[Discontinuation of tyrosine kinase inhibitors before epiphyseal closure leading to improved short stature in pediatric chronic myelogenous leukemia].

A 3-year-old boy was referred to our hospital with splenomegaly. Blood tests revealed hyperleukocytosis and bone marrow examination showed major BCR::ABL1 fusion, leading to the diagnosis of chronic myelogenous leukemia (CML). Due to intolerance, the tyrosine kinase inhibitor (TKI) was changed from imatinib to dasatinib to nilotinib. The patient achieved molecular remission but became markedly short in stature, measuring 129.3 cm (height standard deviation score [SDS] -3.3) at the age of 12. TKI therapy was discontinued at age 12 years and 10 months, which was 9 years and 8 months after the start of TKI and 1 year and 6 months after achievement of MR4.0, as discontinuation before epiphyseal closure would not improve short stature. At 2 years and 6 months after discontinuation, the patient's height improved to 156.1 cm (SDS-2.0) without relapse. Growth suppression by TKIs is a problem in the management of pediatric CML. This case illustrates how improvement in severe short stature can be achieved by discontinuing TKI therapy before epiphyseal closure.

Direct visualization of interstitial flow distribution in aortic walls.

Vascular smooth muscle cells are exposed to interstitial flow across aortic walls. Fluid shear stress changes the phenotype of smooth muscle cells to the synthetic type; hence, the fast interstitial flow might be related to aortic diseases. In this study, we propose a novel method to directly measure the interstitial flow velocity from the spatiotemporal changes in the concentration of a fluorescent dye. The lumen of a mouse thoracic aorta was filled with a fluorescent dye and pressurized in ex vivo. The flow of the fluorescent dye from the intimal to the adventitial sides was successfully visualized under a two-photon microscope. The flow velocity was determined by applying a one-dimensional advection-diffusion equation to the kymograph obtained from a series of fluorescent images. The results confirmed a higher interstitial flow velocity in the aortic walls under higher intraluminal pressure. A comparison of the interstitial flow velocity in the radial direction showed faster flow on the more intimal side, where hyperplasia is often found in hypertension. These results indicate that the proposed method can be used to visualize the interstitial flow directly and thus, determine the local interstitial flow velocity.

Red blood cell fatigue evaluation based on the close-encountering point between extensibility and recoverability.

Red blood cells (RBC) circulate the human body several hundred thousand times in their life span. Therefore, their deformability is really important, especially when they pass through a local capillary whose diameter can be as narrow as 3 µm. While there have been a number of works discussing the deformability in a simulated capillary such as a microchannel, as far as we examined in the literature, no work focusing on the change of shape after reciprocated mechanical stress has been reported so far. One of the reasons is that there have been no appropriate experimental systems to achieve such a test. This paper presents a new concept of RBC fatigue evaluation. The fatigue state is defined by the time of reciprocated mechanical stress when the extensibility and the recoverability characteristics meet each other. Our challenge is how to construct a system capable of achieving stable and accurate control of RBCs in a microchannel. For this purpose, we newly introduced two fundamental components. One is a robotic pump capable of manipulating a cell in the accuracy of ±0.24 µm in an equilibrium state with a maximum response time of 15 ms. The other is an online high speed camera capable of chasing the position of RBCs with a sampling rate of 1 kHz. By utilizing these components, we could achieve continuous observation of the length of a RBC over a 1000 times reciprocated mechanical stress. Through these experiments, we found that the repeat number that results in the fatigue state has a close correlation with extensibility.