[Autoimmune coagulation factor V/5 deficiency during chronic disseminated intravascular coagulation].

Aortic regurgitation, a thoracoabdominal aortic aneurysm, chronic myeloid leukemia, and chronic kidney disease were all being treated at two hospitals for an 83-year-old man. He was admitted to the Department of Orthopedics at our hospital with a lumbar compression fracture. Later, he experienced melena, for which the Department of Internal Medicine was consulted. Due to the aberrant results of PT-INR (7.1) and a PTT > 200 seconds on a coagulation test, we suspected the presence of an autoimmune coagulation factor deficiency, and prednisolone immunosuppressive therapy medication was started right away. Due to a sharp decline in FV/5 activity, the presence of FV/5 inhibitors, and the presence of anti-FV/5 autoantibodies, a final diagnosis of autoimmune coagulation factor V (FV/5) deficiency was made. After the start of immunosuppressive therapy, the FV/5 inhibitor and anti-FV/5 autoantibodies disappeared, and the FV/5 activity progressively returned to normal. Disseminated intravascular coagulation-which may have been caused by a known aortic aneurysm-worsened while tapering off prednisolone. Due to the patient's advanced age and other problems, the aneurysm was extensive and inappropriate for surgical repair. The coagulation test findings improved gradually upon initiation of warfarin therapy. Herein, the patient had autoimmune FV/5 deficiency, a rare disorder that made diagnosis and therapy difficult because of the patient's several coexisting conditions.

A Case of Primary Myelofibrosis in Which Ruxolitinib Therapy Ameliorated the Fibrosis, but Resulted in Fatty Marrow.

A 63-year-old woman was referred to our department in 2015 because of anemia and thrombocytosis. MPL W515/K was positive, JAK-2V617F and CALR exon 9 were negative. Bone marrow(BM)biopsy led to a diagnosis of primary myelofibrosis (PMF)in the prefibrotic/early stage(Grade 1). BMbiopsy performed in 2016 showed overt fibrotic stage(Grade 2). She was classified according to the Dynamic International Prognostic Scoring System(DIPSS)as intermediate(Int)-Ⅱrisk. Ruxolitinib 10 mg daily was initiated. Ruxolitinib was suspended for hepatic dysfunction after the dose was increased to 15 mg. Subsequently, ruxolitinib was resumed at 10 mg. BM biopsy performed in 2017 showed progression of myelofibrosis(MF)to Grade 3. BM biopsy performed in 2018 showed improved to Grade 0-1, however, BM was fatty. Currently in 2019, she continues to be on ruxolitinib. Results of immunohistochemical staining of BM biopsy specimens for cytokines and CD34 suggested the role of cytokines in the pathogenesis of the PMF. It was speculated that ruxolitinib blocked the production of cytokines to ameliorate the MF and restore the hematopoietic function of the BM. Although the pathogenesis of the fatty marrow remained unclear, the possibility of involvement of ruxolitinib cannot be denied.

Clinical Evaluation of the Efficacy and Safety of Anagrelide Used with or without Hydroxycarbamide in Japanese Patients with Essential Thrombocythemia-A Retrospective Single-Center Study of 35 Cases.

OBJECTIVE: The clinical features(CF), laboratory data, disease transformation pattern and drug metabolism in essential thrombocythemia(ET)differ between Japan and Western countries. The CF of ET in clinical practice(CP)are more diverse than in prospective clinical studies. We should conduct retrospective analyses in CP. The present study was aimed at evaluating the efficacy, safety and tolerability of anagrelide(ANA)monotherapy and combined ANA plus hydroxycarbamide(HC)in Japanese ET. PATIENTS AND METHODS: We have a total of 35 cases. Sixteen patients received ANA monotherapy, 10 received ANA plus HC, and 9 received ANA plus other drugs. RESULTS: Comparison among three groups revealed the absence of differences in response rate(platelet count C60×10 / / 4/mL, platelet count C40×104/mL)(43.8%, 6.3% vs. 50.0%, 10.0% vs. 44.4%, 11.1%), treatment continuation rate(81.3% vs. 40.0% vs. 55.6%), median daily dose of ANA(1.00 mg in all three groups)or median treatment period(days)(259 vs. 198.5 vs. 161.0), the treatment continuation rate tended to be lower in the combined ANA plus HC. The incidence of all adverse events(AEs)was higher in the ANA monotherapy(45.7%)than ANA plus HC(28.6%)or ANA plus other drugs(25.7%), the AEs were mild in all groups. CONCLUSION: The tolerability of ANA monotherapy, ANA plus HC, and ANA plus other drugs were good.

A Case of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with Aspergillus Brain Abscess and Invasive Pulmonary Aspergillosis Successfully Treated with Voriconazole Followed by Cord Blood Transplantation.

A 59-year-old female was diagnosed as pulmonary aspergillosis(IPA)while remission induction therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia. Liposomal amphotericin B improved the fungal serodiagnostic markers, however,the IPA worsened. She also developed an Aspergillus brain abscess,which, while being undetectable on CT,was detected as multiple nodular lesions by MRI. A definitive diagnosis was made by polymerase chain reaction(PCR)of brain biopsy specimens. Voriconazole(VRCZ)was effective,and cord blood transplantation was performed. She has received VRCZ for a long time. There are no relapse of either the IPA or the Aspergillus brain abscess.

Retrospective Analysis of 20 Patients with DLBCL Who Received MCVAC Followed by Autologous Peripheral Blood Stem Cell Transplantation.

Autologous peripheral blood stem cell transplantation(auto-PBSCT)combined with high-dose chemotherapy has been considered as the standard therapy for relapsed or induction therapy-refractory aggressive lymphomas sensitive to chemotherapy. While various regimens have been applied as the conditioning,none has yet been established as the standard. We have begun to employ high-dose ranimustine,cytarabine,etoposide and cyclophosphamide(MCVAC)regimen. The present study was undertaken to review the efficacy and safety of MCVAC. Regimen: We carried out a retrospective analysis of 20 patients diagnosed as diffuse large B-cell lymphoma. The median follow-up duration of 20 patients was 13.05 months(range, 0.57-49.5 months). The 4-year OS and PFS were 57.8% and 30.2%,respectively. Relapse was the most frequent cause of treatment failure(n=7). The major toxicities were anorexia/nausea(95%),diarrhea (75%),hypokalemia (70%). One patient died of hepatic veno-occlusive disease(VOD). The serious adverse events included hypokalemia,arrhythmia,cerebral hemorrhage,and heart failure(1 case[5%]each). There was 1 case of a late-onset adverse event: therapy-related myelo- dysplastic syndrome/acute myeloblastic leukemia(MDS/AML). MCVAC regimen was concluded as effective and well-toler- ated. However,we should carefully monitored for the possible development of VOD and MDS/AML. Further follow-up is needed to evaluate the long-term efficacy and safety.

CD56-positive adult T-cell leukemia/lymphoma: a case report and a review of the literature.

A 67-year-old woman presented with a swelling on both sides of the neck. Biopsy of an enlarged cervical lymph node on the left side and flow cytometric analysis revealed CD56-positive CD4(+)CD8(+) abnormal NK/T cells. A Southern blot analysis of the cervical lymph node biopsy specimen showed a human T-cell leukemia virus type 1 provirus DNA monoclonal band. Based on these findings, the patient was diagnosed with CD56-positive adult T-cell leukemia/lymphoma. After five cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, the general condition of the patient gradually declined, indicating resistance to treatment, and approximately 9 months after the onset of symptoms, the patient died. CD56 is recognized as an unfavorable prognostic marker in cases of acute myeloid leukemia with t(8;21), acute promyelocytic leukemia, and anaplastic large cell lymphoma. Only eight cases of CD56-positive adult T-cell leukemia/lymphoma have been reported so far in the literature. Most of these cases were in the advanced stage at diagnosis and had poor outcomes. It appears that the correlation between CD56 expression and outcomes in patients with adult T-cell leukemia/lymphoma should be clarified by investigating a larger number of cases in the future.

Significant role of magnetic resonance imaging for the diagnosis and evaluation of cardiac amyloidosis in primary light chain amyloidosis.

A 47-year-old male with macroglossia presented with dyspnea on effort and chest pain at rest. Cardiac MRI revealed diffuse global subendocardial late gadolinium enhancement below the left ventricular endocardium and a dark blood pool of intracardiac contrast medium. Tongue biopsy revealed amyloid deposition, which was limited in the myocardium. He was diagnosed with primary light chain amyloidosis. His condition was stage I according to the Mayo Clinic staging system. He underwent autologous peripheral blood stem cell transplantation. On Day 10, he developed chest pain and died suddenly on Day 11. Postmortem examination revealed amyloid deposition throughout the heart.

Three cases of relapsed/refractory multiple myeloma under hemodialysis treated with panobinostat/bortezomib/dexamethasone (FVD).

Three patients under hemodialysis (HD) with relapsed/refractory multiple myeloma (MM) were administered panobinostat/bortezomib/dexamethasone (FVD). Case 1: The patient was a 66-year-old male with BJP-κ. FVD was effective, but HD could not be discontinued. He developed Grade 3 adverse events (AEs), including nausea, dehydration, and fatigue, following the common terminology criteria for adverse events v4.0. FVD was discontinued after the third course, while HD was continued. Case 2: The patient was a 65-year-old female with IgG-λ + BJP-λ. Amyloidosis was complicated. The first course of FVD was effective, but HD could not be discontinued. She developed G2 AEs, including nausea and fatigue. The cardiac amyloidosis worsened, and she died of heart and renal failure. Case 3: The patient was a 79-year-old male with BJP-κ. FVD was effective, and the HD could be discontinued on day 12 of treatment. No AEs were noted. However, he declined continuation of the FVD and died of MM relapse and renal failure. We analyzed the pharmacokinetics of panobinostat. There were no correlations between dose level and blood level of panobinostat or between blood level, efficacy, and incidence of AEs. We additionally measured the rate of elimination of the drug by HD.

Occurrence of Carcinoma of the Pancreas Following Nilotinib Therapy for Chronic Myeloid Leukemia: Report of a Case with Review of the Literature.

The patient, a 79-year-old Japanese man, was diagnosed with the chronic phase of chronic myeloid leukemia and begun on nilotinib therapy in April 2011. The therapeutic response was major molecular response in August. About 19 months after the start of nilotinib therapy at 400 mg/day (November 2012), an adenocarcinoma (24 x 20 mm) confined to the head of the pancreas developed. In February 2013, a pancreaticoduodenectomy was performed. The therapy regimen was switched to dasatinib at 100 mg/day, beginning in April. The response was still major molecular response with no recurrence of pancreatic carcinoma in July 2013. There have been 29 reported cases of secondary neoplasms associated with nilotinib therapy. These secondary neoplasms were characterized by relatively frequent occurrence of papilloma (6 cases), gastric cancer (3 cases), fibroma (3 cases), and thyroid neoplasms (2 cases). The present case, however, is the first to be reported as carcinoma of the pancreas. This report describes the case.

Bone formation following lenalidomide-dexamethasone combination therapy in cases of multiple myeloma refractory to high-dose chemotherapy with bortezomib and autologous peripheral blood stem cell transplantation: report of a case and review of the literature.

A 41-year-old man presented with the chief complaint of right hip pain that had persisted for 6 months. F18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging showed FDG accumulation in the right pubic bone. A bone biopsy specimen from the site revealed findings suggestive of a plasma cell tumor. Bone marrow examination and serum and urine immunofixation tests showed no abnormalities. Based on these findings, the patient was diagnosed as having non-secretory multiple myeloma. FDG accumulation in the right pubic bone diminished following four cycles of weekly bortezomib and concomitant dexamethasone therapy. Tandem autologous peripheral blood stem cell transplantation was performed, followed by monthly bortezomib/dexamethasone maintenance therapy. A further FDG-PET/CT scan 9 months after the start of therapy indicated that FDG accumulation in the right pubic bone had worsened. Consequently, the therapy was switched to twice-weekly bortezomib/dexamethasone as remission re-induction therapy. New FDG uptake in the right hip bone was noted after six cycles of the therapy, and plain X-ray examination revealed osteolytic changes. The patient was then administered eight cycles of combined lenalidomide-dexamethasone therapy, which resulted in a marked decrease of the FDG accumulation in the right pubic bone and disappearance of uptake in the right hip bone. There was radiographic evidence of bone formation at these sites. This is only the second reported case in which treatment with the immunomodulatory drug lenalidomide and concomitant dexamethasone has been found to induce bone formation.

Peripheral T cell lymphoma, not otherwise specified with myelofibrosis: report of a case with review of the literature.

A 68-year-old man presented to us with pancytopenia, erythroderma, and multiple lymphadenopathies. Lymph node biopsy led to the diagnosis of peripheral T-Cell lymphoma-not otherwise specified (PTCL-NOS). Immunostaining of the lymph node biopsy specimens for cytokines revealed that the tumor cells were positive for plated-derived growth factor (PDGF), basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), interleukin-2 (IL-2), and transforming growth factor-ß (TGF-ß). Bone marrow biopsy revealed infiltration by the PTCL-NOS and myelofibrosis (MF). Bone marrow blood was negative for JAK-2V617F. Bone marrow immunostaining for cytokines showed that the tumor cells were positive for PDGF, b-FGF, VEGF, TNF-α, IFN-γ, IL-1ß, IL-2, and TGF-ß. The patient was initiated on treatment, and after the first course of CHOP therapy, the bone marrow infiltration by the PTCL-NOS and MF improved. Repeat immunostaining of bone marrow biopsy specimens for cytokines showed that the tumor cells had become negative for PDGF, VEGF, TNF-α and TGF-ß. However, after the second course of CHOP therapy, the bone marrow infiltration by the PTCL-NOS and MF worsened. Immunostaining of bone marrow specimens for cytokines again revealed positive staining results of the tumor cells for PDGF, TNF-α, and TGF-ß. At the completion of the first course of treatment, the infiltration by the PTCL-NOS improved, but not the pancytopenia.

Epstein-Barr virus-positive multiple myeloma developing after immunosuppressant therapy for rheumatoid arthritis: a case report and review of literature.

A 61-year-old woman was diagnosed as having rheumatoid arthritis (RA) and began treatment with salazosulfapyridine (SASP) and methotrexate (MTX) in 2008; the administration of concomitant tacrolimus (TAC) was initiated in 2010. She subsequently developed concurrent multiple myeloma (MM), immunoglobulin G (IgG)-κ type, in 2012. A portion of the tumor cells tested positive for Epstein-Barr virus-encoded small RNA (EBER). MTX treatment was discontinued in 2014, and the exacerbation of MM ensued. The patient received two cycles of bortezomib plus dexamethasone (BD) therapy and attained a complete response (CR). She then underwent an autologous peripheral blood stem cell transplantation. The Epstein-Barr (EB) virus infection arising from the increased RA disease activity and immunosuppressant medication might have influenced the development of MM in this case. Most reported patients with EB virus-positive plasmacytoma are in a state of immunosuppression, and this condition may fall within the category of other iatrogenic immunodeficiency-associated lymphoproliferative disorders. No other reports of plasmacytoma occurring in a background of RA or after TAC or MTX therapy have been made, and the present case is the first such report.

A Case of Advanced Primary Thyroid Double-Hit B Cell Lymphoma in Which Complete Remission has been Maintained After High-Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation Performed During the Second Remission, with a Review of the Literature.

A 50-year-old woman who presented with a mass in the thyroid gland was diagnosed as having diffuse large B-cell lymphoma (DLBCL) by biopsy in August 2011. The tumor had a complex chromosomal karyotype, including 8q24 (C-MYC) and 18q21(BCL-2), and fluorescence in situ hybridization confirmed split signals of C-MYC and BCL-2. BCL-2/IgH and C-MYC/IgH fusion signals were also observed. Three courses of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) therapy were given, followed by thyroid gland irradiation. She was achieved complete remission (CR). In January 2012, a mass appeared in the right breast, which was diagnosed as relapse by biopsy. CR was achieved again after the 4th course of R-CHOP therapy, and one course of rituximab, etoposide, methylprednisolone, cytarabine, cisplatin (R-ESHAP) therapy was given. Thereafter, CR has been maintained after high-dose chemotherapy and autologous peripheral blood stem cell transplantation. There have been only 3 reported cases of primary thyroid C-MYC and BCL-2 double-hit lymphoma, including the present case; 2 of the cases were cases of DLBCL. R-CHOP therapy, irradiation and autologous peripheral blood stem cell transplantation are expected to be effective for such patients.

Patient with refractory multiple myeloma developing eosinophilia after lenalidomide treatment and lung cancer 9 months later: case report and review of the literature.

A 78-year-old man was diagnosed as having advanced symptomatic IgG multiple myeloma in June 2008. Melphalan-prednisolone therapy was effective, however, relapse occurred in January 2011 after 21 courses of melphalan-prednisolone therapy. Addition of bortezomib and dexamethasone led to partial remission, but the treatment needed to be discontinued due to autonomic dysfunction. Combined therapy with lenalidomide and dexamethasone was started in May 2012, which resulted in partial remission. The patient had a persistently elevated eosinophil count (2,350/µL) and increased serum IL-6 level. Pleuritis carcinomatosa developed in January 2013. Lenalidomide was discontinued, which was followed by rapid improvement of the eosinophilia. The patient died of respiratory failure in March 2013. There have been only five reported cases of eosinophilia caused by lenalidomide used for the treatment of multiple myeloma. In these cases, lenalidomide has been speculated to activate cytotoxic T cells to control the plasmacytoma. It would be of interest, therefore, that eosinophilia could serve as a new indicator.

Acquired factor v inhibitor developing after treatment with dabigatran etexilate methanesulfonate: a case report and review of the literature.

A 90-year-old man presented with subcutaneous ecchymoses. He had been under treatment with dabigatran etexilate methanesulfonate (DEM). Prolonged APTT and decreased PT was developed 2 months after the start of DEM, more prolonged 6 months later. DEM was discontinued, the coagulopathy did not improve. Factor V activity was decreased, along with appearance of coagulation factor V inhibitor (FVI). He did not have antiphospholipid syndrome or malignancy. He was diagnosed as having acquired FVI caused by DEM. Steroid pulse therapy was effective. There have been 74 reported cases of AFVI induced by drug treatment, but none after treatment with DEM.

Spontaneous regression of a clinically-advanced histologically low-grade follicular lymphoma involving the breast: case report and review of the literature.

A 68-year-old woman was diagnosed as having grade 1 follicular lymphoma of the left breast in November 2012. Bone marrow infiltration was noted histologically and confirmed by Southern blot analysis of the IgHJH locus. The clinical stage was IVA, advanced stage. According to the Follicular Lymphoma International Prognostic Index, the patient was classified into the high risk group. The general condition was good and there were no organ symptoms, therefore, the patient was kept under observation without treatment. After one year and 2 months of follow up, The mass was regressed spontaneously. As previous studies have suggested a poor prognosis of patients with an advanced clinical stage of the disease, careful follow-up of our patient is necessary.

A case of secondary plasma cell leukemia resistant to novel agents, in which stringent complete remission was achieved and maintained for a long period of time after VAD therapy and tandem autologous transplantation.

A 61-year-old woman was diagnosed in June 2011 as having immunoglobulin G (IgG) ĸ-type multiple myeloma (MM), stage II, according to the International Staging System (ISS). Chromosome analysis showed a complex karyotype, including t(11;14) and del 13q. Analysis of the cell surface markers revealed that the cells were positive for mature plasma cell-1 (MPC-1), and negative for cluster of differentiation (CD) 45 and CD49e, suggestive of an intermediate level of maturity of the cells. The disease was refractory to bortezomib-dexamethasone (BD) therapy and progressed to plasma cell leukemia despite the treatment. Treatment was therefore switched to lenalidomide-dexamethasone (RD) therapy, however, the condition again proved to be refractory to this therapy. A partial response (PR) was achieved with vincristine-doxorubicin-dexamethasone (VAD) therapy. The residual plasma cells became CD45-positive, suggesting a change of the cells from an intermediate level of maturity to mature cells. In December, autologous peripheral blood stem cell transplantation (Auto-PBSCT) was performed after high-dose melphalan therapy (melphalan 200 mg/m(2)) as pretreatment. PR was observed and a second Auto-PBSCT was performed in July 2012. Stringent complete remission (sCR) has been maintained for 2 years since, without any further treatment. This is the first reported case of secondary plasma cell leukemia (sPCL) resistant to new drugs that was successfully treated by high-dose melphalan in combination with VAD therapy and Auto-PBSCT.

Primary platelet-derived growth factor-producing, spindle-shaped diffuse large B-cell lymphoma of the skull: a case report and literature review.

A 39-year-old woman with a right frontal mass underwent a cranial bone tumor biopsy. Histopathologic examination of hematoxylin and eosin-stained slides showed spindle-shaped tumor cells in a storiform pattern, appearing somewhat like a sarcoma. However, the tumor cells were CD20-positive by immunohistochemical staining. Therefore, a diagnosis of spindle-shaped diffuse large B-cell lymphoma (Sp-DLBCL) was made. There have been at least 35 cases of Sp-DLBCL documented in the literature, and most were of the germinal center type, while the present case is the first report of a vimentin-positive primary Sp-DLBCL of the skull. The DLBCL in this case was immunohistochemically stained for six representative cytokines that might give rise to fibrosis, due to the evidence of fibroblastic proliferation. The DLBCL cells were positive for platelet-derived growth factor (PDGF), and some cells were also positive for tumor necrosis factor (TNF) α. Based on these findings, it was inferred that the PDGF and TNFα produced by DLBCL cells induced fibroblastic proliferation. The resultant conspicuous fibrosis caused interfibrous impingement on the DLBCL cells, which deformed them into a spindle shape. The present case is the first reported case of a PDGF-producing Sp-DLBCL.