Masanori Umeda

Development of interstitial pneumonitis during treatment with granulocyte colony-stimulating factor.

Sir, Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor, widely used for the treatment of cytotoxic chemotherapy-induced neutropenia. We report two patients with malignant lymphoma who developed interstitial pneumonitis during or shortly after treatment with G-CSF. Recombinant human GCSF produced by Escherichia coli (Kirin Brewery Co. Ltd., Tokyo) was used in both patients. Patient 1 was a 66-year-old woman with non-Hodgkins lymphoma (diffuse large-cell type, stage liB). She was successfully treated with COPBLAM. After the second course of chemotherapy, her neutrophil count fell to 0.5 x 109/1. She received subcutaneous injections of G-CSF (1.5/zg/kg) for 4 days, and the neutrophil count recovered to 8 x 109/1. Nine days after the cessation of G-CSF treatment, the patient complained of serious dyspnea without fever. The neutrophil count was 5x109/1. Chest examination revealed bilateral fine crackles, and chest X-ray film showed reticular interstitial infiltrates. The pulmonary function tests revealed decreased PaO2 (29.3 torr) and decreased diffusion capacity (AaDO2 261 torr). Before the chemotherapy PaO2 had been 76 torr. The patient was diagnosed as having interstitial pneumonitis. In spite of intensive treatment with steroids, antibiotics, and mechanical ventilation for a month, she died of multiple organ failure. The total dose of bleomycin administered was 20 mg. Patient 2 is a 62-year-old woman with non-Hodgkins lymphoma (diffuse mixed-cell type, stage IVA, with skin infiltration). She was successfully treated

Evaluation of long-term daily administration of oral low-dose etoposide in elderly patients with relapsing or refractory non-Hodgkin's lymphoma

Etoposide produces reversible inhibition of topoisomerase II, leading to cleavage of DNA, and thereby has an antitumor effect. This mechanism suggests that the longer treatment is continued, the greater the antitumor effect will be. In the present study, both therapeutic and adverse effects of long-term treatment with low-dose oral etoposide were studied in 29 patients aged > or = 65 years with non-Hodgkins lymphoma (NHL) for whom standard chemotherapy was not effective or refractory. These patients received etoposide at a dose of 50 mg/d for as long as possible. Treatment was continued until white blood cell count decreased to < or = 2,000/microL or the platelet count decreased to < or = 5 x 10(4)/microL. According to the World Health Organization (WHO) criteria of therapeutic effects, 6 (20.7%) of the 29 patients achieved complete remission and 13 patients (44.8%) had partial remission, for a response rate of 65.5%. Adverse effects of > or = grade 3 included leukopenia in 24 patients (82.8%) and anemia in 7 (24.1%). Granulocyte colony-stimulating factor (G-CSF) was given in combination with etoposide to eight patients because of leukopenia (granulocyte count < or = 1,000/microL). In view of the excellent subjective tolerance, low incidence of serious adverse effects, and good activity, single agent oral etoposide given continuously over prolonged periods represents a useful treatment for elderly patients with NHL.

Biweekly COP‐BLAM (cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin and procarbazine) regimen combined with granulocyte colony‐stimulating factor (G‐CSF) for intermediate‐grade non‐Hodgkin's lymphoma

Abstract:  We evaluated the efficacy and adverse effects of biweekly COP‐BLAM (cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin and procarbazine) therapy combined with granulocyte colony‐stimulating factor (G‐CSF) for treating non‐Hodgkins lymphoma (NHL). A complete remission was achieved in 65 (90.3%) of the 72 patients. The median follow‐up period was 28 months, and 64 patients were alive at the time of writing. Treatment was delivered as scheduled to 61 patients. G‐CSF made it possible to shorten the interval between courses of chemotherapy. One of the 72 patients died of granulocytopenia and pneumonia; no other severe infections were noted. Further studies regarding adverse effects on organs other than the bone marrow are required to improve the long‐term results of combination therapy on NHL.

Salvage chemotherapy for relapsed or refractory non‐Hodgkin's lymphoma with a combination of ACES (high‐dose Ara C, carboplatin, etoposide and steroids) therapy

Abstract:  ACES (Ara‐C, carboplatin, etoposide, steroids) therapy using granulocyte‐colony stimulating factor (G–CSF) was designed for relapsed or refractory non‐Hodgkins lymphoma (NHL), and the therapeutic effects and adverse reactions were studied. The subjects were 40 patients, including 19 relapsed cases and 21 refractory cases, subjected to chemotherapy using anthracycline type agents. The ACES therapy consisted of carboplatin at 100 mg/m2 and etoposide at 80 mg/m2 for 4 d from the first day, Ara‐C at 2 g/m2 on the fifth day, solumedrol at 500 mg for 5 d from the first day and G–CSF at 2 μg/kg from the seventh day. This therapy was performed every 3 weeks, in principle. The doses were reduced to 70% of the above values for patients aged 70 yr or older. Among the 40 patients, complete remission (CR) was achieved in 14 (35%) and partial remission (PR) in 14 (35%) for a response of 70%. The 50% survival period was 526 d, and the 2‐yr disease‐free survival rate was 58.3%. Adverse reactions of grade 3 or higher included granulocytopenia in 62.5%, anemia in 17.5% and thrombocytopenia in 50%, but there was no death related to treatment. Four patients underwent transplantation of hematopoietic stem cells and have survived for long periods. This treatment was effective against relapsed NHL and could be performed safely with few adverse reactions.

Response and adverse drug reactions to combination chemotherapy in elderly patients with aggressive non-Hodgkin's lymphoma: comparison of CHOP, COP-BLAM, COP-BLAM III, and THP-COPBLM.

Abstract: We retrospectively compared therapeutic results and adverse events in 198 elderly patients (≥70 yr old) with aggressive non‐Hodgkins lymphoma diagnosed between 1981 and 1995 who underwent CHOP, COP‐BLAM, COP‐BLAM III, or THP‐COPBLM chemotherapy. Complete remission (CR) was achieved in 138 patients (69.7%). The CR rate was 47.0% for CHOP, 76.3% for COP‐BLAM, 67.9% for COP‐BLAM III, and 74.4% for THP‐COPBLM therapy (p = 0.013). The 5‐yr survival rate was 37.0% for CHOP, 49.0% for COP‐BLAM, and 53.5% for COP‐BLAM III. The event‐free survival rate showed no significant differences between the four treatments. Adverse events of Grade 3 or worse were commonly anemia or granulocytopenia in patients receiving THP‐COPBLM therapy. Cardiac sympathetic dysfunction and cardiac mitochondrial damage were less common with pirarubicin than with doxorubicin.

Human herpes virus-8 associated with two cases of primary-effusion lymphoma.

Abstract Primary-effusion lymphoma (PEL) is a rare form of non-Hodgkins lymphoma which predominantly occurs in patients with acquired immunodeficiency syndrome and is characterized by the presence of a malignant effusion in one or more of the body cavities, generally in the absence of a primary tumor mass. Recently, we encountered two cases of PEL presenting as cardiac tamponade. In both cases, a diagnosis of diffuse large B-cell lymphoma was made by examination of the pericardial fluid. Because human herpes virus-8 (HHV-8) antibodies were positive and human immunodeficiency virus antibodies were negative, HHV-8 seemed likely to be an etiologic agent for the PEL. One of the two patients (case 1) was not treated for religion reasons and died. The other (case 2) achieved complete remission after treatment using the CHOP regimen and is alive at present. The prognosis of this disease is believed to be poor, therefore more cases should be collected to establish reliable therapy for PEL.

COP-BLAM regimen combined with granulocyte colony-stimulating factor and high-grade non-Hodgkin's lymphoma.

Abstract: The clinical efficacy of COP‐BLAM chemotherapy combined with human recombinant granulocyte colony‐stimulating factor (G‐CSF) was evaluated in 104 previously untreated patients with non‐Hodgkins lymphoma (NHL). According to the method of Laurence et al., a modified COP‐BLAM regimen was administered every 21 days. G‐CSF was added when the granulocyte count fell below 1000 × 109/l. Ninety‐eight of 104 (94.2%) patients achieved a complete remission; the 4‐year survival rate was 82.4% with a median duration of observation of 26 months. Survival was significantly longer in patients with low serum LDH levels, B‐cell type or low CRP or in earlier clinical stages, than in patients with high serum LDH levels, T‐cell type or higher CRP levels or in advanced clinical stages. The mean duration of administration of G‐CSF was 5.4 days. Twelve patients developed infections during treatment. The adverse effects of G‐CSF included interstitial pneumonia, bone pain and fever. Patients administered COP‐BLAM combined with G‐CSF achieved a high rate of remission and had a low incidence of infection. Nearly all the patients could be treated in 21‐day cycles. The results suggest that G‐CSF combined with COP‐BLAM was effective in treating NHL, because the patients can tolerate a higher dose of the anticancer agents.

Fungemia in Patients with Hematologic Malignancies: Therapeutic Effects of Concomitant Administration of Fluconazole and Granulocyte-Colony-Stimulating Factor

Serum (beta 1-->3)-D-glucan was elevated in 34 of 126 patients (27%) with hematologic malignancy who were clinically suspected of having a deep-seated mycosis. Although 11 patients (8.8%) were thought to have fungemia, fungi were isolated from blood culture in only 4. These results suggest that measurement of serum beta-D-glucan is useful for early diagnosis. Therapy with fluconazole (FLCZ) was effective in 9 of 11 patients (81.8%) suspected of having fungemia. Fungemia responded in 5 of 7 patients who were given granulocyte-colony-stimulating factor (G-CSF) concomitantly with FLCZ. This result suggested that administration of G-CSF with FLCZ was useful therapy for fungemia, which may occur during granulocytopenia following chemotherapy with anticancer agents.

Selective enhancement of B cell antigen receptor-mediated antigen presentation by treatment with transforming growth factor-β

TGF‐β1 was examined for the ability to regulate Ag‐presentation by B cells, using A20‐HL B lymphoma cells bearing TNP‐specific IgM receptors. Treatment of A20‐HL cells with TGF‐β1 at 1 ng/ml, a concentration that inhibited proliferation, enhanced presentation of Ag internalized via surface IgM (sIgM), but not via fluid‐phase pinocytosis. TGF‐β1‐treatment slightly enhanced surface expression of sIgM, but not of MHC class II molecules. The treatment accelerated recovery of sIgM expression after its removal by ligation with TNP‐OVA, and induced prolonged intracellular residence of TNP‐OVA internalized via sIgM, which co‐localized with intracellular MHC class II molecules. TGF‐β1‐treatment increased accumulation of newly synthesized intracellular MHC class II molecules that were localized in compartments positive for lysosome‐associated membrane protein 1, although cellular protein synthesis was decreased by the treatment. The accumulated intracellular MHC class II molecules were triggered to the cell surface by ligation of sIgM. Finally, TGF‐β1‐treatment induced Igα‐phosphorylation in response to lower concentrations of TNP‐OVA. On the basis of these findings, we conclude that TGF‐β1‐treatment of A20‐HL cells selectively enhances the ability to present Ag internalized via sIgM, not via fluid‐phase pinocytosis, through accelerating sIgM recovery, increasing accumulation of intracellular MHC class II molecules and enhancing the ability of sIgM ligation to induce Igα‐phosphorylation.

Clinical features of testicular non-Hodgkin's lymphoma--focus on treatment strategy.

Testicular primary non-Hodgkins lymphoma (NHL) is said to account for about 5% of all testicular tumors and about 2% of extranodular lymphoma. From a clinical standpoint, we reviewed testicular NHL of stage IE treated at our department over the past 18 years. Among the 865 cases of NHL, 19 (2.2%) were primary testicular NHL, stage IE. The 19 patients had a median age of 62 years (range 48-77 years), all had diffuse B-cell lymphoma. Of the 19 patients, 8 were treated with radiotherapy after high inguinal orchiectomy (Group I), 4 received both postoperative radiotherapy and chemotherapy (Group II), and 7 received additional prophylactic intrathecal chemotherapy (Group III). The 5-year survival rates for Groups I, II and III were 37.5%, 50%, and 100%, respectively. None of the patients receiving prophylactic intrathecal chemotherapy had relapse in the central nervous system and all of them are alive and disease-free. Primary testicular NHL is relatively common among elderly persons, and many patients die as a result of central nervous system recurrence. These results suggest that preventive measures for central nervous system recurrence such as intrathecal injection of anticancer agents should be taken into consideration as early as at the induction of remission.