Nilotinib-induced hypothyroidism in a patient with chronic myeloid leukemia

Peripheral edema often occurs in patients with chronic myeloid leukemia (CML) treated with kinase inhibitors (TKIs). However, there are few reports indicating that the edema is caused by TKIs-induced hypothyroidism. We present the case of a 76-year-old man with chronic-phase CML who suffered from severe systemic edema after introduction of nilotinib. Laboratory tests revealed hypothyroidism; the patient was euthyroid prior to introduction of nilotinib. After further examination, we attributed this hypothyroidism to nilotinib. His edema regressed dramatically after thyroid hormone replacement therapy, with continued treatment with nilotinib. Laboratory examination of thyroid function also improved markedly. Although sunitinib, a multi-targeted TKI, is associated with a high incidence of hypothyroidism, TKIs targeting Bcr-Abl have rarely been reported to cause hypothyroidism. We report nilotinib-induced hypothyroidism, and suggest that hypothyroidism should be considered as a possible etiology when patients receivingTKIs suffer from edema.     

Lymphoma depletion during CD20 immunotherapy in mice is mediated by macrophage FcgammaRI, FcgammaRIII, and FcgammaRIV

Despite the demonstrated clinical efficacy of CD20 monoclonal antibody (mAb) for lymphoma therapy, the in vivo mechanisms of tumor depletion remain controversial and variable. To identify the molecular mechanisms responsible for lymphoma killing by CD20 mAb in a homologous system amenable to mechanistic studies and genetic manipulation, a mouse lymphoma model was developed using primary tumor cells from a C57BL/6 Emicro-cMyc transgenic mouse and mouse antimouse CD20 mAbs. CD20 mAb treatment of syngeneic mice with adoptively transferred lymphomas prevented tumor development or significantly prolonged mouse survival depending on tumor volume, mAb dose, and treatment timing. Cooperative FcgammaRIV, FcgammaRIII, and FcgammaRI interactions mediated optimal lymphoma depletion by CD20 mAb in vivo, whereas clodronate-mediated depletion of macrophages eliminated the therapeutic benefit of CD20 mAb. Although CD20 mAbs activated complement in vitro and in vivo, normal and malignant B-cell depletion was induced through C1q- and C3-independent mechanisms. Thus, the ability of CD20 mAbs to deplete malignant B cells in vivo required FcgammaR-dependent use of the innate mononuclear cell immune system. These findings allow for mechanism-based predictions of the biologic outcome of CD20 mAb therapy and treatment optimization.     

A case of pulmonary and hepatic cystic Echinococcosis of CE1 stage in a healthy Japanese female that was suspected to have been acquired during her stay in the United Kingdom

We herein report a case of a young Japanese female who was confirmed to have cystic echinococcosis (CE) 1 stage based on the World Health Organization Informal Working Group on Echinococcosis pathological classification of CE, and she was also suspected to be infected with eggs of the G1 Echinococcus granulosus sensu stricto during her stay in the United Kingdom and therefore, suffered from synchronous pulmonary and hepatic CE. Oral albendazole was administered initially, but rupture of a lung hydatid cyst was observed. To avoid additional rupture, we performed two surgeries. CE is very rare in Japan; all CE cases in Japan during the past two decades have been confirmed to be imported, and almost all cases are hepatic CE. This case is the first case report of a Japanese patient who had concomitant giant lung and liver CE with early-stage CE1 and was successfully treated by surgery and pharmacotherapy with a serological follow-up.     

Prediction model for CD34 positive cell yield in peripheral blood stem cell collection on the fourth day after G-CSF administration in healthy donors

Allogeneic peripheral blood stem cell transplantation (PBSCT) is an indispensable treatment option for hematological malignancy. The optimal collection day after granulocyte colony-stimulating factor (G-CSF) administration should be determined by peripheral blood pre-apheresis CD34 positive (CD34⁺) cell percentage. However, pre-apheresis CD34⁺ cell analysis is not available for most institutions in Japan. Prediction of the optimal collection day based on objective parameters, other than direct CD34⁺ cell count, is thus an important matter for investigation. To identify potential predictive factors, clinical parameters in 79 related donors who received allogeneic peripheral blood stem cell (PBSC) collection were analyzed. Eight factors were significantly correlated with the number of CD34⁺ cells per donor body weight on the fourth day (day 4) after G-CSF administration in univariate analysis. Using multi-regression analysis, we made a simple scoring system comprising age, sex, LDH on day 4 and RBC count at the baseline, which significantly predicted CD34⁺ cell yield (P = 0.048). This system allows us to determine the optimal PBSC collection day. When the score is 0 or 1 on day 4, starting apheresis on day 5 potentially helps avoiding the need for multiple harvests. Score 3 or 4 on day 4 is indicative of better performance if apheresis is started on day 4.     

Early diagnosis and treatment for remission of clinically amyopathic dermatomyositis complicated by rapid progress interstitial lung disease: a report of two cases

We report two cases of clinically amyopathic dermatomyositis (CADM) complicated by rapid progress interstitial lung disease (RPILD). The diagnosis of CADM was based on Gottron’s papule and RPILD, and the absence of muscle weakness. The female patients were treated with early immunosuppressive therapies including steroid pulse therapy, resulting in significant improvement in respiratory symptoms, clinical data, and imaging. Measurement of anti-CADM-140/MDA5 antibody was useful for obtaining a definitive diagnosis of CADM in these cases.     

CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse

The tight-skin (TSK/+) mouse, a genetic model for human systemic sclerosis (SSc), develops cutaneous fibrosis and autoantibodies against SSc-specific target autoantigens. Although molecular mechanisms explaining the development of fibrosis and autoimmunity in SSc patients or TSK/+ mice remain unknown, we recently demonstrated that SSc patients overexpress CD19, an important regulatory molecule expressed by B lymphocytes. B cells from CD19-deficient mice are hyporesponsive to transmembrane signals, while B cells overexpressing CD19 are hyperresponsive and generate autoantibodies. In this study, TSK/+ B cells also exhibited a hyperresponsive phenotype with decreased surface IgM expression, enhanced serum Ig production, and spontaneous autoantibody production. Moreover, CD19 tyrosine phosphorylation was constitutively augmented in TSK/+ B cells. CD19-mediated [Ca(2+)](i) responses, Vav phosphorylation, and Lyn kinase activity were similarly enhanced. Studies of TSK/+ mice deficient in CD19 expression demonstrated that CD19 deficiency significantly decreased skin fibrosis in TSK/+ mice. Additionally, CD19 loss in TSK/+ mice upregulated surface IgM expression and completely abrogated hyper-gamma-globulinemia and autoantibody production. CD19 deficiency also inhibited IL-6 production by TSK/+ B cells. Thus, chronic B cell activation resulting from augmented CD19 signaling in TSK/+ mice leads to skin sclerosis possibly through IL-6 overproduction as well as autoimmunity.     

Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1

Background

The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region.

Methods

Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing.

Results

Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently.

Conclusions

History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.

     

Successful treatment of three patients with human immunodeficiency virus and hepatitis C virus genotype 1b co-infection by daclatasvir plus asunaprevir

Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) often accelerates the course of HCV-associated liver disease. Daclatasvir (DCV) plus asunaprevir (ASV) have been shown to be highly effective for HCV-infected patients with genotype 1b. Three patients co-infected with HIV/HCV genotype 1b were enrolled in this study. Prior to initiation of HCV treatment, the variants associated with L31 and Y93 in the non-structural protein 5A (NS5A) region of the HCV genome were confirmed to be absent using a direct sequencing method. Taking into consideration the lower risk of drug–drug interaction and the need for immediate treatment, the patients received 60 mg DCV once daily plus 100 mg ASV twice daily for 24 weeks. In one patient, the alanine aminotransferase level was elevated to 228 IU/L at 24 weeks after the start of treatment, but he completed the 24-week treatment course. All three patients achieved sustained viral response, without severe complications (including HIV virological rebound). Thus, in cases where NS5A variants are confirmed to be absent and patients are antiretroviral therapy-naïve, with CD4+ over 500/μL or HIV well controlled by RAL-based cART, DCV plus ASV may represent a good treatment option for HIV and HCV genotype 1b co-infected patients.     

Outcome after first relapse in adult patients with Philadelphia chromosome‐negative acute lymphoblastic leukaemia

To analyse the outcome of adult patients who developed a first relapse of acute lymphoblastic leukaemia (ALL), we collected the clinical data of 332 patients with Philadelphia‐chromosome (Ph) negative ALL, aged 16–65 years, who relapsed after first complete remission (CR1) between 1998 and 2008 in 69 institutions all over Japan, including 58 patients who relapsed after allogeneic haematopoietic stem cell transplantation (Allo‐HSCT) in CR1. The overall survival (OS) was 43·4% at 1 year, and 16·3% at 5 years from relapse in patients who received chemotherapy alone in CR1. Among patients who relapsed after chemotherapy alone in CR1, 123 (52·5%) achieved a second remission (CR2) following salvage chemotherapy, of whom 62 subsequently underwent Allo‐HSCT during CR2. Allo‐HSCT in CR2 was significantly associated with better OS. Moreover, the type of salvage chemotherapy influenced OS from relapse. A doxorubicin, vincristine, and predonisone‐based (AdVP‐type) regimen was related to better OS in patients with longer CR1 (more than 1 year), but was related to worse OS in patients with shorter CR1. In conclusion, the prognosis of patients with relapsed Ph‐negative ALL is poor. Allo‐HSCT after a first relapse could improve the prognosis. Selection of the optimal salvage chemotherapy might depend on the duration of CR1.