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.

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.

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.

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.

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.

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.

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.

A case of severe hypothyroidism causing cardiac tamponade associated with lithium intoxication.

A 70-year-old man was referred to our emergency department for shortness of breath on exertion and systemic edema. He had been taking lithium carbonate for 2 years (500 mg/day over previous 3 months) for bipolar disorder diagnosed at age 60. He was diagnosed with hypothyroidism accompanied by Hashimoto's disease 2 weeks before hospitalization. Massive pericardial effusion and bilateral pleural effusions were demonstrated by transthoracic echocardiography and computed tomography. Cardiac tamponade occurred on the 3rd day. Pericardiocentesis and thoracentesis were performed once and three times, respectively, because of the acute deterioration of hemodynamic status due to pleural and pericardial effusion. Lithium carbonate is a widely used and effective treatment for bipolar disorder. However, lithium has a narrow therapeutic range and many side effects. An important aspect of this case was the rapid development of severe hypothyroidism, although serum lithium concentration was measured regularly and was maintained within the therapeutic range. It is important to note that lithium can cause serious complications, as in this patient, even if serum lithium concentration is measured regularly and maintained within the therapeutic range. We report the first case of cardiac tamponade caused by hypothyroidism associated with administration of lithium. .

[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.