[Refractory ascites caused by lymphatic flow disorder after stem cell transplantation for acute myeloid leukemia].

In allogeneic hematopoietic stem cell transplantation (HSCT), ascites may develop owing to several causes, including sinusoidal obstruction syndrome, infections, malignancies, and malnutrition. However, it is often difficult to determine its precise cause. Here, a 59-year-old male developed chylous ascites three months post allogeneic bone marrow transplantation for relapsed acute myeloid leukemia. None of the attempted treatments resulted in improvement. Lymphangioscintigraphy revealed a lymphatic flow disorder at the level of the cisterna chyli. Autopsy revealed no leukemic cell infiltration or graft-versus-host disease of the liver or pancreas. The pancreatic specimen revealed parenchymal fibrosis and infiltration of plasma cells, suggesting chronic inflammation in addition to pathological changes caused by acute pancreatitis. These findings indicate that acute or chronic pancreatitis caused a lymphatic flow disorder that developed into refractory ascites. Although we could not diagnose pancreatitis while the patient was alive, it is important to recognize that asymptomatic pancreatitis can develop after HSCT. Furthermore, one should attempt to make an accurate diagnosis as early as possible.

[Efficacy and Safety of Ixazomib-Lenalidomide-Dexamethasone Therapy for Relapsed and Refractory Multiple Myeloma].

Ixazomib, an oral proteasome inhibitor, has been demonstrated to significantly improve progression-free survival(PFS)in patients with relapsed and refractory multiple myeloma(RRMM). Ixazomib has recently been approved in Japan, but its effectiveness and safety have not been fully investigated in a clinical setting. We retrospectively analyzed the records of 28 patients with RRMM who were treated with ixazomib in combination with lenalidomide and dexamethasone(IRd)in our institution between June 2017 and June 2018. The median patient age was 75 years at the start of IRd therapy. In total, 46.4% of the patients had previously received more than 3 treatment lines, prior to this study. The overall response rate was 37.0%, and the median PFS was 286 days. Over a median of 5 cycles of IRd, Grade 3 to 4 leukocytopenia, thrombocytopenia, and anemia occurred in 17.9%, 14.3%, and 32.1% of the patients, respectively; these incidences were higher than in previous reports. The severity of diarrhea or rash, however, was comparable with that in other studies. Patients with an estimated glomerular filtration rate of less than 50mL/min/1.73m2 received a lower cumulative dose of ixazomib and lenalidomide than those with other rates. PFS did not significantly differ between the 2 groups. Although it is necessary to carefully observe IRdtreated patients for hematological toxicity, IRd therapy is effective in heavily pretreated RRMM patients. It might be reasonable to reduce the dose of ixazomib in patients with renal impairment.

Lymphocyte-depleted classical Hodgkin lymphoma accompanied by myelofibrosis.

A 91-year-old male with fever of unknown origin was referred to our department. 18F-FDG PET/CT scan revealed a high FDG uptake in abdominal lymph nodes and multiple bones. The bone marrow biopsy showed fibrosis and atypical megakaryocytes, which were consistent with myelofibrosis. The patient died 28 days after admission and an autopsy was performed. The lymph nodes and bone marrow specimens revealed scattered Reed-Sternberg cells and a dearth of lymphoid cells with fibrosis. A final diagnosis of lymphocyte-depleted classical Hodgkin lymphoma (LDCHL) with bone marrow involvement was made. It is necessary to identify LDCHL during differential diagnosis for bone marrow fibrosis accompanied by lymphadenopathy.

Extramedullary hematopoiesis in gastric wall under early gastric cancer in a man with a myeloproliferative disorder: a case report.

Extramedullary hematopoiesis (EMH) is the proliferation of hematopoietic stem cells outside the bone marrow and often observed in the liver, spleen in association with myeloproliferative disorders. On the other hand, EMH in the gastric wall is extremely rare. We report a rare case of EMH foci coexisting with early gastric cancer, which resulted in severe gastrointestinal bleeding. A 70-year-old male was diagnosed with myelofibrosis 4 years ago and visited our emergency room with a complaint of hematemesis and tarry stools. Upper gastrointestinal endoscopy revealed three early-stage gastric cancers in the lower gastric body and antrum, and biopsy was performed. Persistent bleeding at the biopsy site of the hypogastric lesion led to the consideration of surgical intervention. An open distal gastrectomy was performed. Postoperative histopathological examination revealed the tumor of the lower gastric body had EMH foci associated with myelofibrosis.

Intravascular large B-cell lymphoma diagnosed by FDG-PET/CT and endometrial biopsy.

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of non-Hodgkin's lymphoma characterized by a proliferation of tumor cells within the lumina of small to medium-sized vessels. Because there are few or no concomitant solid lesions, a diagnosis of IVLBCL usually cannot be established by CT or MR imaging. Herein, we describe a case of IVLBCL involving the uterus, in which (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) was useful for diagnosis. A 47-year-old woman was referred to our hospital because of fever and anemia. Laboratory examination demonstrated anemia and thrombocytopenia. Bone marrow aspiration and biopsy showed hemophagocytosis without involvement of lymphoma cells. Random skin biopsy did not demonstrate lymphoma involvement. FDG-PET/CT imaging showed FDG accumulation in the uterus. MR imaging demonstrated uterine leiomyoma only. Based on these findings, uterine endometrial biopsy was performed and histological diagnosis of IVLBCL involving the uterus was established. She received 6 courses of R-CHOP therapy and high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation. At present, she remains in complete remission after 33 months.

[Membranous nephropathy with nephrotic syndrome developed after allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia].

A 38-year-old man was diagnosed with acute lymphoblastic leukemia. We performed myeloablative bone marrow transplantation from an unrelated donor during the patient's first complete remission. After engraftment, he developed acute graft-versus-host disease involving the gastrointestinal tract on day 32. Steroids and mycophenolate mofetil were initiated from day 39. His symptoms improved and the dose of immunosuppressants was tapered and then discontinued on day 421. On day 491, he developed nephrotic syndrome (NS). Based on renal biopsy, membranous nephropathy was diagnosed. There were no apparent symptoms or abnormal laboratory data suggestive of chronic graft-versus-host disease (cGVHD). Steroid therapy was initiated from day 518 and proteinuria improved significantly. NS is very rare following allogeneic hematopoietic stem cell transplantation (allo-HSCT). When there is no concomitant cGVHD, as in this case, allo-HSCT-associated NS is difficult to distinguish from idiopathic NS.

Serum cytokine profiles at the onset of severe, diffuse alveolar hemorrhage complicating allogeneic hematopoietic stem cell transplantation, treated successfully with pulse intravenous cyclophosphamide.

A 59-year-old man with lymphoma-type adult T-cell leukemia/lymphoma was admitted to hospital for treatment of a skin relapse on day 398 after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To induce a graft-versus-adult T-cell leukemia/lymphoma effect, we discontinued methylprednisolone and tacrolimus. About a month after the discontinuation, he developed grade II acute graft-versus-host disease (GVHD) with a high fever. Soon after the development of GVHD, all the skin lesions regressed in size and finally vanished. However, he developed diffuse alveolar hemorrhage (DAH), which was resistant to high-dose corticosteroid therapy. He was intubated for respiratory insufficiency on day 451. Cyclophosphamide pulse therapy was administered at a dose of 1 g per day for 2 days and his oxygen saturation then improved, and ventilatory support was released on day 465. On analysis of cytokine profiles at the onset of DAH, we found elevated serum levels of T-helper 2 cytokines as well as T-helper 1 cytokines, suggesting that both T-helper 1 and T-helper 2 cytokines might play a role in the occurrence of DAH following allo-HSCT. Pulse cyclophosphamide treatment might be very effective in suppressing the exaggerated allogeneic immune response in DAH.

[Epstein-Barr virus-associated post-transplant lymphoproliferative disorder diagnosed by the episode of intestinal perforation following allogeneic hematopoietic stem cell transplantation].

A 64-year-old man was diagnosed as having acute myeloid leukemia. We performed sequential treatment with chemotherapy and reduced-intensity stem cell transplantation from an unrelated donor while the patient was in partial remission. After engraftment, he developed acute graft-versus-host disease of the gut on day 42 and steroid therapy was started. Despite transient aggravation of diarrhea, his symptoms slowly improved and the dose of steroid was tapered. On day 159, he complained of acute left lower abdominal pain. A CT scan showed perforation of the digestive tract and ileectomy was performed. At surgery, multiple ulcers of the intestine were found and one of the ulcers was perforated. Pathologically, transmural and diffuse proliferation of atypical cells in the ulcer were confirmed. Since these cells were positive for CD20 and Epstein-Barr-virus (EBV) encoded RNA, we made a diagnosis of EBV-associated post-transplant lymphoproliferative disorder (PTLD). Reduction in the dose of immunosuppressive agents and rituximab led to complete remission of PTLD. PTLD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is relatively rare, and the development of gastrointestinal perforation after allo-HSCT is very rare.

Combination of Frailty Status and Comorbidity Score Improves the Stratification of Survival in Patients With Myelodysplastic Syndrome Owing to Good Predictive Capability for Infection-related Mortality.

BACKGROUND: We investigated the prognostic effects of frailty and its association with comorbidity in patients with myelodysplastic syndrome (MDS). PATIENTS AND METHODS: This retrospective analysis included 118 consecutive patients diagnosed with MDS. Frailty was evaluated using the clinical frailty scale (CFS). Comorbidity was classified using the Charlson comorbidity index (CCI) and MDS comorbidity index (MDS-CI). RESULTS: On multivariate analysis, CFS (≥ 5 vs. < 5; hazard ratio [HR], 3.37; P = .002), CCI (≥ 2 vs. < 2; HR, 2.59; P = .002), and Revised International Prognostic Scoring System (IPSS-R) category (HR, 2.1; P = .009) were independently predictive of overall survival (OS). One-year OS of patients with CFS ≥ 5 or CCI ≥ 2 were significantly worse compared with those with CFS < 5 or CCI < 2 (55% vs. 91%; P < .001; 46% vs. 91%; P < .001, respectively). OS was clearly stratified into 3 groups according to CFS (≥ 5 vs. < 5) and CCI (≥ 2 vs. < 2; P < .001). When comparing these 3 groups, the incidence of infection-related mortality progressively increased with CFS ≥ 5 and/or CCI ≥ 2 (P < .001). This effect was more obvious in patients with lower IPSS-R. CONCLUSION: The present study suggests frailty and comorbidity may be patient-related, independent predictive factors of poor prognosis. This could probably be attributed to increasing infection-related mortality with frailty and comorbidity. Combining the evaluation of frailty and comorbidity with IPSS-R might aid in more precise prediction of OS, especially in patients with low risk of MDS.

The Proportional Relationship Between Pretransplant WT1 mRNA Levels and Risk of Mortality After Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Not in Remission.

BACKGROUND: The relationship between the expression levels of Wilms' tumor-1 gene (WT1) mRNA in peripheral blood before allogeneic hematopoietic cell transplantation (allo-HCT) and risk of mortality in acute myeloid leukemia (AML) patients in noncomplete remission (non-CR) remains quite elusive. METHODS: We retrospectively assessed the impact of the pretransplant WT1 mRNA level on survival after allo-HCT in non-CR AML patients. RESULTS: A total of 125 AML patients, including 46 non-CR patients (36.8%), were analyzed. On multivariate analysis of non-CR AML patients, WT1 mRNA ≥5000 copies/µg RNA was significantly related to increased risk of mortality (hazard ratio, 2.7; 95% confidence interval, 1.3-5.5; P = 0.008). Furthermore, in the entire cohort, log10-transformed WT1 mRNA before allo-HCT was found to be significantly associated with the increased risk of mortality irrespective of whether the disease status was CR or non-CR, using Akaike's information criterion. As the pretransplant WT1 mRNA level elevated, the hazard ratio of mortality monotonically increased in a nonlinear manner regardless of remission status, suggesting that WT1 mRNA level in peripheral blood might reflect tumor burden. CONCLUSIONS: This study demonstrated that the pretransplant WT1 mRNA level was a powerful prognostic factor in allo-HCT even for non-CR AML patients, and there may be a WT1 mRNA threshold in non-CR patients for benefiting from allo-HCT.

Two cases of ampulla (takotsubo-shaped) cardiomyopathy associated with hemophagocytic lymphohistiocytosis.

There have been many reports of patients with ampulla cardiomyopathy described as takotsubo-shaped cardiomyopathy in the cardiovascular field. This unique cardiomyopathy is characterized by transient apical ballooning and hypokinesis of the left ventricle. We describe 2 cases of ampulla cardiomyopathy associated with hemophagocytic lymphohistiocytosis (HLH). In both of the patients, ventricular dysfunction suddenly occurred during the active phase of HLH. In each case, the findings on ECG, echocardiogram and left ventriculogram were compatible with ampulla cardiomyopathy. To our knowledge, this communication is the first to report cases of ampulla cardiomyopathy associated with HLH. Our cases suggest that HLH hypercytokinemia may have a role in causing ampulla cardiomyopathy.

[Improved outcome in brain abscess during induction in acute myelocytic leukemia].

A 31-year-old female with acute myelocytic leukemia was admitted to our hospital in June 2004. She had complications of brain abscess at the WBC nadir after the second course of induction therapy. However,because the platelet count was low, neurosurgical procedures, including craniotomy/abscess resection, or abscess drainage, were not performed, and we could not detect bacteria or fungus as the cause of brain abscess. Combination therapy with meropenem trihydrate and fosfluconazole was effective. Thereafter, she underwent related peripheral blood stem cell transplantation, and has had no recurrence of brain abscess. Brain abscess during chemotherapy for patients with acute leukemia is commonly due to fungus,particularly Aspergillus, which has a very high fatality rate. Therefore, the treatment of brain abscess without the detection of bacteria and fungus requires combination therapy with antifungal agents and antibiotics. In this case, methionine-positron emission tomography was useful for the evaluation of therapeutic effectiveness for brain abscess.

[Myelodysplastic syndrome with cyclosporine A-induced encephalopathy presenting with a mass effect on the right basal ganglia after cord blood transplantation].

An 18-year-old female with myelodysplastic syndrome underwent an allogeneic cord blood transplantation in May 2005. The conditioning regimen consisted of total body irradiation, cytarabine and cyclophosphamide. The day of the cord stem cell transfusion was counted as Day 0. For acute GVHD prophylaxis, cyclosporine A (CsA) and methotrexate were used. Engraftment was achieved on Day 30, acute GVHD grade II developed on Day 45 and treatment with methylprednisolone for acute GVHD was started. On Day 68 the patient had generalized seizures accompanied by loss of consciousness, hypertension and left hemiparesis, and was intubated. A cranial CT scan showed a mass effect on the right basal ganglia, and high signal intensities on the T2-weighted and FLAIR images of a MR examination were detected in the bilateral basal ganglia and posterior lobes, the findings of which were compatible with a brain tumor or infectious disease. Since an increased level of apparent diffusion coefficient (ADC) values on the bilateral basal ganglia was noted, we suspected that vasogenic edema had caused the mass effect. She went into remission immediately after CsA treatment was discontinued. Therefore, this case was diagnosed as atypical reversible posterior leukoencephalopathy syndrome (RPLS) associated with CsA. CsA-induced encephalopathy presenting a mass effect in clinical imaging findings is very rare, and an ADC map may be useful for the diagnosis of RPLS.

[High-dose chemotherapy with autologous hematopoietic stem cell transplantation for non-Hodgkin's lymphoma in complete response as consolidation therapy, second report].

High-dose chemotherapy followed by autologous peripheral blood transplantation (HD-APBSCT) is a therapeutic option for patients with non-Hodgkin's lymphoma (NHL) after complete remission (CR) as consolidation therapy. In this report we describe a retrospective study of such treatment. A total of 38 patients with NHL were treated between November 19 9 1 and March 2005. At five years,the rate of disease-free survival (DFS) and overall survival (OS) was 64.3% and 66.5%, respectively. Patients who underwent transplantation in first CR had a 5-year probability of disease-free survival of 71.6% compared with 35.7% for those who were in second CR at the time of transplantation (p=0.10). In a monovariate analysis, second CR status at the time of transplantation was a relatively adverse predictor of DFS. None of those factors containing surface markers were significantly associated with clinical variables such as the CR status at the time of transplantation. Thirty high intermediate risk and high risk patients with aggressive B-cell lymphoma had a better outcome than patients treated with standard chemotherapy. In this study, 8 patients with T-cell lymphoma had a 3-year DFS and OS of 87.5% and 87.5%, respectively. HDT-APBSCT is a candidate for consolidation therapy for high-intermediate risk and high risk patients with aggressive B-cell and T-cell lymphoma.

Prognostic Effect of Low Subcutaneous Adipose Tissue on Survival Outcome in Patients With Multiple Myeloma.

BACKGROUND: Increasing evidence suggests that decreased skeletal muscle mass (sarcopenia) or adipose tissue assessed using computed tomography (CT) predicts negative outcomes in patients with solid tumors. However, the prognostic value of such an assessment in multiple myeloma (MM) remains unknown. PATIENTS AND METHODS: Consecutive patients with newly diagnosed symptomatic MM were retrospectively analyzed. The cross-sectional area of skeletal muscles and subcutaneous or visceral adipose tissue was measured using CT. Body composition indexes (skeletal muscle index, subcutaneous adipose tissue index [SAI], and visceral adipose tissue index) were calculated. The association between these indexes and overall survival (OS) was examined. RESULTS: Of 56 evaluable patients, 37 (66%) had sarcopenia. The 2-year OS in patients with SAI < median was 58% compared with 91% in those with SAI ≥ median (P = .006). In multivariate analyses, SAI < median was significantly associated with poor OS (hazard ratio, 4.05; P = .02). Sarcopenia was not associated with OS. The maximum value of the standardized uptake value was significantly higher in patients with SAI < median (P = .02). CONCLUSION: The findings of this study suggest that low subcutaneous adipose tissue at baseline predicts poor survival outcome in patients with MM.

[Chronic GVHD with polymyositis after non-myeloablative stem cell transplantation].

A 57-year-old man underwent an autologous hematopoietic stem cell transplant for mantle cell lymphoma in August 1999. Anemia and thrombocytopenia appeared in November 2001. He was diagnosed with further hematological examination as having acute myeloid leukemia with multilineage dysplasia following secondary myelodysplastic syndrome. He received the allogeneic hematopoietic stem cell transplant from his HLA DRB1 locus mismatched brother in May 2002. The nonmyeloablative preparative regimen consisted of fludarabine 30mg/m2 for 6 days and busulfan 4mg/kg for 2 days. Eosinophilia, decrease of lacrimal fluid and liver dysfunction appeared on Day 104. We diagnosed this as chronic GVHD and treated the patient with prednisolone 10 mg/day. Thereafter, his chronic GVHD gradually improved. He had fever and myalgia in the extremities and lumbar region with elevated serum CPK and aldolase in January 2003. Histological examination led to a diagnosis of polymyositis simultaneously with chronic GVHD. Prednisolone 50 mg/day as an initial dose was started for the polymyositis following which the prednisolone dose was gradually tapered off. The polymyositis improved promptly after the administration of prednisolone and remains in remission with a current maintenance program of prednisolone 5 mg/day.

[Temporary effective treatment with L-asparaginase for a patient with refractory nasal NK/T-cell lymphoma].

A 48-year-old man was referred to Sakai Municipal Hospital with nasal discharge and right facial swelling. The pathological findings of a nasal cavity tumor revealed stage IIB NK/T-cell lymphoma. He was admitted to our hospital and received CHOP therapy, resulting in progressive disease. Irradiation therapy combined with DeVIC chemotherapy also could not shrink his lymphoma. Then, two courses of L-asparaginase(L-Asp) were administered, resulting in partial improvement of the nasal and pharynx lesions, resolution of the fever and improvement of his performance status. On the day before a third course of L-Asp, he again developed a lowgrade fever. Although L-Asp was administered for several days, marked elevation of serum LDH, AST, ALT level, and thrombocytopenia persisted, and he died. Post-mortem examinations revealed hemophagocytosis in the bone marrow and liver, and infiltration of lymphoma cells into multiple organs including left lower lung, liver, spleen and kidneys. Although L-Asp was effective against nasal NK/T-cell lymphoma resistant to combination chemotherapy and irradiation therapy, the effectiveness of the single agent with L-Asp was only transient. L-Asp based regimen should be used as first-line therapy if asparagine synthetase protein expression is low using an immunohistochemical method.

[MR imaging provides important clues for the diagnosis of benign intracranial hypertension by all-trans retinoic acid in a patient with acute promyelocytic leukemia].

We report a case of benign intracranial hypertension (BIH) caused by all-trans retinoic acid (ATRA) in a patient with acute promyelocytic leukemia. A 21-year-old male was admitted to our hospital with pancytopenia. He was diagnosed as having acute promyelocytic leukemia due to increased promyelocytes, and PML-RAR alpha chimeric mRNA was detected. The administration of ATRA and idarubicin was started immediately. After 26 days of the chemotherapy, he complained of diplopia. Ophthalmologic examination revealed bilateral papilledema and hemorrhage. The cerebrospinal fluid showed an increase in pressure, but no other abnormalities. Computed tomography showed no intracranial abnormalities. The orbital MR imaging showed distension of the perioptic subarachnoid space and flattening of the posterior sclera. A diagnosis of BIH was made. After the discontinuation of ATRA, the symptoms improved and the MR abnormalities disappeared. As far as we know, there have been no reports illustrating MR abnormalities of BIH caused by ATRA, for the diagnosis and monitoring of which orbital MR imaging can provide important clues.

Refractoriness to platelet transfusion in acute myeloid leukemia correlated with the optical density of anti-platelet factor 4/heparin antibodies.

A small number of reports have described cases of heparin-induced thrombocytopenia complicating hematological disorders with impaired platelet production. We describe the case of a 66-year-old woman with acute myeloid leukemia who exhibited unexplained refractoriness to platelet transfusion, while receiving heparin flushes, and was found to have anti-platelet factor 4 (PF4)/heparin antibodies with high optical density (OD) values (>2 units) detected by an enzyme-linked immunosorbent assay. After cessation of heparin flushes, her refractoriness to platelet transfusion resolved. We retrospectively confirmed that the OD values for anti-PF4/heparin antibodies declined gradually; refractoriness to platelet transfusion resolved when the OD values fell below 1.0 units. Given the absence of any other evident explanation for this phenomenon, and the correlation between the OD values for anti-PF4/heparin antibodies and the efficacy of platelet transfusions, we conclude that the patient's refractoriness to platelet transfusion was most likely caused by anti-PF4/heparin antibodies that had platelet-activating properties.