Biomedical subjects

T Hotta

Publications and source records attributed to T Hotta.

At least 19 recordsLinked to original sources

PubMed1997

Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma.

BACKGROUND: Mutations of the p53 gene are associated with a poor prognosis in several types of cancer. We investigated the prognostic importance of p53 mutations in patients with aggressive B-cell lymphoma. METHODS: We examined the relation between the presence or absence of a detectable p53 mutation in lymphoma cells and the response to chemotherapy and overall survival in 102 previously untreated patients with aggressive B-cell lymphoma. Mutations of the p53 gene were identified by polymerase-chain-reaction-mediated analysis of single-strand conformation polymorphisms and by direct sequencing. RESULTS: Of 102 cases of aggressive B-cell lymphoma, 22 (22 percent) involved p53 mutations. The rate of complete remission was significantly lower in patients with a tumor carrying a p53 mutation (6 of 22 patients, 27 percent) than in those with the wild-type p53 gene (61 of 80 patients, 76 percent) (P<0.001). Overall survival was significantly lower among patients with p53 mutations than among those with the wild-type p53 gene; the Kaplan-Meier estimates of survival at five years were 16 percent and 64 percent, respectively (P<0.001). Multivariate analysis incorporating prognostic factors from the international prognostic index demonstrated that p53 mutations had independent effects on the rates of complete remission and survival. When we categorized patients according to the international prognostic index, we found no effect of p53 mutations in patients in the groups at high-intermediate and high risk. However, these mutations were significantly associated (P< 0.001) with low rates of complete remission (33 percent vs. 91 percent) and survival (27 percent vs. 81 percent at five years) in the groups at low and low-intermediate risk. CONCLUSIONS: Mutations of the p53 gene are associated with a poor prognosis in patients with aggressive B-cell lymphoma.

Aged↗

PubMed1997

Hypermethylation of the p15INK4B gene in myelodysplastic syndromes.

Previous studies have shown that the cyclin-dependent kinase inhibitor (CDKI) genes p15INK4B and p16INK4A are frequently inactivated by genetic alterations in many malignant tumors and that they are candidate tumor-suppressor genes. Although genetic alterations in these genes may be limited to lymphoid malignancies, it has been reported that their inactivation by aberrant methylation of 5' CpG islands may be involved in various hematologic malignancies. In this study, we investigated the p15INK4B and p16INK4A genes to clarify their roles in the pathogenesis of myelodysplastic syndrome (MDS). Southern blotting analysis showed no gross genetic alterations in either of these genes. However, hypermethylation of the 5' CpG island of the p15INK4B gene occurred frequently in patients with MDS (16/32 [50%]). Interestingly, the p15INK4B gene was frequently methylated in patients with high-risk MDS (refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEB-t], and overt leukemia evolved from MDS; 14/18 [78%]) compared with patients with low-risk MDS (refractory anemia [RA] and refractory anemia with ring sideroblast [RARS]; 1/12 [8%]). Furthermore, methylation status of the p15INK4B gene was progressed with the development of MDS in most patients examined. In contrast, none of the MDS patients showed apparent hypermethylation of the p16INK4A gene. These results suggest that hypermethylation of the p15INK4B gene is involved in the pathogenesis of MDS and is one of the important late events during the development of MDS.

Carrier Proteins↗

PubMed1997

Analysis of intramedullary cell density by MRI using the multiple spin-echo technique.

Analysis of the intramedullary cell distribution by magnetic resonance imaging (MRI) using conventional techniques involves subjectively interpreting images and estimating the cell distribution on the basis of signal intensity characteristics. In recent years, attempts have been made to achieve more precise analysis by new techniques, including chemical shift imaging. The multiple spin-echo (MSE) technique offers some advantages over conventional MRI. Since it allows measurement of the transverse magnetization decay curve at 32 or more points, it is capable of separating several tissue components with different relaxation times. In addition, this technique can be used with MRI instruments having a static magnetic field as low as 1.0 Tesla. In the present study, the intramedullary cell density was assessed by MRI using the MSE technique in 4 patients with aplastic anemia (AA), 4 patients with myelodysplastic syndrome (MDS), and 5 normal subjects. The water component of the marrow (with a short relaxation time) and the fat component (with a long relaxation time) were separated from each other by analyzing MR images obtained using the MSE technique, and the signal intensity ratio of the 2 components was calculated. The ratio was significantly higher in the AA group than in the other groups (AA vs. MDS, P = 0.0209, AA vs. normal controls, P = 0.0143). The present technique appears promising for quantitative assessment of the intramedullary cell density.

Adolescent↗

PubMed1997

Enhancement of tumor cell susceptibility to tumor-infiltrating lymphocytes by cisplatin.

Some means of enhancing the susceptibility of tumor cells to tumor-infiltrating lymphocytes (TIL) are required in adoptive immunotherapy. This study was designed to investigate whether or not tumor cell lysis by TIL was enhanced by treatment of the tumor cells with cisplatin, and also to clarify the mechanism of cisplatin's action on tumor cells. Autologous tumor cells and established cancer cell lines, including KATO-III and MKN-28, were used. Cytotoxic activities of TIL, the surface antigens of tumor cells, conjugation of TIL and tumor cells, and the production of TNF alpha from TIL were analyzed. Tumor cells treated with 2 micrograms/ml cisplatin for 12 h in vitro were more susceptible to bulk-cultured TIL and TIL clones. The surface antigens of tumor cells were not altered by the treatment with cisplatin. Cisplatin-treated tumor cells showed a higher binding ratio to TIL than did non-treated tumor cells. The anti-(tumor necrosis factor) (anti-TNF) or anti-TNF receptor antibody blocked the enhancement of cytotoxic activity by cisplatin. Thus, it was clarified that cisplatin enhanced the susceptibility of tumor cells to bulk-cultured TIL and TIL clones. Furthermore, the enhancement of cytotoxic activity by TIL in cisplatin-treated tumor cells was caused by a higher binding ratio to TIL and higher susceptibility to the TNF produced by TIL.

Antigens, Neoplasm↗

PubMed1997

Periosteal chondrosarcoma invading the medullary cavity.

We present a case of periosteal chondrosarcoma of the femur, in which a tumor invaded the medullary cavity and the lesion was clearly demonstrated only on MRI. To the best of our knowledge, there have been no previous reports of an intramedullary lesion caused by periosteal chondrosarcoma demonstrated on MRI.

Adult↗

PubMed1997

A randomized study comparing VMCP and MMPP in the treatment of multiple myeloma.

PURPOSE: To compare VMCP, a multidrug combination chemotherapy comprising vincristine (VCR), melphalan (MPH), cyclophosphamide (CPM) and prednisolone (PSL), with MMPP comprising MPH, ranimustine (MCNU), procarbazine, and PSL as induction, to elucidate the value of alternating combination chemotherapy, and to search for an appropriate maintenance therapy in multiple myeloma. METHODS: At 16 institutions in the Nagoya City area, we carried out a randomized trial of VMCP versus MMPP as the initial treatment. Patients who were refractory or resistant to the initial therapy were crossed over into the other arm (crossover trial). For patients who achieved a partial response (PR) or a minor response (MR) and in whom the paraprotein level ceased to decrease, the maintenance therapy was randomized either to an MPH/PSL combination (MP) or to alternating combination therapy (AT) with VMCP and MMPP. RESULTS: In the 94 evaluable patients of the 111 enrolled, the response rate (PR rate) was 27.7% (13/47) in the VMCP arm and 44.7% (21/47) in the MMPP arm (P = 0.0859). The crossover trial resulted in a PR rate of 15.8% (3/19) for the VMCP-->MMPP crossover and 14.3% (2/14) for the MMPP-->VMCP crossover. The median survival time was 23.4 months for those initially begun in the VMCP arm and 24.9 months for those in the MMPP arm, showing a tendency for better survival during a follow-up of 2-6 years with MMPP treatment, but without statistical significance. The survival time of patients with progressive disease was significantly shorter than that of patients with PR, MR or no change (NC). However, there was no significant difference in the survival rate among those who achieved PR, MR, or NC. As to the maintenance therapy, there was no significant difference in survival between MP therapy and AT. Patients who reached a plateau phase survived significantly longer than those who did not. Except for six cases of grade 3 or 4 neurotoxicity in the VMCP arm, there was no significant difference in the hematologic or gastrointestinal toxicity between the two arms. CONCLUSIONS: We conclude that VMCP is less effective for myeloma than MMPP as the induction treatment, that alternating noncrossresistant chemotherapeutic combinations do not offer an advantage in multiple myeloma, and that patients who reach a plateau phase have a significantly longer survival time.

Adult↗

PubMed1997

IgD monoclonal gammopathy of undetermined significance.

We describe here a case of monoclonal gammopathy of undetermined significance (MGUS) of IgD type. A trace of serum M-protein was noticed on electrophoresis when a Japanese man visited his primary care physician for medical examination. However, he was asymptomatic. Serum immunoelectrophoresis showed IgD lambda M-protein. Bone marrow examination revealed normocellular marrow with 1.5% plasma cells. Renal function, serum calcium level and complete blood cell count were all within normal limits and a systemic bone survey disclosed no lytic lesions. He was followed for 26 months without chemotherapy, and no disease progression to overt myeloma nor development of systemic amyloidosis resulted. This is, to our knowledge, the third case of IgD MGUS and the first one reported from Japan.

Connectin↗

PubMed1997

Complementarity determining region-III is a useful molecular marker for the evaluation of minimal residual disease in mantle cell lymphoma.

Bone marrow (BM) and peripheral blood (PB) involvement in 10 patients with mantle cell lymphoma (MCL) was analysed by a polymerase chain reaction (PCR)-mediated RNase protection assay. The complementarity determining regions (CDR)-III of all 10 MCLs examined was amplified efficiently with consensus V(H) and J(H) primers by PCR. and BM and/or PB involvement was evaluated by RNase protection assay in all 10 patients examined. Our assay showed BM and/or PB of the entire group to have neoplastic cells at presentation, despite the fact that eight patients were found to have BM and/or PB involvement on the basis of morphological examination and/or surface marker analysis. We also examined minimal residual disease (MRD) after conventional chemotherapy, and detected MRD in a patient in complete remission (CR). Although previous studies have shown that t(11;14) breakpoint amplification by PCR was only applicable to about 30-40% of cases, the present study indicates that CDR-III is a useful molecular marker and the PCR-mediated RNase protection assay is a good tool for the evaluation of MRD in MCL. It is suggested that BM and PB of MCL patients are quite frequently involved at presentation and even after conventional chemotherapy at the molecular level.

Aged↗

PubMed1997

Phase I study of cladribine (2-chlorodeoxyadenosine) in lymphoid malignancies. Cladribine Study Group.

Cladribine (2-chlorodeoxyadenosine;) is a purine analogue with clinical activity against hairy cell leukemia, chronic lymphocytic leukemia and indolent lymphoma. To clarify the toxicity profiles of cladribine, we conducted a phase I and pharmacological study of cladribine with a schedule of seven-day continuous intravenous infusion every 28 days up to a maximum of three cycles. We enrolled 10 previously-treated patients with various lymphoid malignancies. No dose-limiting toxicity (grade 4 hematologic and/or grade 3 or more non-hematologic) was observed in the three patients who received 0.06 mg/kg/day (Level 1). Of the seven patients who received 0.09 mg/kg/day (Level 2), one patient developed grade 4 hypoxemia and grade 4 thrombocytopenia, and another developed grade 4 neutropenia. Of the seven patients treated at Level 2, one with cutaneous T-cell lymphoma attained complete remission, and one with mantle cell lymphoma, one with chronic lymphocytic leukemia and one with adult T-cell leukemia-lymphoma attained partial remission. A pharmacokinetic analysis of the seven patients without leukemic cells showed that their area under the concentration versus time curves of plasma cladribine increased dose-dependently from 2661.3 +/- 300.4 nM x h at Level 1 (n = 3) to 3411.3 +/- 341.0 nM x h at Level 2 (n = 4) (P = 0.034). We conclude that the recommended phase II dose of cladribine (0.09 mg/kg/day as a seven-day continuous i.v. infusion) in Caucasian patients can be safely administered to Japanese patients. The encouraging results prompted us to plan subsequent phase II studies of cladribine against adult T-cell leukemia-lymphoma, hairy cell leukemia and indolent lymphoma.

Aged↗

PubMed1997

CDKN2 (MTS1/p16INK4A) gene alterations in hematological malignancies.

Cyclin dependent kinases (CDKs) make complexes with cyclins, and regulate cell cycle progression by their serine/threonine kinase activities. CDK inhibitors (CDKIs) arrest the inappropriate progression of the cell cycle by combining with CDKs. Because the functional loss of CDKIs may permit unlimited cell growth, their disruptions are thought to be associated with tumorigenesis. Recently, one CDKI, p16, was found, and its gene, CDKN2 (MTS1/p16INK4A), was identified on chromosome 9p21. Intensive investigations of the CDKN2 gene in various tumors have shown that alterations frequently occur in this gene, thus suggesting that the CDKN2 gene is a tumor suppressor gene. In hematological malignancies, CDKN2 gene alterations may be limited to lymphoid malignancies, especially T-cell type acute lymphocytic leukemias, in which frequent chromosomal abnormalities in the 9p21 region have been reported. The CDKN2 gene is also inactivated in some patients with non-Hodgkin's lymphomas, adult T-cell leukemias, and lymphoid blastic crisis of chronic myelogenous leukemias. The main mechanism of CDKN2 gene inactivation is thought to be homozygous deletion, but point mutations may also inactivate it in some cases. The CDKN2 gene appears to be the major tumor suppressor gene on chromosome 9p21, and it is thought to be involved in the tumorigenesis of various lymphoid malignancies.

Carrier Proteins↗

PubMed1997

[A case of infected subdural hematoma complicating chronic subdural hematoma in a healthy adult man].

The authors report a case of so-called "infected subdural hematoma" as a complication of chronic subdural hematoma. The patient was a 55-year-old man who had sustained a small laceration of the forehead in a traffic accident on March 29, 1995. No fractures were detected on skull roentgenograms, and general and neurological examinations failed to reveal any abnormal findings. In early August 1995, the patient began to experience headaches, and on August 5 he developed a fever of 38 degrees C. On August 8 he suffered a left motor seizure and was admitted to our hospital. Laboratory studies revealed a peripheral leukocyte count of 10,800/mm3 and a C-reactive protein level of 18.1 mg/dl. Computed tomography scans showed a thick right fronto-parietal subdural low density mass and a thin left frontal subdural low density mass. An emergency operation was performed via a single right fronto-parietal burr hole. A chronic subdural hematoma containing slightly yellowish, bloody, purulent fluid was found beneath an outer membrane. The hematoma was irrigated with physiological saline containing antibiotics, and a drain was inserted into the subdural space. A subdural membrane was also present on the left but it contained no pus. Aggressive antibiotic therapy was performed, and the patient was discharged without any neurological deficit. Histologically the membrane was determined to be the outer membrane of a typical chronic subdural hematoma. Enterococcus faecalis, which has rarely been reported to cause infection of the central nervous system, was detected in a bacterial culture of the pus. Systemic investigation showed no evidence of otorhinologic or other focal infection. The above clinical findings suggested that hematogenous seeding of a chronic subdural hematoma had occurred in this patient. Subdural empyema arising from hematogenous seeding to a pre-existing subdural hematoma by an infection is very rare, but this type of complication must be kept in mind not only in the elderly, infants, and compromised hosts, but in patients without complications as well.

Chronic Disease↗

PubMed1997

[Hypereosinophilia after allogeneic bone marrow transplantation. A possible role of IL-5 overproduction by donor T-cells chronic GVHD].

Chronic graft-versus-host disease (GVHD) is thought to result from abnormalities of several cytokine regulations in vivo. We analyzed interleukin-5 (IL-5) production by peripheral lymphocytes in a patient showing hypereosinophilia associated with chronic GVHD after allogeneic bone marrow transplantation. IL-5 production by activated T-lymphocytes which are known to play a major role in chronic GVHD was upregulated when stimulated by PMA + ionomycin. Therefore, hypereosinophilia observed in our patient may be correlated with IL-5 production in donor T-lymphocytes.

Adolescent↗

PubMed1997

[Magnetic resonance imaging of Kernohan's notch in chronic subdural hematoma].

Compression of the crus cerebri against the free edge of the tentorium contralateral to a supratentorial mass, the so-called Kernohan's notch, can be a cause of false localizing sign. Kernohan's notch has been thoroughly studied clinically and pathologically, but not radiographically. The authors describe a case of left chronic subdural hematoma, which resulted in left hemiparesis caused by Kernohan's notch. Injury to the contralateral cerebral peduncle was clearly shown by magnetic resonance imaging (MRI) performed in the postoperative period. A 43-year-old man was transferred to our hospital in deep coma with dilated pupils, unreactive to light. Computed tomography (CT) scans obtained on admission revealed a left chronic subdural hematoma and a midline shift to the right. After drainage and irrigation of the left chronic subdural hematoma through a single burr hole, his clinical condition improved gradually. But 1 month after the operation, mild left hemiparesis still persisted. MRI T2-weighted images demonstrated an abnormally increased signal area in the right cerebral peduncle. T1-weighted coronal images showed the anatomical relationship between the hypointense lesion in the right cerebral peduncle and tentorial edge. Three-dimensional-MRI (3D-MRI) clearly demonstrated the surface image of Kernohan's notch. We emphasize the utility of 3D-MRI for detecting evidence of brain stem injury, such as Kerno han's notch.

Adult↗

PubMed1997

[Menogaril (TUT-7) late phase II study for malignant lymphoma, adult T-cell leukemia and lymphoma (ATLL)].

A late Phase II multicenter study with menogaril was conducted nationwide in patients with malignant lymphoma [non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD)], and ATLL, menogaril was orally administered at 100 mg daily after breakfast, for seven consecutive days with two- or three-week drug withdrawal, then menogaril administration was repeated. For malignant lymphoma, in 81 patients with NHL and 5 patients with HD registered, 70 and 5 patients were evaluable for efficacy, respectively. The efficacy rates were 32.9% (6 CRs + 17 PRs/70) for NHL and 20.0% (1 PR/5) for HD, respectively; that for the NHL patients with prior anthracycline antibiotic chemotherapy was 30.5% (5 CRs and 13 PRs/59). For ATLL, among the 16 patients registered, 15 were evaluable for efficacy, and the efficacy rate was 40.0% (2 CRs and 4 PRs/15). Adverse drug reactions frequently observed in the patients with malignant lymphoma and ATLL included bone-marrow suppression and gastrointestinal symptoms such as anorexia, and nausea/vomiting. With these results, menogaril was considered to be effective for the treatment of non-Hodgkin's lymphoma and ATLL.

Administration, Oral↗

PubMed1996

Synergistic effects of tamoxifen and cepharanthine for circumventing the multidrug resistance.

We examined the synergistic effects of tamoxifen (TAM) and cepharanthine (CEP) for doxorubicin (DOX) sensitivity using MTT assay. The augmentation of DOX sensitivity by TAM and CEP was significantly correlated with the P-glycoprotein expression. The cytotoxic effect of DOX with TAM and CEP was significantly higher than that of DOX alone, or DOX with TAM, and this synergistic effect was dominant in cell lines with high expression of P-glycoprotein. It was also examined that the intracellular concentration of DOX was increased in combined exposure of TAM and CEP, compared with the exposure of TAM, because TAM and CEP promoted the influx and inhibited the efflux of DOX. Thus, TAM and CEP might be able to circumvent DOX-resistance for treatment in cancer patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Tamoxifen circumvents the multidrug resistance in fresh human gastrointestinal cancer cells.

The resistance to doxorubicin (DOX) is mainly due to the effect of P-glycoprotein encoded by the multidrug resistance-1 (mdr1) gene. Tamoxifen (TAM) has been shown to circumvent multidrug resistance in P-glycoprotein-expressing cell lines. In the present study, we clarified the augmentation of DOX sensitivity by TAM using MTT assay in highly purified fresh human tumor cells obtained from 85 cancer patients. Moreover, the correlation between DOX sensitivity and P-glycoprotein expression was assessed by flow cytometry. DOX sensitivity was decreased in proportion to P-glycoprotein expression. The cytotoxicity of DOX was increased by TAM in tumor cells possessing low DOX sensitivity. Moreover, there was a significant correlation between the effect of TAM on cytotoxicity and P-glycoprotein expression. The concentration of DOX in tumor cells was increased in combined exposure of TAM with DOX, compared with the exposure of DOX alone. Thus, TAM might be able to circumvent DOX-resistance for treatment in cancer patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Effects of different triggering systems and external PEEP on trigger capability of the ventilator.

OBJECTIVE: The triggering capability of both the pressure and flow triggering systems of the Servo 300 ventilator (Siemens-Elema, Sweden) was compared at various levels of positive end-expiratory pressure (PEEP), airway resistance (R(aw)), inspiratory effort and air leak, using a mechanical lung model. DESIGN: The ventilator was connected to a two bellows-in-series-type lung model with various mechanical properties. Lung compliance and chest wall compliance were 0.03 and 0.121/cmH2O, respectively. R(aw) was 5, 20 and 50 cmH2O/l/s. Respiratory rate was 15 breaths/min. To compare the triggering capability of both systems, the sensitivity of pressure and flow triggered pressure support ventilation (PSV) was adjusted to be equal by observing the triggering time at 0 cmH2O PEEP and 16 cmH2O of pressure support (PS) with no air leak. No auto-PEEP was developed. In the measurement of trigger delay, the PS level ranged from 16 to 22 cmH2O to attain a set tidal volume (V(T)) of 470 ml at a R(aw) of 5, 20 and 50 cmH2O/l/s. The PEEP level was then changed from 0, 5 and 10 cmH2O at a PS level of 17 cmH2O and R(aw) of 5 and 20 cmH2O/l/s, and the trigger delay was determined. The effect of various levels of air leak and inspiratory effort on triggering capability was also evaluated. Inspiratory effort during triggering delay was estimated by measurements of pressure differentials of airway pressure (Paw) and driving pressure in the diaphragm bellows (Pdriv) in both systems. MEASUREMENTS AND RESULTS: There were no significant differences in trigger delay between the two triggering systems at the various PEEP and R(aw) levels. At the matched sensitivity level, air leak decreased trigger delay in both systems, and additional PEEP caused auto-cycling. A low inspiratory drive increased trigger delay in the pressure sensing system, while trigger delay was not affected in the flow sensing system. The Paw and Pdriv differentials were lower in flow triggering than in pressure triggering. CONCLUSIONS: With respect to triggering delay, the triggering capabilities of the pressure and flow sensing systems were comparable with and without PEEP and/or high airway resistance at the same sensitivity level, unless low inspiratory drive and air leak were present. In terms of pressure differentials, the flow triggering system may require less inspiratory effort to trigger the ventilator than that of the pressure triggering system with a comparable triggering time. However, this difference may be extremely small.

Lung↗

PubMed1996

Clinical evaluation of chemosensitivity testing for patients with colorectal cancer using MTT assay.

PURPOSE: Colorectal cancer is one of the tumors most refractory to treatment by chemotherapy. The chemosensitivity test should be performed to individualize the chemotherapy for patients with colorectal cancer, which is less sensitive for anticancer drugs. The present study was designed to determine the chemosensitivity in fresh human colorectal cancer, using highly purified tumor cells, and the correlation of this sensitivity with clinical response. METHODS: We determined the chemosensitivity for cisplatin, mitomycin C, adriamycin, and 5-fluorouracil in vitro in 93 fresh human colorectal cancers using the MTT assay and performed chemotherapy according to results of the MTT assay. RESULTS: Inhibition rate of tumor cells for cisplatin was higher than those for other drugs. Fifteen patients who have evaluable lesions received chemotherapy according to results of the MTT assay. Clinical responses were obtained in 5 of 15 patients, and the inhibition rate for cisplatin was higher in responders than in nonresponders. CONCLUSIONS: It is suggested that the chemotherapy according to results of the MTT assay is effective in patients with colorectal cancer.

Adult↗