Yuriko Yahata

JAK2V617F mutation status and allele burden in classical Ph-negative myeloproliferative neoplasms in Japan

JAK2V617F, a gain-of-function mutation in the tyrosine kinase JAK2, is frequently detected in classical myeloproliferative neoplasms (MPNs). In the present study, we determined the JAK2V617F allele burden in Japanese MPN patients using alternately binding probe competitive-polymerase chain reaction, a highly quantitative method recently developed by our group. Although we observed strong similarities in terms of epidemiological parameters associated with the JAK2V617F allele burden between our cohort and others, we found a higher JAK2V617F allele burden in Japanese polycythemia vera (PV) patients and lower frequencies of thrombosis in Japanese MPN patients compared with previous reports. In addition, despite the presence of high red blood cell counts, some patients bearing the JAK2V617F mutation were not diagnosed as PV, as their hemoglobin values were lower than the WHO PV criterion. In these patients, the JAK2V617F allele burden was strikingly similar to that in PV patients fulfilling the 2008 WHO criteria, suggesting that these patients can be classified as PV. Although isotopic measurement of red cell mass (RCM) is required for definitive diagnosis of PV, our data suggest that precise measurement of the JAK2V617F allele burden may improve the diagnosis of PV when RCM has not been determined.

Effect of dose fractionation on pulmonary complications during total body irradiation.

Total body irradiation (TBI) is an important component of conditioning regimens for Allogeneic bone marrow transplantation (BMT). Interstitial pneumonitis (IP) and other pulmonary disorders are known regimen-related complications. The incidence of IP is related to the dose rate and dose fractionation; however, there is a paucity of clinical data regarding the optimal dose fractionation. This retrospective study evaluated patients to determine the influence of dose fractionation during TBI in preparation for allogeneic BMT on the subsequent development of IP and other pulmonary complications. Fifty-six patients were treated with TBI followed by BMT at our institute. All patients received a total TBI dose of 12 Gy given in 6 fractions over 3 days or in 4 fractions over 2 days. The prevalence of unrelated donors in the 4-fraction group was higher than that in the 6-fraction group. The overall and freedom from progression rates for patients in the 4-fraction group were better than those for patients in the 6-fraction group, but the difference did not reach significance. Clinically significant lung complications occurred in 19 (10: infectious and 9: non-infectious diseases) of 33 patients in the 6-fraction group and 12 (7: infectious and 5: non-infectious diseases) of 23 in the 4-fraction group. There was no significant difference between the two groups. There was no significant difference in pulmonary complications between patients treated with a TBI dose of 12 Gy in 6 fractions over 3 days and patients treated with a TBI dose of 12 Gy in 4 fractions over 2 days.

Early CNS relapse in a good-risk primary mediastinal large B-cell lymphoma after combined chemo- and radio-therapy

CNS recurrence of non-Hodgkin lymphoma is fetal in most cases and tends to occur 5–12 months after the initial diagnosis [1]. Risk factors for CNS involvement include advanced stage, increased IPI, raised LDH, young age, [1 extranodal site, B symptoms, low albumin and retroperitoneal disease. A 19-year-old Japanese man presented to our hospital because of persistent cough on October 2007. A CT scan showed an anterior mediastinal tumor of 8 cm in diameter. LDH value and bone marrow examination were normal. After the total resection, the tumor was diagnosed as primary mediastinal large B-cell lymphoma (PMLBL). Involvement of right infraclavicular lymph nodes detected by Ga-SPECT and FDG-PET/CT determined the stage as IIA. One cycle of MACOP-B regime plus bi-weekly rituximab therapy started on November 2007. After confirming complete response (CR) by CT and Ga-SPECT, 30 Gy of involved field irradiation to the mediastinum and bilateral infraclavicular lymph nodes followed. On June 2008, 3 months after the chemoand radio-therapy, FDG-PET/CT revealed diminishment of abnormal accumulation. On July 2008, only 4 months after the completion of treatment, severe headache and nausea started. A cranial MRI scan showed an enhancing mass in the left frontal lobe with the right midline shift (Fig. 1). Although systemic evaluation revealed no recurrence in the other sites, brain biopsy confirmed infiltration of the lymphoma cells. Southern blot analysis of JH region of immunoglobulin heavy chain gene showed identical rearrangement bands in mediastinal tumor and CNS metastatic mass. The result confirmed that the CNS tumor is truly derived from primary mediastinal mass. The CNS lesion was resistant to two cycles of IVAM therapy containing high-dose methotrexate (MTX) and the following whole brain irradiation of 50 Gy. Then, after obtaining informed consent from the patient, we introduced via Ommaya reservoir three times of 10–25 mg of rituximab together with 3 ml of the autologous serum twice a week. The intracranial rituximab therapy failed to reduce the tumor size at least until day 15, when the patient’s condition rapidly deteriorated and subsequently he died of bacterial pneumonia. PMLBL is a relatively rare subtype of diffuse large B-cell lymphoma (DLBL) and usually occurs in young patients. MACOP-B regimen plus rituximab (R-MACOP-B) combined with local mediastinal radiation ([30 Gy) is recommended as a front-line therapy for the PMLBL patients [2]. This approach has demonstrated a stable progression-free survival in about 70% of the patients 2 years after the diagnosis. The presented patient was also treated with R-MACOP-B combined with involved field radiation and had no CNS risk factors except for young age, but he relapsed only 4 months after the completion of treatment. CNS relapse is reported in more than 10% of NHL arising from the testis, breast and paranasal sinuses, and CNS prophylaxis is recommended to these subtypes of DLBCL [3, 4]. Bishop et al. reported that CNS infiltration occurs in 4% of newly diagnosed PMLBL cases and in 11% of relapsed ones [5]. Although CNS recurrence has been reported in 2–10% of PMLBL patients [6–8], only one report has referred the CNS screening and prophylaxis in PMLBL [3]. Stefoni et al. reported a case of PMLBL M. Sasaki (&) K. Sugimoto A. Masuda Y. Tsukune Y. Yahata N. Komatsu Division of Hematology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan e-mail: msasaki@juntendo.ac.jp

Clinical benefits of bortezomib-containing regimens for newly diagnosed AL amyloidosis with severe cardiac impairment.

Cardiac amyloid light-chain amyloidosis (AL amyloidosis) is a rare disease with a very poor prognosis, associated with plasma cell dyscrasias such as monoclonal gammopathy of undetermined significance and multiple myeloma. Though bortezomib-containing regimens have achieved high hematologic response rates, there are still few reports describing the outcomes of Japanese patients. Six patients with severe cardiac AL amyloidosis were treated with bortezomib-containing regimens. Involved free light chain (iFLC) decreased immediately in most of these cases. However, the condition of heart failure and N-terminal pro-B-type natriuretic peptide (NT-proBNP) worsened in the early phase of this treatment and then improved several months later. At 29 months, the median duration of follow-up (2-47months), all patients remain alive except one who died of sudden cardiac arrest. Bortezomib-containing regimens are considered to be among the effective treatments for severe cardiac AL amyloidosis.

Various Neurological Symptoms by Neurolymphomatosis as the Initial Presentation of Primary Testicular Lymphoma

Neurological symptoms induced by the infiltration of malignant lymphoma into the nervous systems are subsumed under the term neurolymphomatosis (NL). Here, we report the case of a 30-year-old Japanese man with primary testicular lymphoma complicated, as seen in various neurological findings, by secondary NL prior to testicular swelling. Painless right scrotal enlargement was noticed more than 1 month after the appearance of neurological complications such as right upper extremity numbness, dysarthria, facial palsy, and diplopia. Proactive investigation and biopsies of extranodal sites at high risk of central nervous system infiltration of malignant lymphoma, such as the testes, should be considered when secondary NL is suspected based on imaging findings.

Clinical and microbiological effects of biapenem in febrile neutropenic patients with hematologic malignancies

Dear Sir, Several therapeutic guidelines for febrile neutropenia (FN) recommend carbapenem usage as a first choice in high-risk febrile patients [1 3]. Although the therapeutic effect of carbapenems has been shown promising, inappropriate use may increase the risk of emergence of carbapenem-resistant species including metallo-b-lactamase (MBL)-producing strains [4]. Biapenem (BIPM) is a new parenteral carbapenem antibiotic with broad spectrum of antibacterial activity [5]. We conducted a pilot study to evaluate the clinical and microbiological effects of BIPM in high-risk FN patients with hematologic malignancies under a strict administration schedule. The high-risk group was defined as patients with severe neutropenia (a neutrophil count ofB1000/ml with a predicted decrease toB500/ml) prolonged over 7 d. Between August 2006 and July 2007, 47 patients met this criterion after chemotherapy and developed FN. Among them, 13 patients received BIPM administration. Venous blood of all patients was collected and tested for culture and other laboratory examinations. Surveillance culture from throat and stool was performed on both d 1 (or 3) and d 8 in the 13 patients after obtaining informed consent. Prophylactic levofroxacin (LVFX) or ciprofloxacin (CPFX) had been administered to the patients before starting BIPM therapy. They received 300 mg of BIPM every 6 h by drip-infusion for at least 72 h (total 12 doses). Continuation of BIPM monotherapy was decided after clinical and laboratory evaluation. Responders were defined as acquired defervescence and improvement in C-reactive protein values within 3 d. Among them, 4 patients were diagnosed to have documented infection, i.e. 3 bacteremia (2 Psuedomonas aeruginosa and 1 Neisseria sicca) and 1 pneumonia (not specified). Although both P. aeruginosa isolates were susceptible to LVFX and CPFX, the N. sicca strain was resistant to them. Clinical effect was observed in 8 patients (61.5%) including 2 bacteremia cases, and 5 patients received additional treatment with other antibiotics and antifungal drugs. The 8 responders received BIPM for up to 18 d (median, 9 d). After administration of BIPM, none of 13 patients developed BIPM associated adverse reaction. Although this study was not designed as a randomized control trial, the clinical effect of BIPM was similar to that observed in the defined neutropenic patients treated with meropenem during the same period (7 of 11 patients, 63.6%). BIPM showed favorable clinical effect without any adverse events even after pretreatment with LVFX or CPFX. Surveillance culture detected several bacterial species (Table I). Some BIPM-resistant enterococci had already been detected in stool specimens at the beginning of the BIPM therapy. Moreover,

Anti‐thymocyte globulin therapy induced a spurious increase of fibrinogen degradation products in hypoplastic myelodysplastic syndrome

To the Editor: A 60-yr-old Japanese woman with hypoplastic myelodysplastic syndrome (MDS, refractory anemia) admitted to our hospital because of uncontrolled bleeding tendency. Physical examination showed multiple purpura on the trunk and extremities. She had no peripheral lymphadenopathy or hepatosplenomegaly. Laboratory analysis revealed a white blood cell count of 3.3 · 10 ⁄L with 47% of neutrophils, hemoglobin 7.5 g ⁄dL, platelet count 11.0 · 10 ⁄L, T-Bil 1.3 mg ⁄dL, lactate dehydrogenase 265 IU ⁄L, aspartate transaminase 59 IU ⁄L, alanine aminotransferase 68 IU ⁄L, fibrinogen 335.0 mg ⁄dL and fibrinogen degradation products (FDP) <5.0 lg ⁄mL. Although bone marrow examination showed hypocellular marrow with 2.9% of blasts and no apparent myelodysplasia, del(20) (q11q13.3) was detected in 5 of 20 analyzed metaphase cells. Hypoplastic MDS was diagnosed, and she started equine anti-thymocyte globulin (ATG) and cyclosporine A. She developed watery diarrhea on day 8. High fever, abdominal pain, skin eruption and arthralgia followed, and C-reactive protein (CRP) increased to 16.4 mg ⁄dL. Immune-complex level elevated to 6.6 lg ⁄dL and hemolytic complement level (CH50) was undetectable on day 11. On day 10, FDP and Ddimer levels abruptly rose to 2865 lg ⁄mL and 999.0 lg ⁄mL, respectively, although neither deterioration of the bleeding tendency nor thrombotic events were observed. Skin biopsy revealed only perivascular dermatitis infiltrated with lymphocytes, a finding compatible with serum sickness after ATG. Methylprednisolone started on day 13 rapidly improved the serum sickness, and the FDP level gradually decreased to 184.6 lg ⁄mL by day 30. Latex turbidimetric immunoassays using anti-human FDP mouse monoclonal antibody showed extremely high levels of FDP and D-dimer in this patient (using Hexamate ; Roche diagnostics, Basel, Switzerland and Nanopia ; Sekisui Medical, Tokyo, Japan, respectively). Western blot analysis of the same serum detected essentially no FDP fractions. Furthermore, removal of IgA, but not IgG or IgM, from the serum corrected the extremely high level of FDP. These results strongly indicate that extremely high levels of FDP and D-dimer were pseudoreaction induced by non-specific latex aggregation. Administration of heterophilic anti-thymocyte globulin induces the production of anti-xenogeneic antibodies, which may yield false-positive results in a variety of immunoassays including CRP, ferritin, chorionic gonadotropin, and Histoplasma antigen (1–4). The hypersensitivity reaction to equine ATG, therefore, seems to have induced non-specific latex aggregation for FDP and D-dimer measurement in addition to serum sickness in this patient. Because an increase in FDP strongly suggests several serious pathological processes like disseminated intravascular coagulation, hematoma formation, and micro-vascular injury, it is important to recognize the possibility of false-positive results of FDP especially after ATG therapy.