[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.

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.

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.

[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.

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.

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.

Identification of a missense mutation (p.Leu1733Pro) in the A3 domain of von Willebrand factor in a family with type 2M von Willebrand disease.

The proband's von Willebrand factor (VWF) antigen and VWF collagen-binding capacity were 14% and 10%, respectively; his sister's were 16% and 9%, respectively; and his nephew's were 30% and 15%, respectively. No apparent loss of high-molecular weight VWF multimers was observed in the plasma of these patients. A single-nucleotide substitution of T to C was found at nucleotide position 113042 in their VWF gene, converting Leu1733 to Pro in the A3 domain. These results suggest that p.Leu1733Pro is responsible for type 2M von Willebrand disease in this family.

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.

Acute myocardial infarction in a patient with essential thrombocythemia who underwent successful stenting--a case report.

Essential thrombocythemia (ET) can cause systemic vascular thrombosis, but involvement of coronary arteries in the setting of ET is rare. This report describes a case of acute myocardial infarction (MI) in a patient with ET. A 67-year-old man with ET complained of severe acute chest pain. Emergent coronary angiography revealed subtotal thrombotic occlusion of the left main trunk (LMT) coronary artery. Coronary angioplasty and stenting were performed successfully. Coronary angiography 4 weeks later revealed no significant restenosis. The patient has done well after primary coronary stenting with the use of only an antiplatelet agent to treat the thrombocythemia.

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.

Unusual skin reactions after mosquito bites and Epstein-Barr virus reactivation in a patient with mantle cell lymphoma.

We detected Epstein-Barr virus (EBV) reactivation in a patient with mantle cell lymphoma (MCL). The patient, a 53-year-old Japanese man, had been referred to our hospital because of generalized lymphadenopathy, hepatosplenomegaly and lymphocytosis and gave a history of intense skin reactions to mosquito bites. The biopsied lymph node contained a monotonous proliferation of medium-sized lymphocytes with scant cytoplasm and slightly irregular nuclei that were CD5+, CD20+ and CD23-. Antibody titers of IgG against EBV viral capsid antigen and early antigen were increased, and EBV was detected in the lymphoma cells. This case may suggest a relationship between EBV and MCL.

Central nervous system lesions associated with hereditary hemorrhagic telangiectasia--three case reports.

Hereditary hemorrhagic telangiectasia (HHT) is easily overlooked in patients with central nervous system (CNS) lesions. Our clinical experience of three patients with CNS lesions associated with HHT stresses the importance of considering HHT. A 23-year-old male presented with consciousness disturbance and right hemiparesis. Emergency cerebral digital subtraction angiography revealed occlusion of the left middle cerebral artery and the left anterior cerebral artery. Pulmonary arteriography showed three pulmonary arteriovenous malformations (AVMs). A 62-year-old male presented with consciousness disturbance and sensory aphasia. Magnetic resonance imaging revealed a ring-enhanced lesion in the left temporal lobe which was removed by left frontotemporal craniotomy. The diagnosis was brain abscess. Chest computed tomography (CT) revealed two pulmonary AVMs. A 32-year-old female presented with progressive mild weakness in her left hand. Initial CT showed subcortical hemorrhage in the right frontal lobe. Cerebral angiography revealed no vascular malformations, but chest CT disclosed five pulmonary AVMs. All three patients had a family history of HHT. The possibility of HHT is important to consider in patients with cerebrovascular disease (CVD) or brain abscess to prevent complications, not only in the patients but also their blood relatives. Therefore, the medical and family history of patients with CVD or brain abscess should be investigated and HHT should be considered during the physical examination.

Acquired pial and dural arteriovenous fistulae following superior sagittal sinus thrombosis in patients with protein S deficiency: a report of two cases.

Two patients with protein S deficiency with acquired multiple pial and dural arteriovenous fistulae (AVFs) following superior sagittal sinus (SSS) thrombosis are reported. Case 1 is a 38-year-old male with protein S deficiency who developed generalized seizure due to SSS thrombosis. Local fibrinolysis was achieved in the acute stage. His 10-month follow-up angiogram revealed an asymptomatic acquired dural AVF arising from the middle meningeal artery and the anterior cerebral artery with drainage to the thrombosed cortical vein in the right frontal lobe. Furthermore, his 2-year follow-up angiogram revealed a de novo pial AVF from the middle cerebral artery in the Sylvian fissure with drainage to the cortical vein initially thrombosed. However, this asymptomatic pial AVF caused bleeding in the ipsilateral cerebral hemisphere 12 years after onset, whereas the dural AVF spontaneously disappeared. Surgical disconnection was successfully performed to eliminate the source of hemorrhage. Case 2 is a 50-year-old male with a past history of SSS thrombosis with protein S deficiency who developed pulsatile tinnitus and generalized seizure. His angiogram showed a cortical dural AVF in the left parietal lobe and a sporadic dural AVF involving the right sigmoid sinus. The parietal lesion was eliminated by transarterial embolization followed by craniotomy. However, a de novo pial AVF emerged from the middle cerebral artery adjacent to the previously treated lesion. Of four cortical AVFs in two patients, thrombosis of cortical veins caused by protein S deficiency might play an important role in their formation. Long-term follow-up is required because this peculiar disorder has an unusual clinical course.

Antithrombin-p.Ala416Pro: the second reported case in Japan.

A 42-year-old man was referred to our department due to recurrent deep venous thrombosis. He, his father and his aunt had low antithrombin (AT) heparin cofactor activity and progressive AT activity levels with normal AT antigen levels. A single nucleotide substitution of G to C was found at nucleotide position c.1246 in exon 7 of the patient's AT gene, resulting in a p.Ala416Pro mutation of AT. The same mutation was identified in his father and aunt, but not his sister, who had a normal AT level. These results show that the AT-p.Ala416Pro mutation was responsible for type IIa AT deficiency in this family.