Erratum to: Seasonal trend and clinical presentation of Bacillus cereus bloodstream infection: association with summer and indwelling catheter.

Bacillus cereus, an opportunistic pathogen, can cause fatal infection. However, B. cereus bloodstream infections (BSIs) have not been well characterised. From 2008 to 2013, B. cereus isolates from all of the specimens and patients with B. cereus BSIs were identified. Environmental samples were collected to detect B. cereus contamination. We also characterised the clinical presentation of B. cereus BSI through analyses of risk factors for BSI and mortality. A total of 143 clinical B. cereus isolates was detected. Fifty-one patients with nosocomial infections were diagnosed as B. cereus BSI, and 37 had contaminated blood cultures. The number of B. cereus isolates and BSI patients was significantly greater from June to September than from January to April (3.4 vs. 1.0 per month and 1.4 vs. 0.2, respectively). All BSIs were nosocomial and related to central or peripheral vascular catheter. Urinary catheter [odds ratio (OR) 6.93, 95 % confidence interval (CI) 2.40-20.0] was the independent risk factor associated with BSI patients when compared to patients regarded as contaminated. In-hospital mortality among BSI patients was 20 % and was associated with urinary catheter (OR 12.3, 95 % CI 0.67-225, p=0.045) and higher Charlson index (OR 1.99, 95 % CI 1.26-3.12). The number of B. cereus isolates and BSI increased during summer. Inpatients with indwelling vascular or urinary catheters should be carefully monitored for potential B. cereus BSIs.

Development and evaluation of MALDI-TOF MS-based serotyping for Streptococcus pneumoniae.

Surveillance of Streptococcus pneumoniae serotypes is important for the successful implementation of vaccination strategies to prevent the spread of invasive pneumococcal diseases. The standard method of serotyping of pneumococcal isolates is the phenotypic Neufeld test, which is cost- and labor-intensive. Recently, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has been implemented as a rapid, simple and inexpensive method for identifying species. We evaluated the performance of MALDI-TOF MS for serotyping ten major serotypes of S. pneumoniae in Japan (serotypes 3, 6B, 15A, 15C, 19A, 19 F, 23A, 24 F, 35B and 38) using the Biotyper and ClinProTools. After optimizing the settings, we validated their serotyping performance for serotypes 3, 15A and 19A using a separate set of isolates that were not used in the creation of the classification algorithms. A total of 574 isolates of S. pneumoniae collected from Japanese nationwide surveillance studies were included. Of these, 407 isolates belonged to the ten major serotypes. Biotyper and ClinProTools correctly identified 77.9 % and 84.0 %, respectively, of the ten major serotype isolates. The validation analysis included a total of 113 isolates of the serotypes 3, 15A and 19A isolates. Biotyper and ClinProTools correctly identified 85.0 % and 69.9 % of the validation cohort isolates, respectively. MALDI-TOF MS has the potential to discriminate the ten major S. pneumoniae serotypes prevalent in Japan.

Quality-of-life outcomes from a randomized phase III trial of dose-dense weekly paclitaxel and carboplatin compared with conventional paclitaxel and carboplatin as a first-line treatment for stage II-IV ovarian cancer: Japanese Gynecologic Oncology Group Trial (JGOG3016).

BACKGROUND: Dose-dense weekly paclitaxel (Taxol) and carboplatin (dd-TC) improved survival compared with conventional tri-weekly paclitaxel and carboplatin (c-TC) as a first-line chemotherapy for newly diagnosed stage II-IV ovarian cancer in the Japanese Gynecologic Oncology Group 3016 trial. We report the quality-of-life (QoL) results from this trial. PATIENTS AND METHODS: A total of 637 patients were randomly assigned to receive c-TC or dd-TC (c-TC, n = 319; dd-TC, n = 312) and were asked to complete a QoL assessment at baseline, just after the third and sixth chemotherapy cycles, and at 12 months after randomization. QoL was assessed using Functional Assessment of Cancer Therapy (FACT)-general (FACT-G), FACT-taxane subscale (FACT-T), and FACT-ovary subscale (FACT-Ov). The overall QoL and that according to each subscale were analyzed using mixed-effects models adjusted for treatment and time. RESULTS: Baseline QoL assessment was completed by 204 out of 319 (63.9%) and 200 out of 312 (64.1%) patients in the c-TC and dd-TC groups, respectively. In these groups, the compliance rates with regard to QoL assessment were 74.5% and 73.0%, respectively, after three chemotherapy cycles; 86.8% and 86.9%, respectively, after six chemotherapy cycles; and 74.2% and 71.6%, respectively, at 12 months after randomization. The overall QoL did not differ significantly between the two treatment groups up to 12 months after randomization (P = 0.46). However, QoL according to the FACT-T subscale was significantly lower in the dd-TC group than in the c-TC group (P = 0.02). CONCLUSION: dd-TC does not decrease overall QoL compared with c-TC.

Seasonal trend and clinical presentation of Bacillus cereus bloodstream infection: association with summer and indwelling catheter.

Bacillus cereus, an opportunistic pathogen, can cause fatal infection. However, B. cereus bloodstream infections (BSIs) have not been well characterised. From 2008 to 2013, B. cereus isolates from all of the specimens and patients with B. cereus BSIs were identified. Environmental samples were collected to detect B. cereus contamination. We also characterised the clinical presentation of B. cereus BSI through analyses of risk factors for BSI and mortality. A total of 217 clinical B. cereus isolates was detected. Fifty-one patients with nosocomial infections were diagnosed as B. cereus BSI, and 37 had contaminated blood cultures. The number of B. cereus isolates and BSI patients was significantly greater from June to September than from January to April (4.9 vs. 1.5 per month and 1.2 vs. 0.2, respectively). All BSIs were nosocomial and related to central or peripheral vascular catheter. Urinary catheter [odds ratio (OR) 6.93, 95% confidence interval (CI) 2.40-20.0] was the independent risk factor associated with BSI patients when compared to patients regarded as contaminated. In-hospital mortality among BSI patients was 20% and was associated with urinary catheter (OR 34.7, 95 % CI 1.89-63.6) and higher Charlson index (OR 1.99, 95 % CI 1.26-3.12). The number of B. cereus isolates and BSI increased during summer. Inpatients with indwelling vascular or urinary catheters should be carefully monitored for potential B. cereus BSIs.

Itraconazole prophylaxis for invasive Aspergillus infection in lung transplantation.

Invasive Aspergillus infection (IA) is a significant cause of morbidity in lung transplantation (LT). However, its optimal prophylaxis is unclear. We routinely administer itraconazole (ITCZ) prophylaxis to all patients undergoing LT. In this study, we retrospectively evaluated the duration of prophylaxis and risk factors of IA. Among 30 adult patients who underwent LT, 5 patients developed IA. All patients with IA stopped ITCZ treatment within 1 year. At least 1 year of ITCZ prophylaxis is essential for the prevention of IA. Cytomegalovirus infection, renal replacement therapy, and tracheotomy were risk factors for IA.

Characterization of a half-wave plate for cosmic microwave background circular polarization measurement with POLARBEAR.

A half-wave plate (HWP) is often used as a modulator to suppress systematic error in the measurements of cosmic microwave background (CMB) polarization. A HWP can also be used to measure circular polarization (CP) through its optical leakage from CP to linear polarization. The CP of the CMB is predicted from various sources, such as interactions in the Universe and extension of the standard model. Interaction with supernova remnants of population III stars is one of the brightest CP sources. Thus, the observation of the CP of CMB is a new tool for searching for population III stars. In this paper, we demonstrate the improved measurement of the leakage coefficient using the transmission measurement of an actual HWP in the laboratory. We measured the transmittance of linearly polarized light through the HWP used in Polarbear in the frequency range of 120-160 GHz. We evaluate the properties of the HWP by fitting the data with a physical model using the Markov Chain Monte Carlo method. We then estimate the band-averaged CP leakage coefficient using the physical model. We find that the leakage coefficient strongly depends on the spectra of CP sources. We thus calculate the maximum fractional leakage coefficient from CP to linear polarization as 0.133 ± 0.009 in the Rayleigh-Jeans spectrum. The nonzero value shows that Polarbear has a sensitivity to CP. Additionally, because we use the bandpass of detectors installed in the telescope to calculate the band-averaged values, we also consider systematic effects in the experiment.

Cefotaxime for the detection of extended-spectrum ß-lactamase or plasmid-mediated AmpC ß-lactamase and clinical characteristics of cefotaxime-non-susceptible Escherichia coli and Klebsiella pneumoniae bacteraemia.

We investigated the performance of cefotaxime for the detection of extended-spectrum ß-lactamase (ESBL) or plasmid-mediated AmpC ß-lactamase (pAmpC) and the clinical characteristics of cefotaxime-non-susceptible Escherichia coli or Klebsiella pneumoniae (CTXNS-EK) bacteraemia. All of the consecutive bloodstream isolates between 2005 and 2010 in a Japanese university hospital were characterised using polymerase chain reaction (PCR). Risk factors and outcomes of CTXNS-EK were analysed by multivariate logistic regression analysis. We identified 58 CTXNS-EK (15.6%) from 249 E. coli and 122 K. pneumoniae. Cefotaxime with a minimum inhibitory concentration (MIC) of >1 µg/mL had a sensitivity of 98.3% and a specificity of 99.7% for the detection of ESBL or pAmpC. CTXNS-EK had increased from 4.5% in 2005 to 23% in 2009. Risk factors for CTXNS-EK were previous isolation of multidrug-resistant bacteria, use of oxyimino-cephalosporins or fluoroquinolones, and high Sequential Organ Failure Assessment (SOFA) score. Patients with CTXNS-EK bacteraemia less frequently received appropriate empirical therapy than patients with cefotaxime-susceptible EK bacteraemia (81% vs. 97%, p<0.001) and died within 30 days (21% vs. 5%, p=0.001). Using the current breakpoints of the Clinical and Laboratory Standards Institute (CLSI) or the European Committee on Antimicrobial Susceptibility Testing (EUCAST), cefotaxime alone can identify ESBL or pAmpC producers. CTXNS-EK is an important and increasingly prevalent bacteraemia pathogen.

Regional spread and control of vancomycin-resistant Enterococcus faecium and Enterococcus faecalis in Kyoto, Japan.

The purpose of this investigation was to control the post-outbreak prevalence of vancomycin-resistant enterococci (VRE) in the affected Kyoto region. The study period was from 2005 to 2010. Faecal samples were subjected to VRE screening, and vancomycin resistance genes were detected by polymerase chain reaction (PCR). The genotype was determined by pulsed-field gel electrophoresis (PFGE) of genomic DNA digested with SmaI and by multilocus sequence typing (MLST). A VRE control programme was established in 2006, consisting of a laboratory-based faecal VRE screening system, annual surveillance of hospital inpatients and the promotion of adequate infection control measures. vanA-Enterococcus faecium, vanB-E. faecium and vanB-E. faecalis were detected at 35, 12 and 5 hospitals, respectively. Genotype analysis revealed that all of the vancomycin-resistant E. faecium isolates obtained since 2005 belonged to ST78, and that clonally related vanB-E. faecalis of ST64 had spread to three hospitals. The rate of faecal VRE carriage among the patients enrolled in the annual surveillance increased until 2007, when it reached 24 (1.2%) of the 2,035 enrolled patients. The rate began to decrease in 2008 and, by 2010, reached a low of 4 (0.17%) of the 2,408 enrolled patients. While VRE did spread within the Kyoto region, the VRE control programme succeeded in controlling the overall VRE spread.

The outcome of Japanese anorexia nervosa patients treated with an inpatient therapy in an internal medicine unit.

OBJECTIVE: To investigate the outcome of Japanese anorexia nervosa (AN) patients who were treated with the standard Japanese inpatient therapy. METHOD: Of the 88 female AN patients treated with our inpatient therapy between January 1997 and December 2002, 67 (76.1%) who agreed to cooperate in this study were assessed by the Global Clinical Score (GCS) at admission and follow-up, 6.3±1.8 years after discharge. Their clinical characteristics at admission and discharge were also examined. RESULTS: Four (6.0%) patients had died before follow-up. BMI was significantly increased during inpatient therapy. At follow-up, excellent, much improved, symptomatic, and poor outcomes on GCS were 57.1%, 14.3%, 14.3% and 14.3%, respectively. Younger age at admission and larger BMI at discharge were significantly associated with a better outcome. DISCUSSION: This study shows the potential for the use of this method for the treatment of AN patients in countries without specialized eating disorder units.

Regional spread of vanA- or vanB-positive Enterococcus gallinarum in hospitals and long-term care facilities in Kyoto prefecture, Japan.

Following an outbreak of vanA-positive Enterococcus faecium in 2005 in Kyoto prefecture, regional surveillance of vancomycin-resistant enterococci (VRE) was initiated. This revealed vanA- or vanB-positive Enterococcus gallinarum in multiple facilities. Eighty-eight vanA-positive E. gallinarum faecal carriers from 12 facilities and ten vanB-positive E. gallinarum faecal carriers from eight facilities were found. Pulsed-field gel electrophoresis profiles of the first isolate from each facility showed that 11 of the 12 vanA isolates and three of the eight vanB-positive E. gallinarum isolates belonged to a single clone. This study confirms the clonal spread of vanA- or vanB-positive E. gallinarum in a region and underlines the importance of surveillance of VRE for the presence of vancomycin resistance determinants.

Predictors of menstrual resumption by patients with anorexia nervosa.

OBJECTIVE: To investigate which factors predict the resumption of menstruation by patients with anorexia nervosa (AN). METHODS: Participants were AN patients who, even after weight recovery by inpatient treatment, had prolonged amenorrhea (N=11), AN patients who resumed menstruation after weight recovery (N=9), and age-matched healthy controls (N=12). Anthropometric data and the serum levels of leptin, insulin-like growth factor I (IGF-1), cortisol, luteinizing hormone (LH), estradiol (E2), and other hormones were measured at the beginning of the inpatient treatment and after weight recovery. RESULTS: Of the baseline anthropometric and hormonal factors, logistic regression analysis extracted a high serum cortisol level as a predictor of the inhibition of the resumption of menstruation. After weight recovery, the E2 and leptin levels were significantly higher for eumenorrheic patients than for amenorrheic patients. CONCLUSION: The baseline serum cortisol level was a predictor of the prolonged inhibition of menstrual recovery.

Identifying pathogenic genetic background of simplex or multiplex retinitis pigmentosa patients: a large scale mutation screening study.

BACKGROUND AND PURPOSE: More than half of the retinitis pigmentosa (RP) cases are genetically simplex or multiplex. To date, 37 causative genes of RP have been identified; however, the elucidation of gene defects in simplex or multiplex RP patients/families remains problematic. The aim of our study was to identify the genetic causes of RP in patients with unknown or non-Mendelian inheritance. METHODS AND RESULTS: Since 2003, 52 simplex RP patients, 151 patients from 141 multiplex RP families, and six sporadic patients with retinal degeneration were studied. A total of 108 exons of 30 RP-causing genes that harboured the reported mutations were screened by an efficient denaturing high performance liquid chromatography (dHPLC) based assay. Aberrant fragments were subsequently analysed by automatic sequencing. Twenty-six mutations, including two frameshift mutations, one single amino acid deletion, and 23 missense mutations, were identified in 28 probands (14.07%). Eighteen mutations have not been reported to date. Three pairs of combined mutations in different genes were identified in two sporadic cases and one multiplex family, indicating the possibility of novel digenic patterns. Of the 23 missense mutations, 21 were predicted as deleterious mutations by computational methods using PolyPhen, SIFT, PANTHER, and PMut programs. CONCLUSION: We elucidated the mutation spectrum in Japanese RP patients and demonstrated the validity of the mutation detection system using dHPLC sequencing for genetic diagnosis in RP patients independent of familial incidence, which may provide a model strategy for identifying genetic causes in other diseases linked to a wide range of genes.

Characterization of a 2,4-dinitrochlorobenzene-induced chronic dermatitis model in rats.

Although many mouse models of atopic dermatitis have been reported, few rat models have been studied. In this study, a rat chronic allergic dermatitis model was developed and evaluated as a pharmacological model of atopic dermatitis. Prominent ear thickening and scratching were induced after the application of 2,4-dinitrochlorobenzene to the right ear of Brown Norway rats 3 times per week for 3 weeks. Histopathologically, infiltration of T cells in the ear was observed on day 7, and eosinophils and mast cells were found in addition to T cells on day 21. The expression of interferon-gamma and interleukin-4 was increased on day 7 when compared with normal rats. However, interferon-gamma expression had disappeared by day 21. Tacrolimus ointment applied after ear tissue thickening fully developed, suppressed chronic dermatitis in a dose-dependent manner. This model has some symptomatic and histopathological similarities to atopic dermatitis and might be useful in pharmacological studies.

Factors related to renal dysfunction in patients with anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) patients were surveyed to determine which disease factors were related to AN influenced renal dysfunction. METHODS: Data were from forty-five AN patients hospitalized in our department between 1995 and 2002. The patients were classified into three groups based on the type of anorexia: restricting (n=18), self-induced vomiting (n=13), and laxative abuse (n=14). Twenty-four hour-creatinine clearance (Ccr) was calculated within two weeks of hospitalization for comparison among the three groups. RESULTS: The Ccr level of the laxative abuse group was significantly lower than that of the restricting group (65.8+/-31.4 ml/min vs restricting type: 104+/-23.3 ml/min, p=0.002). The laxative abuse group had a significantly longer duration of illness than the restricting group (p<0.0001). Multiple regression analysis revealed the duration of illness to be a risk factor for renal function deterioration in AN patients (r=0.580, p<0.001). DISCUSSION: Renal function should be carefully followed during the treatment of AN patients with a long duration of illness, especially those with long-term laxative abuse.

Psychopathological features of patients with prolonged anorexia nervosa as assessed by the Minnesota Multiphasic Personality Inventory.

OBJECTIVE: The duration of illness is quite long in some anorexia nervosa (AN) patients. In the present study, we investigated the psychopathological features of patients with prolonged AN as assessed by the Minnesota Multiphasic Personality Inventory-1 (MMPI-1). METHODS: Fifty-five AN patients completed the MMPI-1 on admission to Kyushu University Hospital from 1999 to 2002. The patients were divided into three groups on the basis of their illness duration: a short-term group, less than 5 years of illness duration (n=31); a middle-term group, from 5 to 10 years (n=14); and a prolonged group, 10 years or more (n=10). RESULTS: The prolonged group scored significantly higher on the MPPI-1 scales of hysteria (Hy), low back pain (Lb) and family conflict than the short-term group. DISCUSSION: AN patients whose illness duration was prolonged characteristically had more hysteria with family conflict. This should be considered in their treatment.

Alterations of the PPP1R3 gene in human cancer.

Recently, the PTEN/MMAC1 gene encoding a protein phosphatase (PP) and the PPP2R1B gene encoding a regulatory subunit of PP2A have been identified as being genetically altered in several types of human cancers, indicating that aberrations of intracellular signaling pathways via PPs are involved in human carcinogenesis. Here we report genetic alterations of the PPP1R3 gene located at chromosome 7q31, which encodes regulatory subunit 3 of PP1, in various types of human cancers. Mutations of the PPP1R3 gene were detected in 5 of 33 (15%) non-small cell lung cancer cell lines and 2 of 38 (5%) primary non-small cell lung cancers and were also observed in cell lines derived from a small cell lung cancer, an ovarian cancer, a colorectal cancer, and a gastric cancer. Mutations were widely dispersed in the coding region of the PPP1R3 gene. Three of the 11 detected mutations were nonsense mutations, whereas the remaining ones were missense mutations, most of which caused substitutions of evolutionarily conserved amino acids. These findings suggest that PPP1R3 alteration plays a role in the development of human cancers and that PPP1R3 could act as a tumor suppressor gene.

Somatic mutations and genetic polymorphisms of the PPP1R3 gene in patients with several types of cancers.

Recently, we found nonsense and missense mutations of the PPP1R3 (protein phosphatase 1, regulatory subunit 3) gene in diverse human cancer cell lines and primary lung carcinomas, indicating that PPP1R3 functions as a tumor suppressor in human carcinogenesis. In this study, to assess the prevalence of PPP1R3 mutations in human primary cancers and the genetic diversity of the PPP1R3 gene in the human population, somatic mutations and genetic polymorphisms in the PPP1R3 gene were examined in 137 pairs of cancerous and non-cancerous tissues of patients with cancers of colon, ovary, and liver. Five somatic mutations including two missense mutations were detected in three cancerous tissues consisting of two colorectal carcinomas and one ovarian carcinoma. Five novel single nucleotide polymorphisms (SNPs) associated with the substitution of amino acids were also identified in cancer patients, in addition to five known nonsynonymous SNPs, including three previously reported ones as having an impact on the susceptibility to insulin resistant disorders. Differences in the activities and properties of multiple PPP1R3 proteins, which are produced in human cells due to variable somatic mutations and genetic polymorphisms in the PPP1R3 gene, can be involved in human carcinogenesis and susceptibility to diseases.

Mutation and expression of the DCC gene in human lung cancer.

Chromosome 18q is frequently deleted in lung cancers, and a common region of 18q deletions was mapped to chromosome 18q21. Since the DCC candidate tumor suppressor gene has been mapped in this region, mutation and expression of the DCC gene were examined in 46 lung cancer cell lines, consisting of 14 small cell lung carcinomas (SCLCs) and 32 non-small cell lung carcinomas (NSCLCs), to elucidate the pathogenetic significance of DCC alterations in human lung carcinogenesis. A heterozygous missense mutation was detected in a NSCLC cell line, Ma26, while homozygous deletion was not detected in any of the cell lines. The DCC gene was expressed in 11 (24%) of the 46 cell lines, and the incidence of DCC expression was significantly higher in SCLCs (7/14, 50%) than in NSCLCs (4/32, 13%) (P = .01, Fisher's exact test). Therefore, genetic alterations of DCC are infrequent; however, the levels of DCC expression vary among lung cancer cells, in particular, between SCLCs and NSCLCs. The present result does not implicate DCC as a specific mutational target of 18q deletions in human lung cancer; however, it suggests that DCC is a potential target of inactivation by genetic defects including intron or promoter mutations and/or epigenetic alterations. The present result also suggests that DCC expression is associated with some properties of SCLCs, such as a neuroendocrine (NE) feature.

Frequent microsatellite instability and BAX mutations in T cell acute lymphoblastic leukemia cell lines.

Allelic status of the BAT26 and BAT25 loci was examined in 117 leukemia/lymphoma cell lines consisting of 44 B-lymphoid lineage cell lines, 30 T-lymphoid cell lines and 43 myeloid cell lines to define the lineage specificity of microsatellite instability (MSI) in hematological malignancies. Seventeen (15%) cell lines were defined as having MSI. The incidence of MSI was significantly (P < 0.01) higher in cell lines of lymphoid lineage (15/74; 20%) than in those of myeloid lineage (2/43; 5%). In the cell lines of lymphoid lineage, the incidence of MSI in T cell acute lymphoblastic leukemia (T-ALL) (11/30; 37%) was significantly (P < 0.01) higher than those in B-lineage malignancies (4/44; 9%). The 17 cell lines with MSI were subjected to the mutation analysis of the coding microsatellites in 13 candidate genes. Frameshift mutations were most frequently detected in the BAX gene (14/17, 82%), while the hMSH3, hMSH6, TGFbetaRII, DRP and IGFIIR genes were less frequently mutated (24-47%). The present result indicates that MSI is involved in the development and/or progression of lymphoid malignancies, especially of T-ALL, through the inactivation of BAX and several other genes.

Alterations of the PPP1R3 gene in hematological malignancies.

PPP1R3 (protein phosphatase 1, regulatory subunit 3) is a candidate tumor suppressor gene at chromosome 7q31, since nonsense and missense mutations of the PPP1R3 gene have been detected in a variety of human cancers. Loss of chromosome 7q is a recurrent abnormality in hematological malignancies, especially of myeloid lineage, and a common region of 7q deletions has been mapped to 7q31. Thus, it has been suggested that 7q31 harbors a tumor suppressor gene whose functional loss contributes to leukemogenesis. To evaluate the possible involvement of the PPP1R3 gene in the development of hematological malignancies, we examined 72 leukemia and lymphoma cell lines for alterations of the PPP1R3 gene by PCR-SSCP and direct sequence analyses. Mutations were detected in 1 (2.8%) of 36 myeloid cell lines, 4 (20.0%) of 20 B-lineage lymphoid cell lines and none of 16 T-lineage lymphoid cell lines. All the mutations were heterozygous, and they consisted of two missense mutations and three silent mutations. The PPP1R3 gene was expressed in cell lines of various cell lineages. These results indicate that PPP1R3 is not a major target of 7q deletions in myeloid leukemia, however, alterations of the PPP1R3 gene may contribute to the development of a subset of hematological malignancies.