Obesity in Survivors of Pediatric Acute Lymphoblastic Leukemia: An Exploration of Body Mass Index and Triponderal Mass Index as Potential Surrogate Markers.

Survivors of pediatric acute lymphoblastic leukemia (ALL) often have altered body composition secondary to treatment effects, including sarcopenic obesity (SO), which increases the risk of both metabolic complications and frailty. SO is difficult to detect without using advanced imaging techniques to which access is often limited. To explore whether common clinical indices can reliably identify the presence of SO in a cohort of long-term survivors of ALL, the discriminatory capacity of body mass index (BMI) or triponderal mass index (TMI, kg/m 3 ) for detecting SO was assessed. Thresholds of BMI and TMI associated with overweight or obesity status had poor sensitivity (<50%) and specificity for detecting SO. Total misclassification rates at these thresholds exceeded 50% and positive likelihood ratios were nonsignificant. Notably, TMI is more strongly correlated with elevated adiposity than is BMI in this survivor population ( R2 =0.73 vs. 0.57), suggesting further exploration is warranted. Our study is limited by the sample size, precluding detailed regression analysis. This study highlights the challenges of identifying SO in survivors of pediatric ALL using common clinical indices. Prospective evaluation of additional potential surrogate markers in survivors, in conjunction with the component features of SO, should be a key focus of future research.

Adiposity in Survivors of Cancer in Childhood: How is it Measured and Why Does it Matter?

Survival of cancer in childhood is increasingly common with modern therapeutic protocols but leads frequently to adverse long-term impacts on health, including metabolic and cardiovascular disease. Changes in body composition, especially an increase in fat mass and a decrease in muscle mass, are found early in patients with pediatric cancer, persist long after treatment has been completed and seem to contribute to the development of chronic disease. This review details the effects of such changes in body composition and reviews the underlying pathophysiology of the development of sarcopenic obesity and its adverse metabolic impact. The authors discuss the particular challenges in identifying obesity accurately in survivors of pediatric cancer using available measurement techniques, given that common measures, such as body mass index, do not distinguish between muscle and adipose tissue or assess their distribution. The authors highlight the importance of a harmonized approach to the assessment of body composition in pediatric cancer survivors and early identification of risk using "gold-standard" measurements. This will improve our understanding of the significance of adiposity and sarcopenia in this population, help identify thresholds predictive of metabolic risk, and ultimately prevent or ameliorate the long-term metabolic and cardiovascular impacts on health experienced by survivors of cancer in childhood.

Force transduction and strain dynamics in actin stress fibres in response to nanonewton forces.

It is becoming clear that mechanical stimuli are crucial factors in regulating the biology of the cell, but the short-term structural response of a cell to mechanical forces remains relatively poorly understood. We mechanically stimulated cells transiently expressing actin-EGFP with controlled forces (0-20 nN) in order to investigate the structural response of the cell. Two clear force-dependent responses were observed: a short-term (seconds) local deformation of actin stress fibres and a long-term (minutes) force-induced remodelling of stress fibres at cell edges, far from the point of contact. By photobleaching markers along stress fibres we were also able to quantify strain dynamics occurring along the fibres throughout the cell. The results reveal that the cell exhibits complex heterogeneous negative and positive strain fluctuations along stress fibres in resting cells that indicate localized contraction and stretch dynamics. The application of mechanical force results in the activation of myosin contractile activity reflected in an ~50% increase in strain fluctuations. This approach has allowed us to directly observe the activation of myosin in response to mechanical force and the effects of cytoskeletal crosslinking on local deformation and strain dynamics. The results demonstrate that force application does not result in simplistic isotropic deformation of the cytoarchitecture, but rather a complex and localized response that is highly dependent on an intact microtubule network. Direct visualization of force-propagation and stress fibre strain dynamics have revealed several crucial phenomena that take place and ultimately govern the downstream response of a cell to a mechanical stimulus.

Inhibiting ice recrystallization and optimization of cell viability after cryopreservation.

The ice recrystallization inhibition activity of various mono- and disaccharides has been correlated with their ability to cryopreserve human cell lines at various concentrations. Cell viabilities after cryopreservation were compared with control experiments where cells were cryopreserved with dimethylsulfoxide (DMSO). The most potent inhibitors of ice recrystallization were 220 mM solutions of disaccharides; however, the best cell viability was obtained when a 200 mM d-galactose solution was utilized. This solution was minimally cytotoxic at physiological temperature and effectively preserved cells during freeze-thaw. In fact, this carbohydrate was just as effective as a 5% DMSO solution. Further studies indicated that the cryoprotective benefit of d-galactose was a result of its internalization and its ability to mitigate osmotic stress, prevent intracellular ice formation and/or inhibit ice recrystallization. This study supports the hypothesis that the ability of a cryoprotectant to inhibit ice recrystallization is an important property to enhance cell viability post-freeze-thaw. This cryoprotective benefit is observed in three different human cell lines. Furthermore, we demonstrated that the ability of a potential cryoprotectant to inhibit ice recrystallation may be used as a predictor of its ability to preserve cells at subzero temperatures.

Mechanically induced deformation and strain dynamics in actin stress fibers.

It is becoming evident that physical forces in the microenvironment play a key role in regulating many important aspects of cell biology. However, although mechanical cues are known to have clear effects over the long-term (days), the short-term (seconds to minutes) cellular responses to mechanical stimuli are less well characterized. In our recent study, we exposed committed fibroblast cells to well controlled nanoscale forces while simultaneously imaging force transduction through the actin cytoskeleton. One of the earliest responses of a cell to physical force is rapid deformation of the cytoskeleton, taking place over the course of seconds. We were able to directly visualize deformation, force-propagation and strain dynamics in actin stress fibers in response to a relatively simple mechanical stimulus. Moreover, these dynamics were also dependent on myosin-driven contractility and the presence of an intact microtubule cytoskeleton. Interestingly, although stem cells are sensitive to mechanical cues, they do not display the same degree of stress fiber organization as observed in committed cells indicating the possibility of alternative sensing and mechanotransduction mechanisms.