Primary central nervous system malignant lymphoma in a patient with rheumatoid arthritis receiving low-dose methotrexate treatment.

We report the first case of primary central nervous system lymphoma (PCNSL) developing in a patient with rheumatoid arthritis (RA) undergoing low-dose methotrexate therapy (LD-MTX). The characteristic clinical management and course in our experience of the present case illustrate the important points about PCNSL in methotrexate-associated lymphoproliferative disorders (MTX-LPD). The number of cases of MTX-LPD in RA patients may increase in the future, since current treatment strategies for RA recommend starting MTX use in early stage RA, and recent insights have tended to show an increase with higher doses.

Basophilic stippling in red blood cells in the bone marrow: indication for lead poisoning diagnosis.

A 40-year-old man presented at our hospital with anaemia that had been undiagnosed for 2 years. Blood tests, endoscopy, and contrast-enhanced computed tomography were performed, but a definitive diagnosis could not be made. A subsequent bone marrow biopsy revealed basophilic stippling in transformed red blood cells, which led to a differential diagnosis of lead poisoning. Additional tests revealed elevated levels of lead in the blood. Basophilic stippling is generally found on a peripheral blood smear in lead poisoning patients; however, in this case, basophilic stippling was found only on the bone marrow smear and not in the blood smear. Even if basophilic stippling is not found in the peripheral blood, lead poisoning cannot be excluded.

A case of fulminant Clostridium perfringens infection: Role of macroscopic examination of the serum and peripheral blood smears.

A 69-year-old man was brought to our hospital by ambulance with a fever. The translucent pink color of the serum sample suggested severe hemolysis. His blood pressure dropped rapidly, and he later suffered a cardiopulmonary arrest and died approximately 30 h after arriving at our hospital. The day after the patient's death, Clostridium perfringens was detected in the blood culture taken at the time of hospital admission. When serum sample shows translucent pink to red color and bacilli from bacteria is identified in peripheral blood smear, Clostridium perfringens should be considered and appropriate medical treatment should be initiated immediately.

Adult acute lymphoblastic leukemia with a rare b3a3 type BCR/ABL1 fusion transcript.

The Philadelphia chromosome (Ph) is the most frequent chromosomal abnormality detected in adult acute lymphoblastic leukemia (ALL). This chromosome forms the BCR/ABL1 fusion gene; thus, ABL1 exon a2 is generally used as a primer-binding region for the detection of the fusion transcript via reverse transcription polymerase chain reaction (RT-PCR). We observed a rare case of adult Ph-positive (Ph(+)) ALL, in which the BCR/ABL1 fusion transcript was not detected using the ABL1 exon a2 region primer. However, we were able to isolate a PCR product by RT-PCR with the BCR exon 13 (b2) and ABL1 exon a3 primers. Analysis of the sequence of the RT-PCR product revealed that the fusion point was between BCR exon 14 (b3) and ABL1 exon a3, and that the transcript lacked ABL1 exon a2. The patient achieved cytogenetic remission through combination chemotherapies, but relapse occurred before hematopoietic stem cell transplantation and the patient died 11 months after the initialization of chemotherapies. If the BCR/ABL1 fusion transcript is undetected with the ABL1 exon a2 region primer in Ph(+) ALL cases, an RT-PCR analysis that can detect the b3a3 type BCR/ABL1 fusion transcript should be considered to improve diagnosis.

[Evaluation of prophylactic use of lamivudine in HBV-positive patients with malignant lymphoma undergoing chemotherapy].

A prospective evaluation was carried out on the effect of lamivudine administration as a prophylactic measure to prevent exacerbation of hepatitis in HBV carrier or chronic hepatitis B patients with malignant lymphoma undergoing chemotherapy. Eighteen patients were registered between 1997 and 2002 from institutions of the Research Group for the Treatment of Malignant Lymphoma. The patients' median age was 53 years old (39-73), and consisted of 8 males and 10 females. HBe-seroconversion had already occurred in 13 and liver biopsy had been performed in 8. No adverse effects of lamivudine were noted and the serum HBV-DNA content did not increase during lamivudine administration. Planned treatment courses could be completed in all patients. In 2, however, the viral load increased and the HBe antibody (Ab) value declined after the cessation of lamivudine, which were reversed to the normal ranges following the resumption of lamivudine. As for the overall outcome, 14 of the patients survived, and there were 4 fatalities due to malignant lymphoma. Serum HBeAb status may be regarded as a useful laboratory marker for deciding the safe cessation of lamivudine. An additional case is described, who had recovered from past HBV infection, but eventually succumbed to fulminant hepatitis after the cessation of lamivudine covering prolonged courses of chemotherapy. This illustrates a need for inclusion of such cases for the prophylactic use of lamivudine.

[Bronchoesophageal fistula in a patient with untreated malignant lymphoma].

Bronchoesophageal fistulae associated with lymphomas are generally associated with chemo-radiotherapy. We report here an unusual case of lymphoma with a therapy-unrelated bronchoesophageal fistula. Previously, only 10 similar cases have been reported. A 70-year-old male was diagnosed as having gastric diffuse large B-cell lymphoma in May 1998. In January 1999, he noted a cough after eating and drinking. Because of the presence of a febrile temperature, productive cough and dyspnea, he was referred to our hospital and diagnosed as having aspiration pneumonia. Antibiotics did not improve his symptoms. When tracheal intubation was performed with bronchoscopy, a bronchoesophageal fistula was revealed. Malignant lymphoma cells were found around the fistula in the biopsy specimen. The patient died of pneumonia after treatment with airway stenting and chemotherapy. Induction of necrosis by chemotherapy or low blood flow with stenting and dopamine probably caused enlargement of the fistula.

Dose-intensified CHOP with rituximab (R-Double-CHOP) followed by consolidation high-dose chemotherapies for patients with advanced diffuse large B-cell lymphoma.

Even after the advent of rituximab, clinical outcomes of conventional immuno-chemotherapy for high-risk diffuse large B-cell lymphoma (DLBCL) remain unsatisfactory. We retrospectively evaluated the efficacy and safety of R-Double-CHOP (R-D-CHOP), consisting of rituximab (375 mg/m(2), day -2), cyclophosphamide (750 mg/m(2), day 1, 2), doxorubicin (50 mg/m(2), day 1, 2), vincristine [1.4 mg/m(2) (maximum 2.0 mg/body), day 1], and prednisolone (50 mg/m(2), day 1-5), followed by consolidation high-dose chemotherapy. This treatment was given to 51 de novo DLBCL patients with a median age of 54 (range 19-65), who were categorized as high/high-intermediate risk by the age-adjusted International Prognostic Index. Treatment was given every 3 weeks up to three courses. The overall response and the complete response rate for R-D-CHOP were 94 and 78 %, respectively. A total of 30 responders proceeded to high-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT), whereas 16 received high-dose methotrexate (HD-MTX) alternatively. The 3-year overall survival and the event-free survival for all patients were 78 and 61 %, respectively. Major adverse events included hematological toxicities, but there were no treatment-related deaths during the observation period. We conclude that the R-D-CHOP regimen followed by HDC/ASCT or HD-MTX is a promising treatment option for younger patients with highly advanced DLBCL.

Spontaneous clinical and cytogenetic remission of aplastic anemia in a patient with del(13q).

We describe the case of a 64-year-old Japanese man with pancytopenia. Bone marrow biopsy findings were consistent with aplastic anemia. The patient was treated by transfusions without immunosuppressive therapy. Chromosome analysis of bone marrow cells at 6 months after onset showed a 46,XY,del(13) (q14q22) karyotype. The pancytopenia resolved gradually over the next 5 years; chromosome analysis of bone marrow cells at that time yielded normal findings. To our knowledge, this is the first report of spontaneous hematologic and cytogenetic remission of aplastic anemia. These findings suggest that the abnormal clone with deletion of the long arm of chromosome 13 was not sufficient for clonal evolution in aplastic anemia in this case.

Dose-intensified CHOP (double-CHOP) followed by consolidation with high-dose chemotherapy for high and high-intermediate risk aggressive non-Hodgkin's lymphomas.

Patients with aggressive non-Hodgkin's lymphoma (NHL) showing several risk factors have a poor prognosis. In such patients, conventional chemotherapy results in a low complete response rate and a high relapse rate. We performed a prospective trial of intensive induction chemotherapy followed by high-dose consolidation therapy to determine the feasibility of such an approach. We treated 39 patients with aggressive poor risk NHL with double-CHOP (D-CHOP) chemotherapy followed by high-dose therapy (HDT) with or without peripheral blood stem cell transfusion (PBSCT). The median age of the patients was 54 years (range 17-65). Twenty-seven were considered to be at high (H) and 12 were at high-intermediate (H-I) risk according to the age-adjusted International Prognostic Index. Thirty-four patients (87%) responded (complete response: 74%, partial response: 13%) to D-CHOP chemotherapy. Of the 34 responders, 24 received HDT followed by PBSCT, 7 received high-dose methotrexate, and 3 refused consolidation therapy. At a median follow-up period of 26 months, the estimated 3-year overall survival rate and event-free survival rate was 64 and 51%, respectively. Our data suggest that dose-intensified D-CHOP followed by consolidation HDT is safe and appears efficacious in aggressive NHL patients with H-I and H risk.

[CD25 positive chronic eosinophilic leukemia with myelofibrosis].

A 70-year-old man was referred to our hospital in March 2001 for the purpose of evaluation for anemia and thrombocytopenia. Physical examination revealed hepatosplenomegaly, normal skin, and normal neurologic findings. Blood examination showed a white blood cell count of 10,900/microliter, with a differential count of 58.5% eosinophils and 3.5% blast cells. Flow cytometric analysis of eosinophils revealed that they were positive for CD33, CD13, CD25, and HLA-DR. Bone marrow aspiration could not be performed due to dry tap, and bone marrow core biopsy specimen revealed severe myelofibrosis with blastoid cells proliferation. Cytogenetic analysis of bone marrow cells showed isochromosome 17. FISH analysis using a RAR alpha probe (17q21.1) demonstrated 62% of peripheral blood nucleated cells having three signals. BCR/ABL gene rearrangement by FISH analysis was not observed. Allergic disease, infectious disease, parasitic disease, collagen vascular diseases, pulmonary disease, and neoplastic disorders were excluded. Therefore, a diagnosis of chronic eosinophilic leukemia was made. The patient had no symptoms of hypereosinophilia. However, eosinophils with sparse granulation, positivity for CD25, elevated serum levels of soluble IL-2 receptor, and elevated serum levels of eosinophil cationic protein suggested activation of eosinophils. Further analysis is needed regarding the activation of eosinophils in chronic eosinophilic leukemia.

[Multiple myeloma of the IgD-lambda type invading CNS].

A 52-year-old woman was admitted to the gynecological department of our hospital on July 29, 2002 because of a right lower abdominal mass. She has been suffering from pain in the right leg and inguinal area for a month before coming to the hospital. She was found to have pancytopenia and high serum levels of LDH and IgD. A bone marrow examination showed 63.8% of plasma cells and serum immunoelectrophoresis showed M-protein of the IgD-lambda type. She was diagnosed as having multiple myeloma and transferred to our department. VAD therapy was started from August 22. Although the plasma cells in the bone marrow almost disappeared, the right lower abdominal mass remained and a new mass appeared on the right frontal chest wall after two courses of the treatment. Combination chemotherapy with vincristine, ranimustine, melphalan, and dexamethasone (ROAD) was started on November 1. This was followed with thalidomide and radiation therapy of the right inguinal region was added. On December 16th, she suddenly experienced speech disturbance, nausea and the disturbance of consciousness. Examination of her cerebrospinal fluid showed 368/microl mononuclear cells with 93% plasma cells. The plasma cells disappeared after the 6th intrathecal injection with MTX and prednisolone and the chemotherapy was resumed. One month later, CNS relapse was apparent followed by generalized spread of the tumor mass, and she died on March 17, 2003.

Safety and efficacy of high-dose cyclophosphamide, etoposide and ranimustine regimen followed by autologous peripheral blood stem cell transplant for patients with diffuse large B-cell lymphoma.

We retrospectively evaluated the safety and efficacy of high-dose chemotherapy consisting of cyclophosphamide, etoposide and ranimustine (CEM) with autologous peripheral blood stem cell transplant (PBSCT) in 55 adult patients with relapsed or high-risk de novo diffuse large B-cell lymphoma (DLBCL) or DLBCL associated with follicular lymphoma. This included 36 patients in the upfront setting in their first complete remission. The median follow-up of 42 patients surviving at the time of the analysis was 52 months (range 1-159). Relapse or disease progression after PBSCT was a frequent cause of death, but no therapy-related mortality associated with PBSCT was observed. The 5-year overall survival and progression-free survival were 70.6% (95% confidence interval [CI], 54.0-82.1) and 57.0% (95% CI, 39.5-71.2), respectively. Chronic renal impairment, therapy-related myelodysplastic syndrome and prostate cancer were the major late complications. The CEM regimen is a tolerable, effective conditioning regimen for autologous PBSCT for DLBCL, with no therapy-related mortality observed.

Efficacy of a dose-intensified CHOP (Double-CHOP) regimen for peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of non-Hodgkin lymphomas, often resulting in poor prognoses. The CHOP chemotherapy regimen, which includes cyclophosphamide, doxorubicin, vincristine and prednisone, has been used previously to treat other types of lymphomas. Here, we examined the efficacy and safety of a dose-intensified CHOP regimen (Double-CHOP), which was followed by autologous stem-cell transplantation (ASCT) or high-dose methotrexate (HDMTX), in PTCL patients. Twenty-eight PTCL patients, who received 3 courses of Double-CHOP at our institution, were retrospectively studied from 1996 to 2012. Patients with anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma (ALK+-ALCL) were excluded from this study. The median age of patients was 58 years (range: 17-69). They had low-intermediate (n=11), high-intermediate (n=10) or high (n=7) risk according to the International Prognostic Index (IPI). The overall complete remission (CR) rate following Double-CHOP treatment was 68%. Of the CR patients, 10 successfully tolerated a consolidated high-dose chemotherapy followed by ASCT and 7 received HDMTX. A single case of treatment-related mortality was recorded during the study. On a median 31-month follow-up, the estimated 3- or 5-year overall survival (OS) rates were 68 or 63%, respectively, while 3- or 5-year relapse-free survival (RFS) rates after CR were 60 or 43%, respectively. Although this study included elderly and excluded low-risk IPI and ALK+-ALCL patients, OS results were superiorly favourable, indicating the efficacy of this Double-CHOP regimen. However, an effective treatment strategy for refractory or relapsing patients needs to be validated and established.

Long-term follow-up of localized, primary gastric diffuse large B-cell lymphoma treated with rituximab and CHOP.

The addition of rituximab to cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP (i.e., R-CHOP)] is considered to be the standard regimen for treating localized, primary gastric diffuse large B-cell lymphoma (PG-DLBCL). However, few studies have reported the long-term efficacy of R-CHOP therapy in the management of localized PG-DLBCL. In the present study, we performed a retrospective analysis of 11 patients with localized PG-DLBCL, who were treated with R-CHOP at Nihon University Itabashi Hospital and Kasukabe Municipal Hospital (Japan) from 2001 to 2008. Limited stage cancer was defined as stage I/II according to the Lugano staging system for gastrointestinal (GI) lymphomas. The relative dose intensity (RDI) of CHOP therapy was calculated for each patient. The median age of the patients was 68 years (range, 48-82). Gastralgia and anemia were common symptoms at initial presentation. All patients except 1 received 6 cycles of R-CHOP treatment without consolidative radiation therapy or prior surgery. RDI was maintained at over 80% in 9 out of 11 patients. All patients achieved complete remission and the estimated overall survival with a median follow-up of 54 months (range, 39-103) was 100%, without relapse or significant GI adverse effects, such as perforation or bleeding during R-CHOP treatment. No long-term adverse effects of rituximab were recorded during the observation period. Helicobacter pylori infection was diagnosed in 72.7% (8 cases) of the patients, but was eradicated in a limited number of patients. Our data suggest the feasibility and effectiveness of the addition of rituximab to conventional CHOP therapy in the management of localized PG-DLBCL.

An effective salvage treatment using ifosfamide, etoposide, cytarabine, dexamethasone, and rituximab (R-IVAD) for patients with relapsed or refractory aggressive B-cell lymphoma.

We evaluated the efficacy and toxicity of a new salvage regimen, consisting of rituximab (375 mg/m(2), day 1), ifosfamide (1500 mg/m(2) on days 3-7), etoposide (150 mg/m(2), days 3-5), cytarabine (100 mg/m(2), days 3-5) and dexamethasone (40 mg/body, days 3-5) (R-IVAD) for relapsed or refractory aggressive B-cell lymphoma. In this study, a total of 32 patients with a median age of 64 years (range 38-79) who received an average of 2.6 cycles of R-IVAD from 2001 to 2009 in our institution were retrospectively analyzed. R-IVAD was given every 3 weeks up to a total of three courses with support by granulocyte colony stimulating factor. The overall response rate was 72%, with 56% complete response. On a median follow-up of 16 months (range 2-99), estimated 2-year overall survival (OS) and event-free survival were 55% and 36%, respectively. Of these patients, 10 successfully proceeded to consolidating high-dose chemotherapy followed by autologous stem cell transplantation, accounting for 90% of the 2-year OS. No treatment-related mortality was observed during the investigation. We, therefore, conclude that R-IVAD regimen is a safe and efficacious alternative for patients with relapsed or refractory aggressive B-cell lymphoma.

A case of treatment-related myelodysplastic syndrome spontaneously resolved by drug discontinuance.

Although great advancements have been witnessed in treatment results for hematopoietic tumors in recent years, development of secondary malignant tumors induced by anti-cancer drugs still remains a serious issue. We experienced a case of secondary myelodysplastic syndrome (MDS), possibly induced by cyclophosphamide (CY), which was spontaneously resolved by discontinuance of CY. A 24-year-old woman was diagnosed with follicular lymphoma in January 1998: she had developed bulky intra-abdominal lymphadenopathy, with repeated relapse and remission by several chemotherapy treatments. Remission was induced by rituximab, administered at the time of relapse in 2001, followed by administration of 50 mg/day of CY since December 2001 for the prevention of relapse. Anemia and thrombocytopenia developed around January 2003. Bone marrow aspiration revealed abnormality in two lineages and a complicated chromosomal anomaly, and the patient was diagnosed with MDS. Discontinuance of CY and administration of an anabolic steroid improved anemia and thrombocytopenia within 2 years. Bone marrow aspiration in 2006 showed improvement in morphological abnormality and disappearance of chromosomal abnormality.

A case of aggressive myeloma recognized shortly after the remission following high-dose chemotherapy with autologous peripheral blood stem cell transplantation.

A 45-year-old woman was referred to our hospital with acute renal failure and pyrexia. In August 2005, the patient was diagnosed with IgA-λ type multiple myeloma with chromosome 13 deletion, and received three cycles of vinclistine, adriamycin and dexamethasone followed by high-dose melphalan-based autologous peripheral stem cell transplantation: this resulted in remission 2 months before admission to our hospital. Serum IgA concentration was within the normal limit, but an excess of myeloma cells in bone marrow was confirmed. Immunoelectrophoresis revealed BJP-λ production with no IgA-λ. The patient received several courses of chemotherapy with mechanical ventilation and regular hemodialysis. The progression of the illness was rapid: multiple organ failure promptly developed and the patient died 2 months after admission. Autopsy revealed deposition of light chain λ protein in multiple organs. We report this unusual case of aggressive myeloma recognized shortly after successful autologous transplantation.

Treatment of high-risk peripheral T-cell lymphomas other than anaplastic large-cell lymphoma with a dose-intensified CHOP regimen followed by high-dose chemotherapy. A single institution study.

We investigated the efficacy of a dose-intensified double-CHOP regimen followed by high-dose chemotherapy with or without peripheral blood stem cell transplantation (PBSCT) in 11 patients with four types of peripheral T-cell lymphoma (PTCL). Three of the 4 patients with unspecified PTCL (PTCLu) achieved complete response (CR); 1 patient relapsed and 1 died of secondary leukemia after consolidation therapy. All angioimmunoblastic T-cell lymphoma (AILT) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients achieved CR; 5 of 6 have remained disease free for more than 3 years. The patient with hepatosplenic lymphoma did not achieve CR even after PBSCT and underwent allogenic bone marrow transplantation (allo-BMT). Thus, our regimen appears to be effective for high-risk AILT and SPTCL. However, allo-BMT should be considered for high-risk of PTCLu and hepatosplenic T-cell lymphoma.