Evaluating women’s labour in 1990s Japan: The changing labour standards Law

This article outlines the legislative changes regarding Japanese working women in the 1990s, specifically the changes to the Labour Standards Law. Th is Law was altered in 1997 (effective 1999) by the removal of a number of provisions known as the Women’s ‘Protection’ Provisions (josei hogo kitei). These gender-specifi c provisions restricted Japanese women from working particular jobs and hours, and limited overtime and holiday work. The role of these gender-specifi c provisions is examined through a collection of articles from four of Japan’s mainstream daily, widely-circulated newspapers: the Asahi Shinbun, the Mainichi Shinbun, the Nihon Keizai Shinbun, and the Yomiuri Shinbun. These newspapers were of the opinion that the provisions were simultaneously protective and restrictive towards women. The newspapers all supported the removal of the provisions in order to increase equality in Japan’s workforce and society. However, all presented strong concerns that Japanese society was unable to support these changes. This article situates the law reform within the wider context of 1990s Japan, by tracing the links between labour legislation and socio-cultural issues in Japan, particularly the low fertility rate. This article closes with an evaluation of changes within Japanese society and working habits since the removal of the provisions

Synthetic and structural investigations of some lithium thiolates and thiocarboxylates

A series of closely related lithium aryl thiolates with pyridine as a donor ligand have been prepared. X-ray structure determination (Dr. W. Clegg) has shown that [PKSLi.(NC(_5)H(_5))] crystallises as an infinite chain polymer. Insertion of a methylene group between the phenyl ring and sulphur as in (PhCH(_2)SLi .NC(_5)H(_5). ] (_oo) produced an infinitely folded ladder polymer with Li-S rungs, while introduction of an 0-methyl group produces the monomeric complex [o-MeC(_6)H(_4)SLi .(NC(_5)H(_5))(_3)].The unusual symmetrical complex [Li(_14) (SCH(_2)Ph)(_12) S(TMEDA.)(_6)] has been prepared, in which a central sulphur atom is surrounded by a distorted cube of lithium atoms, each edge of which is bridged by a benzyl thiolate group such that the twelve S atoms form a cubo- octahedron: a further six Li atoms form a larger outer octahedron. When TMEDA is present in excess it appears that both PhSLi and PhCH(_2)SLi form dimeric compounds with a central Li(_2)S(_2) ring but structure determination of these complexes is incomplete.[PhOOSLi.TMEDA](_2)has been prepared and crystallises as a centrosymmetric dimer containing a chair shaped central eight membered (OOSLi)(_2) ring with the Li atoms out of the (COS)(-2), molecular plane. Lithiation of the related acids PhOOOH and PhCSSH has been carried out in the presence of TMEDA but crystal growth has so far been unsuccessful. Ab initio m.o. calculations on related model compounds are included. A preliminary study has been carried out on the lithiation of the thio-oxime (Ph(_2) C-NSH). Results were encouraging but detailed investigation is needed. The reaction of S(_4) N(_4) with BI(_3) produces, not the expected adduct, S(_4)N(_4) .BI(_3) , but an intractable polymer, empirical formula, S(_3)N(_3)BI. Other adducts of S(_4).N(_4) and (PhCN_2) S(_2))(_2), were prepared but were unsuitable for further reactions. The reaction of lithium borohydride and sulphur in THF to produce sulphurated lithium borohydride has been modified to give a controllable reaction. Further reaction with TMEDA gives clear orange crystals of a complex the composition of which is still unknown

Monoclonal B-cell lymphocytosis in a hospital-based UK population and a rural Ugandan population : a cross-sectional study

BACKGROUND: Reported incidence of B-cell malignancies shows substantial geographical variation, being more common in the Americas and Europe than in Africa. This variation might reflect differences in diagnostic capability, inherited susceptibility, and infectious exposures. Monoclonal B-cell lymphocytosis (MBL) is a precursor lesion that can be screened for in apparently healthy people, allowing comparison of prevalence across different populations independently of health-care provision. We aimed to compare the prevalence and phenotypic characteristics of MBL in age-and-sex-matched populations from rural Uganda and the UK. METHODS: In this cross-sectional study, we recruited volunteers aged at least 45 years who were seronegative for HIV-1 from the established Ugandan General Population Cohort and obtained their whole-blood samples. We also obtained blood samples from anonymised waste material of age-and-sex-matched individuals (aged >45 years, with a normal blood count and no history of cancer) in the UK. We used flow cytometry to determine the presence of MBL, defined according to standard diagnostic criteria, in the samples and compared differences in the proportion of cases with chronic lymphocytic leukaemia (CLL)-phenotype MBL and CD5-negative MBL, as well as differences in absolute monoclonal B-cell count between the two cohorts. FINDINGS: Between Jan 15 and Dec 18, 2012, we obtained samples from 302 Ugandan volunteers and 302 UK individuals who were matched by age and sex to the Ugandan population. Overall MBL prevalence was higher in the Ugandan participants (42 [14%] individuals) than in the UK cohort (25 [8%]; p=0·038). CLL-phenotype MBL was detected in three (1%) Ugandan participants and 21 (7%) UK participants (p=0·00021); all three Ugandan participants had absolute monoclonal B-cell count below one cell per μL, whereas the 21 UK participants had a median absolute number of circulating neoplastic cells of 4·6 (IQR 2-12) cells per μL. The prevalence of CD5-negative MBL was higher in the Ugandan cohort (41 [14%], of whom two [5%] also had CLL-phenotype MBL) than in the UK cohort (six [2%], of whom two [33%] also had CLL-phenotype MBL; p<0·0001), but the median absolute B-cell count was similar (227 [IQR 152-345] cells per μL in the Ugandan cohort vs 135 [105-177] cells per μL in the UK cohort; p=0·13). INTERPRETATION: MBL is common in both Uganda and the UK, but the substantial phenotypic differences might reflect fundamental differences in the pathogenesis of B-cell lymphoproliferative disorders. FUNDING: UK Medical Research Council and UK Department for International Development

Minimal residual disease is an independent predictor for 10-year survival in CLL

Minimal residual disease (MRD) negativity, defined as <1 chronic lymphocytic leukemia (CLL) cell detectable per 10 000 leukocytes, has been shown to independently predict for clinical outcome in patients receiving combination chemoimmunotherapy in the frontline setting. However, the long-term prognostic value of MRD status in other therapeutic settings remains unclear. Here, we retrospectively analyzed, with up to 18 years follow-up, all patients at our institution who achieved at least a partial response (PR) with various therapies between 1996 and 2007, and received a bone marrow MRD assessment at the end of treatment according to the international harmonized approach. MRD negativity correlated with both progression-free survival (PFS) and overall survival (OS) independent of the type and line of treatment, as well as known prognostic factors including adverse cytogenetics. The greatest impact of achieving MRD negativity was seen in patients receiving frontline treatment, with 10-year PFS of 65% vs 10% and 10-year OS of 70% vs 30% for MRD-negative vs MRD-positive patients, respectively. Our results demonstrate the long-term benefit of achieving MRD negativity, regardless of the therapeutic setting and treatment modality, and support its use as a prognostic marker for long-term PFS and as a potential therapeutic goal in CLL

Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders

This is an open access paper.-- et al.The European Myeloma Network (EMN) organized two flow cytometry workshops. The first aimed to identify specific indications for flow cytometry in patients with monoclonal gammopathies, and consensus technical approaches through a questionnaire-based review of current practice in participating laboratories. The second aimed to resolve outstanding technical issues and develop a consensus approach to analysis of plasma cells. The primary clinical applications identified were: differential diagnosis of neoplastic plasma cell disorders from reactive plasmacytosis; identifying risk of progression in patients with MGUS and detecting minimal residual disease. A range of technical recommendations were identified, including: 1) CD38, CD138 and CD45 should all be included in at least one tube for plasma cell identification and enumeration. The primary gate should be based on CD38 vs. CD138 expression; 2) after treatment, clonality assessment is only likely to be informative when combined with immunophenotype to detect abnormal cells. Flow cytometry is suitable for demonstrating a stringent complete remission; 3) for detection of abnormal plasma cells, a minimal panel should include CD19 and CD56. A preferred panel would also include CD20, CD117, CD28 and CD27; 4) discrepancies between the percentage of plasma cells detected by flow cytometry and morphology are primarily related to sample quality and it is, therefore, important to determine that marrow elements are present in follow-up samples, particularly normal plasma cells in MRD negative cases.The meetings were sponsored by the European Myeloma.Peer Reviewe

Telomere length predicts for outcome to FCR chemotherapy in CLL

We have previously shown that dividing patients with CLL into those with telomeres inside the fusogenic range (TL-IFR) and outside the fusogenic range (TL-OFR) is powerful prognostic tool. Here, we used a high-throughput version of the assay (HT-STELA) to establish whether telomere length could predict for outcome to fludarabine, cyclophosphamide, rituximab (FCR)-based treatment using samples collected from two concurrent phase II studies, ARCTIC and ADMIRE (n = 260). In univariate analysis, patients with TL-IFR had reduced progression-free survival (PFS) (P < 0.0001; HR = 2.17) and shorter overall survival (OS) (P = 0.0002; HR = 2.44). Bifurcation of the IGHV-mutated and unmutated subsets according to telomere length revealed that patients with TL-IFR in each subset had shorter PFS (HR = 4.35 and HR = 1.48, respectively) and shorter OS (HR = 3.81 and HR = 2.18, respectively). In addition, the OS of the TL-OFR and TL-IFR subsets were not significantly altered by IGHV mutation status (P = 0.61; HR = 1.24 and P = 0.41; HR = 1.47, respectively). In multivariate modeling, telomere length was the dominant co-variable for PFS (P = 0.0002; HR = 1.85) and OS (P = 0.05; HR = 1.61). Taken together, our data suggest that HT-STELA is a powerful predictor of outcome to FCR-based treatment and could be used to inform the design of future risk-adapted clinical trials

Immunophenotypic studies of monoclonal gammopathy of undetermined significance

<p>Abstract</p> <p>Background</p> <p>Monoclonal gammopathy of undetermined significance (MGUS) is a common plasma cell dyscrasia, comprising the most indolent form of monoclonal gammopathy. However, approximately 25% of MGUS cases ultimately progress to plasma cell myeloma (PCM) or related diseases. It is difficult to predict which subset of patients will transform. In this study, we examined the immunophenotypic differences of plasma cells in MGUS and PCM.</p> <p>Methods</p> <p>Bone marrow specimens from 32 MGUS patients and 32 PCM patients were analyzed by 4-color flow cytometry, using cluster analysis of ungated data, for the expression of several markers, including CD10, CD19, CD20, CD38, CD45, CD56 and surface and intracellular immunoglobulin light chains.</p> <p>Results</p> <p>All MGUS patients had two subpopulations of plasma cells, one with a "normal" phenotype [CD19(+), CD56(-), CD38(bright +)] and one with an aberrant phenotype [either CD19(-)/CD56(+) or CD19(-)/CD56(-)]. The normal subpopulation ranged from 4.4 to 86% (mean 27%) of total plasma cells. Only 20 of 32 PCM cases showed an identifiable normal subpopulation at significantly lower frequency [range 0–32%, mean 3.3%, p << 0.001]. The plasma cells in PCM were significantly less likely to express CD19 [1/32 (3.1%) vs. 13/29 (45%), p << 0.001] and more likely to express surface immunoglobulin [21/32 (66%) vs. 3/28 (11%), p << 0.001], compared to MGUS. Those expressing CD19 did so at a significantly lower level than in MGUS, with no overlap in mean fluorescence intensities [174 ± 25 vs. 430 ± 34, p << 0.001]. There were no significant differences in CD56 expression [23/32 (72%) vs. 18/29 (62%), p = 0.29], CD45 expression [15/32 (47%) vs. 20/30 (67%), p = 0.10] or CD38 mean fluorescence intensities [6552 ± 451 vs. 6365 ± 420, p = 0.38]. Two of the six MGUS cases (33%) with >90% CD19(-) plasma cells showed progression of disease, whereas none of the cases with >10% CD19(+) plasma cells evolved to PCM.</p> <p>Conclusion</p> <p>MGUS cases with potential for disease progression appeared to lack CD19 expression on >90% of their plasma cells, displaying an immunophenotypic profile similar to PCM plasma cells. A higher relative proportion of CD19(+) plasma cells in MGUS may be associated with a lower potential for disease progression.</p

Eradication of minimal residual disease improves overall and progression free survival in patients with chronic lymphocytic leukaemia, evidence from NCRN CLL207: A Phase II trial assessing alemtuzumab consolidation.

With immunochemotherapy, remission duration and survival in patients with CLL is dependent on the level of minimal residual disease after treatment. This phase II trial assessed alemtuzumab consolidation post-chemotherapy in patients who responded with persistent low levels of detectable disease. Blood was screened for MRD using multi-parameter flow cytometry, 6 to 24 months post-chemotherapy. MRD-positive participants received alemtuzumab 30mg subcutaneously 3 times weekly for 6 weeks. Following a marrow assessment, MRD-negative participants or non-responders stopped therapy and MRD-positive participants with 1+ log reduction had 6 more weeks of alemtuzumab. Alemtuzumab consolidation was received by 47 participants. One death and 19 of 22 serious adverse events reported from 17 (36%) participants were alemtuzumab related. MRD eradication from blood and bone marrow was achieved in 39 (83%) participants at the end of consolidation, with 18 (38%) remaining MRD-negative in the blood 6 months later. Of the 18 MRD-negative participants at 6 months, the median time to MRD relapse was 46 months which was similar to patients who were MRD-negative at baseline and were followed up. The 5-year PFS and OS of MRD-negative participants at 6 months was significantly better than MRD-positive participants (PFS: 78%vs39% (p=0.010), OS: 89%vs64% (p=0.029))

Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL

ADMIRE was a multi-center, randomized-controlled, open, phase IIB superiority trial in previously untreated Chronic Lymphocytic Leukemia (CLL). Conventional frontline therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). Initial evidence from non-randomized Phase II trials suggested that the addition of mitoxantrone to FCR (FCM-R) improved remission rates. 215 patients were recruited to assess the primary endpoint of complete remission (CR) rates according to IWCLL criteria. Secondary endpoints were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity and safety. At final analysis, CR rates were 69.8% FCR vs 69.3% FCM-R [adjusted odds ratio (OR): 0.97; 95%CI: (0.53-1.79), P=0.932]. MRD-negativity rates were 59.3% FCR vs 50.5% FCM-R [adjusted OR: 0.70; 95% CI: (0.39-1.26), P=0.231]. During treatment, 60.0% (n=129) of participants received G-CSF as secondary prophylaxis for neutropenia, a lower proportion on FCR compared with FCM-R (56.1 vs 63.9%). The toxicity of both regimens was acceptable. There are no significant differences between the treatment groups for PFS and OS. The trial demonstrated that the addition of mitoxantrone to FCR did not increase the depth of response. Oral FCR was well tolerated and resulted in impressive responses in terms of CR rates and MRD negativity compared to historical series with intravenous chemotherapy

Results of the randomized phase IIB ARCTIC trial of low dose Rituximab in previously untreated CLL

ARCTIC was a multi-center, randomized-controlled, open, phase IIB non-inferiority trial in previously untreated Chronic Lymphocytic Leukemia (CLL). Conventional frontline therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). The trial hypothesized that including mitoxantrone with low-dose rituximab (FCM-miniR) would be non-inferior to FCR. 200 patients were recruited to assess the primary endpoint of complete remission (CR) rates according to IWCLL criteria. Secondary endpoints were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity, safety and cost-effectiveness. The trial closed following the pre-planned interim analysis. At final analysis, CR rates were 76% FCR vs 55% FCM-miniR [adjusted odds-ratio: 0.37; 95% CI: 0.19–0.73]. MRD-negativity rates were 54% FCR vs 44% FCM-miniR. More participants experienced Serious Adverse Reactions with FCM-miniR (49%) compared to FCR (41%). There are no significant differences between the treatment groups for PFS and OS. FCM-miniR is not expected to be cost-effective over a lifetime horizon. In summary, FCM-miniR is less well tolerated than FCR with an inferior response and MRD-negativity rate and increased toxicity, and will not be taken forward into a confirmatory trial. The trial demonstrated that oral FCR yields high response rates compared to historical series with intravenous chemotherapy