Severe Case of Peripheral Leukocytosis Initially Diagnosed as Myelodysplastic Syndrome/Myeloproliferative Neoplasm, Unclassifiable, but Possibly Prefibrotic Primary Myelofibrosis

Leukocytosis is occasionally seen in patients with presumptive but undiagnosed myeloproliferative disorders (MPD). A 74-year-old woman was admitted to our hospital for tarry stools, anemia, and marked peripheral leukocytosis of 1.4×105/μL. Gastroenteroscopy revealed an acute gastric and duodenal mucosal lesion that was treated successfully via endoscopic hemoclipping. Bone marrow aspiration revealed marked megakaryocyte proliferation with atypia of naked nuclei and marrow hypercellularity (90% cellularity). A fluorescence in situ hybridization test could not detect the BCR-ABL fusion gene. Bone marrow aspiration later revealed further abnormalities of megakaryocytes. The patient died from cerebral bleeding. The present case fulfilled 2 of the 3 major criteria of primary myelofibrosis according to the World Health Organization 2008 classification:namely, megakaryocytic hyperplasia with hypercellular marrow and granulocytic hyperplasia. However, the megakaryocytic abnormality was not strictly compatible with the criteria. Instead, we considered prefibrotic primary myelofibrosis as a possibility, although myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) was technically the correct diagnosis. The present case shows that MPN diagnosis remains difficult and suggests that other cases of peripheral leukocytosis with diagnosed MDS/MPN-U might include similar findings

Whole Blood Interferon-Gamma Assay for Baseline Tuberculosis Screening among Japanese Healthcare Students

BACKGROUND: The whole blood interferon-gamma assay (QuantiFERON-TB-2G; QFT) has not been fully evaluated as a baseline tuberculosis screening test in Japanese healthcare students commencing clinical contact. The aim of this study was to compare the results from the QFT with those from the tuberculin skin test (TST) in a population deemed to be at a low risk for infection with Mycobacterium tuberculosis. METHODOLOGY/PRINCIPAL FINDINGS: Healthcare students recruited at Okayama University received both the TST and the QFT to assess the level of agreement between these two tests. The interleukin-10 levels before and after exposure to M tuberculosis-specific antigens (early-secreted antigenic target 6-kDa protein [ESAT-6] and culture filtrate protein 10 [CFP-10]) were also measured. Of the 536 healthcare students, most of whom had been vaccinated with bacillus-Calmette-Guérin (BCG), 207 (56%) were enrolled in this study. The agreement between the QFT and the TST results was poor, with positive result rates of 1.4% vs. 27.5%, respectively. A multivariate analysis also revealed that the induration diameter of the TST was not affected by the interferon-gamma concentration after exposure to either of the antigens but was influenced by the number of BCG needle scars (p = 0.046). The whole blood interleukin-10 assay revealed that after antigen exposure, the median increases in interleukin-10 concentration was higher in the subgroup with the small increase in interferon-gamma concentration than in the subgroup with the large increase in interferon-gamma concentration (0.3 vs. 0 pg/mL; p = 0.004). CONCLUSIONS/SIGNIFICANCE: As a baseline screening test for low-risk Japanese healthcare students at their course entry, QFT yielded quite discordant results, compared with the TST, probably because of the low specificity of the TST results in the BCG-vaccinated population. We also found, for the first time, that the change in the interleukin-10 level after exposure to specific antigens was inversely associated with that in the interferon-gamma level in a low-risk population

Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model

Objective: STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases. We investigated the effect of the JAK1/2 inhibitor AZD1480 on lung tumors induced by an activating EGFR mutation. Materials and methods: Three EGFR tyrosine kinase inhibitor-resistant cell lines (RPC-9, PC-9/Van-R and PC-9/ER3) established from PC-9 harboring an EGFR exon19 deletion mutation were used. Growth inhibition was measured using an MIT assay. Effects of AZD1480 were also evaluated in the xenograft model and in the EGFR transgenic mice model. Protein expressions were assessed by immunoblotting and immunohistochemistry. Group differences were compared using Student's t-test. To evaluate the efficacy of AZD1480 on survival, AZD1480 or vehicle was administered orally from 7 weeks of age of the transgenic mice. Overall survival curves were calculated using the Kaplan-Meier method. Results: The sensitivities of resistant and parent cells to AZD1480 were similar in vitro. AZD1480 (30 or 50 mg/kg/day, per os) reduced angiogenesis and revealed significant tumor regression in a mouse xenograft model: Subsequently, the transgenic mice were treated with AZD1480 (30 mg/kg/day) or vehicle alone. The numbers of lung tumors (long axis exceeding 1 mm) in the AZD1480-treated group and control group were 0.37 +/- 0.18 and 2.25 +/- 0.53 (p <0.001), respectively. AZD1480 treatment suppressed pSTAT3, pJAK1, pJAK2 and angiogenesis. The median survival time in the AZD1480-treated group (217 days) was significantly greater than that in the control group (106 days) (log-rank test, p <0.0001). Conclusion: AZD1480 may be effective against lung tumors driven by an activating EGER mutation

Optical Coherence Tomography Analysis of Attenuated Plaques Detected by Intravascular Ultrasound in Patients with Acute Coronary Syndromes

Background. Recent intravascular ultrasound (IVUS) studies have demonstrated that hypoechoic plaque with deep ultrasound attenuation despite absence of bright calcium is common in acute coronary syndrome. Such “attenuated plaque” may be an IVUS characteristic of unstable lesion. Methods. We used optical coherence tomography (OCT) in 104 patients with unstable angina to compare lesion characteristics between IVUS-detected attenuated plaque and nonattenuated plaque. Results. IVUS-detected attenuated plaque was observed in 41 (39%) patients. OCT-detected lipidic plaque (88% versus 49%, P < 0.001), thin-cap fibroatheroma (48% versus 16%, P < 0.001), plaque rupture (44% versus 11%, P < 0.001), and intracoronary thrombus (54% versus 17%, P < 0.001) were more often seen in IVUS-detected attenuated plaques compared with nonattenuated plaques. Conclusions. IVUS-detected attenuated plaque has many characteristics of unstable coronary lesion. The presence of attended plaque might be an important marker of lesion instability

Afatinib Prolongs Survival Compared with Gefitinib in an Epidermal Growth Factor Receptor-Driven Lung Cancer Model

An irreversible ErbB family blocker is expected to inhibit tumors with activating epidermal growth factor receptor (EGFR) mutations more strongly than reversible EGFR tyrosine kinase inhibitors and to overcome acquired resistance to the T790M secondary mutation. Eleven-week-old transgenic mice with Egfr exon 19 deletion mutation were treated with afatinib, gefitinib, or vehicle for 4 weeks. All mice were sacrificed at 15 weeks of age, and the number of superficial left lung tumors with a long axis exceeding 1 mm was counted. The afatinib-treated group had significantly fewer tumors than the vehicle group (P < 0.01) and tended to have fewer tumors than the gefitinib-treated group (P = 0.06). Pathologically, gefitinib-treated mice had clearer, more nodular tumors than afatinib-treated mice. Immunoblotting showed that afatinib suppressed not only pEGFR but also pHER2, and induced apoptosis for longer periods than gefitinib. Subsequently, when each drug was administered 5 days per week until death, afatinib significantly enhanced mouse survival compared with gefitinib (median survival time: 456 days vs. 376.5 days; log-rank test, P < 0.01). Finally, the combination of afatinib with bevacizumab was found to be superior to either drug alone in exon 19 deletion/T790M and L858R/T790M xenograft tumors. Overall, afatinib was more potent than gefitinib in tumors harboring an exon 19 deletion mutation, and the combination of afatinib with bevacizumab efficiently suppressed tumors harboring the T790M secondary mutation

Assessment of Culprit Lesion Morphology in Acute Myocardial Infarction Ability of Optical Coherence Tomography Compared With Intravascular Ultrasound and Coronary Angioscopy

ObjectivesThe aim of the present study was to evaluate the ability of optical coherence tomography (OCT) for assessment of the culprit lesion morphology in acute myocardial infarction (AMI) in comparison with intravascular ultrasound (IVUS) and coronary angioscopy (CAS).BackgroundOptical coherence tomography is a new intravascular imaging method with a high resolution of approximately 10 μm. This may allow us to assess the vulnerable plaques in detail in vivo.MethodsWe enrolled 30 patients with AMI, and analyzed the culprit lesion by OCT, CAS, and IVUS.ResultsThe average duration from the onset of symptom to OCT imaging was 3.8 ± 1.0 h. The incidence of plaque rupture observed by OCT was 73%, and it was significantly higher than that by CAS (47%, p = 0.035) and IVUS (40%, p = 0.009). Furthermore, OCT (23%) was superior to CAS (3%, p = 0.022) and IVUS (0%, p = 0.005) in the detection of fibrous cap erosion. The intracoronary thrombus was observed in all cases by OCT and CAS, but it was identified in 33% by IVUS (vs. OCT, p < 0.001). Only OCT could estimate the fibrous cap thickness, and it was 49 ± 21 μm. The incidence of thin cap fibroatheroma (TCFA) was 83% in this population by OCT.ConclusionsOptical coherence tomography is a feasible imaging modality in patients with AMI and allows us to identify not only plaque rupture, but also fibrous cap erosion, intracoronary thrombus, and TCFA in vivo more frequently compared with conventional imaging techniques

Effect of Vandetanib on Lung Tumorigenesis in Transgenic Mice Carrying an Activating Egfr Gene Mutation

Vandetanib (ZactimaTM) is a novel, orally available inhibitor of both vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinase. In the present study, a line of transgenic mice with a mouse Egfr gene mutation (delE748-A752) corresponding to a human EGFR mutation (delE746-A750) was established. The transgenic mice developed atypical adenomatous hyperplasia to adenocarcinoma of the lung at around 5 weeks of age and died of lung tumors at approximately 17 weeks of age. In the mice treated with vandetanib (6mg/kg/day), these lung tumors disappeared and the phosphorylations of EGFR and VEGFR-2 were reduced in lung tissues to levels comparable to those of non-transgenic control mice. The median overall survival time of the transgenic mice was 28 weeks in the vandetanib-treated group and 17 weeks in the vehicle-treated group. Vandetanib significantly prolonged the survival of the transgenic mice (log-rank test, p＜0.01); resistance to vandetanib occurred at 20 weeks of age and the animals died from their lung tumors at about 28 weeks of age. These data suggest that vandetanib could suppress the progression of tumors harboring an activating EGFR mutation