[Multiple extramedullary plasmacytomas responding to a reduced dose of carfilzomib following drug-induced thrombotic microangiopathy].

Herein, we report the findings of a 79-year-old male patient who presented with multiple extramedullary plasmacytomas following a relapse of primary plasma cell leukemia. He developed thrombotic microangiopathy (TMA) while receiving carfilzomib, lenalidomide, and dexamethasone (KLd) therapy. He was diagnosed with plasma cell leukemia 3 years ago; he demonstrated a very good partial response (VGPR) after undergoing two regimens, including either bortezomib or lenalidomide, and he had been followed up without any other treatment due to complications of infection. Following relapse, KLd was initiated. On day 7 of KLd, TMA developed; therefore, the treatment was discontinued. The TMA improved only with the discontinuation of KLd. A reduced dose of KLd was readministered; the TMA did not relapse. He demonstrated VGPR after three courses of reduced-KLd; he has since remained in remission through ten courses. Therefore, carfilzomib therapy may be useful in relapsing and refractory cases. Drug-induced TMA has been reported to be caused by either immune-mediated or dose-dependent toxicity mechanisms. In patients who develop dose-dependent TMA with carfilzomib, dose reduction could be considered in cases showing an effective response to the treatment.

Increased SLAMF7high monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab.

Monocyte-derived fibrocytes recently garnered attention because the novel pathogenesis of myelofibrosis (MF), and suppression of fibrocyte differentiation by serum amyloid P remarkably improved MF. We previously revealed that human fibrocytes highly expressed signaling lymphocytic activation molecule F7 (SLAMF7) compared with macrophages and that SLAMF7high monocytes in the peripheral blood (PB) of MF patients were significantly elevated relative to those in healthy controls (HCs). In this study, we evaluated SLAMF7high monocyte percentage in the PB of HCs, myeloproliferative neoplasm (MPN) patients with MF, and MPN patients without MF by using a cross-sectional approach. We found that MPN patients with MF who harbored JAK2V617F had a significantly elevated SLAMF7high monocyte percentage, which correlated positively with the JAK2V617F allele burden. In addition, the serum concentration of interleukin-1ra (IL-1ra) was significantly correlated with the SLAMF7high monocyte percentage and JAK2V617F allele burden. These findings suggest that both SLAMF7high monocytes and IL-1ra could be useful noninvasive markers of MF onset. Furthermore, the JAK2V617F allele burden of SLAMF7high monocytes was significantly higher than that of SLAMF7low monocytes and could be a potential target of elotuzumab (Elo), an anti-SLAMF7 antibody used for treating multiple myeloma. Elo independently inhibited differentiation of fibrocytes derived not only from HCs but also from MF patients in vitro. Elo also ameliorated MF and splenomegaly induced by romiplostim administration in humanized NOG mice. In conclusion, an increase of SLAMF7high monocytes with higher JAK2V617F allele burden was associated with the onset of MF in MPN patients harboring JAK2V617F, and Elo could be a therapeutic agent for MPN patients with MF who harbor JAK2V617F.

Does time of CCI measurement affect the evaluation of platelet transfusion effectiveness?

The measurement of corrected count increment at 1-h post-transfusion (CCI-1 h) of platelet concentrate (PC) transfusion is recommended, but in the revised Japanese Guideline (2017) it was changed to "after 10-min to 1-h", following the revision of the guidelines from Western countries. Here, we aimed to investigate on the feasibility to apply the CCI measured at 10-min or 30-min post-transfusion as the surrogate of CCI-1 h. Peripheral blood was collected at 10-min, 30-min and 1-h post-transfusion of PC and the effectiveness of the transfusion was analyzed based on the CCI. In the period from December 2017 to February 2020, 8 patients, who received multiple PC transfusion (total 208) at our institution, were analyzed. We performed the univariate analyses to examine the relationship between CCI value and the categorical variables, p-value <0.1 was obtained for gender (p = 2.91 × 10-19), fever after transfusion (p = 0.0163). The qualitative variables, namely measurement time (p = 0.0553), also showed p-value <0.1. Using these factors as covariates in the mixed effect model, we found that the measurement time (p = 0.0007) had a significant effect on the CCI value when looking at fixed effects. Although there is a tendency for decreased CCI values with time progression, the slope of the change in the mixed model was -0.00307, indicating that the CCI difference among the 3 measurements was small. Here we provide evidence that CCI measured at 10-min and 30-min post-transfusion give results comparable to those measured at 1-h post-transfusion, under the Japanese practice of platelet transfusion, which relies on 100 % single-donor apheresis PC, and ABO-identical whenever possible.

Azacitidine-associated haemorrhagic enteritis in a case of myelodysplastic syndrome: A case report.

WHAT IS KNOWN AND OBJECTIVE: 5-Azacitidine (AZA) is an agent widely used to treat myelodysplastic syndrome (MDS). CASE DESCRIPTION: We herein report an 83-year-old woman diagnosed with MDS who was treated with AZA. She tolerated the first cycle of AZA; however, severe adverse events involving haemorrhagic enteritis with multiple intestinal ulcers developed after the second and third cycles. Additionally, the interval between the administration of AZA and the development of haematochezia shortened with each cycle of AZA. WHAT IS NEW AND CONCLUSION: We herein report as-yet-undescribed potential side effects, AZA-associated haemorrhagic enteritis that should be kept in mind.

[A Case of an Elderly Individual with Breast Cancer Diagnosed as Paget's Disease after Mastectomy].

We report here a case of a 78-year-old woman, who underwent mastectomy for breast cancer. Mammography showed a mass in the right MO area with an unclear boundary. Ultrasound examination revealed an irregular mass of 40×29×19mm in the right C region. Dynamic contrast-enhanced MRI showed a 34mm tumor with contrast effect in the C area of the right breast. We performed a core needle biopsy on the mass, and the histopathological diagnosis was apocrine carcinoma(ER-, PgR-, HER2 3+, and Ki-67 30%)of clinical T2N0M0, stageⅡA. Right mastectomy and sentinel lymph node biopsy were performed. In the postoperative pathological examination, the main lesion was apocrine carcinoma(ER-, PgR-, HER2 3+, Ki-67 20%)and Paget's disease(ER-, PgR-, HER2 3+, Ki-67 30%). After surgery, the patient was given trastuzumab therapy.

[A Case of Duplicated Cancer Simultaneously Causing Breast and Endometrial Cancer].

Recently, with the increase in the number of young cancer patients, we often encounter multiple primary cancer(MPC). In MPC, careful examination is necessary because the treatment order and policies change greatly depending on the stage and prognosis of each tumor. We report a case of synchronous MPC of endometrialcancer and breast cancer. The patient was a 40-year-old woman who underwent endometrial cytology by a previous doctor due to illicit bleeding. As a result of the diagnosis of classⅢB, she underwent gynecological examination in our hospital. Endometroid adenocarcinoma Grade 2 was diagnosed based on endoscopic findings. On pelvic MRI, a lesion adjacent to the neck showed a low signal in the uterine body compared to that in the endocardium. During the preoperative examination, CT showed contrast nodules in the right breast, and ultrasonography was performed at the department of breast surgery. Ultrasonography showed a low-echo mass of 23 mm in the right upper midline region. The needle biopsy results were papillotubular cancer(ER-negative, PgR-negative, HER2 1+, Ki-67 77%). Based on these findings, right breast cancer and endometrial cancer were diagnosed. Initially, we performed right mastectomy and sentinel lymph node biopsy; we then performed pancreatectomy in the gynecology department 2 weeks after discharge. After surgery, gynecology studied 6 courses of TC therapy, and currently, EC is undergoing breast surgery.

[Treatment Experience of Palbociclib as a New Checkpoint Inhibitor].

We encountered a case of multiple metastases from breast cancer. The patient was administered palbociclib, which was a new checkpoint inhibitor. The patient received various chemotherapies and endocrine therapies. We observed episode of care, a harm phenomenon, and tolerability. We did not recognize adverse events more severe than Grade 3 during the 6 weeks after initiating palbociclib therapy. Diagnostic imaging showed that the metastatic lesions maintained stable disease during the 6 weeks after initiating palbociclib therapy. This case suggested that palbociclib therapy is useful for patients with metastatic breast cancer.

[Indoleamine 2,3-Dioxygenase Activity during Letrozol Therapy for an Elderly Breast Cancer Patient].

We evaluated the clinical significance of indoleamine 2,3-dioxygenase(IDO)during letrozol therapy for an elderly patient with locally advanced breast cancer. IDO activity was measured by the tryptophan(Trp)/kynurenine(Kyn)ratio. Trp and Kyn levels were measured using high performance liquid chromatography(HPLC). Serum Trp/Kyn levels of the patient before endocrine therapy were lower than those after endocrine therapy. IDO activity decreased after endocrine therapy and correlat- ed with the number of metastatic lymph node lesions during letrozol therapy. These results suggest that measuring the Trp/ Kyn ratio may be useful for evaluating immunological metastatic status during endocrine therapy in elderly patients with locally advanced breast cancer.

[Clinical Evaluation of Immunosuppressive Acidic Protein in the Serum of Patients with Inflammatory Breast Recurrence].

Inflammatory breast recurrence after breast conserving surgery often compromises patient quality of life(QOL)and is associated with a poor prognosis. For this type of recurrence, the immunological situation of the patient is uncertain. We evaluated the clinical significance of immunosuppressive acidic protein(IAP)in the serum of patients with inflammatory breast recurrence during treatment. We collected serum from 3 patients at three different time points: the pre-treatment phase, recurrence phase, and the post-treatment phase. IAP was then measured from these multiple serum samples. There was a significant difference between serum IAP values in the pre-treatment and recurrence phases. The recurrence phase had a mean IAP value that was higher than the pre-treatment phase. The IAP values were indicative of the disease condition. These results suggest that serum IAP is a useful quantification of the immunological condition of patients with inflammatory breast recurrence.

[Indoleamine 2,3-Dioxygenase Activity during Fulvestrant Therapy for Aromatase Inhibitor Resistant Metastatic Breast Cancer].

We evaluated the clinical significance of indoleamine 2,3-dioxygenase(IDO)for breast cancer patients between different clinical stages and patient ages. IDO activity was measured by the tryptophan(Trp)/kynurenine(Kyn)ratio. Trp and Kyn levels were measured using high performance liquid chromatography(HPLC). Serum Trp/Kyn levels in Stage IV breast cancer patients were lower than in patients at other stages. Serum Trp/Kyn levels of breast cancer patients over the age of 70 years were lower than in patients under the age of 69 years. Within the same clinical stage, serum Trp/Kyn levels of breast cancer patients over the age of 70 years were lower than in patients under the age of 69 years. These results suggest that the immunological profile of breast cancer patients over the age of 70 years may be immunosuppressive compared to breast cancer patients under the age of 69 years.

[Clinical Evaluation of Indoleamine 2, 3-Dioxygenase in the Serum of Patients with Locally Advanced Breast Cancer during Mohs Paste Treatment].

Locally advanced breast cancer lesions often compromise patients' quality of life(QOL). Mohs paste is a histopathological fixative with zinc chloride as the main ingredient. It is applied when performing chemosurgery for skin tumors. In recent years, this paste has reportedly been very effective for the control of various symptoms of skin metastases in inoperable advanced cancers, such as pungent odor and hemorrhage, in the field of palliative care. We evaluated the clinical significance of indoleamine 2, 3-dioxygenase(IDO)in the serum of patients with locally advanced breast cancer during Mohs paste treatment. IDO activity was measured by the tryptophan(Trp)/kynurenine(Kyn)ratio. Trp and Kyn levels were measured using high performance liquid chromatography(HPLC). We collected serum samples from 3 locally advanced breast cancer cases: once in the pre-treatment phase, 2 times in the post-treatment phase, and 5 times in the post-treatment phase. Then, we measured the Trp/Kyn ratio and CRP in these samples during Mohs paste treatment. There were no significant differences in serum Trp/ Kyn ratios between the phases, but serum CRP values decreased after Mohs paste treatment. These results suggest that Mohs paste treatment for locally advanced breast cancer lesions may be useful in enhancing patients' QOL without immunosuppression.

Myeloid leukemoid reaction after initial azacitidine therapy for chronic myelomonocytic leukemia.

The development of myeloid leukocytosis in leukemia patients during antileukemic treatment requires a differential diagnosis between myeloid leukemoid reaction and leukemia progression. We herein report the case of an 80-year-old Japanese man with chronic myelomonocytic leukemia (CMML) who developed marked myeloid leukocytosis (36.3 × 109/L) with 32.5% monocytes and 48% neutrophils about 4 weeks after the initial 5-azacitidine (AZA) treatment. The leukocytosis was unlikely to be attributed to infection and adverse drug reaction. As it resolved in a few days without any interventions, the transient myeloid leukocytosis was confirmed to be a myeloid leukemoid reaction. After four cycles of AZA treatment, leukemic blasts in the bone marrow decreased and the patient became transfusion-independent. Interestingly, levels of serum G-CSF showed a similar trend to the myeloid leukocytosis, while those of serum GM-CSF and IL-17 were undetectable throughout the clinical course, suggesting that a differentiation response to AZA treatment might lead to the myeloid leukemoid reaction. Our case implies that a marked but transient myeloid leukemoid reaction mimicking CMML progression can develop during AZA treatment, which requires careful clinical monitoring and differential diagnosis.

Radiation-induced gastrointestinal syndrome is exacerbated in vitamin C-insufficient SMP30/GNL knockout mice.

OBJECTIVES: Accidental exposure to high-dose radiation causes life-threatening acute radiation syndrome, features that include gastrointestinal syndrome (GIS) and hematopoietic syndrome (HS). Administration of vitamin C (VC), a free radical scavenger, has been reported to increase survival of mice in GIS and HS models. The effect of nutritional VC status on radiation injury remains unknown because, unlike humans, mice can synthesize VC. The aim of this study was to investigate the effect of VC insufficiency on acute radiation syndrome using senescence marker protein 30 (SMP30)/gluconolactonase knockout (SMP30-KO) mice. METHODS: SMP30-KO mice, which cannot synthesize VC, were given water with or without sufficient VC supplementation, and were analyzed in GIS and HS models. RESULTS: In the GIS model, in which bone marrow failure is rescued by bone marrow transplantation, VC-insufficient mice had a lower survival rate than VC-sufficient mice. The intestine of VC-insufficient GIS mice showed epithelial cell atrophy, inflammatory cell infiltration, and decreased crypt cell proliferation. We observed rapid VC oxidation after total body irradiation in the intestine of mice supplemented with VC-sufficient water. In the HS model, which was not combined with bone marrow transplantation, there was no difference in survival between VC-insufficient and -sufficient mice. CONCLUSION: The results of this study demonstrated that nutritionally sufficient VC exerts a radioprotective effect against radiation-induced GIS.

Sudden blast phase in chronic myeloid leukemia developed during nilotinib therapy after major molecular response was achieved.

Sudden blast phase (SBP) is a rare event in which patients with chronic myeloid leukemia (CML) in complete cytogenetic response (CCyR) rapidly progress to the blast phase. Few patients on second-generation tyrosine kinase inhibitors (2nd TKIs) have been reported to develop SBP. Here, we report a 45-year-old man diagnosed with CML in the chronic phase in April 2008 and immediately started on imatinib therapy. He achieved CCyR 12 months after starting imatinib therapy. Imatinib was followed by treatment with the 2nd TKIs nilotinib and dasatinib from January 2011 to yield a better response. He achieved major molecular response (MMR) during dasatinib therapy in February 2012, but did not tolerate dasatinib well; hence, he was switched to nilotinib in July 2012. In December 2015, he presented at our hospital with fever and lumbago. A complete blood count revealed a white blood cell count of 30,500/µL with 60% blasts, leading to diagnosis of SBP. After dasatinib therapy and conventional chemotherapy, he again achieved MMR. This case demonstrates that SBP may occur after achieving MMR on treatment with 2nd TKIs. Continuous careful monitoring is required for the early detection of SBP, even in patients who have achieved MMR.

CBL mutation and MEFV single-nucleotide variant are important genetic predictors of tumor reduction in glucocorticoid-treated patients with chronic myelomonocytic leukemia.

Glucocorticoid (GC) therapy occasionally relieves tumor-related fever and promotes tumor reduction in patients with chronic myelomonocytic leukemia (CMML). A mutation analysis of 24 patients with CMML revealed the relationship of GC effectiveness, defined as a monocyte reduction of > 50% within 3 days of methylprednisolone administration, with the MEFV single-nucleotide variant (SNV) and CBL mutation. Lipopolysaccharide-stimulated monocytes harboring MEFV E148Q produced greater amounts of IL-1ß and TNF-α than did wild-type monocytes; this was effectively suppressed by GC. Primary CMML cells harboring the MEFV SNV and CBL mutation, and the myelomonocytic leukemia cell line GDM-1, harboring the CBL mutation, were both more significantly suppressed than non-mutated cells following GC treatment in the presence of GM-CSF. A loss-of-function CBL mutation prolonged STAT5 phosphorylation after GM-CSF stimulation, which was rapidly terminated in both patient samples and GDM-1 cells. In conclusion, GC therapy effectively treats CMML cells harboring the MEFV SNV and CBL mutation by reducing inflammatory cytokine production and terminating prolonged STAT5 phosphorylation in the GM-CSF signaling pathway.