BackgroundEpithelial cell adhesion molecule (EpCAM)-based enumeration of circulating tumor cells (CTC) has prognostic value in patients with solid tumors, such as advanced breast, colon, and prostate cancer. However, poor sensitivity has been reported for non-small cell lung cancer (NSCLC). To address this problem, we developed a microcavity array (MCA) system integrated with a miniaturized device for CTC isolation without relying on EpCAM expression. Here, we report the results of a clinical study on CTCs of advanced lung cancer patients in which we compared the MCA system with the CellSearch system, which employs the conventional EpCAM-based method.MethodsPaired peripheral blood samples were collected from 43 metastatic lung cancer patients to enumerate CTCs using the CellSearch system according to the manufacturer’s protocol and the MCA system by immunolabeling and cytomorphological analysis. The presence of CTCs was assessed blindly and independently by both systems.ResultsCTCs were detected in 17 of 22 NSCLC patients using the MCA system versus 7 of 22 patients using the CellSearch system. On the other hand, CTCs were detected in 20 of 21 small cell lung cancer (SCLC) patients using the MCA system versus 12 of 21 patients using the CellSearch system. Significantly more CTCs in NSCLC patients were detected by the MCA system (median 13, range 0–291 cells/7.5 mL) than by the CellSearch system (median 0, range 0–37 cells/7.5 ml) demonstrating statistical superiority (p = 0.0015). Statistical significance was not reached in SCLC though the trend favoring the MCA system over the CellSearch system was observed (p = 0.2888). The MCA system also isolated CTC clusters from patients who had been identified as CTC negative using the CellSearch system.ConclusionsThe MCA system has a potential to isolate significantly more CTCs and CTC clusters in advanced lung cancer patients compared to the CellSearch system.

In this study, we present a method for efficient enrichment of small-sized circulating tumor cells (CTCs) such as those found in the blood of small-cell lung cancer (SCLC) patients using a microcavity array (MCA) system. To enrich CTCs from whole blood, a microfabricated nickel filter with a rectangular MCA (10(4) cavities/filter) was integrated with a miniaturized device, allowing for the isolation of tumor cells based on differences in size and deformability between tumor and blood cells. The shape and porosity of the MCA were optimized to efficiently capture small tumor cells on the microcavities under low flow resistance conditions, while allowing other blood cells to effectively pass through. Under optimized conditions, approximately 80% of SCLC (NCI-H69 and NCI-H82) cells spiked in 1 mL of whole blood were successfully recovered. In clinical samples, CTCs were detectable in 16 of 16 SCLC patients. In addition, the number of leukocytes captured on the rectangular MCA was significantly lower than that on the circular MCA (p < 0.001), suggesting that the use of the rectangular MCA diminishes a considerable number of carryover leukocytes. Therefore, our system has potential as a tool for the detection of CTCs in small cell-type tumors and detailed molecular analyses of CTCs.

Hemiplegia is a common sequel of stroke and assisted living care is needed in many cases. The purpose of this study was to evaluate the effect of using surface electrode stimulation device in rehabilitation, in terms of functional improvement in upper limb and the changes in brain activation related to central nervous system reconstruction. Five patients with chronic hemiplegia received electrical stimulation therapy using the orthosis-type surface electrode stimulation device for 12 weeks. Training time was 30 min/day for the first weeks, and increased 30 min/day in every 4 weeks. Upper limb outcome measures included Brunnstrom stage, range of motion, Fugl-Meyer assessment and manual function test. Brain activation was measured using functional MRI. After therapy with therapeutic electrical stimulation (TES) for 12 weeks upper limb function improved in all cases. The results of brain activation showed two patterns. In the first, the stimulation produced an activity in the bilateral somatosensory cortices (SMC), which was seen to continue over time. The second, activation was bilateral and extensive before stimulation, but localized to the SMC after intervention. Treatment with TES using an orthosis-type electrode stimulation device improves upper limb function in chronic hemiplegia patients. The present findings suggest that there are not only efferent but also afferent effects that may promote central nervous system remodeling.Stroke is the main cause of disability in industrialized countries, with a significant impact on individual, family, and societal healthcare. Although many hemiplegic survivors after stroke achieve independent ambulatory functions with orthotic devices, half of them are unable to use their upper extremity in their activities of daily living (ADL) after months of standard stroke rehabilitation (31). A common approach in rehabilitation for upper limb hemiplegia in chronic stage has been training the healthy side, especially if it contains the nondominant hand, and learning to perform tasks with only one arm. In recent years, it has been recognized that the phenomenon of "learned non-use" (30, 33), which results from use of the healthy side only, invites a state of further inability to use the affected side. Because this can lead to exacerbation of secondary disorders such as edema, pain, decreased range of motion, and shoulder subluxation, attention has focused on approaches for rehabilitating the affected upper limb based on the plasticity of the central nervous system. Reports that rehabilitation for the affected upper limb produces reconstruction of the central nervous system as upper limb function improves (27) have also attracted attention. One of the most promising alternate interventions to help hemiplegic survivors recover upper limb function is functional electrical stimulation (FES). FES is a method of restoring functionality to upper or lower extremities by electrically stimulating the lower motor neurons of hemiplegic survivors after stroke (26). FES training involves t...

These results suggest that pasireotide is a promising option in patients with dumping syndrome after bariatric or upper gastrointestinal cancer surgery.

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Mast cells (MCs) are crucial cells in the development of various types of diseases, including allergy, atopic dermatitis and hair disorders. Corticotropin releasing hormone (CRH) plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal (HPA) axis. However, CRH and its receptors (CRHR) have been recently identified within the skin and reported to play important roles in local cutaneous HPA axis. MCs are also reported to act as CRH mediated stress sentinels in tissue. We have previously shown that CRH induces connective tissue type (CT)-MC degranulation and promotes maturation. Here, we investigated whether CRH can also affect mucosal type (M)-MC biology by using human nasal polyp organ culture. The expression of both CRH and CRHR was detected within nasal polyp samples by immunohistochemistry and RT-PCR. CRH treatment in the organ culture increased the expression of ACTH receptor as well as glucocorticosteroid receptor in situ. Kit or tryp-tase+ M-MCs of isolated nasal polyps was shown to express CRHR by double immunofluorescence. CRH treatment significantly increased tryptase+ M-MC number and induced degranulation in situ. This was partially abrogated by the co-administration of stem cell factor (SCF) neutralizing antibody and CRHR antagonist, antalarmin. Just as human hair follicles organ culture, CRH also increased SCF expression within the epithelium of organ cultured nasal polyp samples. In contrast to CT-MC, CRH treatment significantly increased tryptase+ M-MC proliferation in situ. Furthermore, the effect of CRH on M-MCs degranulation and number was partially diminished by CRHR gene knockdown in situ. These results indicate that CRH induces both cutaneous and mucosal type neuroinflammation by promoting MC activity and increasing the number of it and that blockade of SCF and CRHR might be a novel future target for treating stress-induced disorders including atopic dermatitis and asthma.

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