Genotypic and Phenotypic Characteristics of Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Korean Patients

Background@#Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome. HLRCC is characterized by the development of cutaneous leiomyomas, early-onset uterine leiomyomas, and HLRCC-associated renal cell cancer (RCC) and caused by germline fumarate hydratase (FH) deficiency. We investigated the genotypic and phenotypic characteristics of Korean patients with HLRCC. @*Methods@#We performed direct sequencing analysis of FH in 13 patients with suspected HLRCC and their family members. A chromosomal microarray test was performed in female patients with negative sequencing results but highly suspected HLRCC. In addition, we analyzed the clinical characteristics and evaluated the genotype–phenotype correlations in Korean patients with HLRCC. @*Results@#We identified six different pathogenic or likely pathogenic FH variants in six of the 13 patients (46.2%). The variants included two nonsense variants, two splicing variants, one frameshift variant, and one missense variant. Of the six variants, two (33.3%) were novel (c.132+1G > C, and c.243dup). RCC and early-onset uterine leiomyoma were frequently observed in families with HLRCC, while cutaneous leiomyoma was less common. No significant genotype–phenotype correlation was observed. @*Conclusions@#We describe the genotypic and phenotypic spectrum in a small series of Korean patients with HLRCC. Our data reveal the unique characteristics of Korean patients with HLRCC and suggest a need for establishing an optimal diagnostic approach for them.

Performance of Copeptin for Early Diagnosis of Acute Myocardial Infarction in an Emergency Department Setting

BACKGROUND: Rapid and accurate diagnosis of acute myocardial infarction (AMI) is critical for initiating effective treatment and achieving better prognosis. We investigated the performance of copeptin for early diagnosis of AMI, in comparison with creatine kinase myocardial band (CK-MB) and troponin I (TnI). METHODS: We prospectively enrolled 271 patients presenting with chest pain (within six hours of onset), suggestive of acute coronary syndrome, at an emergency department (ED). Serum CK-MB, TnI, and copeptin levels were measured. The diagnostic performance of CK-MB, TnI, and copeptin, alone and in combination, for AMI was assessed by ROC curve analysis by comparing the area under the curve (AUC). Sensitivity, specificity, negative predictive value, and positive predictive value of each marker were obtained, and the characteristics of each marker were analyzed. RESULTS: The patients were diagnosed as having ST elevation myocardial infarction (STEMI; N=43), non-ST elevation myocardial infarction (NSTEMI; N=25), unstable angina (N=78), or other diseases (N=125). AUC comparisons showed copeptin had significantly better diagnostic performance than TnI in patients with chest pain within two hours of onset (AMI: P=0.022, ≤1 hour; STEMI: P=0.017, ≤1 hour and P=0.010, ≤2 hours). In addition, TnI and copeptin in combination exhibited significantly better diagnostic performance than CK-MB plus TnI in AMI and STEMI patients. CONCLUSIONS: The combination of TnI and copeptin improves AMI diagnostic performance in patients with early-onset chest pain in an ED setting.

Transfusion in RhD Mismatch Hematopoietic Stem Cell Transplantation / 대한수혈학회지

In some cases, hematopoietic stem cell transplants (HSCT) show differences in the D antigen. In previous studies, there have been few cases of de novo anti-D alloimmunization, and even rarer cases of serious side effects or the outcomes. De novo anti-D alloimmunization has been reported to occur more frequently in minor D mismatch than in major D mismatch. For the RhD type of blood components, RhD-negative type is recommended in transfusion in RhD mismatch HSCT without anti-D in donors and recipients. But in situations of insufficient RhD-negative blood supply, this study suggests that the RhD type of blood components depends on the patients’ RhD type before transplantation, and it depends on the donors’ RhD type after transplantation, and an RhD-positive platelet transfusion may be available.

Evaluating the Performance of the Sysmex DI-60 Automated Cell Image Analyzer for the Differential Analysis of Leukocytes

Background@#The Sysmex DI-60 system (Sysmex, Japan) is an automated cell image analyzer. This study aimed to evaluate the performance of the DI-60 system for the differential analysis of leukocytes. @*Methods@#A total of 220 samples were analyzed in this study. The agreement between DI-60 pre-classification and manual verification by experts was determined. The correlation between the differential leukocyte counts obtained using the DI-60 system and those manually obtained in the peripheral blood smears were determined. @*Results@#The pre-classification agreement of DI-60 was 91.0%. The correlation coefficients of normal five-part differentials were 0.9163 (segmented neutrophils), 0.9017 (lymphocytes), 0.8533 (monocytes), 0.8345 (eosinophils), and 0.3505 (basophils). The sensitivity, specificity, positive predictive value, negative predictive value, and the efficiency of counting the abnormal cells, including blasts, promyelocytes, myelocytes, metamyelocytes, lymphocyte variants, and erythroblasts, were determined. The efficiency of the DI-60 system in counting the blasts, promyelocytes, myelocytes, metamyelocytes, lymphocyte variants, and erythroblasts was 99.5%, 100.0%, 95.9%, 96.5%, 98.6%, 100.0%, and 95.9%, respectively. @*Conclusions@#The pre-classification agreement of DI-60 was higher than that of previous studies. The correlation between the differential leukocyte counts obtained with the DI-60 system and those of manual counting was acceptable. The performance of DI-60 as a screening tool in clinical laboratories may be good; however, it is yet to replace manual slide review.

The 2016 WHO versus 2008 WHO Criteria for the Diagnosis of Chronic Myelomonocytic Leukemia

The 2016 WHO diagnostic criteria for chronic myelomonocytic leukemia (CMML) require both absolute and relative monocytosis (≥1×10⁹/L and ≥10% of white blood cell counts) in peripheral blood. Moreover, myeloproliferative neoplasm (MPN) features in bone marrow and/or MPN-associated mutations tend to support MPN with monocytosis rather than CMML. We assessed the impact of the 2016 WHO criteria on CMML diagnosis, compared with the 2008 WHO criteria, through a retrospective review of the medical records of 38 CMML patients diagnosed according to the 2008 WHO classification. Application of the 2016 WHO criteria resulted in the exclusion of three (8%) patients who did not fulfill the relative monocytosis criterion and eight (21%) patients with an MPN-associated mutation. These 11 patients formed the 2016 WHO others group; the remaining 27 formed the 2016 WHO CMML group. The significant difference in the platelet count and monocyte percentage between the two groups indicated that the 2016 WHO criteria lead to a more homogenous and improved definition of CMML compared with the 2008 WHO criteria, which may have led to over-diagnosis of CMML. More widespread use of molecular tests and more sophisticated clinical and morphological evaluations are necessary to diagnose CMML accurately.

Performance Evaluation of the Preanalytic Module of the ACL TOP 750 Hemostasis Lab System

No abstract available.

Eosinophilic Meningitis after Bovine Graft Duraplasty for Arnold-Chiari Malformation Type 1 in a 33-year-old Man

Cases of pediatric eosinophilic meningitis following duraplasty with a bovine graft have been reported. These patients recovered following the surgical removal of the dural graft or steroid therapy. Decompression for Chiari malformation is a common procedure in both pediatric and adult neurosurgery. We describe the case of a 33-yr-old male patient with eosinophilic meningitis following Chiari decompression via bovine graft duraplasty. Cerebrospinal fluid (CSF) study showed 49 red blood cells/μL and 129 leukocytes/μL with 17% eosinophils. There was no evidence of infectious disease. To our knowledge, this is the first report of adult eosinophilic meningitis after bovine graft duraplasty in Korea.

Multiple Brain Abscesses Caused by Nocardia asiatica in a Patient With Systemic Lupus Erythematosus: The First Case Report and Literature Review

No abstract available.

Analysis of Blood Culture Data at a Tertiary University Hospital, 2006-2015 / 대한임상미생물학회지

BACKGROUND: Cumulative blood culture data provide clinicians with important information in the selection of empiric therapy for blood stream infections. METHODS: We retrospectively analyzed blood culture data from a university hospital during the period from 2006 to 2015. Only the initial isolates of a given species for each patient were included. RESULTS: The number of blood cultures per 1,000 inpatient-days increased from 64 in 2006 to 117 in 2015. The ratio of significant pathogens to total isolates was 0.56-0.63. The most common organisms were Escherichia coli in 2006-2010 but changed to coagulase-negative staphylococci (CoNS) in 2011. The proportion of Staphylococci aureus was decreased during the study period, but Klebsiella pneumoniae was increased. Enterococci were increased, especially E. faecium, which was more frequently isolated than E. faecalis in 2015. Pseudomonas aeruginosa was decreased during the study, but Acinetobacter baumannii was increased. The prevalence of methicillin-resistant S. aureus (MRSA) changed from 62.2% to 53.9%, while vancomycin-resistant E. faecium increased to 35.8%. Extended-spectrum beta-lactamase (ESBL)-producing E. coli and K. pneumoniae increased to 25% and 34%, respectively, in 2015. Starting in 2008, three E. coli and 11 K. pneumoniae isolates were carbapenem-resistant Enterobacteriaceae (CRE), and three were carbapenemase-producing Enterobacteriaceae (CPE). The prevalence of imipenem-resistant A. baumannii rapidly increased during the study period. CONCLUSION: About 60% of all blood isolates were significant pathogens. The most common isolates changed from E. coli to CoNS in 2011. ESBL-producing E. coli and K. pneumoniae, vancomycin-resistant E. faecium, and imipenem-resistant A. baumannii were increased during the study, while the proportion of MRSA tended to decrease slightly. Of the total isolates, 14 were CRE, and 3 were CPE.

Baseline renal function as a prognostic indicator in patients with newly diagnosed diffuse large B-cell lymphoma

BACKGROUND: The association between baseline renal impairment (RI) and the prognosis of diffuse large B-cell lymphoma (DLBCL) was previously not defined. The aim of this study was to evaluate the prognostic value of RI in patients with DLBCL treated with three-weekly rituximab plus cyclophosphamide, Adriamycin, vincristine, and prednisolone immunochemotherapy (R-CHOP21). METHODS: Patients with newly diagnosed de novo DLBCLs treated with ≥1 cycle of R-CHOP21 were analyzed retrospectively. Pretreatment blood samples were collected and the glomerular filtration rate (GFR) was calculated. RI was defined by a GFR of <60 mL/min/1.73 m2 according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. RESULTS: Of the 185 patients enrolled in the present study, 19 patients (10.3%) had RI. The reasons for baseline RI were pre-existing CKD (N=5), acute kidney injury due to either obstruction (N=2) or electrolyte imbalance (N=2) related to DLBCL, and undefined causes (N=10). Patients with baseline RI showed inferior overall survival (OS) compared to those without RI (P<0.001). In multivariate analysis, RI was identified as an International Prognostic Index (IPI)-independent prognostic indicator. A baseline hemoglobin level of <10 g/dL and the presence of RI effectively discriminated a portion of the patients with far inferior event-free survival and OS among the patients having high or high-intermediate risk cancers according to either the standard- or the National Comprehensive Cancer Network-IPI. CONCLUSION: Pretreatment RI was an independent prognostic marker for inferior OS in patients with DLBCL treated with R-CHOP21 immunochemotherapy.

Acute myeloid leukemia with t(4;12)(q12;p13): report of 2 cases

No abstract available.

Eosinophilic granulomatosis with polyangiitis accompanied by rapidly progressive glomerulonephritis

Eosinophilic granulomatosis with polyangitis (EGPA) should be considered in asthmatic patients who present with severe systemic symptoms and eosinophilia. Progressive renal insufficiency can occur during the acute phase of EGPA accompanied by renovascular involvement. A 58-year-old man visited local clinic with complaints of malaise, weight loss, fever, and dyspnea. Eosinophilia was revealed in peripheral blood. Pulmonary function tests were carried out, which yielded decreased lung function with positive bronchodilator response. Kidney and skin biopsies were performed, and histological examination showed acute necrotizing crescentic glomerulonephritis and leukoclastic vasculitis in the skin, which led to a diagnosis of EGPA (Churg-Strauss syndrome) associated with rapidly progressive glomerulonephritis. The patient received pulse steroid therapy with parenteral methylprednisolone, followed by oral prednisolone. Clinical and laboratory findings improved dramatically, and remission was attained rapidly. The patient continued to be in remission for 5 months. Prompt and aggressive treatment with systemic corticosteroids is mandatory to control disease activity and to achieve remission.

Bone Marrow Oxalosis in a Patient With Pancytopenia Following Bilateral Nephrectomy

No abstract available.

The Prognostic Value of Serum Levels of Heart-Type Fatty Acid Binding Protein and High Sensitivity C-Reactive Protein in Patients With Increased Levels of Amino-Terminal Pro-B Type Natriuretic Peptide

BACKGROUND: Amino-terminal pro-B type natriuretic peptide (NT-proBNP) is a well-established prognostic factor in heart failure (HF). However, numerous causes may lead to elevations in NT-proBNP, and thus, an increased NT-proBNP level alone is not sufficient to predict outcome. The aim of this study was to evaluate the utility of two acute response markers, high sensitivity C-reactive protein (hsCRP) and heart-type fatty acid binding protein (H-FABP), in patients with an increased NT-proBNP level. METHODS: The 278 patients were classified into three groups by etiology: 1) acute coronary syndrome (ACS) (n=62), 2) non-ACS cardiac disease (n=156), and 3) infectious disease (n=60). Survival was determined on day 1, 7, 14, 21, 28, 60, 90, 120, and 150 after enrollment. RESULTS: H-FABP (P<0.001), NT-proBNP (P=0.006), hsCRP (P<0.001) levels, and survival (P<0.001) were significantly different in the three disease groups. Patients were divided into three classes by using receiver operating characteristic curves for NT-proBNP, H-FABP, and hsCRP. Patients with elevated NT-proBNP (≥3,856 pg/mL) and H-FABP (≥8.8 ng/mL) levels were associated with higher hazard ratio for mortality (5.15 in NT-proBNP and 3.25 in H-FABP). Area under the receiver operating characteristic curve analysis showed H-FABP was a better predictor of 60-day mortality than NT-proBNP. CONCLUSIONS: The combined measurement of H-FABP with NT-proBNP provides a highly reliable means of short-term mortality prediction for patients hospitalized for ACS, non-ACS cardiac disease, or infectious disease.

Massive Transfusion Protocols for Pediatric Patients

The number of massive transfusions for pediatric patients has risen owing to the increasing number of complex surgeries and trauma centers. However, as there are only a few studies on pediatric massive transfusion, adult massive transfusion protocols are used for pediatric patients in many hospitals and institutions. Although massive transfusion protocols would improve the outcomes and reduce the received blood products during transfusion, pediatric patients differ from adults in the tolerability to transfusion, incidence of coagulopathy, and mechanisms of injuries. Therefore clinical physicians have requested for a pediatric massive transfusion protocol. Herein, we reviewed pediatric massive transfusion protocols that have been used in various clinical settings. To date, only a few single-center studies with a small number of pediatric patients have been performed. Even though these studies did not show improvement in outcomes such as mortality and side effects, they reported a short preparation time for fresh frozen plasma products and a low coagulopathy rate in pediatric massive transfusion groups. Therefore, large, prospective, multicenter studies are needed to identify the empiric ratio of blood products for improving outcomes of pediatric patients who need massive transfusion.

Screening PCR Versus Sanger Sequencing: Detection of CALR Mutations in Patients With Thrombocytosis

BACKGROUND: Mutations in calreticulin (CALR) have been reported to be key markers in the molecular diagnosis of myeloid proliferative neoplasms. In most previous reports, CALR mutations were analyzed by using Sanger sequencing. Here, we report a new, rapid, and convenient system for screening CALR mutations without sequencing. METHODS: Eighty-three bone marrow samples were obtained from 81 patients with thrombocytosis. PCR primers were designed to detect wild-type CALR (product: 357 bp) and CALR with type 1 (product: 302 bp) and type 2 mutations (product: 272 bp) in one reaction. The results were confirmed by Sanger sequencing and compared with results from fragment analysis. RESULTS: The minimum detection limit of the screening PCR was 10 ng for type 1, 1 ng for type 2, and 0.1 ng for cases with both mutations. CALR type 1 and type 2 mutants were detected with screening PCR with a maximal analytical sensitivity of 3.2% and <0.8%, respectively. The screening PCR detected 94.1% (16/17) of mutation cases and showed concordant results with sequencing in the cases of type 1 and type 2 mutations. Sanger sequencing identified one novel mutation (c.1123_1132delinsTGC). Compared with sequencing, the screening PCR showed 94.1% sensitivity, 100.0% specificity, 100.0% positive predictive value, and 98.5% negative predictive value. Compared with fragment analysis, the screening PCR presented 88.9% sensitivity and 100.0% specificity. CONCLUSIONS: This screening PCR is a rapid, sensitive, and cost-effective method for the detection of major CALR mutations.

A Successful Planned Pregnancy and Delivery with Eculizumab Maintenance in a Woman with Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematologic disorder characterized by complement-mediated hemolysis leading to severe complications, such as life threatening thrombosis. Eculizumab, a humanized anti-C5 monoclonal antibody, has dramatically improved outcomes of patients with PNH. Despite this new revolutionary treatment, clinical information regarding eculizumab use in pregnant women with PNH is limited. A 30-year-old female with PNH underwent acute aggravation of PNH presented with acute kidney injury (AKI) triggered by an infectious event. After the stabilization of AKI with supportive care and later continuous eculizumab use, a planned pregnancy was attempted and achieved because she and her spouse wanted to have a baby. We monitored the patient carefully throughout her pregnancy with 100 mg/day of aspirin and the maintenance of 900 mg of intravenous eculizumab every 2 weeks. She remained stable during pregnancy and a successful delivery was achieved without maternofetal complication.

Ahcyl2 upregulates NBCe1-B via multiple serine residues of the PEST domain-mediated association

Inositol-1,4,5-triphosphate [IP3] receptors binding protein released with IP3 (IRBIT) was previously reported as an activator of NBCe1-B. Recent studies have characterized IRBIT homologue S-Adenosylhomocysteine hydrolase-like 2 (AHCYL2). AHCYL2 is highly homologous to IRBIT (88%) and heteromerizes with IRBIT. The two important domains in the N-terminus of AHCYL2 are a PEST domain and a coiled-coil domain which are highly comparable to those in IRBIT. Therefore, in this study, we tried to identify the role of those domains in mouse AHCYL2 (Ahcyl2), and we succeeded in identifying PEST domain of Ahcyl2 as a regulation region for NBCe1-B activity. Site directed mutagenesis and coimmunoprecipitation assay showed that NBCe1-B binds to the N-terminal Ahcyl2-PEST domain, and its binding is determined by the phosphorylation of 4 critical serine residues (Ser151, Ser154, Ser157, and Ser160) in Ahcyl2 PEST domain. Also we revealed that 4 critical serine residues in Ahcyl2 PEST domain are indispensable for the activation of NBCe1-B using measurement of intracellular pH experiment. Thus, these results suggested that the NBCe1-B is interacted with 4 critical serine residues in Ahcyl2 PEST domain, which play an important role in intracellular pH regulation through NBCe1-B.

Unexpected Antibody Screening Tests Including Di(a) in Patients with a History of Multiple Packed Red Cell Transfusion / 대한수혈학회지

BACKGROUND: The Di(a) antigen has been detected with a relatively higher incidence among Koreans with a frequency of 6.4 to 14.5%. In South Korea, commonly used unexpected antibody screening panels do not include Di(a) antigen positive cells. We screened patients who previously received multiple packed red cell transfusion using two cells without Di(a) antigen and three cells including Di(a) antigen to evaluate the effectiveness of three screening cells. METHODS: A total of 307 patients who had received packed red cell transfusion more than three times during the last 6 months in our hospital were enrolled. They were employed for unexpected antibody screening test using two sets of screening cells not including Di(a) antigen and three sets including Di(a) antigen by LISS/Coombs gel card. RESULTS: Among 307 patients, 12 were positive using two cells and 15 were positive using three cells. Three patients showed discordant result and one of them was positive for the cell including Di(a) antigen (0.33%). Antibody identification was performed using the panel which does not include Di(a) antigen and it was negative for all of the antigens listed on the panel so that the presence of anti-Di(a) was suspected. CONCLUSION: It can be difficult to use three cells including Di(a) antigen for all patients due to cost, however, use of three cells is recommended in patients with multiple transfusion history.

A Patient with Common Variable Immunodeficiency Followed by Severe Aplastic Anemia Successfully Treated with Allogenic Stem Cell Transplantation

A twenty-year-old male was diagnosed with common variable immunodecifiency (CVID) according to decreased blood level of immunoglobulins along with a history of recurrent sinopulmonary infection since early childhood, no response to prior vaccination, and the absence of all other defined immunodeficiency. Eleven months after the initiation of intravenous immunoglobulin replacement, he presented with petechiae on both lower legs for three weeks. Bone marrow exam was conducted as pancytopenia was not resolved over a month and severe aplastic anemia was diagnosed. Allogenic stem cell transplantation (Allo-SCT) with reduced intensity conditioning (RIC) enabled both a clinical resolution from propensity to infection with an appropriate production of immunoglobulins and a successful rescue of hematopoiesis. This report suggests that Allo-SCT using RIC is a potentially curable option in patients with CVID complicated by SAA if adequate efforts to minimize Allo-SCT-related complications are accompanied.