Pretransplantation Inflammatory and Nutritional Status in Elderly Allogeneic Hematopoietic Stem Cell Transplantation: Prognostic Value of C-Reactive Protein-to-Albumin Ratio.

There are no clear criteria for selecting elderly patients with hematologic malignancies eligible for allogeneic hematopoietic stem cell transplantation (HSCT). This study aimed to evaluate inflammatory and nutritional status biomarkers as prognostic indicators of allogeneic HSCT in elderly patients. We compared the prognostic effects of 4 representative pretransplantation biomarkers: C-reactive protein-to-albumin ratio (CAR), Glasgow Prognostic Score (GPS), prognostic nutritional index (PNI), and albumin-to-globulin ratio (AGR). A total of 143 patients age ≥60 years who underwent their first allogeneic HSCT for a hematologic malignancy were enrolled between 2010 and 2020 in our single-center cohort. The median patient age was 65 years (range, 60 to 72 years). Pretransplantation high CAR, high GPS, and low PNI scores were associated with poor overall survival (OS), but the AGR was not associated with OS. Among the 4 biomarkers, CAR stratified OS most significantly (P < .001). Multivariate analyses identified only high CAR as an independent prognostic factor associated with OS (hazard ratio [HR], 1.98; P = .031) and showed that a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score ≥3 also was associated with OS (HR, 2.04; P = .012). High CAR was correlated with poor performance status, male sex, and high Disease Risk Index, but not with high HCT-CI score. When the patients were stratified into 3 groups according to a composite risk assessment using CAR and HCT-CI, the 3-year OS decreased significantly with increasing scores (82.8%, 50.3%, and 27.0%, respectively; P < .0001). In conclusion, CAR is the most useful prognostic indicator among the inflammatory and nutritional status biomarkers for allogeneic HSCT in elderly patients. Inflammatory and nutritional status in the elderly may be important prognostic factors for allogeneic HSCT independent of HCT-CI score.

[Successful treatment of pure red cell aplasia complicated by multicentric Castleman disease with prednisolone].

A 76-year-old man presented with shortness of breath and the laboratory tests suggested anemia and reticulocytopenia. CBC showed only anemia, and the bone marrow aspiration smear demonstrated absence of erythroid hematopoietic cells. Consequently, pure red cell aplasia (PRCA) was diagnosed. Computed tomography (CT) showed mediastinal multiple lymph node enlargement and ground-glass opacity in both the lung fields. Biopsy specimens of the mediastinal lymph node showed mild follicular hyperplasia and polyclonal plasma cells proliferation in the interfollicular area. These findings suggest idiopathic multicentric Castleman disease plasma cell type (iMCD PC type). Ciclosporin (CyA) was administered but there was no clinical improvement after 6 weeks of therapy. Therefore, prednisolone (PSL) was started at 0.5 mg/kg/day and was very effective for the PRCA and MCD. A total of 3 cases of CD (2 cases of MCD PC type and 1 case of CD HV type) with PRCA have been previously reported. In the 2 cases of MCD PC type, anemia was improved using PSL combination therapy. However, in the single case of CD HV type, PSL was not effective and anemia was improved with CyA treatment. This case suggests the possibility of using PSL as the first-line drug for MCD PC type with PRCA.

Treatment-free remission after first-line dasatinib treatment in patients with chronic myeloid leukemia in the chronic phase: the D-NewS Study of the Kanto CML Study Group.

Treatment outcomes for chronic myeloid leukemia (CML) have dramatically improved with the development of tyrosine kinase inhibitors (TKI). However, due to the improved prognosis for CML, problems have arisen from long-term administration of TKI. The present study sought to verify whether more patients could achieve treatment-free remission (TFR) after stopping the administration of dasatinib using dasatinib as frontline treatment. Treatment-naïve chronic phase CML cases were treated with dasatinib as frontline treatment. Dasatinib treatment was stopped for 26 patients who achieved deep molecular response (DMR) within 24 months and were able to maintain DMR for an additional 2 years. Ten patients (38.5%) achieved DMR maintenance after 12 months. Recurrence was confirmed in 16 patients, and the median recurrence-free survival time was 5.1 months. The cumulative DMR rates at six and 12 months after restarting treatment were 84.6% and 100%, respectively. The results of this study demonstrated that the DMR maintenance rate after 12 months was 38.5%, which was not significantly different from previous TKI stop trials. The 2-year dasatinib administration period after reaching DMR did not contribute to improve TFR rates. These results suggest that the type of TKI is not associated with better TFR rates.

Primary Central Nervous System Lymphoma with Peripheral Nerve Involvement: Case Report.

A 50-year-old man presented with dizziness and hearing disturbance in the right ear. Magnetic resonance imaging (MRI) revealed a well-enhanced mass lesion in the right cerebellopontine (CP) angle that appeared to originate in the cerebellum. A surgical specimen obtained at the subtotal resection with craniotomy revealed a diffuse large B-cell lymphoma (DLBCL). During the three courses of chemotherapy with high-dose methotrexate (MTX) with leucovorin rescue, he developed a right abducens palsy, left oculomotor palsy, left facial palsy, right trigeminal sensory disturbance, and paraparesis. Although the brain MRI showed that the CP angle tumor had disappeared completely following chemotherapy, enhanced lesions along the cauda equina were detected on a lumbar spine MRI. FDG-PET (18 F-fluorodeoxyglucose positron emission tomography) revealed multiple high-uptake abnormalities in the cranial nerves and spinal nerves. Tumor cells were found in the cerebrospinal fluid specimen from a lumbar puncture. Craniospinal irradiation was performed, including all the abnormal FDG high-uptake areas, and was effective in relieving the patient's symptoms. On FDG-PET, the high-uptake abnormalities in the peripheral nerves disappeared. However, five weeks after the irradiation, he developed right trigeminal sensory disturbance, hoarseness, dysphagia, and right arm pain. FDG-PET disclosed multiple high-uptake abnormalities in more peripheral portions of the cranial nerves and spinal nerves. Chemotherapy with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine (Oncovin®), and prednisolone (R-CHOP) was then resorted to which mitigated his symptoms. On follow-up FDG-PET, the high-uptake abnormalities in the peripheral nerves disappeared again.

Efficacy and Safety of a Weekly Cyclophosphamide-Bortezomib-Dexamethasone Regimen as Induction Therapy Prior to Autologous Stem Cell Transplantation in Japanese Patients with Newly Diagnosed Multiple Myeloma: A Phase 2 Multicenter Trial.

We assessed the efficacy and safety of weekly cyclophosphamide-bortezomib-dexamethasone (CBD) induction prior to autologous stem cell transplantation (ASCT) in newly diagnosed Japanese patients with multiple myeloma (MM). This regimen consisted of four 28-day cycles of once-weekly oral cyclophosphamide (300 mg/m2), subcutaneous bortezomib (1.3 mg/m2), and oral dexamethasone (40 mg). Responding patients underwent stem cell collection followed by ASCT. The primary endpoint was the postinduction rate of achieving a near complete response (nCR) or better. Among the 38 enrolled patients, a complete response (CR), an nCR, a very good partial response (VGPR), and a partial response (PR) were achieved in 10.5, 2.6, 23.7, and 36.8% of cases, respectively. A grade 4 hematological adverse event (AE) was observed in 1 patient. Grade 3-4 infection, including febrile neutropenia, was observed in 4 patients (10.5%). Although 2 patients dropped out due to AE, 94.7% of the patients completed the induction phase. However, because of a poor response to induction chemotherapy (

Early water intake restriction to prevent inappropriate antidiuretic hormone secretion following transsphenoidal surgery: low BMI predicts postoperative SIADH.

OBJECTIVE: The goals of this study were to assess the incidence of and risk factors for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in patients following transsphenoidal surgery (TSS), and to validate the effectiveness of early prophylactic restriction of water intake. DESIGN: Retrospective analysis was performed for 207 patients who had undergone TSS, including 156 patients not placed on early prophylactic water restriction. Sixty-four patients received treatment for SIADH. METHODS: We compared the incidence of SIADH between patients with and without early water intake restriction, and analyzed various risk factors for SIADH using statistical analyses. RESULTS: BMI was significantly lower for patients with SIADH than for those patients without SIADH. Statistical analysis revealed that the threshold BMI predicting SIADH was 26. Serum sodium levels on postoperative days 5-10 and daily urine volumes on postoperative days 5-10 were significantly lower in patients with SIADH than in those without SIADH. Postoperative body weight loss on days 6, 8, 10, and 11 was significantly higher in patients with SIADH. The incidence of SIADH after starting prophylactic water intake restriction (14%) was significantly lower than the rate before early water restriction (38%; P<0.05). CONCLUSIONS: SIADH is relatively common after TSS, and serum sodium concentrations and daily urine volumes should be carefully monitored. Patients with low preoperative BMI should be closely observed, as this represented a significant preoperative risk factor for SIADH. Early prophylactic water intake restriction appears effective at preventing postoperative SIADH.

[Chronic eosinophilic leukemia with complex karyotypic abnormalities including trisomy 8].

We report a 61-year-old man with chronic eosinophilic leukemia (CEL). The patient was referred to our hospital because of pyrexia and eosinophilia. He was diagnosed with CEL based on an increase in blasts and eosinophils in his peripheral blood and bone marrow, and clonal complex karyotypic abnormalities including trisomy 8. The FIP1L1-PDGFRA fusion transcript was not detected by RT-PCR analysis. Although he had no obvious organ damage at diagnosis, pulmonary infiltrates in the right lung and multiple skin nodules over his whole body appeared over 4 months and progressed rapidly, accompanied by a marked increase in blasts in his peripheral blood. CEL with trisomy 8 has been reported to be associated with transformation into acute leukemia and granulocytic sarcoma in the literature. It is notable that the present case was associated with complex karyotypic abnormalities and the exceptionally marked disease progression. Further analyses of clinical data as well as molecular genetic findings of CEL without known karyotypic abnormalities leading to constitutive activation of tyrosine-kinase genes are needed to gain insight into the pathogenesis of CEL and to develop a new disease classification and treatment strategies.

[Acute promyelocytic leukemia associated with hemophagocytic syndrome].

A 19-year-old man was referred to our hospital with pancytopenia and disseminated intravascular coagulation (DIC). Bone marrow aspiration revealed 93.6% of atypical promyelocytes and marked hemophagocytosis by macrophages. The diagnosis of acute promyelocytic leukemia (APL) associated with hemophagocytic syndrome (HPS) was made. As there was no evidence of infection, collagen diseases, or abuse of medicine, his HPS was classified as malignancy-associated HPS (MAHS). The DIC improved after administration of idarubicin and all-trans-retinoic acid (ATRA). On the 11th day, however, DIC and elevation of serum LDH recurred with the appearance of hepatosplenomegaly. Although APL cells had decreased in the bone marrow, hemophagocytes persisted. After administration of dexamethasone and etoposide, DIC and HPS improved, and complete remission of APL was obtained. ATRA was implicated in the aggravation of APL-induced MAHS in the present case.

SDF-1 synergistically enhances IL-3-induced activation of the Raf-1/MEK/Erk signaling pathway through activation of Rac and its effector Pak kinases to promote hematopoiesis and chemotaxis.

Stromal cell-derived factor 1 (SDF-1) cooperates with cytokines to promote hematopoiesis. Here we demonstrate that SDF-1 activates Erk synergistically with interleukin-3 (IL-3) in hematopoietic cells. Small GTPases Ras and Rac were prominently activated by IL-3 and SDF-1, respectively. In accordance with this, Raf-1 was significantly activated by IL-3 but not by SDF-1. SDF-1 strongly induced phosphorylation of Raf-1 on S338, the target site for the Rac effector Paks, and enhanced the IL-3-induced activation of Raf-1 and MEK. Furthermore, the synergistic activation of Erk was inhibited by expression of a dominant-negative mutant of Pak1 or that of Rac and was enhanced by an activated mutant of Pak1. SDF-1 and IL-3 also showed synergistic effects on expansion of hematopoietic cells and on induction of chemotaxis, which were both inhibited by the MEK inhibitor PD98059. These results suggest that SDF-1 synergistically enhances IL-3-induced Erk activation by up-regulating Raf-1 activity through the Rac effector Pak kinases to promote hematopoiesis.

[Successful treatment with drainage of hematoma and chemotherapy in a case of Burkitt leukemia presenting with subdural hematoma].

A 53-year-old male was admitted because of pancytopenia and chronic subdural hematoma. Bone marrow was hypercellular with 97% blasts, which expressed CD10, CD19, CD20, and immunoglobulin mu and gamma chains on the cell surface and had chromosomal abnormalities including t(8 ; 22)(q24 ; q11). The patient was diagnosed as having Burkitt leukemia. Because hemiplegia and disturbance of consciousness developed rapidly, the patient was treated with an emergency drainage operation followed by Hyper-CVAD therapy and achieved a sustained complete remission. Dural infiltration of leukemic cells as well as thrombocytopenia was implicated in the pathogenesis of the subdural hematoma, which contained numerous blasts.

[An abdominal follicular dendritic cell tumor in Castleman's disease].

A 57-year-old man was referred to our hospital because of elevated ALP. CT and MRI scans together with abdominal angiography showed multiple masses in his abdomen and portal vein obstruction. A diagnostic laparoscopic examination revealed a tumor of 3 cm x 3 cm near the portal vein and para-aortic lymphadenopathy. Histopathological examination of the tumor showed abnormal follicles with poorly formed germinal centers, scattered large spindle cells with proliferation of small lymphocytes, and hypervascular interfollicular tissue. The spindle cells were positive for follicular dendritic cell markers CD21, CD35, and epithelial membrane antigen. The diagnosis was made of a follicular dendritic cell (FDC) tumor in Castleman's disease (CD) of the hyaline-vascular type. Although the portal vein was obstructed by the FDC tumor, blood flow to the liver was retained by collateral vein. The patient did not show any response to four courses of CHOP therapy and died of obstructive jaundice, biliary tract infection and sepsis. So far, 17 cases of FDC tumor complicating CD have been reported, with a poor prognosis in all cases.

Secondary near-tetraploidy with double der(15)t(15;17) in acute promyelocytic leukemia in relapse.

Tetraploidy or near-tetraploidy is a rare cytogenetic abnormality in acute myelocytic leukemia. We report here a case of acute promyelocytic leukemia that showed near-tetraploidy with double der(15)t(15;17) the leukemia relapsed. At diagnosis, cytogenetic analysis failed to reveal any karyotypic abnormality; however, a promyelocytic leukemia-retinoic acid receptor alpha (PML/RARA) fusion transcript of the bcr3-type was detected with reverse transcriptase-polymerase chain reaction analysis, and a single PML/RARA fusion signal was observed with fluorescence in situ hybridization analysis. At the first relapse, the majority of leukemic cells showed pseudodiploid karyotypes with der(15)t(15;17), as well as additional chromosomal abnormalities, and exhibited a single PML/RARA fusion signal. A small fraction of leukemic cells, however, showed near-tetraploid karyotypes with double der(15)t(15;17), as well as some additional chromosomal abnormalities in common with the pseudodiploid clones, and exhibited double PML/RARA fusion signals. At the second and third relapses, leukemic cells with near-tetraploidy and double PML/RARA fusion signals became predominant. The PML/RARA fusion transcript of the bcr3 type was also observed at each relapse. In addition, Southern blot analysis of the RARA gene at diagnosis and at the second relapse showed a common rearranged band. Notably, giant, bizarre, and hypogranular promyelocytes expressing CD2, CD34, and HLA-DR appeared at the first relapse and became predominant at the second and third relapses. These observations indicate that the APL cells with near-tetraploidy and double der(15)t(15;17) clonally evolved from the pseudodiploid leukemic cells and exhibited the bizarre morphology and aberrant surface immunophenotypes.

Aberrant expression of the LHX4 LIM-homeobox gene caused by t(1;14)(q25;q32) in chronic myelogenous leukemia in biphenotypic blast crisis.

Chromosomal aberrations observed in addition to the Philadelphia chromosome in chronic myelogenous leukemia (CML) are likely to be involved in disease progression to the blast crisis. We describe here a t(1;14)(q25;q32) as an additional chromosomal aberration in a patient with CML in biphenotypic blast crisis. By use of long-distance inverse polymerase chain reaction (PCR), we cloned the chromosomal breakpoint and revealed that the immunoglobulin heavy chain gene is fused near its Emu enhancer region to the 5' region of the LHX4 LIM-homeobox gene, whose expression is restricted to the central nervous system. By use of quantitative real-time reverse-transcription PCR, we found that the LHX4 mRNA is expressed at high levels in the patient's leukemic cells and in an acute lymphoblastic leukemia (ALL) cell line. The aberrant expression of the LHX4 gene by the t(1;14)(q25;q32) has very recently been reported in a case of ALL, thus, representing a rare, but recurrent genetic abnormality of possible importance in leukemogenesis.

T-cell prolymphocytic leukemia with der(11)t(1;11)(q21;q23) and ATM deficiency.

T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell malignancy and is similar to a mature T-cell leukemia seen in some patients with ataxia telangiectasia, which is a recessive hereditary chromosomal instability syndrome caused by mutations of the ataxia telangiectasia mutated (ATM) gene located on 11q23. Intriguingly, recent studies have strongly implicated ATM in the pathogenesis of T-PLL as a tumor suppressor gene, because biallelic inactivation of ATM is frequently observed in this disease; however, translocations involving 11q23 have rarely been reported in T-PLL. We report here a case of T-PLL with der(11)t(1;11)(q21;q23). Southern blot analysis did not reveal any abnormality of ATM, nor of MLL, which is also located on 11q23 and is involved in t(1;11)(q21;q23) in acute myelomonocytic leukemia. Northern blot analysis further showed that the ATM transcript of normal size is expressed in the leukemic cells at a level higher than that in normal peripheral blood lymphocytes. Western blot analysis, however, revealed that expression of ATM in the leukemic cells is much lower than that in normal lymphocytes. These results imply that translation of the ATM transcript is impaired or that the ATM protein is highly unstable in the leukemic cells, thus suggesting the presence of nucleotide changes in both alleles.

Positive modulation of IL-12 signaling by sphingosine kinase 2 associating with the IL-12 receptor beta 1 cytoplasmic region.

IL-12 is a key immunoregulatory cytokine that promotes Th1 differentiation and cell-mediated immune responses. IL-12 stimulation results in the activation of Janus kinase 2 and tyrosine kinase 2 and, subsequently, STAT4 and STAT3. In addition, mitogen-activated protein kinase kinase 6/p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt pathways have been recently demonstrated to be activated by IL-12 and play an important role in IL-12 signaling. To further elucidate the molecular mechanism underlying IL-12 signaling, we have performed a yeast two-hybrid screening and identified mouse sphingosine kinase 2 (SPHK2) as a molecule associating with the mouse IL-12Rbeta1 cytoplasmic region. Analyses of various mutants of each molecule revealed that the region including the proline-rich domain in SPHK2 is probably responsible for the binding to IL-12Rbeta1, while the regions including the carboxyl terminus and Box II in the IL-12Rbeta1 cytoplasmic region appear to be involved in the binding to SPHK2. Transient expression of wild-type SPHK2 in T cell hybridoma augmented IL-12-induced STAT4-mediated transcriptional activation. Ectopic expression of dominant-negative SPHK2 in Th1 cell clone significantly reduced IL-12-induced IFN-gamma production, while that of wild-type SPHK2 enhanced it. In contrast, the expression minimally affected IL-12-induced proliferation. A similar decrease in IL-12-induced IFN-gamma production was observed when dominant-negative SPHK2 was expressed in activated primary T cells using a retroviral expression system. These results suggest that SPHK2 associates with the IL-12Rbeta1 cytoplasmic region and probably plays a role in modulating IL-12 signaling.

[Late appearance of Philadelphia chromosome with the p190 BCR/ABL chimeric transcript in acute myelogenous leukemia progressing from myelodysplastic syndrome].

We report a late appearance of the Philadelphia chromosome (Ph) with the p190 BCR/ABL chimeric transcript in a 69-year-old patient with acute myelogenous leukemia (AML) that had evolved from myelodysplastic syndrome (MDS). In July 1997, the patient was found to have pancytopenia caused by refractory anemia with excess of blasts, which evolved into AML in 4 months. The leukemic cells were positive for CD13, CD14, CD33, and HLA-DR and had a normal karyotype. The patient achieved a complete remission after combination chemotherapy. However, his leukemia relapsed in November 1999, with the appearance of leukemic cells positive for CD7, CD13, CD34, and HLA-DR with a 46, XY, add (18) (p11) karyotype. The patient failed to achieve the second remission after several courses of intensive chemotherapy. When the number of blastic cells, showing the same surface phenotypes, in the peripheral blood increased drastically in April 2000, chromosomal analysis of leukemic cells revealed a 46, XY, t(9;22) (q34;q11), add(18)(p11) karyotype. The fusion of the BCR and ABL genes was confirmed by fluorescence in situ hybridization analysis, and the reverse transcription-polymerase chain reaction analysis further revealed the presence of the p190 BCR/ABL chimeric transcript. The appearance of the Ph chromosome in the course of MDS transforming to AML is very rare and may be correlated to the disease progression.

Fusion of MLL and MSF in adult de novo acute myelomonocytic leukemia (M4) with t(11;17)(q23;q25).

The MLL gene at chromosome band 11q23 is frequently rearranged and fused to partner genes in acute leukemias. Previously, the MSF gene, also called AF17q25, has been cloned as a fusion partner of the MLL gene in therapy-related or infant acute myelogenous leukemias with t(11;17)(q23;q25). MSF belongs to the septin family of proteins, which includes other MLL fusion partners, hCDCrel1 and Septin 6, and has also been implicated in the pathogenesis of human ovarian tumor and murine T-cell lymphoma. We describe here a 64-year-old man with de novo acute myelomonocytic leukemia (French-American-British subtype M4) with t(11;17)(q23;q25). His leukemia was successfully induced into a first remission, which, however, lasted only briefly. A second remission was never attained, and the patient died of sepsis 16 months after the diagnosis of leukemia. Examination of his leukemic cells at diagnosis revealed an MLL gene rearrangement, by Southern blotting, and an MLL-MSF fusion transcript, by the reverse transcriptase polymerase chain reaction (RT-PCR) method. Sequence analysis of the RT-PCR product further revealed that MLL exon 5 was fused in-frame to MSF exon 3. Further clinical and molecular analyses of acute leukemias with the MLL-MSF transcript may shed more light on the clinical characteristics and molecular mechanisms of the MLL-septin type leukemias.

[Hypercalcemia mediated by parathyroid hormone-related protein in the blastic phase of chronic myelogenous leukemia].

A 45-year-old man with chronic myelogenous leukemia (CML) in the accelerated phase was admitted to our hospital because of lower back pain and hypercalcemia. On admission, he was confused and found to have massive splenomegaly. The hypercalcemia and splenomegaly improved significantly after administration of incadronate, hydroxyurea, vincristine and prednisolone. Splenomegaly recurred after cessation of the chemotherapy, and examination of the peripheral blood showed 31% blasts, positive for both CD13 and CD33, on which basis myeloid blastic transformation was diagnosed. Vindesine, cytarabine and prednisolone were administered, and the splenomegaly improved again. On admission, when the patient's serum calcium level was 16.0 mg/dl, his serum parathyroid hormone-related protein (PTHrP) level was elevated to 118.3 pmol/l. Furthermore, RT-PCR analysis revealed that the patient's CML cells expressed PTHrP mRNA, and a high level of PTHrP was detected in the supernatant of cultured mononuclear cells derived from the patient's peripheral blood. These findings indicated that the hypercalcemia was due to production of PTHrP by the leukemic cells. Several cases of PTHrP. mediated hypercalcemia associated with CML have been reported previously, and are reviewed here.