Low-dose MTX for the treatment of acute and chronic graft-versus-host disease in children.

We report the results of a retrospective analysis in 27 pediatric patients who received low-dose MTX as the second-line treatment for steroid-refractory or -dependent acute and chronic GVHD. Between July 2000 and May 2006, 10 patients with aGVHD and 17 with cGVHD were treated with MTX at a dose of 3-10 mg/m(2) weekly. Seven of ten patients (70%) with aGVHD responded well to MTX, thus resulting in the achievement of either a complete response (CR) or a partial response (PR). The dose of prednisone could be reduced to equal to or lower than 1 mg/kg in the responding patients at the end of MTX therapy. The median number of MTX administrations was five (range, 1-7). Ten (58.8%) of seventeen patients with cGVHD achieved CR or PR. The dose of prednisone could be reduced to lower than 0.4 mg/kg in 16 of 17 patients and seven patients could discontinue prednisone. The median duration of MTX administration was 18 months (range, 1-68). The toxicities of grade III to IV occurred in only six patients presenting cytopenias or elevated levels of serum transaminases. Low-dose MTX was tolerable and effective for the steroid-refractory or -dependent GVHD in reducing the dose of steroid without increasing the risk of opportunistic infection.

Unrelated donor bone marrow transplantation for 100 pediatric patients: a single institute's experience.

In all, 100 unrelated donor bone marrow transplantations (UD-BMT) were performed in our institute between October 1993 and January 2003. Of 93 evaluable patients, 73 patients had hematological malignancy, 13 had nonmalignancy and seven had lymphoproliferative disease. The estimated 9-year event-free survival (EFS) rate was 57.1+/-5.5% in all patients. In the following analyses of the patients with hematological malignancy, the standard group had significantly better EFS than the high-risk group (61.5+/-7.0 vs 35.6+/-9.7%, P=0.02), and the EFS rate of the tacrolimus (FK-506)+methotrexate (MTX)+/-methylprednisolone prophylactic group for graft-versus-host disease was superior to that of the FK-506 without MTX group (75.7+/-8.0 vs 55.8+/-7.6%, P=0.02). When we compared the EFS rates of the FK506+MTX+/-methylprednisolone (mPSL) group and the HLA-matched related donor BMT group in our institute, these were almost similar (75.7+/-8.1 vs 68.4+/-9.3%). Therefore, UD-BMT using FK-506+MTX+/-mPSL is a safe and useful method for children with hematological malignancy who require allogeneic BMT.

Clinical results of nonsurgical treatment for spinal metastases.

PURPOSE: In contrast with many analyses of surgical treatment for spinal metastases, there have been only a few recent well-documented publications assessing nonsurgical treatment. This paper is a study of the outcome of nonsurgical therapy for metastatic tumors of the spine. METHODS AND MATERIALS: One hundred and one patients with spinal metastases were treated with radiation therapy and/or chemotherapy without surgical intervention between 1990 and 1995, in prospective analysis, and had follow-up for more than 24 months. This study included 59 men and 42 women with a mean age of 61 years (range: 14 to 81). Mean follow-up periods were 11 months for patients dying of the disease and 53 months for the survivors. Neurological status, pain relief, functional improvement, and cumulative survival rate were assessed. RESULTS: Of the total treated, 67 patients (66%) were evaluated as being neurologically stable or improved after treatment. Pain relief was achieved in 67%, and 64% showed functional improvement. Primary lesion responsiveness to nonsurgical therapy influenced the survival, neurological recovery, pain control, and function. Neurological findings before therapy were useful in predicting ambulatory status after treatment. CONCLUSION: Nonsurgical treatment was often successful when primary tumors had responsiveness to radiation therapy and/or chemotherapy. We found this to be evident even when neurological deficits were found, particularly in lumbar spines. Spinal metastases of tumors with less responsiveness, unless patients were neurologically intact, responded poorly to therapy. Most of the patients who were successfully treated enjoyed relief lasting nearly until death. Their functional ability was limited by general debility, rather than by local tumor regeneration.

A stereoselective synthesis of the C10-C31 (BCDEF ring) portion of pinnatoxin A.

[reaction: see text] An efficient synthesis of the C10-C31 (BCDEF ring) portion of pinnatoxin A has been achieved. The key step is a highly stereoselective construction of the dispiroketal (BCD ring) system employing an intramolecular hetero-Michael reaction of a reversibly formed hemiketal alkoxide through the use of LiOMe.

Pharmacokinetics of doxorubicin and its active metabolite in patients with normal renal function and in patients on hemodialysis.

The comparative pharmacokinetics of doxorubicin (DOX) were investigated in five hemodialysis (HD) and eight non-hemodialysis (non-HD) patients who were infused with a 40- to 60-mg dose of DOX at a constant rate over 30 min. A significant difference was observed in the total body clearance (Cl tot) of DOX between HD and non-HD patients. The area under the curve (AUC) for both DOX and doxorubicinol (DOXol), an active metabolite, showed increases of approximately 1.5 and 3 times in HD patients as compared with non-HD patients. Although these differences were not statistically significant (P < 0.1), the mean residence time (MRT) of DOX and DOXol in HD patients showed a 2-fold increase in comparison with those in non-HD patients. Compartmental analysis indicated that the greater AUC values and longer MRT of DOX and DOXol in HD patients resulted from the lesser DOXol formation and disappearance of rate constants. As a consequence of the decrease in Cl tot for DOX and the marginal hemodialysis clearance of both DOX and DOXol, the present study suggests that the exposure to DOX and DOXol obtained in HD patients greater than achieved in non-HD patients. Careful attention should therefore be paid to HD patients receiving DOX.

A randomized trial of adriamycin, cyclophosphamide, ftorafur (ACF) and adriamycin, cyclophosphamide, ftorafur, methotrexate (ACFM) in patients with advanced breast cancer.

A prospective randomized trial was conducted comparing the clinical response of 60 patients with advanced breast cancer to a combination of adriamycin, cyclophosphamide, and oral ftorafur (ACF), or to a combination of ACF plus methotrexate (ACFM). The response rate was 12 of 28 (43%) in ACF and 18 of 30 (60%) in ACFM. Responses were seen more frequently in patients in whom fewer than two organs were involved, and responses at dominant metastatic sites were equal for the two arms. The response duration was 21 + (3.5-49.5+) months with ACF, as against 6.9 (1.9-30.8+) months with ACFM (P less than 0.05). The median survival time from start of therapy was 20.8+ months for ACF, while that for ACFM was 13+ months (statistically not significant). The major toxicities were hair loss, GI toxicity, and leukopenia. The response rate with ACFM was higher than that with ACF, but the addition of methotrexate to ACF did not increase the complete response rate or prolong response duration.

Phase I study of NKT-01.

A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20-500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the alpha and beta phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.

Linalyl and bornyl disaccharide glycosides from Gardenia jasminoides flowers.

(R)-Linalyl 6-O-alpha-L-arabinopyranosyl-beta-D-glucopyranoside and bornyl 6-O-beta-D-xylopyranosyl-beta-D-glucopyranoside were isolated as aroma precursors of linalool and borneol from flower buds of Gardenia jasminoides, guided by enzymatic hydrolysis followed by GC and GC-MS analyses.

Chemiluminometric flow-injection method for determination of free l-malate in wine with co-immobilized malate dehydrogenase/NADH oxidase.

A flow-injection system with a co-immobilized malate dehydrogenase/reduced nicotineamide adenine dinucleotide (NADH) oxidase reactor and a chemiluminometer is described for the determination of free l-malate in wine. Malate dehydrogenase and NADH oxidase were co-immobilized on poly(vinyl alcohol) beads and packed into a stainless-steel column (5 cm x 4 mm i.d.). The hydrogen peroxide produced was detected chemiluminometrically via a luminol-hexacyanoferrate(III) reaction. The calibration graph was linear from 3 x 10(-7) M to 2.5 x 10(-4) M (the linear correlation coefficient was 0.9998); the detection limit (signal-to-noise ratio, 3) was 8 x 10(-8) M. The sample throughput was 30 h(-1) without carryover. The ractor was renewed every 2 weeks.

[Abnormal cluster formation in a patient with myelodysplastic syndrome with trisomy-11--periodical approach by colony assay].

59 year old female was admitted to Nagoya Memorial Hospital for anemia unknown etiology after the work up of the gastrointestinal tract. Peripheral blood count at admission was as follows: WBC 2,400/microliters, RBC 321 X 10(4)/microliters, Hb 9.8 g/dl, Ht 30.1%, Plt 8.2 X 10(4)/microliters, which showed pancytopenia with normocytic, normochromic anemia. She had no hepatosplenomegaly, vitamin B12 nor folate deficiency. Bone marrow was hyperplastic and showed trilineage megalodysplastic changes. The diagnosis of myelodysplastic syndrome (Refractory anemia) was made. Progenitor assay showed no colony formation of BFU-E but showed normal growth of CFU-GM colony and cluster. She had chromosomal abnormality of 47, XX, + 11. Administrated anabolic steroid, prednine and activated vitamin D3 were not effective and she died of brain hemorrhage in April 1987. Colony assay at this stage showed numerous leukemic clusters and no normal colonies. Re-performed chromosome assay showed 47, XX, + 11. There are only a few reports of trisomy-11 in a patient with MDS. Especially we could follow this case till her leukemic transformation by colony assay.

[Adjuvant chemotherapy for localized non-Hodgkin's lymphoma with CVP therapy].

Fifty-two patients with localized (stage I-II) non-Hodgkin's lymphoma were treated with a combination of vincristine, cyclophosphamide and prednisolone (VCP) as an adjuvant therapy between 1975 and 181. Forty-two patients had extended-field radiotherapy, and ten patients had only surgical excision (6 gastrointestinal tract, 2 breast, one each of skin and axillary lymph node). Clinical stages of these patients were divided into stage I (21 patients) and stage II (31 patients). With a median follow-up time of relapse-free survival (RFS) were calculated by Kaplan and Meier method. At two years after the initiation of chemotherapy, survival and RFS were 95% and 83% for stage I, and 76% and 74% for stage II, respectively. These ratios remained stable for 7 years. Survival and RFS of diffuse histiocytic lymphoma (34 patients) were 90% and 83% at 7 years, while these of diffuse poorly differentiated lymphocytic lymphoma (18 patients) were 75% and 69% at 4 years. Of 52 patients, 10 had relapsed (Stage I: 3 patients and stage II: 7 patients) within the first 2 years. Side effect was minimal with moderate peripheral neuropathy due to vincristine. The result suggests that adjuvant chemotherapy is necessary to improve prognosis of patients with localized non-Hodgkin's lymphoma.

[Chemotherapy for advanced non-Hodgkin's lymphoma with CVP therapy].

Thirty-one patients with advanced non-Hodgkin's lymphoma were treated with a combination chemotherapy (VCP therapy), including vincristine (1 mg, weekly), cyclophosphamide (350mg/m2, IV every two weeks) and prednisolone (60mg/day, 1-5 days PO, every two weeks), as an out-patient basis, from May 1974 to October 1977. Characteristics of 31 patients were as follows: median age (56 years), histological types by Rappaport's classification (nodular 2, diffuse 29, NPDL 2, DWDL 5, DPDL 10 and DH 14), clinical stages (II 4, III 9, IV 18), systemic symptoms (A 13, B 18), extranodal presentation (28) and prior treatment (17). Response was evaluated in 28 patients with measurable disease. Complete response (CR) was obtained in 15 patients (53%) and partial response (PR) in 5 (18%). Median time to CR was 20 (6-79) days, and response duration of CR was 14 (1.5-78+) months. Survival time was 19 (1-76) months for all patients, 26 (3-78) months for patients with CR, 9 (3-51) months for patients with PR, and 4 (1-41) months for non-responders. Survival of complete responders was significantly better than that of patients with non-CR. Survival rates of complete responders were 80% (1 year), and 47% (3 year). Toxicities of VCP therapy were relatively mild and reversible with peripheral neuropathy, hair loss and leukopenia. The results indicate that it is necessary to perform more intensive combination chemotherapy adding potent agents for a higher CR rate and a longer CR duration.

[Eligibility from clinical science for domiciliary cancer treatment].

To establish domiciliary treatment for cancer patients, following conditions must be settled. They are eligibility from clinical science, intentions of patients and their family, social and economical aspects, compatibility with medical service laws in Japan, and so on. Eligibility from clinical science should be the first matter to be settled among them. From the view of clinical science, medical care practices must be carried on in a correct manner even in patients' homes. In this study we focused on suitability from clinical science and examined possibility of domiciliary treatment for 111 inpatients in our hospital on April 6 th 1994. When the possibility was respectively judged by two nurses in our domiciliary cancer treatment committee, a difference appeared in the numbers of the candidates for domiciliary treatment. Finally the committee decided that 37 inpatients could receive medical care practices in their homes. The analysis of the reason in difference by two nurses made us recognize that the process of the selection of cancer treatment must be properly constructed for the well-qualified domiciliary treatment.

[Case report of meningeal carcinomatosis of gastric cancer successfully treated with intrathecal and systemic chemotherapy].

A 36-year-old housewife in the U.S.A. was diagnosed as having gastric cancer with meningeal carcinomatosis and admitted to our hospital in September, 1982. She had severe headache, nausea, vomiting, diplopia and neck stiffness. She was treated by intrathecal chemotherapy using methotrexate, cytosine arabinoside and prednisolone, and by systemic chemotherapy using adriamycin and ftorafur, resulting in complete disappearance of cancer cells from the cerebrospinal fluid and partial response for the primary tumor. She lived for more than 1 year following the first symptoms of her disease and for 10 months following the initiation of chemotherapy. This case suggested the usefulness of employing an intrathecal chemotherapy using methotrexate and cytosine arabinoside with simultaneous systemic chemotherapy for meningeal carcinomatosis of gastric cancer.

[Factors promoting acceptance of death at home].

We have provided home treatment mainly for cancer patients since June 1995 and had 7 such patients until March 1996. Among them two patients died not at home but in the hospital, although the patients and their family understood that the patients were in the terminal stage of illness. It home was thought to be difficult that they accept death at their homes. From the standpoint of physical and mental conditions, social status and actual medical care, the factors to promote death at home were examined. The two cases mentioned above and their families wished to have treatment at home. The reasons why we decided to discontinue medical care at their homes were twofold: 1) the difficulty of palliating patients' symptoms and anxiety; and 2) the uneasiness of the family in caring for patients at home. Therefore sufficient palliation of symptoms and "death education" for patients and families are required to encourage death at home.

[Arterial infusion of combination chemotherapy consisting of adriamycin and mitomycin C for liver metastases of breast cancer].

Forty-nine patients with liver metastases of breast cancer were treated with arterial infusion involving simultaneous use of adriamycin: 30-50 mg and mitomycin C: 10-20 mg through the hepatic artery by Seldinger catheter. Of 45 evaluable patients, there were 5 complete and 12 partial responses (CR + PR: 38%), 21 no change and 7 cases of progressive disease. The median duration of response was 5 months. The median survival time was 7.5 months in all cases, 8.7 months for responders and 6.4 months for non-responders. Leukopenia less than 4 X 10(3)/mm3 was observed in 73% of cases, thrombocytopenia less than 100 X 10(3)/mm3 in 35%, and a decreased hemoglobin value of more than 2 g/dl in 4%, but these were well tolerated. Nausea (53%), vomiting (43%), fever (12%), abdominal pain (6%) and liver toxicity (2%) were observed, but these were manageable. We conclude that this arterial infusion therapy is a useful treatment modality for controlling liver metastases of breast cancer.

[A combination chemotherapy consisting of vincristine, etoposide and cyclophosphamide (VEC) for small cell carcinoma of the lung].

Twenty-nine patients with small cell carcinoma of the lung were treated with a combination therapy consisting of vincristine 1 mg/m2 i.v. day 1, etoposide 200 mg/body p.o day 1-5 and cyclophosphamide 500 mg/m2 i.v. day 1 (VEC) in 3 week interval. After 2 courses of VEC, four out of 10 patients with limited disease (LD) showed a complete response (CR), while 7 out of 19 patients with extensive disease (ED) obtained a CR. Six patients with LD and 6 patients with ED received subsequent radiotherapy to primary tumors and to regional lymph nodes, and 5 with LD and 3 with ED attained a CR. Overall complete response was observed in 9 patients (90%) in LD and 10 patients (53%) in ED. The median duration of survival was 17 months in complete responders with LD and that was 12 months in those with ED. Dose limiting toxicity of the VEC regimen was leukopenia which occurred in most patients and thrombocytopenia was less frequent. Non-hematologic toxicities containing alopecia, numbness, nausea and others were acceptable and well tolerated.

[Co-administration of adriamycin and 5-fluorouracil for the treatment of advanced stomach cancer].

Twenty-one patients with advanced gastric cancer were treated with a combination chemotherapy of adriamycin and 5-fluorouracil (AF). The AF regimen consisting of adriamycin 35-50 mg/m2 intravenously on day 1, 5-fluorouracil 350-500 mg/m2 intravenously on days 1-3 was repeated in every three weeks intervals. Partial response was obtained in four patients (25%) in 16 evaluable patients and responded lesions were abdominal mass and skin metastasis. Two patients had minor responses, seven had stable diseases, and three had progressive diseases. The median duration of response for responders was three months ranging one to five months and the median survival time of responders was twelve months ranging two to fourteen months, whereas that of non-responders was eight months. Moderate bone marrow suppression was seen; that is, seven (33%) out of twenty-one patients had leukopenia less than 2,000/mm3 and two (10%) out of twenty-one patients had thrombocytopenia less than 10 X 10(4)/mm3. Moderate nausea occurred in thirteen patients (62%), whereas vomiting did in nine patients (43%). Nearly total alopecia was observed in sixteen patients (76%). Based on these results, we conclude that AF regimen can be administered without severe toxicities and it is one of the useful regimens for advanced gastric cancer.

[Clinical trial of human lymphoblastoid interferon on advanced malignancy].

A clinical study on human lymphoblastoid interferon (HLBI) in various advanced malignant diseases was performed. HLBI was administered to a total of 25 patients with various advanced malignant diseases in order ot investigate antitumor effect and toxicity. The diseases evaluated were as follows: 8 multiple myeloma (MM), 2 chronic lymphocytic leukemia (CLL), 2 adult T cell leukemia (ATL), 1 acute lymphocytic leukemia (ALL), 8 breast cancer, 3 gastric cancer and 1 ovarian cancer. Twenty-three patients received either 3 million or 6 million units of HLBI by daily intramuscular injection or every other day. One patient with ATL received 18 million units of HLBI by i. v. daily and 1 patient with ALL received 30.32 million units of HLBI i. v. daily. Tumor regression (PR) was observed in 2 patients with MM, each one patient with ATL and ALL, respectively. Major toxicities were pyrexia, myelosuppression, general malaise and G.I. toxicity. Several patients showed abnormality of hepatic or renal function. Two patients who received HLBI for more than a year developed cardiac toxicity.

[A phase I trial of 4'-epiadriamycin].

A phase I study of a new anthracycline, 4'-epiadriamycin was conducted in a total of 28 patients with various advanced cancers refractory to standard chemotherapies and 26 were evaluable. A dose limiting factor was leukopenia reaching a nadir approximately 2 weeks later and about one week needed for the recovery. Thrombocytopenia was milder and less frequent than leukopenia but dose-related. Nausea and alopecia were observed in the majority of patients but vomiting was relatively rare and therefore non-hematologic toxicities were judged to be milder than adriamycin. A recommended dose for patients having prior extensive chemotherapies was determined to be 60 mg/m2 in 3 weeks intervals.