[Successful treatment with imatinib for a patient with myeloid neoplasms with eosinophilia and abnormalities of PDGFRB due to t (5;14)(q33;q22)].

A 50-year old man with a 1-year history of eosinophilia presented with an eosinophil count exceeding 13,800/mm3 in the peripheral blood at the first visit. Bone marrow examination revealed that eosinophils accounted for 30% of the nucleated cell count, and G-band karyotyping analysis detected t (5;14)(q33;q22). Using peripheral blood FISH test, he was found to have platelet-derived growth factor receptor ß (PDGFRB) locus rearrangement at 5q32-33. The level of eosinophils in the peripheral blood reduced markedly 3 days after the initiation of Imatinib mesylate, 400 mg daily. This treatment was administered for 2 years, after which the peripheral blood FISH test was negative for PDGFRB. In this disease, although most cases are with t (5;12), those with t (5;14) are relatively rare, and the long-term course of this translocation is unknown.

Comparative Study of Tacrolimus and Short-Term Methotrexate: 2-Day versus 3-Day Methotrexate as Graft-versus-Host-Disease Prophylaxis after Umbilical Cord Blood Transplantation in Adults.

Methotrexate (MTX) in combination with a calcineurin inhibitor has been commonly used for prophylaxis of graft-versus-host disease (GVHD) following umbilical cord blood transplantation (UCBT) in Japan. However, the appropriate prophylactic MTX dosage in UCBT has not been established to date. To determine the preferential GVHD prophylaxis in UCBT, this study retrospectively investigated the administration of short-term MTX for 2 days versus 3 days. Of 103 adult patients submitted to UCBT enrolled in the study, 73 received tacrolimus (TAC) with 2 days of MTX given at 10 mg/m2 on day 1 and 7 mg/m2 on day 3 (very short-term [vs] MTX), whereas 30 patients received TAC with 3 days of MTX given at 10 mg/m2 on day 1, 7 mg/m2 on day 3, and 7 mg/m2 on day 6 (short-term [s] MTX). In univariate analysis, neutrophil engraftment was shown to be significantly better (P = .039) in the vsMTX/TAC group. Among high-risk patients, the vsMTX/TAC group also exhibited earlier neutrophil engraftment (P = .042); however, the incidence of acute GVHD was higher in the vsMTX/TAC group (P = .035) on univariate analysis. In multivariate analysis, compared with sMTX/TAC, vsMTX/TAC was associated with lower risk of relapse (hazard ratio, .27; 95% confidence interval, .11 to .64; P = .003) . These results suggest that vsMTX/TAC can be appropriate GVHD prophylaxis after UCBT, especially in higher-risk patients.

[Case of Primary Mediastinal Non-Seminomatous Germ Cell Tumor with Pathological Complete Response after Induction Chemotherapy and Residual Tumor Resection Accompanied by Late-Onset Bilateral Pneumothorax].

A man in his late teens presented to our hospital with left-sided chest pain. CT showed a 12 cm sized anterior mediastinal tumor and tiny nodules in the bilateral lower lobe of the lungs. The patient also had elevated serum AFP and hCG levels. Pathological findings of the CT-guided biopsy specimen suggested a yolk sac tumor, and no testicular abnormality was seen on ultrasound. Following whole body examination, he was diagnosed with primary mediastinal non-seminomatous germ cell tumor. After sperm cryopreservation, 4 courses of BEP(bleomycin[BLM]plus etoposide[ETP]plus cisplatin[CDDP]) chemotherapy were administered to normalize the tumor markers. The mediastinal tumor shrank but was still widely in contact with the left pulmonary artery. He underwent mediastinal tumor resection and segmentectomy of the left upper lobe via a median sternotomy. The maximum tumor size was 9 cm in diameter, and pathological examination of the specimen revealed only an immature teratoma with no malignant findings. At the same time, both the lower lung nodules were resected and pathologically identified as intrapulmonary lymph nodes. No recurrence was observed, but 6 months after surgery, he made an emergency visit to our department due to dyspnea. Bilateral pneumothorax was detected, and chest tube insertion was rapidly performed that improved with only right chest drainage. Cytology of the right hemorrhagic pleural effusion showed no evidence of malignancy. It was possible that a postoperative right-to-left shunt of the anterior mediastinum was present, leading to bilateral pneumothorax.

[A Case of Philadelphia Chromosome-Positive Acute Myeloid Leukemia Extramedullary Recurrence in a Patient Undergoing Thoracoscopy for Massive Pleural Effusion].

A man in his early 70s visited a previous hospital because of pancytopenia and was diagnosed with acute myeloid leukemia based on a bone marrowexamination. The karyotype was 46,XY, t(9;22)(q34;q11.2)[2/20], and real-time polymerase chain reaction(PCR)revealed minor bcr-abl chimeric mRNA. Finally, the patient was judged as having Philadelphia chromosome- positive acute myeloid leukemia, and remission induction chemotherapy with the JALSG AML 201 protocol was initiated in combination with dasatinib to achieve complete remission. After 3 courses of consolidation chemotherapy, the anticancer drugs were discontinued because of deterioration of his general condition and renal insufficiency. Six months after the initial treatment, he was referred to our department, and no evidence of recurrence was confirmed on bone marrow examination. However, 2 months later, right massive pleural effusion was detected, and he was admitted to the department of pneumology at our hospital. Thoracoscopic pleural biopsy was performed at the time of chest tube insertion, and he was diagnosed with acute myeloid leukemia extramedullary recurrence. Peripheral myeloblasts appeared and increased rapidly, accompanied by further exacerbation of renal function; thus, he received palliative care at the department of hematology and oncology.

[A Case of Synchronous Diffuse Large B-Cell Lymphoma of the Right Breast and Invasive Ductal Carcinoma of the Left Breast].

A woman in her early 60s noticed bilateral breast masses and visited a different hospital. Core needle biopsy showed diffuse large B-cell lymphoma of the right breast and invasive ductal carcinoma of the left breast. After referral to our department, PET-CT was performed. Compared with mild fluorodeoxyglucose accumulation in left breast cancer(BC), highly accumulated lesions were found on the right breast, left anterior chest wall, nasopharynx, and tonsil. The right breast lesion was the largest with a diameter of 30mm and was considered the primary lesion of malignant lymphoma(ML). The ML was classified as stage Ⅳ, pathologically proven with erythema of the left breast and nasopharynx. Three courses of R-CHOP were performed. However, due to suspicion of heart failure, chemotherapy was changed to R-CEOP(non-anthracycline-containing regimen)and 3 courses were additionally performed. The therapeutic effect of R-Chemo for ML was CR. Left BC showed a tendency of shrinkage. After intrathecal administration of anticancer drugs to prevent infiltration of ML into the central nervous system and preoperative endocrine therapy with aromatase inhibitor, left lumpectomy and sentinel lymph node biopsy were performed. BC was classified as clinical stage ⅠA and had an estrogen receptor score of 3b. Postoperative whole breast radiotherapy was completed, and the planned internal use of exemestane was more than 5 years. With multidisciplinary therapy, 3.5 years had passed since the initial treatment without recurrence.

[A Case of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Achieving Complete Molecular Response with Ponatinib Therapy despite the Development of Hemorrhagic Stroke during Remission Induction Chemotherapy].

A man in his late 50s had lumbago and thrombocytopenia. He was diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia(Ph plus ALL). Remission induction chemotherapy was initiated with JALSG Ph plus ALL 208 protocol, but cerebral infarction in the right occipital lobe developed on day 2 and, to make matters worse, was accompanied by hemorrhagic cerebral infarction in the left occipital lobe on day 9. We decided that chemotherapy with multiple drugs was difficult to continue, and it was stopped. After improvement of the general condition, dasatinib therapy was started on day 52. After about 5 months, Ph plus ALL relapsed. Although mild disorientation and visual field defects remained due to old cerebral infarction, organ function was maintained, and patient performance status(PS)was classified as 1. Introduction of ponatinib was considered feasible, and ponatinib was started from a dose of 15mg/day to prevent the occurrence of vaso- occlusive adverse events. It was gradually increased to 30mg /day and continued about 4 months without recurrence of cerebral infarction. Complete molecular response was achieved with ponatinib therapy. It was suggested that, in patients with Ph plus ALL with a history of cerebral infarction, ponatinib could be a treatment option under careful risk management.

[A Case of POEMS Syndrome Treated by Ld Prior to HDCTx Followed by aPBSCT].

A man in his late 40s was presented to a hospital with complaints of peripheral numbness and fatigue. Systemic edema, pleural effusion and ascites, pigmentation, splenomegaly, and CT findings of osteoplastic changes suggested POEMS syndrome. He was referred to our division, and a bone marrow examination indicated MGUS. However, his serum level of vascular endothelial growth factor(VEGF)was elevated to 1,520 pg/mL, and IgA-l type M protein was detected. He was diagnosed with POEMS syndrome and received four cycles of induction chemotherapy containing lenalidomide and dexamethasone( Ld). All symptoms improved gradually, and after auto peripheral blood stem cell harvest(aPBSCH), high-dose melphalan was administered, followed by auto peripheral blood stem cell transplantation(aPBSCT)being performed. Pleural effusion and ascites disappeared, while numbness remained slightly. His serum level of VEGF decreased to 68 pg/mL when the planned primary treatment was completed. Many cases of POEMS syndrome involve peripheral neuropathy; therefore, a lenalidomide-containing regimen may be a more adequate strategy than ones containing thalidomide and bortezomib.

[A Patient Surviving More Than Five Years Due to the Effect of Sequential Alternating Chemotherapy Administered to Metachronous Overlapping Cancer of Multiple Myeloma and Stageâ £ EGFR Positive Non-Small Cell Lung Cancer].

A woman in her late 50s visited our department because an abnormal shadow of her right lung was seen on her chest radiographs. She was diagnosed with Stage ⅠA primary lung adenocarcinoma with EGFR exon 19 deletion mutation by performing thoracoscopic middle lobe resection and lymph node dissection. After 1 and a half years, the lung metastasis recurred and she received gefitinib(GEF)monotherapy for 9 months and withdrew because of the sustained complete response(CR). Three years and 7 months after the first visit, she was diagnosed as having complication of revised international staging system(R-ISS)Ⅱ multiple myeloma with anemia, retinal vein occlusion, and M proteinemia. It was decided that treatment for myeloma should be given priority and hence, Bd, high dose chemotherapy with auto-peripheral blood stem cell transplantation(aPBSCT), Ld, ELd and Pd therapy were performed sequentially until progressive disease(PD)and survival benefit were evident. As lung metastasis of adenocarcinoma also progressed, myeloma treatment was terminated, GEF was administered intermittently and consequently, shrinkage of the lung metastasis was confirmed. Depending on sequential alternating chemotherapy for both malignancies, a relatively long survival time of 5.4 years from the initiation of treatment for myeloma and 7.5 years from the recurrence of lung adenocarcinoma was achieved.

[Azacitidine for Therapy-Related Myelodysplastic Syndrome Following Oxaliplatin (L-OHP)Therapy for Metastatic Rectal Cancer].

Therapy-related myelodysplasticsyndrome(t-MDS)has been reported to occur after treatment with cytotoxic agents and radiation. Here, we report a case of t-MDS following oxaliplatin(L-OHP)exposure, which was successfully treated with azacitidine(AZA). A 71-year-old man was referred to our department because of pancytopenia. He had been diagnosed with rectal cancer(cT4aNXM0, stage II B-III C, RAS gene status wild-type)3 years ago and had received 8 courses of capecitabine(CAP)and L-OHP(XELOX regimen), followed by 48 courses of CAP and bevacizumab. Before referral, recurrence of rectal cancer was detected using CT after the last course of chemotherapy. A bone marrow examination revealed multilineage dysplasia and 9.0%myeloblasts. Cytogenetic analysis disclosed a chromosome 7 abnormality. The diagnosis of t- MDS was made and treatment with AZA was initiated. Subsequently, temporary but significant hematological improvements were observed, which enabled the patient to receive additional palliative radiation therapy against the locally relapsed rectal cancer. AZA might be useful in t-MDS because of its efficacy and low toxicity.

Characteristics and predictors of post-transplant-associated hemophagocytic lymphohistiocytosis in adults.

Hemophagocytic lymphohistiocytosis (HLH) is an uncontrolled hyperinflammatory disorder driven by an overactive immune system that results in high mortality. Post-transplant-associated hemophagocytic lymphohistiocytosis (PT-HLH) is a type of secondary HLH that occurs following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical features of PT-HLH remain unclear and diagnostic and prognostic tools have not yet been established. Here, we retrospectively evaluated the clinical manifestations and outcomes of PT-HLH in 94 patients who underwent allo-HSCT. According to our PT-HLH criteria (hyperferritinemia and increased macrophage count in bone marrow), PT-HLH occurred in 12 patients (12.8%). The PT-HLH patients showed splenomegaly (P = .001), a higher risk of engraftment failure (P = .013), and an increased percentage of macrophages and hemophagocytes in bone marrow aspirates (P = .0009 and P = .0006, respectively). Moreover, univariate and multivariate analyses revealed that the survival rate was lower in PT-HLH patients than non-PT-HLH patients (P = .0017 and P = .034, respectively). This study defines the clinical features of PT-HLH and PT-HLH criteria that could be useful tools for diagnosing PT-HLH.

Increased MYC expression without MYC gene translocation in patients with the diffuse large B-cell-lymphoma subtype of iatrogenic immunodeficiency-associated lymphoproliferative disorders.

Post-transplant lymphoproliferative disorder (PTLD) and other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are iatrogenic lymphoproliferative disorders (LPD) that develop in association with immunosuppressive treatment in the setting of organ transplantation and autoimmune disease, respectively. Each has a spectrum of pathologies ranging from lymphoid hyperplasia to lymphoma. To clarify the characteristics of the diffuse large B-cell lymphoma (DLBCL) subtype in a cohort of 25 patients with PTLD or OIIA-LPD from our institute, we selected 13 with a histological subtype of DLBCL, including 2 cases of PTLD and 11 of OIIA-LPD. The median patient age at diagnosis was 70 years, with a female predominance. Both PTLD cases developed after kidney transplant. Of the patients with OIIA-LPD, 10 had rheumatoid arthritis, 1 had mixed connective tissue disease, and 8 were treated using methotrexate. Both of the PTLD patients and 6 of the OIIA-LPD patients had extranodal manifestations. All patients except for one were classified as having the non-germinal center B-cell (non-GCB) subtype according to the Hans algorithm. Tissue samples from 8 patients were positive for CD30 and 8 were positive for Epstein-Barr virus (EBV)-encoded small RNA. Seven patients had MYC-positive tissue samples, but none had MYC translocation. Our study suggests that extranodal manifestations and the non-GCB subtype are common, that EBV is associated with the DLBCL subtype of PTLD and OIIA-LPD, and that anti-CD30 therapy is applicable. In addition, our patients with the DLBCL subtype of PTLD and OIIA-LPD exhibited MYC overexpression without MYC translocation, suggesting an alternative mechanism of MYC upregulation.

Elevated C-reactive protein level is associated with poor prognosis in follicular lymphoma patients undergoing rituximab-containing chemotherapy.

Although follicular lymphoma (FL) is a pathological entity characterized by relatively uniform histological and molecular findings, its clinical course is highly variable. Establishment of therapeutic strategies based on a simple and practical prognostic model is important. C-reactive protein (CRP) is an adverse prognostic marker for various tumors and aggressive lymphomas. However, the significance of serum CRP levels as a prognostic index in low-grade lymphomas, such as FL, has not been thoroughly investigated. We retrospectively analyzed the relationship between serum CRP levels at diagnosis and the prognosis in patients with FL (n = 61) undergoing rituximab-containing chemotherapy. Elevated CRP levels showed a significant association with elevated fibrinogen (P = 0.002) in univariate analysis. Patients with higher CRP levels (> 5 mg/L) had a significantly shorter progression-free survival in multivariate analysis (P = 0.044). We concluded that serum CRP levels are important in prognostic stratification of patients with FL.

Refined Disease Risk Index for Hematological Malignancies, Including Rare Disorders, After Allogeneic Stem Cell Transplantation.

OBJECTIVE: The refined disease risk index (R-DRI) is a well-designed prognostic parameter that is based on only the disease type and status and is used for stratifying patients undergoing allogeneic hematopoietic stem cell transplantation (allo HSCT) into 4 risk groups. However, the application of the R-DRI for rare diseases has remained unclear. METHODS: We evaluated 135 patients who underwent allo HSCT for hematological malignancies including rare diseases, such as acute leukemia of ambiguous lineage, acute T-cell leukemia/lymphoma, extranodal natural killer T-cell lymphoma, and lymphoblastic lymphoma, at our institute. RESULTS: According to the R-DRI, overall survival (OS) and progression-free survival at 2 years for patients with the low, intermediate, high, and very high groups were 66.7% and 66.7%, 60.8% and 56.0%, 27.1% and 23.7%, and 5.9% and 5.1%, respectively (P < .0001 and P < .0001, respectively). OS showed no significant difference between B-cell non-Hodgkin lymphoma (B-NHL) and T-cell non-Hodgkin lymphoma (T-NHL) (P = .71). Moreover, OS at 1 year was 80%, 14.3%, 60%, and 0% for the intermediate risk group, the very high-risk group of B-NHL, the intermediate risk group, and the high-risk group of T-NHL, respectively (P = .035). CONCLUSION: We showed the applicability of the R-DRI for hematological malignancies, including rare disorders. However, we suggest that T-NHL patients may be better to be assigned between the nodal group and the extranodal group in the R-DRI.

Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma.

We report the case of a 52-year-old woman with lung adenocarcinoma treated with EGFR tyrosine kinase inhibitor (TKI) therapy. After disease progression, histological examination of a secondary biopsy specimen revealed small-cell lung cancer (SCLC) that was sensitive to standard SCLC treatment. Tumor markers, including ProGRP and NSE, were elevated. Transformation to SCLC is a mechanism for acquired resistance to EGFR-TKI therapy. Secondary biopsy is important for evaluation of genetic and histological changes and selection of appropriate treatment. Furthermore, ProGRP and NSE may be useful for early detection of SCLC transformation in cases resistant to EGFR-TKI therapy.