Sadaya Matano

Effect of granulocyte colony‐stimulating factor on neutropenia due to chemotherapy for non‐Hodgkin's lymphoma

The authors administered recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) to 16 patients with advanced non‐Hodgkins lymphoma treated with combination chemotherapy. Groups of three to five patients were treated with 50, 100, 200, and 400 μ/m2 per day of rhG‐CSF by intravenous infusion for 14 days, beginning 3 days after chemotherapy. There was a strong linear relationship between the dose and the area under the curve over this dose range. The rhG‐CSF was rapidly cleared from serum, with a mean half‐life of 5.97 hours for the second phase (t1/2). In patients treated with a dose of more than 100 μg/m2 per day, the duration of neutropenia (P < 0.01) and the duration of fever (P < 0.05) were significantly decreased. The rhG‐CSF was well tolerated and the only clinical observation that appeared relating to rhG‐CSF administration was slight bone pain. This study strongly suggests that an optimum dose of rhG‐CSF in patients after chemotherapy is 100 to 200 μg/m2. Our study shows that rhG‐CSF is a clinically useful drug for patients treated with myelosuppressive chemotherapy.

Deletion of the long arm of chromosome 20 in a patient with chronic neutrophilic leukemia: Cytogenetic findings in chronic neutrophilic leukemia

We encountered a 67‐year‐old female with chronic neutrophilic leukemia (CNL). Cytogenetic study showed she had a deletion in the long arm of chromosome 20. This finding indicates that CNL, in this case, is a clonal disorder. Most CNL patients have normal karyotypes, and only four patients with cytogenetic abnormalities, including two cases who received chemotherapy before the cytogenetic abnormality was detected, have been reported. Four of those cases, including our case, had abnormalities in the long arm of chromosome 20. This locus may be associated with the development of CNL. To our knowledge, this is the first case with CNL who showed deletion of the long arm of chromosome 20 before treatment was started. Am. J. Hematol. 54:72–75, 1997

Monomorphic agranular natural killer cell lymphoma/leukemia with no Epstein-Barr virus association.

The conceptual view of natural killer (NK) cell malignancies has recently undergone a significant evolution. The majority of such diseases are associated with Epstein-Barr virus (EBV), while only a limited number of EBV-negative cases has been reported. We report an unusual case of NK cell lymphoma/leukemia showing a monomorphic histology, absence of intracytoplasmic azurophilic granules, and no EBV association. The patient was a 57-year-old woman who died 26 months after the diagnosis. Autopsy revealed tumor infiltration in the liver, spleen, lymph node, blood, and bone marrow. There was no involvement of the skin or nasal cavity throughout the clinical course. The tumor showed the monotonous proliferation of medium-sized cells without intracytoplasmic azurophilic granules. Phenotypic analysis showed CD2+, CD3/Leu4–, cytoplasmic CD3ε+, CD4–, CD5–, CD7+, CD8–, CD16–, CD38+, CD56+, CD57–, TdT–, granzyme B–, and TIA1+ phenotype. There were no detectable rearrangements of T cell receptor genes or immunogloublin heavy chain genes. Furthermore, there were no EBV-encoded small RNAs. These findings provide information to improve the understanding of poorly defined entities, i.e. aggressive NK cell lymphoma/leukemia and blastic NK cell lymphoma/leukemia.

Primary hepatic lymphoma in a patient with chronic hepatitis B.

Primary hepatic lymphoma is a rare disorder and the clinical behavior remains unknown. We report a patient with primary hepatic lymphoma who had chronic hepatitis B. She was asymptomatic; however, a solitary tumor in the left lobe was incidentally detected. After left hepatic lobectomy was performed, a diagnosis of non-Hodgkins lymphoma was made. No tumor was found except in the liver. Immunohistochemical stains for hepatitis B surface and core antigens were positive in hepatocytes; however, both were negative in the tumor tissue. The patient received no chemotherapy and the tumor relapsed. After chemotherapy, the tumor disappeared. However, exacerbation of hepatitis occurred after the fourth chemotherapy. The patient was followed up without chemotherapy, and she remains in apparent remission. Chemotherapy is effective against primary hepatic lymphoma and, if possible, patients with this disorder should be treated with chemotherapy postoperatively.

Primary leptomeningeal lymphoma.

Primary leptomeningeal lymphoma is a rare disorder, and the neuroradiological characteristics or the complication of this rare disorder have not been well reported. We reported herein a patient with a primary leptomeningeal lymphoma who has complication with subdural hematoma. The patient complained of headache and vomiting. Neurological examination revealed progressive cranial nerve palsy. Cerebrospinal fluid examination disclosed monoclonal proliferation of atypical B-lymphocytes. Cranial computed tomographic scans showed a left frontal mass with convex form to the brain parenchyma. T1-weighted magnetic resonance (MR) images disclosed subacute subdural hematoma. However, proton-weighted MR images showed high signal intensity in subarachnoid space, which suggested leptomeningeal lymphoma. He underwent craniotomy, and the diagnosis of leptomeningeal lymphoma complicated with subdural hematoma was confirmed. Systemic examinations disclosed no lymphomatous lesions except for leptomeningus, and the diagnosis of primary leptomeningeal lymphoma was established. We suggested that subdural hematoma was associated with primary leptomeningeal lymphoma in this patient. Cerebrospinal fluid examination and proton-weighted MR imaging should be performed when progressive neurological abnormalities are found in patients with subdural hematoma.

Leukemic hypopyon in acute myelogenous leukemia.

Abstract We encountered a patient with acute myelogenous leukemia (AML) who developed leukemic hypopyon. Leukemia initially spread into the pharynx, gingiva, lymphnode, and bone marrow. He achieved complete remission after chemotherapy but developed blurred vision and hypopyon. Anterior chamber paracentesis disclosed leukemic infiltration of the anterior chamber. Infiltration of the central nervous system also occurred. He received systemic chemotherapy, intrathecal chemotherapy, and local chemotherapy. However, he did not achieve prolonged remission. These findings suggest that these chemotherapy treatments have an inadequate effect for AML with anterior chamber infiltration. This rare complication is associated with extramedullary infiltration of leukemia.

Establishment of a metastatic murine cell line carrying the human c-Ha-ras

Dear Editor: Development of new modalities to control metastasis is an urgent requirement of cancer therapy. However, the available methods have an inherent limitation in detecting and quantifying micro-metastases. It is possible to experimentally detect metastasis if genes of a species are detected in the tissues of another animal. Therefore, a new system needs to be established which consists of: 1) ceils that grow and metastasize in immunocompetent syngeneic animals, a n d 2) cells that have genes which are distinguishable from those of the animal tissues. The combination of r/mHM-SFME-1 cells and Balb/c mice provides a good model system for this application. The r/mHM-SFME1 cells are derived from ras/myc SFME cells transformed by activated human c-Ha-ras and mouse c-myc genes (5,7). Since original serum-free mouse embryo (SFME) cells were established from a Balb/c mouse embryo (3), immunocompetent Balb/c mice are syngeneic for both ras/myc SFME and r/mHM-SFME-1 cells. Here we describe the establishment of the r/mHM-SFME-1 cell line in vitro. One million of G418-resistant ras/myc SFME cells, which were transfected with pSV2-neo by calcium-phosphate co-precipitation (7), were injected subcutaneously into the backs of Balb/c mice. All of mice, which developed solid tumors within 2 months, were sacrificed to check metastases. One of them had metastases in the subaxillary and submaxillary lymph nodes, the lung and the liver. The metastases were excised from each organ and transplanted subcutaneously again into the mice. Only mice that received the tung metastases developed solid tumors and pulmonary metastases. Thereafter, these pulmonary metastases were serially transplanted subcutaneously into Balb/c mice. The solid tumors of the 7th passage were excised under sterile conditions and the cells were then cultured in serum-free medium (3) followed by colonization in soft agar. One of the clones derived from a colony was designated as r/mHM-SFME1. The r/mHM-SFME-1 cells were no longer resistant to G418. The profiles of the two cell lines in culture are shown in Figure 1. The r/mHM-SFME-1 cells tended to aggregate in culture whereas the ras/myc SFME cells did not. Aggregates always appeared 3 4 days after plating whether in serum-free or in serum-supplemented media and did not disappear upon adding fresh media. The aggregates sometimes detached from cells on dishes so that freely floating cells were observable in aged cultures even maintained by frequent media change. In order to confirm that the r/mI-LM-SFME-1 cells were derived from the ras/myc SFME cells, we determined whether the r/mHMSFME-1 cells had human ras genes. Hind III-digested fragments of DNA from r/mHM-SFME-1 and ras/myc SFME ceils were hybridized with the human c-Ha-ras exon-2 (6). A plasmid pUCC-H-ras, which contains normal human ras gene from placenta, for probe was obtained from the Japanese Cancer Research Resources Bank (JCRB). Six bands were detected in each of the fragments and no significant differences in the band profiles of either fragment were observed (Fig. 2). A faint band detectable in the DNA fragments from non-transformed SFME cells may be due to endogenous

Thickening of multiple cranial nerves in a patient with extranodal peripheral T-cell lymphoma.

A 57‐year‐old male became aware of a subcutaneous tumor in March 2001. Histopathological examination showed peripheral T‐cell lymphoma. He achieved complete remission after chemotherapy. Later the lymphoma relapsed in the subcutaneous lesion and chemotherapy was performed again. In April 2003, he developed diplopia, dysarthria, and dysphagia. Abnormal lymphoid cells were found in the cerebrospinal fluid. An immunophenotypical study disclosed that CD2, CD3, CD5, and CD8 were positive. Rearrangement of TCR was detected by Southern blotting. Cranial magnetic resonance imaging did not detect any intraparenchymal lesions, but thickening of multiple cranial nerves was detected. These nerves were homogenously enhanced by gadolinium‐DTPA. After intrathecal chemotherapy, atypical cells disappeared from the cerebrospinal fluid and thickening of the cranial nerves was resolved. Finally, lymphoma spread to the bone marrow, and the patient died in July 2003.

Scintigraphic prediction of therapeutic outcomes of splenectomy in patients with thrombocytopenia.

In patients with thrombocytopenia, platelet scintigraphy has been used to locate the site of platelet sequestration and destruction and to determine whether splenectomy will be of benefit. However, its efficacy in predicting the outcome of splenectomy is controversial. We assessed the feasibility of platelet scintigraphy in this regard.Methods: Platelet scintigraphy was performed in five patients (2 women, 3 men, mean age 48 years) before splenectomy. Four patients were diagnosed with idiopathic thrombocytopenic purpura and one with hypersplenism due to portal hypertension caused by intrahepatic chemotherapy against metastatic liver tumors of rectal cancer. Platelets labeled with 37 MBq of In-111 oxine or 1110 MBq of Tc-99m HMPAO were intravenously injected. Anterior images were obtained with a gamma camera 3–5 and 23–29 hours post-injection in five patients. Additional images were obtained 48 hours post-injection in three patients. For the analysis, a spleen/liver ratio (S/L ratio) was calculated using mean counts in regions of interest defined on the spleen and the liver. Serum platelet counts were measured before and after the operation; in three patients, splenectomy effectively resolved the thrombocytopenia (Group A), while it was ineffective in two patients (Group B).Results: The S/L ratios were apparently higher in group A than in Group B; in Group A, the ratios were 6.05, 6.97 and 3.16 at 3–5 hours, 12.67, 7.48 and 3.46 at 23–29 hours and 17.66, and 8.12 at 48 hours, whereas, in Group B, they were 0.67 and 0.66 at 3–5 hours, 0.52 and 0.54 at 24 hours, and 0.42 at 48 hours.Conclusion: The results of this study indicate that platelet scintigraphy is of value in predicting the therapeutic efficacy of splenectomy in patients with thrombocytopenia.

Primary T Cell Non-Hodgkin’s Lymphoma of the Central Nervous System

A 42-year-old man developed primary non-Hodgkins lymphoma of the central nervous system (CNS). Immunohistochemical examination suggested that tumor cells were derived from T cells. Primary T cell non-Hodgkins lymphoma of the CNS is a rare tumor, with only 12 well-documented cases in the literature. The clinical features of these 12 cases were similar to those of other CNS lymphomas, and the effect of treatment and prognosis were usually worse than those of extranodal lymphoma. Our patient, who was treated with partial tumor resection and whole-brain irradiation with a boost to the primary site and 5 courses of CHOP therapy (cyclophosphamide, doxorubicin, vincristine, prednisolone), is still alive and in remission 38 months after diagnosis.