Influence of an SGLT2 inhibitor, tofogliflozin, on the resting heart rate in relation to adipose tissue insulin resistance.

AIMS: To examine the effects of a sodium-glucose co-transporter 2 (SGLT2) inhibitor, tofogliflozin, on resting heart rate by exploring baseline factors that independently influenced changes in the resting heart rate. METHODS: Data on 419 participants in tofogliflozin phase 2/3 trials were analysed. Changes in resting heart rate from baseline to week 24 were analysed using an analysis of covariance (ANCOVA) model with groups (tofogliflozin/placebo) as a fixed effect and baseline values as covariates. The antilipolytic effect was evaluated as adipose tissue insulin resistance (Adipo-IR) and was calculated as the product of fasting insulin and free fatty acid. Multivariate analysis evaluated independent factors for changes in resting heart rate from baseline to week 24. RESULTS: Of the participants, 58% were men, and mean age, HbA1c , BMI and resting heart rate were 57.6 years, 65 mmol/mol (8.1%), 25.5 kg/m2 and 66 bpm, respectively. At week 24, adjusted mean difference vs. placebo in the change from baseline was -2.3 bpm [95% confidence interval (CI) -4.6, -0.1] with tofogliflozin. Changes in resting heart rate were positively correlated with changes in Adipo-IR, whereas reductions in HbA1c , body weight and blood pressure were similar independent of changes in resting heart among quartiles of resting heart rate change. On multivariate analysis, higher baseline resting heart rates and Adipo-IR values were significantly associated with greater reductions in resting heart rate. CONCLUSIONS: Tofogliflozin corrected resting heart rate levels in accordance with baseline levels. Correction of high resting heart rates may be attributed to improved adipose tissue insulin resistance, leading to correction of hyperinsulinaemia.

Interferon-gamma release assay for diagnosing Mycobacterium tuberculosis infections in patients with systemic lupus erythematosus.

Our aim was to analyze the performance of an interferon-gamma release assay, QuantiFERON-TB Gold (QFT-2G), for diagnosing Mycobacterium tuberculosis (MTB) infection in patients with systemic lupus erythematosus (SLE). We performed the QFT-2G and tuberculin skin test (TST) in 71 SLE patients. The QFT-2G results of 279 patients with other connective tissue diseases (CTD) and 35 healthy controls were analyzed. Of the 71 SLE patients, two (2.8%) were positive and 46 (64.8%) were negative by QFT-2G. All SLE patients had no evidence of active MTB infection, apart from one. QFT-2G produced a significantly higher number of indeterminate results in patients with SLE (23/71, 32.4%) compared with those with other CTD (5.7%) or healthy controls (0%) (p < 0.0001 and p < 0.0001). Decreased lymphocyte counts and high SLEDAI scores in SLE patients were shown to be risk factors for indeterminate results by multivariate analysis (p = 0.02 and p = 0.04). Among all patients with CTD, SLE itself and lymphocytopenia were found to be independent risks for indeterminate results (p = 0.00000625 and p = 0.000107). In conclusion, QFT-2G may have more potential to assist in the diagnosis of active and latent MTB infection than TST in SLE patients. However, because of the high frequency of indeterminate results, caution must be used when interpreting the results of QFT-2G among SLE patients, especially those who have parallel or subsequent flares.

Associations of PD-L1, PD-L2, and HLA class I expression with responses to immunotherapy in patients with advanced sarcoma: post hoc analysis of a phase 1/2 trial.

BACKGROUND: Although immunotherapy is thought to be a promising cancer treatment, most patients do not respond to immunotherapy. In this post hoc analysis of a phase 1/2 study, associations of programmed death ligand 1 (PD-L1), PD-L2, and HLA class I expressions with responses to dendritic cells (DCs)-based immunotherapy were investigated in patients with advanced sarcoma. METHODS: This study enrolled 35 patients with metastatic and/or recurrent sarcomas who underwent DC-based immunotherapy. The associations of PD-L1, PD-L2, and HLA class I expressions in tumor specimens, which were resected before immunotherapy, with immune responses (increases of IFN-γ and IL-12) and oncological outcomes were evaluated. RESULTS: Patients who were PD-L2 (+) showed lower increases of IFN-γ and IL-12 after DC-based immunotherapy than patients who were PD-L2 (-). The disease control (partial response or stable disease) rates of patients who were PD-L1 (+) and PD-L1 (-) were 0% and 22%, respectively. Disease control rates of patients who were PD-L2 (+) and PD-L2 (-) were 13% and 22%, respectively. Patients who were PD-L1 (+) tumors had significantly poorer overall survival compared with patients who were PD-L1 (-). No associations of HLA class I expression with the immune response or oncological outcomes were observed. CONCLUSIONS: This study suggests that PD-L1 and PD-L2 are promising biomarkers of DC-based immunotherapy, and that addition of immune checkpoint inhibitors to DC-based immunotherapy may improve the outcomes of DC-based immunotherapy.

Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study.

BACKGROUND: Tumour necrosis factor (TNF) inhibitors enable tight control of disease activity in patients with rheumatoid arthritis (RA). Discontinuation of TNF inhibitors after acquisition of low disease activity (LDA) is important for safety and economic reasons. OBJECTIVE: To determine whether infliximab might be discontinued after achievement of LDA in patients with RA and to evaluate progression of articular destruction during the discontinuation. METHODS: 114 patients with RA who had received infliximab treatment, and whose Disease Activity Score, including a 28-joint count (DAS28) was <3.2 (LDA) for 24 weeks, were studied. RESULTS: The mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5 and mean modified total Sharp score (mTSS) 63.3. After maintaining LDA for >24 weeks by infliximab treatment, the drug was discontinued and DAS28 in 102 patients was evaluated at year 1. Fifty-six patients (55%) continued to have DAS28<3.2 and 43% reached DAS<2.6 at 1 year after discontinuing infliximab. For 46 patients remission induction by Remicade in RA (RRR) failed: disease in 29 patients flared within 1 year and DAS28 was >3.2 at year 1 in 17 patients. Yearly progression of mTSS (DeltaTSS) remained <0.5 in 67% and 44% of the RRR-achieved and RRR-failed groups, respectively. The estimated DeltamTSS was 0.3 and 1.6 and Health Assessment Questionnaire-Disability Index was 0.174 and 0.614 in the RRR-achieved and RRR-failed groups, respectively, 1 year after the discontinuation. CONCLUSION: After attaining LDA by infliximab, 56 (55%) of the 102 patients with RA were able to discontinue infliximab for >1 year without progression of radiological articular destruction.

Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders.

BACKGROUND: Mikulicz's disease (MD) has been considered as one manifestation of Sjögren's syndrome (SS). Recently, it has also been considered as an IgG(4)-related disorder. OBJECTIVE: To determine the differences between IgG(4)-related disorders including MD and SS. METHODS: A study was undertaken to investigate patients with MD and IgG(4)-related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG(4)-positive multiorgan lymphoproliferative syndrome (IgG(4)+MOLPS). The preliminary diagnostic criteria include raised serum levels of IgG(4) (>135 mg/dl) and infiltration of IgG(4)(+) plasma cells in the tissue (IgG(4)+/IgG+ plasma cells >50%) with fibrosis or sclerosis. The clinical features, laboratory data and pathologies of 64 patients with IgG(4)+MOLPS and 31 patients with typical SS were compared. RESULTS: The incidence of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and antinuclear, antiSS-A/Ro and antiSS-B/La antibodies was significantly lower in patients with IgG(4)+MOLPS than in those with typical SS. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG(2), IgG(4) and IgE levels were significantly increased in IgG(4)+MOLPS. Histological specimens from patients with IgG(4)+MOLPS revealed marked IgG(4)+ plasma cell infiltration. Many patients with IgG(4)+MOLPS had lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG(4)+ cells were seen in the tissue of patients with typical SS. Thirty-eight patients with IgG(4)+MOLPS treated with glucocorticoids showed marked clinical improvement. CONCLUSION: Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG(4)+MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG(4)+MOLPS.

Electric-field-induced superconductivity in an insulator.

Electric field control of charge carrier density has long been a key technology to tune the physical properties of condensed matter, exploring the modern semiconductor industry. One of the big challenges is to increase the maximum attainable carrier density so that we can induce superconductivity in field-effect-transistor geometry. However, such experiments have so far been limited to modulation of the critical temperature in originally conducting samples because of dielectric breakdown. Here we report electric-field-induced superconductivity in an insulator by using an electric-double-layer gating in an organic electrolyte. Sheet carrier density was enhanced from zero to 10(14) cm(-2) by applying a gate voltage of up to 3.5 V to a pristine SrTiO(3) single-crystal channel. A two-dimensional superconducting state emerged below a critical temperature of 0.4 K, comparable to the maximum value for chemically doped bulk crystals, indicating this method as promising for searching for unprecedented superconducting states.

Mobile phone base station radiation does not affect neoplastic transformation in BALB/3T3 cells.

A large-scale in vitro study focusing on low-level radiofrequency (RF) fields from mobile radio base stations employing the International Mobile Telecommunication 2000 (IMT-2000) cellular system was conducted to test the hypothesis that modulated RF fields affect malignant transformation or other cellular stress responses. Our group previously reported that DNA strand breaks were not induced in human cells exposed to 2.1425 GHz Wideband Code Division Multiple Access (W-CDMA) radiation up to 800 mW/kg from mobile radio base stations employing the IMT-2000 cellular system. In the current study, BALB/3T3 cells were continuously exposed to 2.1425 GHz W-CDMA RF fields at specific absorption rates (SARs) of 80 and 800 mW/kg for 6 weeks and malignant cell transformation was assessed. In addition, 3-methylcholanthrene (MCA)-treated cells were exposed to RF fields in a similar fashion, to assess for effects on tumor promotion. Finally, the effect of RF fields on tumor co-promotion was assessed in BALB/3T3 cells initiated with MCA and co-exposed to 12-O-tetradecanoylphorbol-13-acetate (TPA). At the end of the incubation period, transformation dishes were fixed, stained with Giemsa, and scored for morphologically transformed foci. No significant differences in transformation frequency were observed between the test groups exposed to RF signals and the sham-exposed negative controls in the non-, MCA-, or MCA plus TPA-treated cells. Our studies found no evidence to support the hypothesis that RF fields may affect malignant transformation. Our results suggest that exposure to low-level RF radiation of up to 800 mW/kg does not induce cell transformation, which causes tumor formation.

Gains, losses, and amplification of genomic material in rhabdomyosarcoma analyzed by comparative genomic hybridization.

In this study, 10 embryonal and 14 alveolar rhabdomyosarcoma (RMS) tumor samples, including 4 cell lines derived from tumors of the alveolar subtype, were analyzed by comparative genomic hybridization. In the embryonal tumors, the gain of whole or most of various chromosomes, notably chromosomes 2 (60% of cases), 13 (60%), 12 (60%), 8 (60%), 7 (50%), 17 (40%), 18 (40%), and 19 (40%), and the loss of chromosomes 16 (40%), 10 (30%), 15 (20%), and 14 (20%) were found. One case showed evidence of genomic amplification at 12q13-15. In contrast, the alveolar tumors and cell lines showed consistent evidence of genomic amplification, with multiple amplicons in some cases. The amplicons were localized to l2q13-15 (50%), 2p24 (36%), 13q14 (14%), l3q32 (14%), 1q36 (14%), 1q21 (7%), and 8q13-21 (7%). Four cases had additional copies of chromosome 17 or l7q. These changes were in addition to the presence of fusion gene transcripts that are associated with translocations specific to alveolar RMS. The results show that distinct patterns of primarily gains of specific chromosomal material are associated with the embryonal subtype of RMS, and that genomic amplification seems to play an important role in the alveolar subtype. Notably, these distinct changes predominantly involved chromosomes 2, 12, and 13 in both subtypes.

Adiponectin, T-cadherin and tumour necrosis factor-alpha in damaged cardiomyocytes from autopsy specimens.

This study determined the presence of adiponectin, T-cadherin (an adiponectin receptor) and tumour necrosis factor-alpha (TNF-alpha) in damaged myocytes from autopsied patients with acute or old myocardial infarction (MI) or dilated cardiomyopathy (DCM), using immunohistochemical staining. The enrolled patients included eight with acute MI, six with old MI and seven with DCM. Four autopsied individuals with no cardiac lesions were also enrolled as controls. Adiponectin and TNF-alpha were not observed in normal myocytes from control subjects, but T-cadherin was weakly detected. Immunoreactivity for adiponectin and T-cadherin was observed at the periphery of damaged myocytes from MI and DCM patients; intracellular reactivity for TNF-alpha was also seen. There were no statistically significant differences in the degree of reactivity for each molecule in the myocytes between the MI and DCM patients. These results suggest that the presence of adiponectin and TNF-alpha in damaged myocytes may contribute to the processes of myocardial injury occurring in MI and DCM.

The role of radiotherapy in the management of extrahepatic bile duct cancer: an analysis of 145 consecutive patients treated with intraluminal and/or external beam radiotherapy.

PURPOSE: To determine the feasibility of high dose radiotherapy and to evaluate its role in the management of extrahepatic bile duct (EHBD) cancer. METHODS AND MATERIALS: Between 1983 and 1991, 145 consecutive patients with EHBD cancer were treated by low dose rate intraluminal 192Ir irradiation (ILRT) either alone or in combination with external beam radiotherapy (EBRT). Among the primarily irradiated, 77 patients unsuitable for surgical resection, 54 were enrolled in radical radiotherapy, and 23 received palliative radiotherapy. Fifty-nine received postoperative radiotherapy, and the remaining 9 preoperative radiotherapy. The mean radiation dose was 67.8 Gy, ranging from 10 to 135 Gy. Intraluminal 192Ir irradiation was indicated in 103 patients, and 85 of them were combined with EBRT. Expandable metallic biliary endoprosthesis (EMBE) was used in 32 primarily irradiated patients (31 radical and 1 palliative radiotherapy) after the completion of radiotherapy. RESULTS: The 1-, 3-, and 5-year actuarial survival rates for all 145 patients were 55%, 18%, and 10%, for the 54 patients treated by radical radiotherapy (mean 83.1 Gy), 56%, 13%, and 6% [median survival time (MST) 12.4 months], and for the 59 patients receiving postoperative radiotherapy (mean 61.6 Gy), 73%, 31%, and 18% (MST 21.5 months), respectively. Expandable metallic biliary endoprosthesis was useful for the early establishment of an internal bile passage in radically irradiated patients and MST of 14.9 months in these 31 patients was significantly longer than that of 9.3 months in the remaining 23 patients without EMBE placement (p < 0.05). Eighteen patients whose surgical margins were positive in the hepatic side bile duct(s) showed significantly better survival compared with 15 patients whose surgical margins were positive in the adjacent structure(s) (44% vs. 0% survival at 3 years, p < 0.001). No survival benefit was obtained in patients given palliative or preoperative radiotherapy. Gastroduodenal complications increased in those receiving doses of 90 Gy or more, and serious biliary bleeding was experienced in three preoperatively irradiated patients. Complications in other patients was tolerable. CONCLUSIONS: High-dose radiotherapy, consisting of ILRT and EBRT, appears to be feasible in the management of EHBD cancer, and it offers a survival advantage for patients not suited for surgical resection and patients with positive margins in the resected end of the hepatic side bile duct. Expandable metallic biliary endoprosthesis assists the internal bile flow and may lengthen survival after high dose radiotherapy.

Periosteal chondroma and periosteal chondrosarcoma.

A clinicopathologic study of 46 patients with periosteal chondroma and 14 patients with periosteal chondrosarcoma revealed that periosteal chondroma tended to affect younger patients and that the lesion was usually smaller. Radiographically, the typical periosteal chondroma was a small, well-marginated tumor on the outer surface of a long bone. Erosion of the cortical surface and marginal buttresses were usually present. Periosteal chondrosarcoma had a more aggressive appearance and was seen as a large mass located superficially on the cortex; the margins of the mass were more irregular than those of chondroma. Histologically, periosteal chondroma frequently showed hypercellularity, plump nuclei, and binucleation. Thus, the differentiation of chondroma from chondrosarcoma is difficult and is based mainly on evidence of invasion. The prognosis in periosteal chondroma is good: only one patient had a local recurrence, none of the tumors underwent malignant change, and excision seems to be curative. However, the prognosis in periosteal chondrosarcoma is not as good: two patients died of metastasis to the lungs after local excision and two patients had recurrences after local resection. Periosteal chondrosarcoma should be treated more aggressively than periosteal chondroma.

Extraosseous osteosarcoma presenting with intestinal hemorrhage: case report and literature review.

A 23-year-old man presented with intestinal bleeding due to an extraosseous osteosarcoma of the jejunum. A lesion was also found in the deltoid muscle, and other metachronous soft tissue sites developed subsequently. The presence of malignant osteoid was documented by immunohistochemical studies of one of the lesions. The patient died of metastatic disease 19 months after diagnosis, despite surgical resections and adjuvant chemotherapy. This unique presentation is discussed, and the literature concerning extraosseous osteosarcoma is reviewed.

Prognostic significance of an interface pattern of central fibrosis and tumor cells in peripheral adenocarcinoma of the lung.

Fifty-nine surgically resected pulmonary adenocarcinomas were histologically classified into four types (A, B, C, and D) according to the pattern of invasion, ie, the extent of invasive tumor cell growth in the interface zone between alveoli replaced by cancer cells and the central region of fibrosis (so-called "scar"). In pattern A cancer cells proliferate along the alveolar walls without forming a frankly invasive lesion. In pattern B invasive lesions occupy less than 30% and in pattern C more than 30% of the fibrosing area. Pattern D refers to invasion of the bronchial lumen by cancer cells. The 59 tumors included 14 of pattern A, 12 of pattern B, 16 of pattern C, and 17 of pattern D. The 5-year survival rate for patients with pattern A tumors was 100%, and the rates for patients with pattern B, C, and D tumors were 64.2%, 30.0%, and 11.8%, respectively. Each difference between pairs of survival curves was statistically significant (P < .05). We found a correlation between the pattern of invasion and other prognostic factors. However, even in the cases evaluated as favorable by other prognostic factors (stage I, tumor less than 35 mm in diameter, negative for lymph node metastases, well-differentiated histology, negative for subpleural invasion, negative for vascular invasion) the survival curves became steeper going from pattern A to patterns B, C, and D. We conclude that the pattern of invasion is correlated with the prognosis of surgically treated patients. Our study may provide new histological criteria for the prognostic evaluation of pulmonary adenocarcinoma.

Alpha-fetoprotein-producing acinar cell carcinoma of the pancreas.

A pancreatic carcinoma and liver metastases associated with marked elevation of the serum alpha-fetoprotein (AFP) level were resected from a 57-year-old man. On microscopic examination, the tumor cells showed a predominantly acinar arrangement, with tubular and trabecular structures; in some foci it had features of a medullary pattern. Alpha-fetoprotein, lipase, trypsin, chymotrypsin, and alpha 1-antitrypsin were strongly demonstrated in tumor tissue by immunohistochemical techniques. A biochemical analysis of AFP on affinity sepharose columns revealed that the AFP derived from the tumor tissues was similar to that of hepatocellular carcinoma. Ultrastructural study showed that most of the tumor cells had abundant rough endoplastic reticulum and numerous zymogen granules. No squamoid corpuscles, neuroendocrine granules, bile production, or bile canaliculi were recognized. These findings suggest that this unique tumor originated from acinar cells.

CD8+ cell-dominant alveolitis in pulmonary sarcoidosis.

A 55-year-old woman had bilateral hilar lymphadenopathy and retinouveitis. Microscopic examination of a biopsy specimen from a mediastinal lymph node revealed noncaseating epithelioid cell granulomas. Since granulomatous diseases of infectious origin and sarcoid reaction were reasonably excluded, she was diagnosed as having pulmonary sarcoidosis. Bronchoalveolar lavage findings were atypical in that the ratio of helper T cells to suppressor T cells (CD4/8 ratio) was 0.5 in two separate examinations, despite a moderately increased proportion of lymphocytes. Immunohistochemical examination of the lymph node also showed a predominancy of suppressor T cells. The inversion of the CD4/8 ratio suggests the presence of heterogeneity in the immunoregulatory mechanism in pulmonary sarcoidosis and may have a prognostic significance.

A computer simulation of the plasma leakage through a vascular prosthesis made of expanded polytetrafluoroethylene.

We explored the blood-retaining mechanism of a vascular prosthesis made of expanded polytetrafluoroethylene through analysis of its structure and physicochemical properties. Plasma leakage through this vascular prosthesis was simulated by computer to explore its etiology. These examinations disclosed that leakage is dependent upon the inner pressure and the density of fibers. In other words, the study revealed that the mean distance between fibers constituting the wall of the expanded polytetrafluoroethylene vascular prosthesis is increased by tension (that is, inner pressure), resulting in an increased probability of leakage. It was additionally found that a thin membrane is formed on the polytetrafluoroethylene surface if blood in contact with the surface is dried. This membrane was found to reduce the water-repelling property of polytetrafluoroethylene and to make it impossible to preserve the inter-fiber liquid surface, thus causing leakage through the expanded polytetrafluoroethylene vascular prosthesis.

The effect of pulsatile perfusion on cerebral blood flow during profound hypothermia with total circulatory arrest.

In 39 mongrel dogs, regional cerebral blood flow was measured during pulsatile and nonpulsatile deep hypothermic cardiopulmonary bypass with total circulatory arrest. Total circulatory arrest was performed at 20 degrees C cerebral temperature for 40 minutes in 15 dogs, 60 minutes in 12 dogs, and 80 minutes in 12 dogs. Cerebral blood flow in both groups decreased as cerebral temperature fell and there was no significant difference in cerebral blood flow between the two groups during the cooling period. After circulatory arrest for 40 minutes, as cerebral temperature increased to 35 degrees C, cerebral blood flow in both groups recovered to values as high as the respective initial values, which were measured just after the beginning of cardiopulmonary bypass for cooling (102.5% +/- 10.2% in the pulsatile group and 97.2% +/- 12.6% in the nonpulsatile group). After circulatory arrest for 60 minutes, cerebral blood flow in the pulsatile group increased to 141.8% +/- 16.1% of its initial value when the cerebral temperature became 35 degrees C, but it remained significantly lower (64.5% +/- 9.2%) in the nonpulsatile group (p < 0.01). After circulatory arrest for 80 minutes, cerebral blood flow in both groups remained lower than the respective initial values. These results suggest that pulsatile perfusion maintains cerebral blood flow even during profound hypothermia and that it may protect the brain from ischemic and hypoxic damage caused by profound hypothermia and total circulatory arrest in cardiac operations.

A clinical study on the effects of pulsatile cardiopulmonary bypass on the blood endotoxin levels.

Levels of endogenous endotoxins have been reported to increase after cardiopulmonary bypass. Endotoxin levels have also been implicated in multiple organ failure and may contribute to the immunocompromised state seen after bypass. We evaluated the effects of pulsatile cardiopulmonary bypass circulation on endogenous endotoxin levels. The study population consisted of 15 consecutive adult patients who underwent cardiac operations with cardiopulmonary bypass. Pulsatile flow was used during aortic crossclamping in eight patients (group I) and nonpulsatile flow was used in the remaining seven patients (group II). Changes in blood endotoxin levels were monitored during aortic crossclamping, after release of the clamp, and after weaning from bypass. The blood endotoxin level at each stage was expressed as a percentage of the level at the beginning of bypass. Group I patients a significantly lower blood endotoxin percentage than group II (from 20 to 120 minutes after the initiation of aortic crossclamping). In group I, the blood endotoxin percentage was nearly constant during aortic crossclamping. After release of aortic crossclamping, group I also had a lower blood endotoxin percentage than group II. Endogenous endotoxin levels appear to increase in the presence of intestinal congestion and ischemia. Improvement in intestinal circulation by pulsatile cardiopulmonary bypass may prevent increases in endogenous endotoxin levels by reducing these factors.

Congenital-infantile fibrosarcoma. A clinicopathologic study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues.

Congenital-infantile fibrosarcoma (CIFS) is a relatively indolent sarcoma that should be distinguished from more aggressive spindle cell sarcomas of childhood. CIFSs have been found to have a novel recurrent reciprocal translocation t(12;15)(p13;q25) resulting in the gene fusion ETV6-NTRK3 (ETS variant gene 6; neurotrophic tyrosine kinase receptor type 3). We studied immunohistochemical expression of NTRK3, and conducted a reverse transcription-polymerase chain reaction (RT-PCR) assay to detect the ETV6-NTRK3 fusion transcripts using archival formalin-fixed paraffin-embedded tissues from 10 CIFSs. Thirty-eight other spindle cell tumors were included as controls. The ETV6-NTRK3 fusion transcripts were identified in 7 (70%) of 10 CIFSs. Nucleotide sequence analysis showed that the fusion occurred between ETV6 exon 5 and NTRK3 exon 13. The 38 control tumors were negative for the fusion transcript. Immunohistochemically, CIFSs consistently expressed NTRK3. But the expression of NTRK3 also was observed in 22 of 38 control tumors. These results show the diagnostic usefulness of RT-PCR methods to detect ETV6-NTRK3 fusion transcripts in archival formalin-fixed paraffin-embedded tissue and the important role of NTRK3 in the development of CIFS, despite its being a protein of little importance in differential diagnosis.