Vanishing bile duct syndrome (VBDS) is a rare hepatic disorder which leads to liver failure as a result of progressive destruction of the intrahepatic bile ducts. There are no treatment modalities ...for VBDS itself and severe hepatic dysfunction restricts the treatment of underlying diseases. We safely treated a case of classic Hodgkin lymphoma (HL) with VBDS using brentuximab vedotin (BV). The patient was treated with 5 cycles of reduced BV and a partial metabolic response was obtained. Moreover, a standard dose of BV for another 5 cycles was accomplished with minimal adverse events. Our experience indicates that BV could be a treatment option for classic HL with VBDS.
In paroxysmal nocturnal hemoglobinuria (PNH), various symptoms due to intravascular hemolysis exert a negative impact on patients’ quality of life (QOL). To determine clinical factors related with ...improvements in QOL in PNH patients treated, we analyzed changes in QOL scales in PNH patients treated with eculizumab based on data collected from post-marketing surveillance in Japan. Summary statistics were obtained using figures from QOL scoring systems and laboratory values, and evaluated by
t
test. One-year administration of eculizumab improved the most QOL items in comparison with the baseline. In particular, significant improvement of EORTC QLQ-C30 was observed in fatigue, dyspnea, physical function, and global health status. Canonical correlation analysis revealed a high correlation between QOL and laboratory values. Changes in serum lactate dehydrogenase (LDH) and hemoglobin showed strong correlations with QOL improvement. Quality of life improvement was independent of patients’ baseline characteristics of co-occurrence of bone marrow failure (BMF), or the degree of LDH. In this analysis, we found that the degree of QOL improvement was independent of the baseline LDH before eculizumab treatment and of co-occurrence of BMF. Paroxysmal nocturnal hemoglobinuria patients who have not received eculizumab treatment due to mild hemolysis may benefit from eculizumab treatment.
Central nervous system graft-versus-host disease can present quite a diagnostic challenge. We herein present a case of histologically-confirmed chronic graft versus host disease (GVHD) involving the ...central nervous system that occurred at 19 months after peripheral blood stem cell transplantation. Cranial magnetic resonance imaging showed areas of confluent hyperintensity in the deep/subcortical white matter with multiple punctate and curvilinear gadolinium enhancements, suggesting the disruption of the blood-brain barrier. A brain biopsy revealed perivascular CD3-positive T cell infiltration around the small vessels. We propose that the detection of punctate-enhanced lesions by magnetic resonance imaging may be a useful finding that facilitates the early diagnosis of chronic GVHD involving the central nervous system.
Hypoxia‐inducible factor 1 (HIF‐1) plays essential roles in tumor angiogenesis and growth by regulating the transcription of several key genes in response to hypoxic stress and growth factors. HIF‐1 ...is a heterodimeric transcriptional activator consisting of inducible α and constitutive β subunits. In oxygenated cells, proteins containing the prolyl hydroxylase domain (PHD) directly sense intracellular oxygen concentrations. PHDs tag HIF‐1α subunits for polyubiquitination and proteasomal degradation by prolyl hydroxylation using 2‐oxoglutarate (2‐OX) and dioxygen. Our recent studies showed that 2‐OX reduces HIF‐1α, erythropoietin, and vascular endothelial growth factor (VEGF) expression in the hepatoma cell line Hep3B when under hypoxic conditions in vitro. Here, we report that similar results were obtained in Lewis lung cancer (LLC) cells in in vitro studies. Furthermore, 2‐OX showed potent antitumor effects in a mouse dorsal air sac assay and a murine tumor xenograft model. In the dorsal air sac assay, 2‐OX reduced the numbers of newly formed vessels induced by LLC cells. In a murine tumor xenograft model, intraperitoneal injection of 2‐OX significantly inhibited tumor growth and angiogenesis in tumor tissues. Moreover, 5‐fluorouracil combined with 2‐OX significantly inhibited tumor growth in this model, which was accompanied by reduction of Vegf gene expression and inhibited angiogenesis in tumor tissues. These results suggest that 2‐OX is a promising anti‐angiogenic therapeutic agent. (Cancer Sci 2009; 100: 1639–1647)
Nestin-expressing stromal cells (NESCs) and Schwann cells in the bone marrow (BM) play crucial roles as a niche for normal hematopoietic stem cells in mice. It has been reported that both types of ...cells are decreased in myeloproliferative neoplasms in patients and also in a mouse model, whereas an increase in NESCs was reported in acute myeloid leukemia. It is thus of interest whether and how these BM stromal cells are structured in myelodysplastic syndromes (MDS). Here, we focused on NESCs and glial fibrillary acidic protein (GFAP)-expressing cells in the BM of MDS patients. We found a marked increase of NESCs in MDS with fibrosis (MDS-F) at a high frequency (9/19; 47.4%), but not in MDS without fibrosis (0/26; 0%). Intriguingly, in eight of the nine (88.9%) MDS-F cases with elevated NESCs, a majority of NESCs also expressed GFAP, with an additional increase in GFAP single-positive cells. Furthermore, in seven of them, we found a prominent structure characterized by neurofilament heavy chain staining surrounded by NESCs with GFAP expression. This structure may represent peripheral nerve axons surrounded by Schwann cells, and could be relevant to the pathophysiology of MDS-F.
Background
Hypomethylating agents, including azacytidine (AZA), are standard therapeutics for patients with high‐risk myelodysplastic syndromes (MDS), a group of myeloid neoplasms. However, treatment ...schedules are not unified in real‐world practice; in addition to the standard 7‐day (standard‐dose) schedule, shortened (reduced‐dose) schedules are also used.
Aims
The aim of this study was to discover the patient group(s) which show differential efficacy between standard‐and reduced‐dose AZA to MDS.
Methods and Results
The outcome of different AZA doses in a cohort of 151 MDS patients were retrospectively analyzed. Overall survival (OS) was not significantly different between standard‐ and reduced‐dose AZA groups by multivariate analysis. However, an interaction was found between either the sex (female vs. male), the platelet counts (< 40 × 103/μl vs. ≥ 40 × 103/μl), or the karyotype risk (< poor vs. ≥ poor) and standard‐dose AZA for longer OS. Subgroup analyses revealed better OS with standard‐ over reduced‐dose AZA in female patients (HR, 0.27 95% CI, 0.090‐0.79; p = 0.011), and those with platelet counts ≥ 40 × 103/μl (HR, 0.51 95% CI, 0.26‐0.99; p = 0.041). The union of female and preserved platelet count subgroups also benefited from standard‐dose AZA. With this as a test cohort, we next analyzed patients registered in the JALSG MDS212 study, for whom 7‐day and 5‐day AZA treatment strategies were prospectively compared, as a validation cohort (N = 172). That cohort showed the same tendency as the retrospective results.
Conclusion
We identified the union of female and preserved platelet count subgroups which benefited from standard‐dose AZA, imparting crucial information to physicians planning treatment regimens in MDS patients.
Primary central nervous system lymphoma (PCNSL) is a rare subtype of lymphoma that arises within the brain or the eyes. PCNSL recurs within the central nervous system (CNS) in most relapsed cases, ...whereas extra‐CNS relapse is experienced in rare cases. The present study aimed at identifying the presence of common precursor cells (CPC) for primary intra‐ and relapsed extra‐CNS tumors, and further assessing the initiating events in bone marrow (BM). Targeted deep sequencing was carried out for five paired primary intra‐ and relapsed extra‐CNS tumors of PCNSL. Two to five mutations were shared by each pair of intra‐ and extra‐CNS tumors. In particular, MYD88 mutations, L265P in three and P258L in one, were shared by four pairs. Unique somatic mutations were observed in all five intra‐CNS tumors and in four out of five extra‐CNS tumors. Remarkably, IgH clones in the intra‐ and the extra‐CNS tumors in two pairs were distinct from each other, whereas one pair of tumors shared identical monoclonal IgH rearrangement. In a cohort of 23 PCNSL patients, L265P MYD88 mutations were examined in tumor‐free BM mononuclear cells (MNC) in which the PCNSL tumors had L265P MYD88 mutations. L265P MYD88 mutations were detected by a droplet digital PCR method in nine out of 23 bone marrow mononuclear cells. These results suggest that intra‐ and extra‐tumors are derived from CPC with MYD88 mutations in most PCNSL, arising either before or after IgH rearrangement. The initiating MYD88 mutations may occur during B‐cell differentiation in BM.
It was suggested that primary intra‐central nervous system (CNS) tumors and relapsed extra‐CNS tumors are derived from common precursor cells with MYD88 mutations in most primary CNS lymphomas. The initiating MYD88 mutations may occur during B‐cell differentiation in BM.
Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are subtypes of T-cell lymphoma. Due to low tumor cell content and substantial reactive ...cell infiltration, these lymphomas are sometimes mistaken for other types of lymphomas or even non-neoplastic diseases. In addition, a significant proportion of PTCL-NOS cases reportedly exhibit features of AITL (AITL-like PTCL-NOS). Thus disagreement is common in distinguishing between AITL and PTCL-NOS. Using whole-exome and subsequent targeted sequencing, we recently identified G17V RHOA mutations in 60-70% of AITL and AITL-like PTCL-NOS cases but not in other hematologic cancers, including other T-cell malignancies. Here, we establish a sensitive detection method for the G17V RHOA mutation using a quantitative allele-specific polymerase chain reaction (qAS-PCR) assay. Mutated allele frequencies deduced from this approach were highly correlated with those determined by deep sequencing. This method could serve as a novel diagnostic tool for 60-70% of AITL and AITL-like PTCL-NOS.
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