Outcomes of Patients Who Undergo Transfusion of Fresh Frozen Plasma: A Prospective, Observational, Multicentre Cohort Study in Hiroshima, Japan.

PURPOSE: Given the chronic shortage of blood for transfusion in Japan, promotion of appropriate use of fresh frozen plasma (FFP) urgently needs to be addressed by the national blood project in Japan. Whether FFP transfusions are administered appropriately in Japan is currently unclear. In this study, we aimed to investigate the outcomes of patients who undergo FFP transfusion and the appropriateness of use of FFP. PATIENTS AND METHODS: This multicentre, prospective, observational cohort study was conducted from September 2017 to April 2019 at the 15 medical institutions in Hiroshima Prefecture that are the top providers of FFP. All patients who underwent FFP transfusion during the study period were included, relevant data being extracted from the medical records. The indications for FFP transfusion were classified in accordance with the Guidelines of the Ministry of Health, Labour and Welfare of Japan. Factors associated with patient outcomes at day 28 after FFP transfusion were subjected to multivariable logistic regression analysis. RESULTS: In total, data of 1299 patients were eligible for analysis. At least 63.8% of indications for FFP were in accordance with the guideline for FFP transfusions. The mortality rate at day 28 after FFP transfusion was 16.2%. Older age (65-74 years: adjusted odds ratio [AOR]=4.3, ≥75 years: AOR=4.1), non-perioperative use (AOR=4.5), coagulopathy associated with liver damage (AOR=2.7), large volume of FFP transfused (AOR=2.5), and lack of improvement in blood coagulation following FFP transfusion were independently and significantly associated with death within 28 days after FFP transfusion. CONCLUSION: Our findings do not support the simple conclusion that FFP transfusions contribute to prognosis. However, given that coagulopathy in patients with end-stage liver disease is infrequently improved by FFP transfusion, "inappropriate" use of FFP should be avoided. It is important to promote appropriate use of FFP so as not to waste blood resources.

Association Between Immune-Related Adverse Events and the Prognosis of Patients with Advanced Gastric Cancer Treated with Nivolumab.

BACKGROUND: Little is known about the association between immune-related adverse events (irAEs) and the efficacy and survival outcomes of nivolumab in patients with advanced gastric cancer (AGC). OBJECTIVE: The present study examined the association between irAEs and the prognosis of patients with AGC treated with nivolumab. PATIENTS AND METHODS: From July 2017 to November 2020, patients who had been diagnosed with advanced unresected gastric cancer and treated with nivolumab at our institution were included in this analysis. We compared the clinical and survival outcomes between the irAE and non-irAE groups. We also evaluated the factors associated with better survival in patients treated with nivolumab. RESULTS: A total of 52 patients were included in the present study, and irAEs were observed in 13 (25%). Among the patients with measurable lesions (n = 29), the disease control rates were significantly higher in the irAE group than in the non-irAE group (88 vs. 24%; P = 0.0033). At the 8- and 12-week landmark analyses, the median overall survival (OS) in the irAE group was significantly longer than that in the non-irAE group, whereas the median progression-free survival was comparable between the groups. A multivariate analysis by Cox proportional hazard regression at the 8-week landmark revealed that the development of irAEs (hazard ratio 0.18; 95% confidence interval 0.0099-0.86) alone was positively associated with a longer OS. CONCLUSIONS: The development of irAEs might be associated with survival outcomes with nivolumab treatment in patients with AGC.

The Progression of Esophageal Mucosa-associated Lymphoid Tissue Lymphoma after Helicobacter pylori Eradication Therapy: A Case Report and Discussion of Therapeutic Options.

A 50-year-old woman with epigastric discomfort was referred to our hospital. Esophagogastroduodenoscopy showed flat, elevated, submucosal tumor-like lesions in the esophagus. Extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) of the esophagus was diagnosed based on the examination of an endoscopic biopsy specimen. Computed tomography showed the enlargement of a lymph node in the gastric cardia. The present case showed disease progression despite Helicobacter pylori eradication therapy and achieved partial remission after rituximab monotherapy. The patient remained in partial remission for 20 months. This case suggests that esophageal MALT lymphoma with lymph node involvement does not respond to H. pylori eradication therapy and that it requires systemic treatment.

A case of primary extranodal natural killer/T-cell lymphoma in the orbit and intraocular tissues with cerebrospinal fluid involvement.

PURPOSE: To report a rare case of primary orbital natural killer (NK)/T-cell lymphoma without nasal lesions but with cerebrospinal fluid involvement. OBSERVATIONS: A 73-year-old woman was referred to the uveitis clinic with suspected unilateral acute uveitis in her right eye and a right orbital tumor. Epstein-Barr virus DNA was detected in the aqueous humor in her right eye, and orbital biopsy revealed the presence of extranodal NK/T-cell lymphoma (ENKTL), nasal type. Positron emission tomography showed significant 18F-fluorodeoxyglucose uptake in the right orbit, with no other signs of systemic involvement. Cerebrospinal fluid analysis demonstrated lymphoma cell infiltration. She was diagnosed with stage IV ENKTL and treated with orbital radiotherapy and systemic chemotherapy, with subsequent remission. However, the lymphoma relapsed in her left vitreous at 10 months after therapy, suggesting metastasis of lymphoma cells to the contralateral eye via the vitreous and cerebrospinal fluid. CONCLUSIONS AND IMPORTANCE: A few cases of ocular-tissue ENKTL have been reported, mostly involving invasion or dissemination of primary nasal lesions; in contrast, primary orbital and intraocular ENKTL has rarely been reported. To the best of our knowledge, this is the first report of a primary orbital ENKTL metastasizing to the vitreous of the contralateral eye. Although ENKTL is rare in the orbit and intraocular tissues, it should be considered as a possible differential diagnosis in patients with orbital tumors or intraocular inflammation resistant to steroid therapy because ENKTL has a very poor prognosis in the advanced stage.

Successful management of recurrent bleeding with tocilizumab in an acquired hemophilia A patient with rheumatoid arthritis.

A 61-year-old woman with rheumatoid arthritis was diagnosed as having acquired hemophilia A with extensive subcutaneous bleeding. The patient was treated with a corticosteroid, and her symptoms improved temporarily. However, these recurred during the tapering of her corticosteroid dose, and neither the re-increase in the dose nor the addition of cyclophosphamide could control her bleeding tendency. After the administration of an anti-IL-6 receptor antibody (tocilizumab), the doses of corticosteroid and cyclophosphamide could be tapered. Tocilizumab combined with another immunosuppression therapy might be effective in the treatment of acquired hemophilia A.

Bortezomib and dexamethasone for multiple myeloma: higher AST and LDH levels associated with a worse prognosis on overall survival.

BACKGROUND: Bortezomib offers a novel approach to the treatment of multiple myeloma producing rapid control. The aim of this study was to investigate the outcomes of bortezomib and dexamethasone-treated patients with multiple myeloma. METHODS: We conducted a retrospective study of 44 consecutively-treated multiple myeloma patients with bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11 of a 21-day cycle or 1.3 mg/m(2) intravenously 1, 8, 15, and 22 of every 35-day cycle) and dexamethasone. RESULTS: The median time to progression, progression free survival time, and overall survival time in the treatment groups was 14.9, 14.9, and 38.3 months, respectively. The present study also suggests the possibility that the prognosis of patients with high levels of AST and LDH might be worse. CONCLUSIONS: Our results indicate that the treatment of multiple myeloma with bortezomib and dexamethasone is feasible.

Clinical significance of sIL-2R levels in B-cell lymphomas.

Elevated soluble interleukin-2 receptor (sIL-2R) in sera is observed in patients with malignant lymphoma (ML). Therefore, sIL-2R is commonly used as a diagnostic and prognostic marker for ML, but the mechanisms responsible for the increase in sIL-2R levels in patients with B-cell lymphomas have not yet been elucidated. We first hypothesized that lymphoma cells expressing IL-2R and some proteinases such as matrix metalloproteinases (MMPs) in the tumor microenvironment can give rise to increased sIL-2R in sera. However, flow cytometric studies revealed that few lymphoma cells expressed IL-2R α chain (CD25) in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), and most CD25-expressing cells in the tumor were T-cells. Distinct correlations between CD25 expression on B-lymphoma cells and sIL-2R levels were not observed. We then confirmed that MMP-9 plays an important role in producing sIL-2R in functional studies. Immunohistochemical (IHC) analysis also revealed that MMP-9 is mainly derived from tumor-associated macrophages (TAMs). We therefore evaluated the number of CD68 and CD163 positive macrophages in the tumor microenvironment using IHC analysis. A positive correlation between the levels of sIL-2R in sera and the numbers of CD68 positive macrophages in the tumor microenvironment was confirmed in FL and extranodal DLBCL. These results may be useful in understanding the pathophysiology of B-cell lymphomas.

[A case of neurotoxicity reduced with pregabalin in R-CHOP chemotherapy for diffuse large B-cell lymphoma].

When performing R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)for diffuse large B-cell lymphoma(DLBCL), neurotoxicity of vincristine(VCR)is the serious dose-limiting factor.Pregabalin is one of the first-line treatments for painful diabetic peripheral neuropathy in many countries, and we have administered it to relieve the neurotoxicity associated with adverse effects of VCR in a DLBCL patient treated with the R-CHOP regimen.A 49-year-old man with kidney DLBCL had surgery performed.Afterward, the R-CHOP regimen was introduced.In order to relieve the neurotoxicity of VCR, pregabalin was used from day 8 in the second course.The severity of sensory neurotoxicity after the administration of pregabalin was improved from CTCAE(v4.0)grade 3 to grade 1.Therefore, there is a possibility that VCR-induced neurotoxicity is relieved by pregabalin.Further trials are needed to confirm the value of pregabalin.

Good's syndrome-associated pure red cell aplasia with myelodysplastic syndrome.

We report a case of Good's syndrome-associated pure red cell aplasia (PRCA) with myelodysplastic syndrome (MDS). In this case, effector memory T (T(EM)) cells were expanded in the bone marrow. It remains uncertain whether the development of MDS was caused by the basic marrow defects or radiation therapy. However, since CD8(+) perforin(+) T(EM) cells expanded in the bone marrow, as was previously described for 3 of our patients with thymoma-associated PRCA, it is highly possible that the pathogenic mechanism of PRCA that is accompanied by thymoma is related to the expanded CD8(+) perforin(+) T(EM) cells in this MDS-complicated case.

Clinical and genetic features of therapy-related myeloid neoplasms after chemotherapy for acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a highly curable disease with excellent complete remission and long-term survival rates. However, the development of therapy-related myeloid neoplasms (t-MN) is being reported with increasing frequency in patients successfully treated for APL. We attempted to clarify the different clinical features and hematologic findings between t-MN and relapse cases, and to identify gene alterations involved in t-MN. We compared 10 relapse and 11 t-MN cases that developed in 108 patients during their first complete remission from APL. At APL diagnosis, t-MN patients had lower white blood cell counts than did relapse patients (P = .048). Overall survival starting from chemotherapy was significantly worse in t-MN patients than in relapse patients (P = .022). The t-MN cases were characterized as CD34(+)/HLA-DR(+) and PML-RARA(-), and 4 RUNX1/AML1 mutations were detected. T-MN is easily distinguished from APL relapse by evaluating these hematologic features, and it may originate from primitive myeloid cells by chemotherapy-induced RUNX1 mutations.

Ectopic cyclin D1 overexpression increases chemosensitivity but not cell proliferation in multiple myeloma.

We established a myeloma cell line (RPMI8226) with cyclin D1 overexpression in which the transfected cyclin D1 gene was stably expressed. D1 transfectants showed down-regulation of cyclin D2. Cell proliferation analysis did not show any differences among RPMI8226, mock control, and D1 transfectants. The number of S-phase cells increased while the number of G0/G1- and G2/M-phase cells decreased in D1 transfectants, which indicates a prolonged S-phase caused by cyclin D1 transfection. A decreased number of G2/M-phase cells was also detected in myeloma cells of patients with translocation t(11;14)(q13;q32). Western blot analysis revealed an increase in the hyperphosphorylated form of retinoblastoma (Rb) protein in D1 transfectants; however, the expression of p53, p16, Bax, Bad, Bcl-2, and Mcl-1 did not significantly change. Treatment with anti-myeloma drugs (melphalan, dexamethasone, bortezomib and immunomodulatory compounds) induced apoptosis earlier in D1 transfectants compared with RPMI8226 and mock control via the activation of both caspase-8 and -9. However, we could not detect a relationship between cyclin D1 expression and the response to treatment with VAD and bortezomib. Therefore, we assume that high sensitivity to anti-myeloma drugs depends on the duration of the S-phase, but a clinical response might depend on the number of myeloma cells with cyclin D1 overexpression.

Unrelated umbilical cord blood transplantation using a TBI/FLAG conditioning regimen for adults with hematologic malignancies.

A combined chemotherapy regimen comprising fludarabine, cytosine arabinoside, and granulocyte colony-stimulating factor (FLAG) has been used in the treatment of relapsed or refractory leukemias. We here report 38 patients with hematologic malignancies who underwent single-unit cord blood transplantation (CBT) with a conditioning regimen comprising 12-Gy total-body irradiation (TBI) and FLAG therapy (TBI/FLAG). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus or cyclosporin A and/or methotrexate. The median nucleated cell dose was 2.43 x 10(7)/kg (range: 1.96-3.55 x 10(7)/kg). Of 34 evaluable recipients, the cumulative incidence of donor engraftment was 97%. The median time to reach an absolute neutrophil count of 500/microL was 23 days (range: 18-35 days). The median time to an untransfused platelet count of 50,000/microL was 45.5 days (range: 28-208 days). Sixteen patients developed grades II-IV of acute GVHD. Fourteen patients were alive at a median follow-up of 46 months (range: 4-77 months). The estimated event-free survival at 3 years for all patients was 33.5%, with 72.7% in the standard-risk group (n = 11) and 17.7% in the high-risk group (n = 27) (P = .0075). These results showed that this novel regimen was well tolerated by patients and able to establish sustained donor cell engraftment, indicating the feasibility of TBI/FLAG as a conditioning regimen for CBT in adults with hematologic malignancies.

Osteoprogenitor differentiation is not affected by immunomodulatory thalidomide analogs but is promoted by low bortezomib concentration, while both agents suppress osteoclast differentiation.

We investigated the effects of bortezomib (PS-341) and immunomodulatory thalidomide analogs (immunomodulatory compounds; CC-4047, CC-6032, and CC-5013, or lenalidomide) on osteoblast and osteoclast differentiation in vitro using human mesenchymal stem cells (hMSC) to commit to osteoprogenitor cells and peripheral blood mononuclear cells (PBMCs) isolated from healthy donors, respectively. First, the concentration of bortezomib for an anti-myeloma effect was more than 1.0 nM in myeloma cells of multiple myeloma (MM) patients and more than 2.5 nM in myeloma cell lines. In contrast, anti-myeloma effects of immunomodulatory compounds on myeloma cells differed among myeloma cells and these compounds themselves. Subsequently, these agents (bortezomib; 0.5-5.0 nM, immunomodulatory compounds; 10 microM) were added to the osteoprogenitor cell culture media or the media for osteoclast differentiation. Low bortezomib concentrations (0.5 and 1.0 nM) increased ALP activity, and the delayed addition of bortezomib further increased ALP activity. Mineralized nodular formation with <2.5 nM bortezomib was not impaired. BMP2 expression on osteoprogenitor cells was found to increase in a time-dependent manner irrespective of treatment with bortezomib. On the other hand, the anti-osteoclast effect with low bortezomib concentration (< or =2.5 nM) depended on MM patients. In contrast, immunomodulatory compounds at 10 microM showed an anti-osteoclast effect without cytotoxicity to osteoblast differentiation, at which dose myeloma cells underwent apoptosis. These findings might improve the treatment strategy for MM patients without damaging BM stromal cells by combining bortezomib with immunomodulatory compounds.

Connective tissue growth factor is an indicator of bone involvement in multiple myeloma, but matrix metalloproteinase-9 is not.

Bone disease (BD) in multiple myeloma (MM) is because of the activation of osteoclasts and impairment of osteoblast differentiation. Connective tissue growth factor (CTGF) is known to participate in the differentiation of mesenchymal stem cells to committed osteoprogenitor cells. We analysed the concentration of circulating CTGF in 35 MM patients and 22 malignant lymphoma (ML) patients and 14 normal individuals. CTGF is protease-sensitive and thus is found as both an N-terminal half fragment (N-half CTGF) and whole (W-CTGF). Serum levels of W-CTGF and N-half CTGF + W-CTGF were determined by separate sandwich enzyme-linked immunosorbent assays. The level of W-CTGF was significantly lower (P < 0.005) in MM patients compared with ML patients and normal individuals, while N-half + W-CTGF was similar in all groups. Furthermore, W-CTGF was significantly lower in MM patients with BD compared with those without BD (P < 0.005) and this was independent of previous treatment. Matrix metalloproteinase (MMP)-9 is produced by myeloma cells and is thought to be related to BD in MM. However, MMP-9 does not cleave CTGF and serum MMP-9 level was not related to BD in MM. Thus, CTGF is an indicator of BD in MM; its metabolism and function in MM should be clarified.

Changes of clotting factors (7, 9 and 10) and hepatocyte growth factor in patients with thrombotic microangiopathy after bone marrow transplantation.

To investigate risk factors for thrombotic microangiopathy (TMA) after bone marrow transplantation (BMT), the levels of three clotting factors (7, 9 and 10) and hepatocyte growth factor (HGF) were measured. Among 46 consecutive patients who underwent BMT, six developed TMA and 40 did not. The levels of the clotting factors and HGF did not differ significantly between the six patients with TMA and the 40 patients without it. In two patients who developed TMA during the earlyperiod after BMT, however, the levels of the three clotting factors were significantly decreased even before BMT, along with a significant increase of HGF. These findings suggest that patients with severe hepatic dysfunction before BMT, especially those with impaired protein synthesis, had an increased risk of developing TMA soon after BMT. It was also suggested that measurement of clotting factors (7, 9 and 10) and HGF may be useful to predict the occurrence of TMA in the early period after BMT.

Prognosis value of atrial natriuretic peptide and brain natriuretic peptide for heart failure in patients undergoing allogeneic bone marrow transplantation.

It is essential to evaluate the organ function of the recipient before bone marrow transplantation (BMT). This study investigated the usefulness of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels as indicators of cardiac function. Seventy-five consecutive patients undergoing allogeneic BMT were enrolled. All of them had an ejection fraction of 55% or more on echocardiography. Six of the 75 patients died of heart failure after transplantation and these 6 patients were compared with the other 69 patients to assess the prognostic value of the two natriuretic peptides. Both peptides remained normal from before conditioning until recovery from leukopenia in all 69 surviving patients. Among the 6 patients who died of heart failure, however, BNP was increased in all 6 patients and ANP was increased in five of them at an average of 43.6 +/- 16.7 days before the onset of heart failure. Monitoring of these peptides may not only be useful for assessment of cardiac function but also for predicting the occurrence of heart failure.

The maturation of myeloma cells correlates with sensitivity to chemotherapeutic agents.

We analyzed both morphologic and phenotypic findings of myeloma cells before and after chemotherapy in 21 patients with multiple myeloma. The morphologic analysis was based on the Greipp classification, and phenotypic analysis was performed by 3-color flow cytometry using the CD38 plasma gating method (Marrow plasma 38). Results with flow cytometry using a combination of MPC1, CD49e, and CD45 supported the morphologic findings for the myeloma cells. Treatment with 3 or 4 cycles of VAD (vincristine, doxorubicin, and dexamethasone) therapy was effective in reducing the total numbers of myeloma cells, but the proportion of immature myeloma cells increased after this treatment. However, the immature myeloma cells were reduced by high-dose melphalan (HD-Mel) therapy followed by autologous stem cell transplantation (ASCT). High-dose cyclophosphamide treatment for stem cell harvesting did not show an effect on the residual immature myeloma cells after VAD treatment. In addition, thalidomide was not effective in reducing the numbers of immature myeloma cells. These results suggest that VAD (3 or 4 cycles) therapy plus HD-Mel followed by ASCT is a reasonable treatment for multiple myeloma and that Marrow plasma 38 analysis is a useful method for monitoring the response of multiple myeloma to chemotherapy.

[Angioimmunoblastic T-cell lymphoma complicated with EBV-associated B-cell lymphoma].

A 71-year-old man with high fever and enlargement of the bilateral submandibular, cervical and inguinal lymph nodes was hospitalized at Hiroshima University Hospital. The immunohistochemical and pathologic findings from the biopsy specimens led to the diagnosis of angioimmunoblastic T-cell lymphoma (AILT) with a cluster of CD20-positive cells. Flow cytometry analysis by two-color staining did not reveal any neoplastic B cells. Southern blot analysis showed rearrangement of both the IgH gene and the TCR gene. Furthermore, PCR of the IgH gene using DNA extracted from purified CD19-positive cells from the lymph nodes showed a monoclonal band, and it was different from that of purified CD138-positive cells from the bone marrow. Furthermore, monoclonal Epstein-Barr virus (EBV) infection was detected with PCR using the SL18 and SL19 primers of the LMP-1 gene. Numerous EBER-positive cells were detected diffusely in the lymph nodes. These findings indicated a diagnosis of angioimmunoblastic T-cell lymphoma complicated with EBV-associated B-cell lymphoma, and that immunodeficiency in AILT led to an expansion of EBV infected B-cells.