Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia

Recently, somatic mutations of the nucleophosmin gene (NPM1), which alter the subcellular localization of the product, have been reported in acute myeloid leukemia (AML). We analyzed the clinical significance of NPM1 mutations in comparison with cytogenetics, FLT3, NRAS, and TP53 mutations, and a partial tandem duplication of the MLL gene (MLL-TD) in 257 patients with AML. We found NPM1 mutations, including 4 novel sequence variants, in 64 of 257 (24.9%) patients. NPM1 mutations were associated with normal karyotype and with internal tandem duplication (ITD) and D835 mutations in FLT3, but not with other mutations. In 190 patients without the M3 French-American-British (FAB) subtype who were treated with the protocol of the Japan Adult Leukemia Study Group, multivariate analyses showed that the NPM1 mutation was a favorable factor for achieving complete remission but was associated with a high relapse rate. Sequential analysis using 39 paired samples obtained at diagnosis and relapse showed that NPM1 mutations were lost at relapse in 2 of the 17 patients who had NPM1 mutations at diagnosis. These results suggest that the NPM1 mutation is not necessarily an early event during leukemogenesis or that leukemia clones with NPM1 mutations are sensitive to chemotherapy.     

Intrahepatic cholangiocarcinoma arising 10 years after the excision of congenital extrahepatic biliary dilation

Received: October 6, 2000 / Accepted: January 26, 2001     

A case report of cribriform carcinoma of the pancreas with long time survival

A 62-year-old man had complained of left abdominal pain and tenderness and a body weight loss. Abdominal ultrasonography and computed tomography revealed homogeneous tumor with clear margin, and an irregular shape (3.5 x 2.0 cm) in the body of the pancreas. Endoscopic retrograde cholangiopancreatography showed a shadow defect in the main pancreatic duct adjacent to the tumor, which suggested intraductal tumor spread. Distal pancreatectomy with splenectomy and left paraaortic lymph node dissection was performed. Microscopically, the tumor showed microtubular carcinoma, which was characterized by a cribriform pattern, medullary growth, and little interstitium. The tumor was encapsulated by a relatively thick fibrous capsule. The patient was discharged uneventfully, and he is alive 33 months after operation without a distinct sign of recurrence. In conclusion, cribriform carcinoma of the pancreas has specific characteristics, such as good prognosis, expansive growth with little invasion, intraductal growth and spread without mucin production and histological marked cribriform pattern. This type of carcinoma should be classified as a new disease entity of carcinoma of the pancreas.     

Impact of shear stress and atherosclerosis on entrance-tear formation in patients with acute aortic syndromes

Weak aortic media layers can lead to intimal tear (IT) in patients with overt aortic dissection (AD), and aortic plaque rupture is thought to progress to penetrating atherosclerotic ulcer (PAU) with intramural hematoma (IMH). However, the influences of shear stress and atherosclerosis on IT and PAU have not been fully examined. Ninety-eight patients with overt AD and 30 patients with IMH and PAU admitted to our hospital from 2002 to 2007 were enrolled. The greater curvatures of the aorta, including the anterior and right portions of the ascending aorta and anterior portion of the aortic arch, were defined as sites of high shear stress. The other portions of the aorta were defined as sites of low shear stress based on anatomic and hydrodynamic theories. Aortic calcified points (ACPs) were manually counted on computed tomography slices of the whole aorta every 10 mm from the top of the arch to the abdominal bifurcation point. IT was more often observed at sites of high shear stress in overt AD than in PAU (73.5 vs 20.0 %, P < 0.0001). Significantly more ACPs were present in PAU than in overt AD (18.6 ± 8 vs 13.3 ± 10, P = 0.007). The present study suggests that high shear stress and less severe atherosclerosis could induce the occurrence of an IT, thereafter progressing to overt AD, and that low shear stress and more severe atherosclerosis could proceed to PAU with IMH. These findings may help to identify the entrance-tear site.     

S100A Expression and Interleukin-10 Polymorphisms Are Associated with Ulcerative Colitis and Diarrhea Predominant Irritable Bowel Syndrome

Background

Both ulcerative colitis (UC) and diarrhea-predominant irritable bowel syndrome (IBS-D) are associated with alterations in enteric serotonin (5-HT) signaling.

Aims

The purpose of this study was to compare the rectal and sigmoid colonic mucosal expression of S100A proteins and functional polymorphisms of the 5-HT transporter (5HTT) and interleukin-10 genes in patients with IBS-D or UC with healthy controls.

Methods

mRNA expression of S100 proteins was measured in sigmoid and rectal biopsies and in rectal epithelium isolated by laser-captured microdissection. Leucocyte DNA was analyzed by PCR-based reaction fragment length polymorphisms and direct sequencing. Clinical symptoms were assessed by the self-rating depression scale and by the gastrointestinal symptom rating scale.

Results

Fifty patients with IBS-D, 56 with UC and 50 healthy controls were studied. Colonic mucosal expression of S100A8 and S100A9 in UC was significantly higher than in IBS or controls and correlated with the UC disease activity index (r = 0.65, p < 0.001). S100A10 expression in the rectal epithelium of the IBS patients was significantly higher (0.643 vs. 0.402, p = 0.01) than in controls and correlated with the SDS scores (r = 0.41, p = 0.002). The frequency of IL10-819 CC genotype was significantly higher in IBS-D (10.7 vs. 0 %, p = 0.047) and UC (16 vs. 0 %, p = 0.007) than that in controls.

Conclusion

Overexpression of S100A10 in the rectum may play a role in IBS as it is involved in modulating 5-HT1B receptors. The IL10-819 CC is a candidate genotype for both IBS and UC in Japanese.     

Safety and efficacy of non-vitamin K oral anticoagulant treatment compared with warfarin in patients with non-valvular atrial fibrillation who develop acute ischemic stroke or transient ischemic attack: a multicenter prospective cohort study (daVinci study)

The safety and efficacy of non-vitamin K oral anticoagulant (NOAC) compared with warfarin in treating patients with non-valvular atrial fibrillation (NVAF) who developed acute ischemic stroke or transient ischemic attack (AIS/TIA), particularly those receiving tissue-plasminogen activator (tPA) therapy, remains unclear. Between April 2012 and December 2014, we conducted a multicenter prospective cohort study to assess the current clinical practice for treating such patients. We divided the patients into two groups according to the administration of oral anticoagulants (warfarin or NOACs) and tPA therapy. The risk of any hemorrhagic or ischemic event was compared within 1 month after the onset of stroke. We analyzed 235 patients with AIS/TIA including 73 who received tPA therapy. Oral anticoagulants were initiated within 2–4 inpatient days. NOACs were administered to 49.8 % of patients, who were predominantly male, younger, had small infarcts, lower NIHSS scores, and had a lower all-cause mortality rate (0 vs. 4.2 %, P = 0.06) and a lower risk of any ischemic events (6.0 vs. 7.6 %, P = 0.797) compared with warfarin users. The prevalence of all hemorrhagic events was equivalent between the two groups. Early initiation of NOACs after tPA therapy appeared to lower the risk of hemorrhagic events, although there was no significant difference (0 vs. 5.6 %, P = 0.240). Although more clinicians are apt to prescribe NOACs in minor ischemic stroke, NOAC treatment may provide a potential benefit in such cases. Early initiation of NOACs after tPA therapy may reduce the risk of hemorrhagic events compared with warfarin.     

Design and Rationale of the RE‐DUAL PCI Trial: A Prospective,Randomized, Phase 3b Study Comparing the Safety and Efficacy of Dual Antithrombotic Therapy With Dabigatran Etexilate Versus Warfarin Triple Therapy in Patients With Nonvalvular Atrial Fibrillation Who Have Undergone Percutaneous Coronary Intervention With Stenting

Antithrombotic management of patients with atrial fibrillation (AF) undergoing coronary stenting is complicated by the need for anticoagulant therapy for stroke prevention and dual antiplatelet therapy for prevention of stent thrombosis and coronary events. Triple antithrombotic therapy, typically comprising warfarin, aspirin, and clopidogrel, is associated with a high risk of bleeding. A modest‐sized trial of oral anticoagulation with warfarin and clopidogrel without aspirin showed improvements in both bleeding and thrombotic events compared with triple therapy, but large trials are lacking. The RE‐DUAL PCI trial (NCT 02164864) is a phase 3b, a strategy of prospective, randomized, open‐label, blinded‐endpoint trial. The main objective is to evaluate dual antithrombotic therapy with dabigatran etexilate (110 or 150 mg twice daily) and a P2Y12 inhibitor (either clopidogrel or ticagrelor) compared with triple antithrombotic therapy with warfarin, a P2Y12 inhibitor (either clopidogrel or ticagrelor, and low‐dose aspirin (for 1 or 3 months, depending on stent type) in nonvalvular AF patients who have undergone percutaneous coronary intervention with stenting. The primary endpoint is time to first International Society of Thrombosis and Hemostasis major bleeding event or clinically relevant nonmajor bleeding event. Secondary endpoints are the composite of all cause death or thrombotic events (myocardial infarction, or stroke/systemic embolism) and unplanned revascularization; death or thrombotic events; individual outcome events; death, myocardial infarction, or stroke; and unplanned revascularization. A hierarchical procedure for multiple testing will be used. The plan is to randomize ～ 2500 patients at approximately 550 centers worldwide to try to identify new treatment strategies for this patient population.