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The Vulnerable Elders Survey-13 (VES-13) is a well-studied simplified frailty screening tool for elderly patients in the oncology setting. We conducted a prospective clinical trial to evaluate the efficacy and safety of dose-adjusted treatment based on the VES-13 in transplant-ineligible patients with newly diagnosed multiple myeloma (MM). In the Fit group (VES-13 <3), patients were treated with 4 cycles of standard-dose VCD (bortezomib, cyclophosphamide, and dexamethasone) followed by 4 cycles of standard-dose VTD (bortezomib, thalidomide, and dexamethasone). In the Frail group (VES-13 ≥3), patients were treated with 4 cycles of reduced-dose VCD followed by 4 cycles of reduced-dose VTD. The median age was 75 years (66-86 years), and 34% of the cases were classified as PS 3. Among the Fit group (n=16), the overall response rate (ORR) was 87.5%. Among the Frail group (n=31), the ORR was 87.1%. There were no significant differences in progression-free survival (PFS) and overall survival (OS) between the Fit and Frail groups (3-year PFS: 68.8% vs 53.3%, P = 0.658; 3-year OS: 70.0% vs 77.6%, P = 0.919). Personalized VCD-VTD sequential therapy based on the VES-13 was associated with high response rates and showed acceptable safety in elderly frail patients with MM. The study is registered as UMIN000011235., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m 2 ) or Id-MTX (0.5 g/m 2 ). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.

In the present study, in order to investigate the role of signal transducer and activator of transcription 3 (STAT3) in estrogen receptor (ER)-positive breast cancer prognosis, we evaluated the phosphorylated STAT3 (p-STAT3) status and investigated its effect on the outcome in a pooled analysis and in a large prospective adjuvant trial. By using the TCGA repository, we developed gene signatures that reflected the level of p-STAT3. Using pooled analysis of the expression data from luminal breast cancer patients, we assessed the effects of the p-STAT3 expression signature on prognosis. We further validated the p-STAT3 prognostic effect using immunohistochemistry (IHC) and immunofluorescence staining of p-STAT3 tissue microarrays from a large randomised prospective trial. Our analysis demonstrated that p-STAT3 expression was elevated in luminal A-type breast cancer (Kruskal-Wallis test, P<10e-10) and was significantly associated with a good prognosis (log-rank, P<10e-10). Notably, the p-STAT3 expression signature identified patients with a good prognosis irrespective of the luminal subtype (log-rank: luminal A, P=0.026; luminal B, P=0.006). p-STAT3 staining by IHC in the stroma or tumour was detected in 174 out of 610 ER-positive samples (28.5%) from the BIG 2-98 randomised trial. With a median follow-up of 10.1 years, p-STAT3 was associated with a reduced risk of recurrence in ER-positive/HER2-negative breast cancer (Cox univariate HR, 0.66; 95% CI, 0.44-0.98; P=0.04). On the whole, our data indicate that p-STAT3 is associated with an improved outcome in ER-positive breast cancer.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive T-cell lymphoma. A 63-year-old man was diagnosed with AITL. He received 6 cycles of CHOP therapy, but showed progressive disease. Subsequently, he received ESHAP chemotherapy; however, it was not effective. He received mogamulizumab (an anti-CCR4 monoclonal antibody). After 4 cycles, his respiratory condition worsened and he was diagnosed with cytomegalovirus (CMV) pneumonia. Despite antiviral and antibiotic therapy, he died. We speculate that the combination of progressive lymphoma with mogamulizumab and chemotherapy likely caused CMV pneumonia. Because mogamulizumab therapy causes immunosuppression, if CMV pneumonia is suspected, then rapid treatment should be initiated.

A multicenter retrospective study was performed to determine the significance of adding cytarabine (CA) or thiotepa (TT) in the context of total body irradiation (TBI) and cyclophosphamide (CY). A total of 322 patients who underwent allogeneic hematopoietic cell transplantation (HCT) were distributed to the following three groups: TBI/CY (n = 75), TBI/CY/CA (n = 77), and TBI/CY/TT (n = 170). In the TBI/CY/TT group, 164 of patients (96 %) received HCT during the previous year (2000-2005). Multivariate analysis revealed that the TBI/CY/TT group demonstrated a trend of poorer survival rate than the TBI/CY group, [hazard ratio (HR) = 1.49, 95 % confidence interval (CI) 0.99-2.24, P = 0.055] with a higher non-relapse mortality (NRM) (HR = 2.34, 95 % CI 1.35-4.06, P = 0.002) rates, while TBI/CY/CA group demonstrated similar outcomes. Even in the subgroup analyses of disease type or disease risk, the outcomes with intensified conditioning regimens were not superior to those with TBI/CY. In conclusion, although the significant bias has to be carefully considered, the clinical benefit of adding CA or TT to the TBI/CY regimen was not demonstrated.

Irradiation therapy alone is a standard strategy for limited-stage FL, leading to a 10-year progression-free survival (PFS) rate of 30-50%. However, we have been administering R-CHOP therapy alone to patients with limited-stage FL. A total of 35 patients with newly diagnosed FL received R-CHOP therapy with curative intent between 2002 and 2009. The median age of the 35 patients was 61 years; 7 patients had in CS 1 FL, and 28 patients, CS 2 FL. The median number of R-CHOP cycles was 6. On completion of the R-CHOP therapy, 33 patients achieved complete response and 1 showed partial response (PR). The patient showing PR after the completion of R-CHOP was administered additional irradiation. The remaining 1 patient was not evaluated because of discontinuation of hospital visit. In all the 35 patients, the 5-year PFS rate was 70%, and the 5-year overall survival rate was 92%. In the 15 patients with a PFS>5 years, only 1 patient showed disease progression. The outcome of R-CHOP therapy alone in patients with limited-stage FL was at least equivalent to the reported outcome of irradiation therapy alone. R-CHOP therapy could be an alternative to irradiation therapy in limited-stage FL patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We retrospectively analyzed, and herein discuss, the outcomes of and prognostic factors for 35 untreated multiple myeloma patients less than 65 years of age who received induction therapies with bortezomib (Bor) and dexamethasone (BD) for the purpose of up-front autologous peripheral blood stem cell transplantation (SCT). The overall response rate was 77% (27 cases, including 4 [11%] complete response and 13 [37%] very good partial response cases). The rate of SCT accomplishment was 51% (18 cases). The 3 year-progression free survival (PFS) rate for the SCT group was significantly higher than that of the non-SCT group (41% vs 0%, P=0.0037). This result reflects the significantly more severe adverse effects of induction therapy for the non-SCT than the SCT group. Among reasons for SCT drop-out, 29% of cases suffered severe peripheral neuropathy with features such as irreversible numbness and pain. The analysis of PFS revealed a cytogenetic factor, favorable chromosomal type at diagnosis, to predict a better outcome (P values on univariate and multivariate analyses were 0.0004 and 0.0405, respectively). Our observations suggest establishment of induction therapy, aimed at reducing adverse effects and overcoming unfavorable cytogenetic abnormalities, to be necessary for improving the outcomes of patients with multiple myeloma.

Pirarubicin tetrahydropyranyl adriamycin (THP-ADR) is an analogue of doxorubicin. This agent exhibits activity against some doxorubicin-resistant cell lines. We performed a phase II study of biweekly THP-COP [50 mg/m(2) pirarubicin, 750 mg/m(2) cyclophosphamide, 1.4 mg/m(2) vincristine (2.0 mg maximum) on day 1, and 100 mg/body predonisolone on days 1-5] in patients with peripheral T-cell lymphoma (PTCL). Seventeen patients with newly diagnosed PTCL were enrolled. Histological diagnoses were of PTCL, not otherwise specified (n = 5), or angioimmunoblastic T-cell lymphoma (n = 12). All diagnostic specimens including those of the historical control group were centrally reviewed by hematological pathologists. All patients received six cycles of biweekly THP-COP. The patient group included 13 male and 4 female patients, with a median age of 62 years. The median follow-up time in surviving patients was 30 months. Overall response rate was 94% with 15 cases of complete remission (88%). The 3-year progression-free survival and overall survival rates were 57% and 75%, respectively. The most frequent adverse events associated with biweekly THP-COP were leukocytopenia (100%), neutropenia (100%), and lymphopenia (100%), followed by alopecia (92%) and anaemia (88%). All of these occurred only transiently, and the patients subsequently recovered. Biweekly THP-COP is a safe and promising therapy for patients with newly diagnosed PTCL. This study is registered in a public database (UMIN000010485)., (Copyright © 2014 John Wiley & Sons, Ltd.)

The prognostic implications of infra-diaphragmatic (InD) versus supra-diaphragmatic (SpD) primary lesions in limited-stage diffuse large B-cell lymphoma (DLBCL) remains unknown. This retrospective study aimed to assess the prognostic impact of spD and InD lesions as well as presence of gastrointestinal (GI) involvements in adults with limited-stage DLBCL. We analyzed data from 178 patients with limited-stage DLBCL who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy at 7 institutions of the Yokohama City University Hematology Group between 2003 and 2009. The median age was 63 years (range, 18-80 years). The primary sites were SpD in 109 patients, and InD in 69. No statistical differences in progression-free survival (PFS) or overall survival (OS) were observed between patients with SpD lesions and those with InD lesions. However, when patients with SpD lesions, InD lesions with (n=35), and without (n=34) GI involvement were compared, the presence of GI lesions was associated with favorable PFS. The multivariate analysis revealed that SpD or InD localization had no independent effect on PFS or OS, whereas the presence of GI lesions was correlated with favorable PFS (P=0.024, HR 0.09)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Elevated absolute monocyte counts (AMCs) have been reported to indicate poor prognosis for patients with lymphoproliferative disease, including those with follicular lymphoma (FL) receiving various treatments. We evaluated the prognostic impact of AMC in 150 consecutive FL patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Progression-free survival (PFS) did not differ significantly according to the AMC level. Univariate and multivariate analyses did not indicate a prognostic significance of AMC for PFS. Thus, the AMC is not a prognostic factor for FL patients treated with R-CHOP. However, immunochemotherapy might influence the prognostic impact of AMC., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Although rituximab added to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) is the standard chemotherapy for untreated DLBCL, its therapeutic effect is limited in younger patients with high-intermediate risk or high-risk disease according to the age-adjusted international prognostic index. In fact, the efficacy and safety of HDT plus rituximab followed by ASCT for such patients remain unclear., Patients and Methods: We retrospectively investigated the safety and effectiveness of HDT/ASCT in patients with untreated DLBCL. Twenty-two patients, aged 60 years and younger, with untreated DLBCL (classified as high-intermediate [n = 14 (64%)] or high [n = 8 (32%)] risk) underwent upfront HDT/ASCT between January 2004 and December 2008, achieving either a complete response (CR; n = 15 (68%)) or a partial response (PR; n = 7 (32%))., Results: The 5-year overall survival rate was 81.0% and the progression-free survival rate was 73.0%, with no significant difference between risk groups based on the international prognostic index. The most common nonhematologic toxicity was febrile neutropenia [n = 9 (41%)]. The cause of all 3 fatalities was exacerbation of the underlying disease, and no treatment-related mortality was observed. No variables with a significant influence on overall survival were identified, but a correlation of the treatment response before transplanation with progression-free survival was suggested (CR vs. PR: 92% vs. 30%, P = .002)., Conclusion: These results suggest that adding rituximab to upfront HDT/ASCT is feasible and can improve the outcome in untreated patients with poor-prognosis DLBCL. In the future, upfront HDT/ASCT should be more extensively evaluated in clinical trials., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Long-term observation has identified a pattern of continuing relapse in limited stage diffuse large B-cell lymphoma (DLBCL) treated by three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved-field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R-CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full-dose R-CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5-year progression-free survival and 5-year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the 'standard' strategy of three cycles of R-CHOP followed by involved-field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R-CHOP alone., (© 2013 Blackwell Publishing Ltd.)

The management of acute leukemia during pregnancy is challenging. Delays in treatment for acute leukemia can adversely affect maternal prognosis, but chemotherapy during pregnancy may induce severe adverse effects on the fetus. Here, we report a case of a pregnant woman with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) who underwent remission induction therapy and successfully delivered a live infant after chemotherapy. The case is a 36-year-old woman diagnosed with Ph(+)ALL in the 27th week of pregnancy. She underwent remission induction therapy including daunorubicin, vincristine, cyclophosphamide, and prednisolone. Imatinib was not used in the induction therapy. She delivered the infant after one course of chemotherapy. The infant and the patient are both alive now, without any major complications.

The introduction of rituximab (R) has measurably improved the outcome of patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). To evaluate the outcome of patients with FL and DLBCL under R plus CHOP therapy, we performed a retrospective analysis in Yokohama City University Hematology Group in Japan. Five hundred and twenty-six patients (158, FL ; 368, DLBCL) were scheduled to undergo primary therapy with 6 cycles of full-dose R-CHOP therapy with curative intent. The median observation periods in living patients with FL and DLBCL were 45 months and 43 months, respectively. The complete response, 5-year progression-free survival (PFS), and 5-year overall survival (OS) rates were 86%, 50%, and 92% in the FL group, and 89%, 72%, and 80% in the DLBCL group, respectively. Although PFS was significantly better in the DLBCL group than in the FL group, OS was significantly better in FL patients. We also found that the OS and PFS of grade 3 FL patients were not statistically different from those with grade 1-2. These findings indicate that all grades of FL should be categorized simply as "FL" with regard to R-CHOP therapy. Our results also demonstrate the incurability of FL (grade 1-3B), even with R-CHOP therapy.

A 60-year-old male with POEMS syndrome received lenalidomide and high-dose dexamethasone combination therapy as an initial treatment, with no severe adverse events occurring during the treatment. Two cycles of the therapy led to significantly decreased serum VEGF level, and IgA-λ type M-protein was not detected by immunofixation electrophoresis. We next performed autologous stem cell transplantation, without severe complications such as engraftment syndrome. He improved enough to walk independently and now is being followed up without treatment. This case suggests that lenalidomide-dexamethasone therapy is highly effective and can be a good option for pre-transplant treatment for POEMS syndrome.

Rituximab (R) plus doxorubicin, cyclophosphamide, vincristine, and prednisolone (CHOP) chemotherapy (R-CHOP) is widely accepted as standard care for diffuse large B-cell lymphoma (DLBCL) patients. The revised International Prognostic Index (R-IPI) was established in 2007 after the addition of rituximab to standard DLBCL treatment. To reassess the utility of R-IPI, we carried out a retrospective analysis of patients with DLBCL uniformly treated with standard R-CHOP. Progression-free survival (PFS) curves in "very good" and "good" risk groups as defined by the R-IPI showed no statistical difference. We added soluble interleukin-2 receptor (sIL-2R) level to the factors comprising the R-IPI. Five levels of sIL-2R were weighed with respect to their impact on PFS. sIL-2R of >2500 U/mL was determined as the most appropriate threshold. We developed a new prognostic SIL index, which includes three independent prognostic risk factors: clinical stage (S); sIL-2R level over 2500 U/mL (I); and elevated lactate dehydrogenase level (L). This index indicates standard risk (0 or 1 risk factors, 4-year PFS 83%, 4-year overall survival 91%) and high risk (2 or 3 risk factors, 4-year PFS 52%, 4-year overall survival 67%) outcomes. The SIL index is a simple and objective prognostic index for DLBCL patients to identify candidates for experimental therapy other than R-CHOP., (© 2012 Japanese Cancer Association.)

We conducted a prospective randomized study to assess the optimal postremission therapy for adult acute myeloid leukemia in patients younger than 65 years in the first complete remission. A total of 781 patients in complete remission were randomly assigned to receive consolidation chemotherapy of either 3 courses of high-dose cytarabine (HiDAC, 2 g/m(2) twice daily for 5 days) alone or 4 courses of conventional standard-dose multiagent chemotherapy (CT) established in the previous JALSG AML97 study. Five-year disease-free survival was 43% for the HiDAC group and 39% for the multiagent CT group (P = .724), and 5-year overall survival was 58% and 56%, respectively (P = .954). Among the favorable cytogenetic risk group (n = 218), 5-year disease-free survival was 57% for HiDAC and 39% for multiagent CT (P = .050), and 5-year overall survival was 75% and 66%, respectively (P = .174). In the HiDAC group, the nadir of leukocyte counts was lower, and the duration of leukocyte less than 1.0 × 10(9)/L longer, and the frequency of documented infections higher. The present study demonstrated that the multiagent CT regimen is as effective as our HiDAC regimen for consolidation. Our HiDAC regimen resulted in a beneficial effect on disease-free survival only in the favorable cytogenetic leukemia group. This trial was registered at www.umin.ac.jp/ctr/ as #C000000157.

Fifty-eight newly diagnosed patients with Hodgkin lymphoma were treated with ABVD chemotherapy at Yokohama City University Hematology group from October 1996 to June 2005. The median age of patients age was 41 years old and ranged from 15 to 75. Thirty-eight patients were in the early stage and 20 patients were in the advanced stage. Patients in the early stage received 3 cycles of ABVD chemotherapy and involved-field radiation therapy, while those in the advanced stage received 6 cycles of ABVD chemotherapy. The overall response rate in patients was 100% (CR 87%, PR 13%) in the early stage and 95% in the advanced stage. With a median follow-up of 44 months, the 3-year progression-free survival and overall survival were 89% and 95% in the early stage, and 70% and 81% in the advanced stage, respectively. The results of this study were similar to those previously reported in Western countries.

We analysed the long-term outcome of the L86 protocol using L-asparaginase (L-asp), vincristine (VCR) and prednisolone (PSL), collectively known as LVP or L97 protocol using LVP along with pirarubicin hydrochloride (THP-ADR) for 97 patients with acute lymphoblastic leukemia (ALL) diagnosed between 1986 and 2002. No significant differences were seen in the two protocols regarding the complete remission (CR) rate or survival. Seventy-five of the 97 patients (77%) achieved a CR. The overall survival (OS) and disease-free survival (DFS) rates were 32.1% and 30.4% at 10 years, respectively. By univariate analysis, we identified seven adverse factors for DFS which included the L2 subtype by French-American-British classification, hepatosplenomegaly, a white blood cell count of more than 30 x 10(9)/L, a blast cell count of more than 10 x 10(9)/L in the peripheral blood, hemoglobin concentration greater than 10 g/dL, a serum lactate dehydrogenase value greater than twice the upper limit of normal and the presence of the Philadelphia chromosome (Ph). According to multivariate analysis, only the presence of Ph was a significant unfavourable factor for DFS and OS. In the 30 patients under 35 years of age without Ph, the OS in the 20 patients treated with L86 and in the 10 patients treated with L97 were 48 and 86%, respectively (P = 0.011). These results indicate that intensified chemotherapy, such as the L97 protocol that includes an anthracycline, might be beneficial for younger patients who are Ph-negative.

The role of adjuvant radiotherapy to the site of the initial bulky mass in lymphoma remains to be determined. We retrospectively analyzed clinical data for 35 consecutive patients with diffuse large B-cell lymphoma who had an initial bulky mass were treated successfully by chemotherapy reaching complete remission or complete remission unconfirmed according to International Workshop Criteria. Median age was 57 years. Median follow-up period for surviving patients after completion of chemotherapy was 45 months. Twenty patients (group A) received adjuvant radiotherapy to the bulky mass, while 15 (group B) did not. Median dose of radiation in group A was 40 Gy (range, 30-60 Gy). In group A, four relapses occurred, all from other sites; group B included three relapses from bulky and one from other sites. Overall survival (P = 0.15) and recurrence-free survival (P = 0.48) did not differ significantly between groups. Although adjuvant radiotherapy to the initial bulky site is useful for controlling local disease, no survival benefit was seen.

Recently, the cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen plus rituximab (R-CHOP) have been used widely to treat patients with follicular lymphoma. We investigated a fixed scheme of combination chemotherapy protocol including CHOP, granulocyte colony stimulating factor (G-CSF) and rituximab (CHOP-GR) for patients with advanced-stage grade 1 or grade 2 follicular lymphoma in a phase II clinical trial, assessing enhancement of antibody-dependent cellular cytotoxicity of rituximab by G-CSF. Twenty-one untreated patients received two courses of CHOP chemotherapy followed by four courses of CHOP-GR, including G-CSF (s.c.) on days 11 - 14 and rituximab on day 15. Overall response rate was 76% (16 of 21 patients). Two patients, one with no response and subsequent allogeneic hematopoietic stem cell transplantation and one with progressive disease, died of lymphoma. One patient refused to continue therapy, whereas two were rediagnosed and no longer met histologic criteria; these three patients were classified as nonresponders. After a median observation time of 23 months, the 19 histologically assessable patients showed a 2-year progression-free survival rate of 82%, whereas 2-year overall survival was 95%. Fifteen patients (79%) continued in remission during this median follow-up period. Of seven patients with initial bulky mass, five responded to therapy. The most frequent adverse events were leukocytopenia (100%) and neutropenia (100%), followed in turn by alopetia (94%) and nausea/vomiting (79%). Of 11 patients examined for bcl-2 translocation in peripheral blood or marrow by polymerase chain reaction (PCR), four were positive, whereas three of the four had complete remissions and converted to PCR negativity after therapy. According to short-term observation, CHOP-GR is a safe and effective therapy for patients with advanced-stage follicular lymphoma.

BPA (bisphenol A or 2,2-bis(4-hydroxy-phenol)propane) and hydroquinone (HQ, 1,4-benzenediol) are present in dental resin materials, and small quantities of these substances may be eluted from the resins. Recently, attention has focused on the estrogen-like and carcinogenic adverse effects of BPA and HQ. Thus, it is important to investigate the cytotoxicity and apoptosis-inducing activity of these compounds. BPA and HQ reduced the viable cell number of human promyelocytic leukemia (HL-60), human oral squamous cell carcinoma (HSC-2) and human submandibular gland (HSG) cell lines in a concentration-dependent manner. The cytotoxic activity of HQ, but not of BPA, was significantly reduced by the addition of N-acetyl-L-cysteine (NAC). In biomimetic studies of the prooxidant/antioxidant activity of thiols during oxidation of BPA or HQ, the radical-scavenging activities of mixtures of BPA or HQ and 2-mercapto-1-methylimidazole (MMI, a thiol) were investigated by the induction period method. BPA without MMI showed a higher induction period (antioxidant activity) than did HQ, but BPA with MMI did not cause oxygen uptake. In contrast, HQ with MMI caused oxygen uptake, suggesting formation of MMI thiyl radicals during oxidation of HQ followed by reaction with molecular oxygen. This indicates that HQ may produce intracellular reactive oxygen species (ROS) and provides an explanation for the decrease in the cytotoxicity of HQ by NAC. BPA induced internucleosomal DNA fragmentation, a biochemical marker of apoptosis, only in HL-60 cells. BPA activated caspase-9 and caspase-3, suggesting induction of apoptosis via caspase activation by the caspase recruitment domain. The cytotoxicity of BPA was 2-fold less than that of HQ, whereas the apoptosis-inducing activity of BPA was 10-fold less than that of HQ.

High-intermediate (HI)- and high (H)-risk non-Hodgkin lymphoma was treated with front-line intensive chemotherapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT). Twenty-eight cases were enrolled after obtaining informed consent, from November, 1998 to October, 2003. Initial treatment was 2 or 3 cycles of CHOP-V regimen, followed by three high-dose therapy, one each of cyclophosphamide, methotrexate and etoposide. The final high-dose therapy was a combination of ranimustine, ifosphamide and etoposide, which was followed by auto-PBSCT. Patients with a bulky mass received involved-field radiation therapy (IF-RT) after auto-PBSCT. Complete remission (CR) was achieved in 16 cases (57%) and partial remission (PR) in 9 cases (32%), after auto-PBSCT The final responses after IF-RT were CR in 20 cases (71%) and PR in 5 cases (18%). Overall survival of cases with 2 cycles of CHOP-V regimen was 56% after a median observation time of 30 months, compared with 82% in cases with 3 cycles (p = 0.0732). The results suggested that the reduction of tumor size with the initial CHOP-V treatment was most important. In all cases, progression-free survival was 64% and the overall survival was 74% after a median observation time of 30 months, which showed a good outcome compared with that of HI- and H-risk group defined by the age-adjusted international prognostic index reported by Shipp et al.

In all, 18 patients (30-56 years; median 49) with MDS underwent allogeneic HSCT from related (n=12) or unrelated (n=6) donors after a conditioning regimen comprising thiotepa, cyclophosphamide, and TBI. GVHD prophylaxis consisted of cyclosporine (n=15) or tacrolimus (n=3) with short-course methotrexate. Four patients had low-risk disease (refractory anemia or complete remission after chemotherapy) and 14 patients had high-risk disease (RAEB, RAEB-t, or AML). Grade II-IV acute GVHD developed in six patients and chronic GVHD in 10. With a median follow-up of 31 months, the 2-year survival probability is 75% for low-risk patients and 57% for high-risk patients. One patient died of leukemia and six of treatment-related causes. This conditioning regimen requires further study in patients with MDS.

We conducted a multi-center phase I/II trial of nonmyeloablative stem cell transplantation for patients with hematologic malignancies. The aim of this trial was to assess the safety and feasibility of this treatment modality for older or younger patients with significant organ dysfunction, who could not be treated with conventional high dose chemoradiotherapy. Twelve patients were treated with a conditioning regimen consisting of fludarabine and cyclophosphamide, followed by peripheral blood stem cell transplantation from human leukocyte antigen (HLA) identical siblings. Nonhematologic toxicities were mild. Median time to absolute neutrophils above 0.5 x 10(9)/l, 1.0 x 10(9)/l and platelets above 50 x 10(9)/l were 8, 10 and 12 days, respectively. Donor dominant hematopoiesis was achieved in all patients, with or without donor leukocyte infusion. The cumulative incidence of acute and chronic graft-versus-host disease (GVHD) was 75 and 56%, respectively. Only one patient experienced early death within 100 days, caused by acute GVHD complicated by fungal infection. All patients except one achieved complete remission. With a median follow-up of 330 days, expected progression-free survival is 75%. Overall survival is 76%. Our study confirms that nonmyeloablative stem cell transplantation with cyclophosphamide and fludarabine conditioning is a safe and promising treatment for elderly patients with hematologic malignancies. A further study in large-scale setting is warranted.

Between January 1990 and May 1994, 59 previously untreated adult patients with acute myeloblastic leukemia (AML) were treated with a combination of behenoyl-cytosine-arabinoside (BHAC), daunorubicin (DNR), 6-mercaptopurine (6-MP) and prednisolone (PSL). Forty one patients (69.5%) achieved complete remission (CR). The Kaplan-Meier analysis revealed an actuarial probability for remaining in remission of 36% in patients who achieved remission and a survival of 29% in all patients at 5 years. A favorable factor relative to achieving CR was performance status (P=0.04). In addition the presence of 300 cells/microl or less of residual leukemic cell counts in the bone marrow at the end point of induction therapy tended to favor remission (P=0.06) using the multivariate analysis with a multiple logistic regression model. In addition the residual leukemic cells counts of less than 300/microl in the bone marrow at the end point of induction therapy was the most significant factor for durable remission (P=0.05) by the Cox's proportional hazard model. We concluded that residual leukemic cells counts in the bone marrow at the end point of intensive induction therapy is a valuable prognostic factor for adults receiving response-oriented individualized induction therapy for AML.

The efficacy of various combination chemotherapies employed for the 37 patients with low-grade non-Hodgkin's lymphoma between 1981 and 1994 was evaluated retrospectively. The overall survival at 5 years was 68%. The 5-year survival of the 27 patients achieving complete response (CR) was 87%, which was significantly higher than that of 9 patients with partial response (p = 0.0005). The CR rate of stage III and IV patients was 64% for the 22 patients treated with ACOMP-B (D), and was 38% for 8 others treated with milder chemotherapy regimens including VEPA. The 22 advanced stage patients had a 5-year survival of 88% after the treatment with ACOMP-B (D) and 69% of them remained free of disease at 5 years. In this group no relapse occurred beyond 1.6 years after treatment. These findings suggest a possible role of third generation chemotherapy in the treatment of patients with advanced-stage low-grade non-Hodgkin's lymphoma.

Eleven therapy related leukemias (TRL) who were hospitalized in the Department of Hematology and Chemotherapy, Kanagawa Cancer Center between October 1983 and December 1993 were identified. Six of the patients were males and five were females. Their median age was 62 years (range from 14 to 75). Three patients had previously received treatment for breast cancer and two patients for malignant lymphoma. The other patients had received treatment for lung cancer, urinary bladder cancer, gastric cancer, brain tumor, maxillary sinus cancer and macroglobulinemia, respectively. Seven patients had been treated with chemotherapy and four patients had been treated with chemotherapy and irradiation for the primary tumor. The TRL cases consisted of 8 acute non-lymphoid leukemias, two acute lymphoid leukemias and one hypoplastic leukemia, respectively. The status of primary tumors at the development of TRL was complete remission in ten patients and partial remission in one patient. Three of the 10 patients who received anti-leukemic therapy entered complete remission and the median survival time was 36 days (from 7 days to 489 days). One patient expired of pneumonia before he received anti-leukemic therapy. TRL patients showed poor response to chemotherapy and had poor prognosis. These data suggest that the use of reduced doses of carcinogenic drugs for primary tumors might be required to prevent the development of TRL.

A 50-year-old female was admitted with acute promyelocytic leukemia (APL) in August, 1988. She was treated with behenoyl-ara-C, daunomycin, 6-mercaptopurine and prednisolone (BH-AC.DMP), which led to a complete remission. Thereafter, she was treated with 2 courses of BH-AC.DM and discharged from hospital. Intensification therapy was performed twice a year, with 1 course of BH-AC.DM and 5 courses of intermittent-dose ara-C/mitoxantrone which ended in March, 1992. She had a relapse in September, 1993 and was treated with all-trans retinoic acid, which led to a second remission. A second relapse occurred in May, 1994, and intermittent-dose ara-C/mitoxantrone, combined with granulocyte colony-stimulating factor (G-CSF), led to a third remission. However, she had a third relapse in September, 1994. She was treated with a trial of G-CSF (300 micrograms/body, day 1-7), to stimulate dormant leukemic cells to enter the cell cycle, and cyclosporin-A (78 mg/kg, day 2-5), in order to overcome daunomycin resistance in refractory leukemia, combined with daunomycin (45 mg/m2, day 3-5) and ara-C (1.4 g/m2, day 3-7), after obtaining informed consent. The fourth remission needed 46 days after combination chemotherapy because of severe myelosuppression. It was suggested that intermittent-dose ara-C/daunomycin therapy combined with G-CSF and cyclosporin-A may be useful for relapsed and refractory leukemia.

A retrospective analysis was performed on forty nine elderly (34 males and 15 females) patients aged 65 years or more (median age 73, range 65-82) with acute non-lymphocytic leukemia (ANLL). Patients were studied to examine factors according to age group (65-69 years, 70-74, 75-79 and 80 or over), respectively. Patients were treated with either low dose Ara-C therapy or BHAC-DMP therapy according of the choice of their attending physicians. Complete remission (CR) was obtained in 20 of 49 patients (43%), and in 6 of 14 patients (43%) aged 65-69, in 8 of 18 (44%) aged 70-74, in 5 of 12 (42%) aged 75-79 years and in 1 of 3 (33%) aged 80 or over, respectively. The median survivals of these groups were 263, 298, 260, 168.5 and 38.5 days, respectively. Multivariate analysis revealed that the achievement of CR was associated with normal karyotype, and serum GOT level < or = 30 mu/ml and GPT < or = 40 mu/ml. Prolonged survival was related to the achievement of CR. The results indicated that liver function before chemotherapy was an important prognostic factor.

In our series of investigations concerning immunopotentiators, we evaluated the host immunocompetence of patients triggered by PSK. Our subjects for screening consisted of seven patients with malignant tumors of female reproductive organs chosen at random from our patients. Four of them were treated with chemotherapy (CAPF) alone and served as controls, whereas the other three were administered PSK, 3.0 g/day, plus chemotherapy as above. Cellular and humoral immunities were measured at three points. Firstly prior to chemotherapy, secondly, two weeks after the start of chemotherapy, and thirdly, prior to next chemotherapy. The results indicated higher values of T-cell subset ratio OKT-4/8 of 2.73 +/- 0.56 on the average for cellular immunocompetence as compared to 1.35 +/- 0.45 for normal subjects in the PSK-administered group, whereas there was no increase in the non-PSK-administered group, in which the value was 1.28 +/- 0.30. Thus, PSK was considered to extert an immunopotentiating effect on the T-lymphocytes.

Four patients with non-seminomatous testicular tumor who already had brain metastasis were treated with combination chemotherapy. Three patients had received craniotomy in an effort to remove the metastatic lesion and intracranial hematoma. Two of them who were treated with PVB chemotherapy, which was effective against pulmonary and retroperitoneal metastasis but not against the brain metastatic lesions, died within 3 months; the other patient is receiving intense postcraniotomy chemotherapy using Cisplatin and large doses of Methotrexate administered with the Leucovorin rescue method which has shown a remarkable response against the brain metastasis of choriocarcinoma. The remaining patient has been receiving VAB VI protocol for 3 months. The metastatic lesion in the temporal lobe of his brain may consolidate through calcification, similar to the calcified change observed in the retroperitoneal lymph-node after chemotherapy. We discuss potential ways to induce improved therapeutic effects against brain metastasis of the non-seminomatous testicular tumor: It may be difficult to achieve an effective drug concentration level in the tissue immediately adjacent to the intracerebral tumor, because of the blood brain barrier. As induction therapy, a large dose of Cisplatinum (230 mg/body) or Methotrexate (10 g/body) was effective in attaining an effective drug concentration level in the tissue adjacent to tumor. Prior to the stem cell assay of the brain metastatic tumor, 1,100 mg Cisplatinum and 1,700 mg VP 16 were administered for treatment. The results of the stem cell assay in vitro showed a resistance to Cisplatinum and VP 16. Routine brain CT scanning is useful for detecting a metastatic lesion in its development. If detected, multidisciplinary chemotherapy should be performed.(ABSTRACT TRUNCATED AT 250 WORDS)