Prognostic significance of immunoglobulin heavy chain gene rearrangement in patients with acute myelogenous leukemia.

Recently the immunoglobulin heavy chain (IgH) gene rearrangement in B cell malignancies has been analyzed. Clonality can be determined using the polymerase chain reaction (PCR). Little attention, however, has been given to the relationship between prognosis and IgH gene rearrangement in patients with acute myelogenous leukemia (AML). In this study, we examined IgH gene rearrangement in 35 untreated AML patients by PCR. PCR was performed using consensus heavy chain complimentarity-determining region (CDR)-3 primers. Clonal IgH gene rearrangement was detected in 14 patients (40%). Four of five patients (80%) who were positive for B cell markers had clonal IgH gene rearrangement. Ten of 30 B cell antigen-negative patients (33%) also showed IgH rearrangement. All patients were treated with a daunorubicin-based regimen, resulting in complete remission for 29 patients (83%). Sixty-four percent of those with IgH rearrangement and 95% of those without rearrangement had complete remission. Overall survival of IgH-PCR positive and negative patients at 25 months was 29 and 88%, respectively. IgH-PCR positivity may be a poor prognostic factor in AML.

Application of the polymerase chain reaction (PCR) to quantify micro-metastasis in an experimental animal.

In vitro cultured r/mHM-SFME-1 cells were injected into the hind foot pads of Balb/c mice. Metastasis was detected in the lungs of tumor-bearing mice by means of both PCR and histological methods. Primers for the PCR were set to amplify a 128 bp exon-1 sequence of the human c-Ha-ras1 gene which had been introduced into the cells. Resulted PCR bands were densitometorically quantified using a bioimage analyzer, and more than 1 x 10(4) tumor cells were detectable in the mouse lung. The number of tumor cells per lung estimated from the amount of PCR products was 1 x 10(5), 15 x 10(5), 1 x 10(5) and 40 x 10(5) on days 7, 14, 21 and 28 respectively after the tumor injection. No metastases were histologically observed on days 7 and 14. Then, the possibility of using this model system for evaluation of a treatment against micro-metastases is discussed.

Plasma and leukemic cell pharmacokinetics of high-dose N4-behenoyl-1-beta-D-arabinofuranosylcytosine in acute leukemia patients.

The pharmacokinetics of N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a lipophilic antitumor analog of 1-beta-D-arabinofuranosylcytosine (ara-C), was investigated, by assay of plasma and leukemic cells of ten acute leukemic patients receiving 60-minute intravenous (IV) infusion of 700 mg/m2 BHAC, for BHAC and 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) by high-performance liquid chromatography, ara-C by radioimmunoassay, and 1-beta-D-arabinofuranosyluracil (ara-U) by gas chromatography-mass fragmentography. The plasma concentration of BHAC reached a maximum (173.4 +/- 75.3 micrograms/mL) at the end of the infusion and then declined in a biphasic pattern with an initial-phase half-life (t1/2 alpha) of 1.00 +/- .36 hours and a second-phase half-life (t1/2 beta) of 4.28 +/- 2.35 hours. That of ara-C similarly reached a maximum (102.2 +/- 39.9 mg/mL) at the end of the infusion and then declined with t1/2 alpha of 1.37 +/- 1.11 hours and t1/2 beta of 11.2 +/- 4.31 hours. Intracellular ara-CTP concentration increased in a linear-accumulation manner for the first 4 hours after the infusion, reached a maximum of .081 +/- .112 micrograms/10(7) cells at approximately 7 hours, and then declined very slowly in accordance with a one-compartment model with t1/2 of 13.56 +/- 9.62 hours.

Treatment of acute myeloid leukemia and myelodysplastic syndrome with orally administered cytarabine ocfosfate and granulocyte colony-stimulating factor.

Cytarabine ocfosfate (SPAC) was administered orally to 19 patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). SPAC was administered at doses of 200-300 mg/day for more than 14 days with granulocyte colony-stimulating factor (G-CSF). Four of the 12 patients with AML and 1 of the 7 patients with MDS achieved complete remission (CR) after one cycle of SPAC treatment. Especially, 3 of the 6 patients with newly diagnosed AML achieved CR. Major side effects of SPAC were myelosuppression and tolerable gastrointestinal disorders. The treatment with SPAC is a therapeutic option in elderly patients or patients with organ failure.

Salvage chemotherapy of refractory non-Hodgkin's lymphoma with aclacinomycin, behenoyl ara-C, etoposide, and prednisolone.

A total of 40 patients with recurrent non-Hodgkin's lymphoma were treated with ABEP combination chemotherapy (aclarubicin, N4-behenoyl-1-beta-D-arabinofuranosylcytosine, etoposide, and prednisolone). A complete remission (CR) was achieved in 37.5% of the patients and partial remission, in 15.0%. The ABEP regimen proved to be effective in T-cell as well as B-cell lymphoma. It appears that the ABEP regimen may be partially non-cross-resistant with front-line doxorubicin-containing combinations. Survival for 39 months was achieved in 42.0% of the CR responders compared with 6.7% of partial responders (PRs) and nonresponders (NRs) (P less than 0.01). Disease-free survival for 45 months was seen in 66% of the CR patients. The ABEP regimen was effective in the treatment of patients with recurrent or refractory lymphoma, enabling hope for long-term survival in the majority of CR cases.

The cells of origin of cat trigeminothalamic projections: especially in the caudal medulla.

Thalamic projections from the caudal medulla of the cat were examined using the method of retrograde axonal transport of horseradish peroxidase (HRP). Injections were made unilaterally in various thalamic regions. Large injections labeled cells in the subnuclei: zonalis (Vcz), gelatinosus (Vcg), magnocellularis (Vcm), reticularis dorsalis (Vcrd) and ventralis (Vcv) medullae oblongatae. The largest number of labeled cells were in Vcz, Vcrd and Vcrv. Most of the labeled cells in Vcz and Vcrd were contralateral to the injection site, although the labeled cells in the Vcrv were bilateral. Small injections were made into the medial, lateral and dorsal regions of the nucleus ventralis posteromedialis (VPM), rostral regions of the posterior nuclei (POm and PO1), caudal POm, the nucleus centralis lateralis (CL) and the center median-parafascicular nuclear complex (CM-Pf). Most of the neurons in Vcz were found to project to the medial VPM and some to the caudal POm. A small number of cells in the Vcrd project to the medial VPM, but a large number project to the caudal POm and CM-Pf complex. The largest number of neurons projecting to the CM-Pf complex was present in Vcrv, where the labeled cells were bilateral. The types of trigeminothalamic projecting cells and the sizes of their somata were observed for different subnuclei and a considerable difference was found to exist among the subnuclei. This anatomical differentiation of the trigeminothalamic projections probably reflects a functional specialization of neuronal location since the functional properties of neurons vary according to their locations.

Specific cholinergic destruction in the basal magnocellular nucleus and impaired passive avoidance behavior of rodents.

A nerve growth factor (NGF)-diphtheria toxin conjugate (NGDT) was found to selectively abolish or depress the activity of NGF receptor-bearing cholinergic neurons of the basal magnocellular nucleus (BMN). Bilateral cortical injections of NGDT impaired the retention of passive avoidance behavior in mice. A memory deficit was also revealed when cortical injections of NGDT were administered after the acquisition of a passive avoidance response. Thus, retrograde destruction of BMN cholinergic neurons by the cortical injection of NGDT interfered with both learning and memory processes. The animal model outlined here should be useful in analyzing the pathogenesis of Alzheimer's disease and the functions of the cholinergic system in the BMN.

The relation of argyrophilic proteins of nucleolar organizer regions (AgNORs) to the proportions of Ki-67 or DNA polymerase alpha-reacting cells in non-Hodgkin's lymphomas.

In order to examine the relationship between argyrophilic proteins of nucleolar organizer regions (AgNORs) and the proliferation activity of cells, we investigated lymph nodes obtained from 25 untreated non-Hodgkin's lymphoma (NHL) patients. Two monoclonal antibodies (MoAb) (Ki-67 antibody and anti-DNA polymerase alpha antibody) were used for evaluating cell proliferation activity. A linear relation between the mean number of agNORs per nucleus and the proportion of NHL cells reacting with Ki-67 MoAb was observed (r = 0.48, P less than 0.05). A similar relation between AgNORs and DNA polymerase alpha MoAb was also observed (r = 0.51, P less than 0.01). From these data, it was confirmed that AgNORs reflect the proliferation activity of NHL cells. We conclude that the AgNOR staining procedure is one of the simplest and most reliable methods for analyzing cell proliferation potential.

Coronary to bronchial artery anastomosis in patients with noncyanotic cardiopulmonary disease: report of seven cases.

An angiographically visible coronary to bronchial artery anastomosis was found in seven (0.12%) of 6045 patients with noncyanotic cardiopulmonary disease who underwent coronary angiography between 1989 and 1995. Aortitis syndrome was associated with four patients, whereas pulmonary embolism, aortic regurgitation and vasospastic angina were the diagnoses in the others. Coronary stenotic lesions were not observed in any patients. In five of six patients who underwent pulmonary perfusion scintigraphy, perfusion defect was observed in the area supplied by the bronchial artery, which had the anastomosis to the coronary artery. In each patient this anastomosis seemed to function as collateral circulation, compensating for decreased perfusion in either the lung or the heart. When coronary to bronchial artery anastomosis is found, ischemic conditions in either the lung or the heart are likely.

Transesophageal echocardiography for detection of mitral regurgitation due to papillary muscle rupture or dysfunction associated with acute myocardial infarction: a report of five cases.

Severe mitral regurgitation was associated with cardiogenic shock in five (0.8%) of 623 patients with acute myocardial infarction who were urgently admitted to the authors' hospitals between 1994 and 1996. The infarct was located in the inferior wall in four patients and in the inferoposterior wall in one patient. Severe mitral valve regurgitation occurred concurrently with cardiogenic shock between one and six days after the onset of myocardial infarction. A mitral regurgitant murmur was not audible in four of five patients. Similarly, mitral regurgitant Doppler signals were not detected in four patients by transthoracic echocardiographic examination, while transesophageal echocardiographic examination detected mitral regurgitant signals clearly in all patients. Thus, when cardiogenic shock is unexpectedly associated with inferior or inferoposterior wall acute myocardial infarction, severe mitral regurgitation should be suspected, even when a mitral regurgitant murmur is not audible. Furthermore, mitral regurgitant flow signals may not always be detected by transthoracic echocardiography. Thus, examination for mitral regurgitation by transesophageal echocardiography should be considered.

Coronary artery stenting with high-pressure post-dilation followed by adjunctive thrombolysis after failed coronary angioplasty for acute myocardial infarction: report of three cases.

We successfully implanted coronary stents into refractory reoccluded lesions after failed coronary angioplasty in three patients with acute myocardial infarction (AMI). Lesion location was the proximal left anterior descending coronary artery in two patients and the dominant right coronary artery in one patient. The reference diameters of the lesions were 3.64, 3.33, and 3.50 mm, respectively. A stent with a luminal diameter of 3.0 mm was implanted in all patients. Poststenting dilation of the stent was performed at high pressure (18 atm), and urokinase was administered immediately thereafter. Heparin was administered for 24 h with maintenance of activated coagulation time within 180-200 s. Warfarin was then administered to keep the international normalized ratio within 2.5-3.5. Luminal diameters immediately after stenting were 3.14, 2.89, and 3.26 mm, and those at 1 month after stenting were 3.09, 2.81, and 3.12 mm, respectively, indicating good patency. Our experience in these cases suggests that coronary stenting can be applied after unsuccessful coronary angioplasty in selected patients with AMI. The present report includes informative reference data on diameter, postdilation, adjunctive thrombolytic agent administration, and adequate anticoagulation therapy in coronary stenting in this acute application.

Cavernous sinus syndrome associated with nonsecretory myeloma.

The case of a 53-year-old man who developed cavernous sinus syndrome (CSS) four years after being diagnosed as having nonsecretory myeloma is described. He was admitted with diplopia and dull pain over the right infraorbital and zygomatic region in June 1997. The cause of CSS was the intracranial involvement of myeloma, which was diagnosed by fiberscopic biopsy. The results of endocrinologic evaluation were almost normal. The response to radiotherapy and chemotherapy was mild. CSS caused by nonsecretory myeloma is rare and its prognosis is poor. More aggressive chemotherapy with stem cell support may be indicated.

Prevalence of deep venous thrombosis in the lower limbs and the pelvis and pulmonary embolism in patients with positive antiphospholipid antibodies.

BACKGROUND: Antiphospholipid antibodies (AA) are immunoglobulins that cross-react with phospholipid on cell membrane, and are therefore associated with a hypercoagulable state manifested by arterial/venous thromboses. We aimed to determine the prevalence of deep venous thrombosis in the lower limbs and the pelvic region (DVT) and pulmonary embolism (PE) in patients with positive AA. METHODS: Sixty-six patients (48 female, 18 male) with positive lupus anticoagulant (LA) and/or positive anticardiolipin antibody (aCL) underwent radionuclide (RN) venography with 370 MBq of 99mTc-MAA. Pulmonary perfusion scintigraphy was performed in 58 patients. Fifteen patients had positive LA and positive aCL (LA+/aCL+), 33 patients had positive LA only (LA+/ aCL-) and 18 patients had positive aCL only (LA-/aCL+). 43 patients were diagnosed with primary antiphospholipid syndrome (APS) and 19 were diagnosed with APS associated with SLE. RESULTS: DVT was detected in 21 of 66 patients (32%). Patients with LA+/aCL+ showed higher prevalence of DVT (53%) as compared to LA+/aCL- (27%) and LA-/aCL+ (22%). PE was found in 13 of 58 patients (22%). The prevalence of PE was higher in patients with positive aCL (33% in LA+/aCL+; 36% in LA-/aCL+) than in patients with negative aCL (10%). CONCLUSION: Because of the high prevalence of DVT and PE in patients with AA, RN scintigraphy must be recommended in screening for these clinical troubles. These results indicate that the prevalence of DVT and PE may vary in subgroups of AA.

Convergence of ampullar and macular inputs on vestibular nuclei unit of the rat.

181 vestibular nucleus neurons were examined for their responsiveness to rotation about the vertical axis and static tilts in roll and pitch planes in the rat. 68 of these units were sensitive to rotation and tilts (canal-otolith cells). In other words, 41.0% of the neurons responded to rotation (68/166). There was no significant difference in percentage of canal-otolith cells in type I and II neurons, which were 48.6% and 37.0% respectively. Vertical axis rotation when the head was tilted produced a simultaneous stimulation of the canal and otoliths. Using this stimulus method, the bias effect was observed in 72.5% of the canal-otolith cells (29/40). Furthermore, since vertical axis rotation with the head tilted elicited vertical canal responses, the rate of ampullary convergence was estimated by analysing response profiles obtained such rotations. The results obtained in the rat were compared with those in other species.

[Multiple myeloma preceding myelodysplastic syndrome with eosinophilia and der (1;7)].

Multiple myeloma (IgG kappa + IgA kappa type, clinical stage IA) was diagnosed in a 82-year-old woman in January 1986. Chemotherapy (melphalan, prednisolone, vindesine, cyclophosphamide), caused prolonged myelosuppression. Therefore she was given other treatment. In October 1992, her peripheral blood examination demonstrated 2% blastic cells and 12% eosinophils. Bone marrow aspiration showed dysplastic features of trilineage blood cells with 4.8% myeloblasts. The karyotype of bone marrow cells from this patients was 47, XX, +der(1)t(1;7) (p11;p11), -7, +8. A diagnosis of therapy-related myelodysplastic syndrome (refractory anemia) was established. Eleven months after diagnosis of myelodysplastic syndrome, she is alive without leukemic transformation.

[A case report of multiple intracranial tuberculoma associated with miliary tuberculosis and review of the literature].

We reported a case of multiple intracranial tuberculoma associated with miliary tuberculosis and reviewed the cases reported as intracranial tuberculoma in the past 11 years. A 41-year-old diabetic man was admitted to our hospital for the treatment of miliary tuberculosis and respiratory insufficiency. On admissIon, he had no neurological deficits except mild consciousness disturbance due to respiratory failure. He developed headache and mental confusion three weeks after the beginning of antituberculous therapy with isoniazid, streptomycin, rifampicin, and ethambutol. Neurological examination revealed that he had progressive right hemiparesis and was in a confusional state. Enhanced CT showed multiple intracranial nodular lesions. During 6 weeks, he had progressive neurological manifestations in spite of his initial antituberculous treatment. He responded well, however, to the chemotherapy with combination of isoniazid, kanamycin, pyrazinamide and ethionamide that were sensitive to tuberculous bacilli separated from his sputum. He became minimally right-hemiparetic by 6 weeks after the change of antituberculous medication. Serial enhanced CT scan proved to be of great value in the diagnosis and follow-up study of intracranial tuberculoma. From 1978 to 1988, there were 72 reported cases of intracranial tuberculoma in Japan; 37 were male, 32 were female and 3 were uncertain because of no detailed document. The age of onset was distributed from 6 month to 81 years in age and 2 peaks were seen in the second decade and fifth to seventh decade. Thirty-three (48%) out of 69 cases had multiple intracranial lesions. A few reports commented that neurological complications tended to appear even if they were under antituberculous therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

[Gross spreading multiple extramedullary plasmacytomas to the skin in the terminal stage of multiple myeloma].

A 71-year-old woman with an 8-year history of IgG-kappa type multiple myeloma was admitted because of severe lumbago and bone destruction. Her serum IgG level was elevated to 5,565 mg/dl at admission. Despite treatment with doxorubicin, vincristine, dexamethasone, melphalan and interferon-alpha, the response was transient. Nine months later, multiple skin nodules appeared on her chest, abdominal wall and right thigh accompanied by elevation of the serum IgG level. Response to combination chemotherapy with cyclophosphamide, ranimustine, vincristine and prednisolone was also transient. The skin tumors on the bilateral thighs, especially on the left side, acquired chemotherapy resistance and gradually enlarged. Although the serum IgG level was maintained by chemotherapy within the range 1, 790-2,676 mg/dl, the skin tumors on the left thigh had spread very rapidly and appeared "rock-like". The enlarged tumors caused necrosis with erosions and oozing hemorrhage. A skin biopsy from the tumors on the left thigh showed plasmacytoma in which infiltration of large anaplastic plasma cells was observed. The patient died of sepsis 8 months after the skin tumors initially developed. This is a very rare case of multiple myeloma in which multiple large plasmacytomas of the skin developed and grew aggressively at the terminal stage after a long-term indolent course.

[MMIP chemotherapy for the treatment of the relapsed and refractory non-Hodgkin's lymphoma].

For salvage chemotherapy, 30 cases of relapsed or refractory non-Hodgkin's lymphoma (NHL) were treated with MMIP regimen (mitoxantrone 15 mg/m2, methotrexate 400 mg/m2, and ifosfamide 2 g/m2 intravenously in day 1, respectively, and prednisolone 20 mg/m2 orally from day 1 to 5). The overall complete response rate (CR rate) was 20% and the median survival duration was 153 days. In patients with favorable performance status (PS), the CR rate and survival duration were 30% and 407 days, respectively. These results were almost equivalent to previously proposed salvage regimens. The overall disease free survival rate of CR cases at 4 years was 62%, which was excellent as compared with the other salvage regimens. Five of 8 (62.5%) patients previously treated with etoposide-non-containing regimens achieved CR, and the CR rate was significantly superior to that of patients previously treated with etoposide-containing ones. These results indicate that MMIP is a useful salvage regimen for relapsed or refractory NHL, while it seems to be difficult to salvage patients previously treated with etoposide-containing regimens.

[Primary pleural non-Hodgkin's lymphoma without chronic pyothorax].

Most cases of primary pleural malignant lymphoma develop following chronic pyothorax. We report a case of primary pleural non-Hodgkin's lymphoma without chronic pyothorax. A 63-year-old woman was referred and admitted to our hospital with a right pleural effusion that was detected during a routine physical checkup. Her liver, spleen, and superficial lymph nodes were not palpable on physical examination. The massive right pleural effusion and a pleural mass were demonstrated on chest X-ray films and thoracic computed tomograms. Diffuse large B-cell non-Hodgkin's lymphoma was diagnosed by needle biopsy from the pleura, and the clinical stage was IE. Pleural effusion specimens contained no identifiable lymphoma cells, and examinations for Mycobacterium species were also negative. Human herpes virus 8 (HIV-8) DNA was detected in lymphocytes from the peripheral blood and pleural effusion. Epstein-Barr virus-encoded small RNAs and HHV-8 DNA were both negative in biopsied tissue from the pleural mass. Although a complete remission was achieved, the lymphoma relapsed about 8 months later. The patient is currently receiving salvage chemotherapy. Cases of primary pleural non-Hodgkin's lymphoma with massive pleural effusion that are not preceded by chronic pyothorax or Kaposi's sarcoma are very rare.

[Metastatic behavior of footpad-inoculated tumors in mice and the impact of OK-432 per os administration].

In the surgical treatment of cancer patients, it is very important to investigate the immunological potential of regional lymph nodes. The purpose of this study was to clarify the defence mechanisms of regional lymph nodes against cancer cell dissemination. The materials used for the study were C3H/He mice and a syngeneic breast cancer cell line (MM-48). When MM-48 tumor, 5 X 10(6) cells per mouse, was inoculated into the footpad, the footpad gradually increased in size, and half of the mice died within 20 days. The frequencies of metastasis for ipsilateral inguinal lymph nodes, axillary lymph nodes and mesenteric lymph nodes were as follows. On day 3 after tumor inoculation, no metastasis was found in any node. On day 6, all mice had inguinal lymph node metastasis, and half of the mice had metastases to axillary lymph nodes and mesenteric lymph nodes. On day 10, all mice had metastasis to all nodes. When 100KE/kg of OK-432 was administered orally every day, the titer of natural killer activity of mesenteric lymph nodes was remarkably increased after 7 days (from 12.3% to 62.9%). When mice were administered OK-432 simultaneously with tumor inoculation and on each day thereafter, the frequency of metastasis mesenteric lymph nodes was markedly decreased after day 7. It is thus suggested that regional lymph nodes may operate effectively against tumor cell attachment to the nodes.