Systemic osteosclerosis associated with primary bone marrow B-cell lymphoma.

Systemic osteosclerosis is a rare complication of hematological malignancies. Primary myelofibrosis and acute megakaryocytic leukemia are known as underlying diseases; however, lymphoid tumors have rarely been reported. Here we describe a case of a 50-year-old man with severe systemic osteosclerosis associated with primary bone marrow B-cell lymphoma. Analysis of bone metabolic markers revealed a high turnover of bone metabolism and an increase in serum osteoprotegerin levels. These results suggest the involvement of osteoprotegerin in the pathogenesis of osteosclerosis associated with hematological malignancies.

Clinical relevance of high-risk cytogenetic abnormalities and the second revision of the International Staging System (R2-ISS) in patients with multiple myeloma in clinical practice.

High-risk cytogenetic abnormalities (HRCAs) are the most critical factor affecting prognosis in multiple myeloma (MM). However, the clinical significance of HRCAs in routine practice has not been fully elucidated. We retrospectively analyzed clinical features and outcome in 60 newly diagnosed MM patients with or without HRCAs including t(4;14), t(14;16), del(17p), and 1q gain/amplification. The median age was 71 years (range, 35-90). Abnormalities with t(4;14), t(14;16), del(17p), and 1q gain/amplification were found in 10, 1, 6, and 21/14 patients, respectively, and 10 patients had ≥ 2 HRCAs. Patients with HRCAs exhibited progressive clinical features such as anemia, high ß2-microglobulin, and high LDH. Symptomatic relapse was more common in patients with HRCAs. The median progression-free survival (PFS) by number of HRCAs (0, 1, and ≥ 2) was 51.7, 21.4, and 26.1 months (p = 0.011), and the median overall survival (OS) was not reached, 60.7, and 46.8 months (p = 0.045), respectively. Multivariate analysis revealed that HRCAs were an independent factor for PFS. Accordingly, the second revision of International Staging System (R2-ISS), which incorporates HRCA scores, was more useful for prognostic stratification (p = 0.0023). These results suggest that presence of multiple HRCAs including 1q gain/amplification is associated with advanced stage and poor prognosis in clinical practice as well.

[Clinical features of five cases of acquired factor V deficiency].

Acquired factor V deficiency is a rare disease that presents with various bleeding symptoms because of the acquired production of factor V inhibitors and decrease in factor V activity. We have experienced five cases of acquired factor V deficiency diagnosed on the basis of abnormalities in coagulation tests in the last 10 years. All five patients were older men, of whom one had no bleeding symptoms, and three had a history of renal failure and malignant tumors. In the cross-mixing test, two of three cases demonstrated an inhibitor pattern, but one case showed a deficient pattern. In all cases, steroid treatment improved factor V activity as well as prothrombin time and activated partial thromboplastin time. However, patients with intracranial hemorrhage had a poor prognosis. Although this disease is rare, careful management is necessary, especially in the absence of bleeding symptoms and where cross-mixing test does not show an inhibitor pattern.

Polyclonal Immunoglobulin Recovery after Autologous Stem Cell Transplantation Is an Independent Prognostic Factor for Survival Outcome in Patients with Multiple Myeloma.

We retrospectively analyzed multiple myeloma (MM) patients who underwent autologous stem cell transplantation (ASCT) without maintenance therapy to assess the impact of recovery of normal immunoglobulin (Ig) on clinical outcomes. The recovery of polyclonal Ig was defined as normalization of all values of serum IgG, IgA, and IgM 1 year after ASCT. Among 50 patients, 26 patients showed polyclonal Ig recovery; 14 patients were in ≥complete response (CR) and 12 remained in non-CR after ASCT. The patients with Ig recovery exhibited a significantly better progression-free survival (PFS, median, 46.8 vs 26.7 months, p = 0.0071) and overall survival (OS, median, not reached vs 65.3 months, p < 0.00001) compared with those without Ig recovery. The survival benefits of Ig recovery were similarly observed in ≥CR patients (median OS, not reached vs 80.5 months, p = 0.061) and non-CR patients (median OS, not reached vs 53.2 months, p = 0.00016). Multivariate analysis revealed that non-CR and not all Ig recovery were independent prognostic factors for PFS (HR, 4.284, 95%CI (1.868-9.826), p = 0.00059; and HR, 2.804, 95%CI (1.334-5.896), p = 0.0065, respectively) and also for OS (HR, 8.245, 95%CI (1.528-44.47), p = 0.014; and HR, 36.55, 95%CI (3.942-338.8), p = 0.0015, respectively). Therefore, in addition to the depth of response, the recovery of polyclonal Ig after ASCT is a useful indicator especially for long-term outcome and might be considered to prevent overtreatment with maintenance therapy in transplanted patients with MM.

Hematopoietic neoplasms accompanied by severe enterocolitis due to Aeromonas species.

Aeromonas species are known to be a cause of diarrhea and acute enterocolitis. However, only a few cases have been reported and the pathophysiology of Aeromonas infection has not as yet been clarified. We experienced 2 cases developing severe enterocolitis during the course of hematological malignancies, specifically multiple myeloma and diffuse large B-cell lymphoma. Both patients presented with watery diarrhea that persisted for more than a week, followed by bloody diarrhea. Total colon endoscopy showed multiple ulcers on the mucosa from the sigmoid colon to the rectum, and biopsies from the ulcer revealed infiltration of neutrophils and eosinophils in the mucosa and submucosa. Aeromonas hydrophila and Aeromonas sobria were isolated from stool cultures, respectively. Treatment with oral ciprofloxacin was effective in both patients and clinical symptoms showed significant improvement. These cases raise the possibility of Aeromonas infection as a cause of severe enterocolitis and the importance of making a correct differential diagnosis and appropriate antibiotic treatment in immunocompromised patients including those with hematological malignancies.

[Azacitidine treatment for acute myeloid leukemia with myelodysplasia-related changes during peritoneal dialysis].

Azacitidine (AZA) is useful for the treatment of myelodysplastic syndrome; however, there are a few case reports involving patients receiving hemodialysis and no case reports involving patients receiving peritoneal dialysis. We describe a patient with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) receiving peritoneal dialysis who was treated with AZA. Peritoneal dialysis was initiated for an 85-year-old man with chronic renal failure in April 2014. In February 2015, peripheral blood analysis showed pancytopenia and bone marrow examination revealed excess of myeloblasts and dysplasia of trilineage cells. He was diagnosed with AML-MRC and treated with AZA because of being elderly and suffering from chronic renal failure. He achieved transfusion independence after 1 course and hematological remission after 3 courses of AZA treatment, without severe side effects. This case suggests that AZA is an effective therapeutic option for patients with AML-MRC receiving peritoneal dialysis.

Diffuse large B-cell lymphoma recurring with zosteriform cutaneous lesions.

A 75-year-old woman presented with edema of the left leg in December 2012. On examination, there was a palpable 5-cm tumor in the left lower abdomen, and PET/CT showed lymphadenopathy of the tracheal, para-aortic, left iliac and inguinal regions with increased FDG uptake. We performed histopathological examination of the iliac lymph node and diagnosed diffuse large B-cell lymphoma (DLBCL), stage IIIA. The patient received 8 courses of R-CHOP chemotherapy and achieved a complete response. In April 2014, she noticed seven new painful erythematous vesicles <1 cm in size on the skin of the left lower abdominal region. Herpes zoster was suspected and valacyclovir was administered. However, this medication had no effect, and the vesicles enlarged and became nodular. Histopathological examination of one of the skin lesions revealed the infiltration of DLBCL and the diagnosis of zosteriform cutaneous recurrence of DLBCL was thus made. Skin lesions mimicking herpes zoster have been reported in certain types of hematological malignancies, and histopathological diagnosis should be performed in such cases.

Factor VII Tokushima: the first case of factor VII Cys22Gly with the development of myocardial infarction in the proband receiving recombinant factor VIIa replacement therapy.

An 81-year-old man was referred to our department because of suspected factor VII (FVII) deficiency. His FVII activity was under 1%, whereas the FVII activity levels of his son and granddaughter were 65 and 109%, respectively. The nucleotide at position 3886 of his FVII gene was homozygous for G. A single T to G substitution results in the replacement of wild-type Cys at residue 22 by Gly. His son was heterozygous for G and T at position 3886, whereas his granddaughter was homozygous for wild-type T. These results suggest that he was homozygous for FVII Cys22Gly. He underwent radiofrequency ablation (RFA) for hepatocellular carcinoma, receiving 20 µg/kg of recombinant FVIIa prior to RFA and 10 µg/kg of recombinant FVIIa twice after RFA. He showed no bleeding tendency; however, a myocardial infarction was diagnosed and percutaneous coronary intervention was performed.

Testicular nocardiosis accompanied by cutaneous lesions in an immunocompetent man.

We herein report the case of a 77-year-old man admitted for an acute cutaneous infection and persistent fever. A physical examination revealed systemic small blisters and scrotal swelling. He was suspected of having complications from chickenpox or bullous impetigo as the initial diagnosis. Nocardia was detected on an aspiration biopsy of the small blisters and the surgically removed testis at a later date. Testicular nocardiosis is a rare condition; however, we should consider nocardiosis in the differential diagnosis because delay in providing treatment may worsen a patient's general condition.

[Rapidly progressive AL amyloidosis in a patient with relapsed multiple myeloma after achieving a complete response to tandem autologous PBSCT].

A 56-year-old male presented with pathological rib fracture and lumbago in 2006. He was diagnosed with multiple myeloma (IgG-lambda type, D&S stage IIIA, ISS 2). He was treated with VAD therapy and tandem auto-PBSCT, and achieved CR in 2007. He was followed without chemotherapy, but relapsed in 2009. He received lenalidomide plus dexamethasone and bortezomib plus dexamethasone and achieved PR which was sustained for 25 months. In 2012, he developed edema of the lower legs and pleural effusion, and was diagnosed as having nephrotic syndrome and heart failure due to AL amyloidosis. He died of renal failure and heart failure 3 months after this diagnosis. Autopsy findings showed amyloid deposition in many organs including the heart, kidneys, liver, spleen, and intestines. Development of rapidly progressive AL amyloidosis is a rare complication of relapse after the achievement of CR, but careful monitoring is needed in patients with multiple myeloma.

A single-chain Fv diabody against human leukocyte antigen-A molecules specifically induces myeloma cell death in the bone marrow environment.

Cross-linked human leukocyte antigen (HLA) class I molecules have been shown to mediate cell death in neoplastic lymphoid cells. However, clinical application of an anti-HLA class I antibody is limited by possible side effects due to widespread expression of HLA class I molecules in normal tissues. To reduce the unwanted Fc-mediated functions of the therapeutic antibody, we have developed a recombinant single-chain Fv diabody (2D7-DB) specific to the alpha2 domain of HLA-A. Here, we show that 2D7-DB specifically induces multiple myeloma cell death in the bone marrow environment. Both multiple myeloma cell lines and primary multiple myeloma cells expressed HLA-A at higher levels than normal myeloid cells, lymphocytes, or hematopoietic stem cells. 2D7-DB rapidly induced Rho activation and robust actin aggregation that led to caspase-independent death in multiple myeloma cells. This cell death was completely blocked by Rho GTPase inhibitors, suggesting that Rho-induced actin aggregation is crucial for mediating multiple myeloma cell death. Conversely, 2D7-DB neither triggered Rho-mediated actin aggregation nor induced cell death in normal bone marrow cells despite the expression of HLA-A. Treatment with IFNs, melphalan, or bortezomib enhanced multiple myeloma cell death induced by 2D7-DB. Furthermore, administration of 2D7-DB resulted in significant tumor regression in a xenograft model of human multiple myeloma. These results indicate that 2D7-DB acts on multiple myeloma cells differently from other bone marrow cells and thus provide the basis for a novel HLA class I-targeting therapy against multiple myeloma.

Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2.

Multiple myeloma (MM) develops devastating bone destruction with enhanced bone resorption and suppressed bone formation. In contrast to enhanced osteoclastogenesis, little is known about the mechanism of impaired bone formation in MM. Because a canonical Wingless-type (Wnt) signaling pathway has recently been shown to play an important role in osteoblast differentiation, we examined whether MM cells affect a canonical Wnt pathway to suppress bone formation. Conditioned media from RPMI8226 and U266 MM cell lines and primary MM cells suppressed in vitro mineralization as well as alkaline phosphatase activity in osteoblasts induced by bone morphogenetic protein 2 (BMP-2). These cell lines constitutively produced a soluble Wnt inhibitor, secreted Frizzled-related protein 2 (sFRP-2), but not other Wnt inhibitors including sFRP-1, sFRP-3, and dickkopf 1 (DKK-1) at the protein level. Most MM cells from patients with advanced bone destructive lesions also expressed sFRP-2. Furthermore, exogenous sFRP-2 suppressed osteoblast differentiation induced by BMP-2, and immunodepletion of sFRP-2 significantly restored mineralized nodule formation in vitro, suggesting a predominant role for MM cell-derived sFRP-2 in the impairment of bone formation by MM. Thus, in addition to enhanced osteolysis, MM cells also suppress bone formation at least in part through an inhibition of the canonical Wnt pathway by secreting sFRP-2.