Relationship between the Peripheral Lymphocyte Response to Mycophenolic Acid in vitro and the Level of ATP in Peripheral CD4+ Lymphocytes before and after Renal Transplantation.

OBJECTIVE: The lymphocyte immunosuppressant sensitivity test has been used to predict the pharmacodynamics of immunosuppressive drugs for the purpose of preventing acute rejection and infection after renal transplantation. On the other hand, measuring the ATP levels in peripheral CD4+ lymphocytes is also able to monitor the risks of rejection and infection in transplant recipients. In the present study, we examined the relationship between the mycophenolic acid pharmacodynamics and the ATP levels in peripheral lymphocytes before and after renal transplantation. METHODS: We examined both the pharmacological efficacy of mycophenolic acid and the lymphocyte ATP levels before and 2, 4 and 6 weeks after the operation in 20 renal transplant recipients. The drug's pharmacological efficacy was evaluated by the 50% inhibitory concentration of the drug against the in vitro proliferation of peripheral blood lymphocytes activated by T cell mitogen. The ATP levels in peripheral CD4+ lymphocytes were measured by the Immuknow assay kit. The relationships between the mycophenolic acid pharmacodynamics and ATP levels in peripheral lymphocytes were examined in these recipients. RESULTS: The immunosuppressive effects of mycophenolic acid against mitogen-activated lymphocyte proliferation were significantly and positively correlated with the lymphocyte ATP levels, but only at 6 weeks after transplantation. The relationship was not significant before or at 2 or 4 weeks after the operation. CONCLUSION: Our present data raised the possibility that evaluating the pharmacological efficacy of mycophenolic acid pre-transplantation and monitoring the ATP level 6 weeks after transplantation can predict the risk of rejection and/or infection in renal transplant recipients.

Successful unrelated BMT in a patient with Kostmann syndrome complicated by pre-transplant pulmonary 'bacterial' abscesses.

Kostmann syndrome, severe congenital neutropenia, is often associated with life-threatening bacterial infections. A 5-year-old girl with Kostmann syndrome developed pulmonary abscesses. She was refractory to granulocyte colony-stimulating factor and antibiotics. She underwent unrelated HLA-matched BMT. Myeloablative conditioning consisted of 12-Gy TBI with lung shielding, antithymocyte globulin, etoposide, and cyclophosphamide. After successful engraftment, the pulmonary abscesses resolved by day 75 post-transplant. Although the option of transplantation is not established in the setting of unrelated HLA-matched BMT in Kostmann syndrome, this case may provide useful information. Furthermore, pre-transplant pulmonary bacterial abscesses may not be a contraindication for BMT in some patients with Kostmann syndrome.

Evaluation of accumulated mucopolysaccharides in the brain of patients with mucopolysaccharidoses by (1)H-magnetic resonance spectroscopy before and after bone marrow transplantation.

In seven patients with mucopolysaccharidoses (1 Hurler, 1 Hurler-Scheie, 4 Hunter, 1 Sly), cranial (1)H-magnetic resonance spectroscopy was performed to evaluate the accumulation of mucopolysaccharides and biochemical changes in the CNS in vivo before and after bone marrow transplantation (BMT). In two of seven patients, (1)H-magnetic resonance spectroscopy was performed before and after BMT. Nuclear magnetic resonance spectra of dermatan sulfate and chondroitin sulfate-C and magnetic resonance spectroscopy of chondroitin sulfate-C and urine from patients with mucopolysaccharidoses showed resonance higher than the chemical shift of myoinositol in the brain (3.7 ppm). The resonance was considered to contain signals from mucopolysaccharide molecules. The resonance was measured as presumptive mucopolysaccharides (pMPS). In white matter lesions detected by magnetic resonance imaging, pMPS/creatine ratios and choline/creatine ratios were consistently higher than control ratios. In white matter without lesions, choline/creatine ratios were higher than control ratios. Patients with higher developmental quotient or intelligence quotient tended to show higher N:-acetylaspartate/creatine ratios and lower pMPS/creatine ratios in basal ganglia. After BMT, the pMPS/creatine ratio in white matter lesions of patient 3, with Hunter syndrome, was slightly decreased, but in none of the patients was the ratio ever below the control ratios, even 7 y after BMT. In white matter without lesions, the pMPS/creatine ratio in patient 3 was decreased to the control ratios after BMT, but although the choline/creatine ratios were gradually decreased, they remained higher than the control ratio, 2 y after BMT. These results suggest that evaluation of pMPS, choline, and N:-acetylaspartate by (1)H-magnetic resonance spectroscopy is an important technique that may provide useful biochemical information in vivo on the neurologic process and the efficacy of BMT in patients with mucopolysaccharidoses.

Mixed connective tissue disease following interstitial cystitis.

A 64-year-old woman complained of severe infrapubic pain and pollakisuria with nausea, vomiting and diarrhea, but with normal urinalysis since 1987. The clinical diagnosis of interstitial cystitis (IC) was made, and cystectomy was performed in 1996. The bladder taken was markedly shrunken with a capacity of 50 ml, and showed bleeding on the mucosal surface. Histological findings of the bladder showed ulcer formation in the mucous membrane, and marked infiltration of mononuclear cells, edema and fibrosis in the submucosal tissue. She had noticed exudative erythema, swelling and sclerosis on the bilateral fingers and dorsal aspects of the hands since 1993, and Raynaud's phenomenon and morning stiffness of the fingers from November, 1998. Laboratory data showed positive anti-nuclear antibody (titer: 1: 2,560) and anti-U1 RNP antibody (titer: 69.5 by ELISA). A diagnosis of mixed connective tissue disease following IC was made.

Bone marrow transplantation for the treatment of X-linked adrenoleukodystrophy.

The effects of bone marrow transplantation (BMT) in X-linked childhood adrenoleukodystrophy (ALD) are described in four Japanese patients. Two older patients, 10-year-old boys with IQ 60 and difficulty in school, had favourable results. IQ levels and MRI findings were generally maintained after BMT. One patient showed improvement of gait disturbance. They have both attended ordinary schools after BMT, although a learning disorder persists. On the other hand, two other younger patients with a rapid course and indeterminate IQ at BMT showed deterioration of neurological functions. Indication for BMT seems to be a maintained IQ level, preferably higher than 80, since it seems to be difficult to normalize IQ level after BMT. Younger patients have higher risk of developing a rapidly progressive form of the disease. Identification of presymptomatic boys, and serial and careful follow-up by neuropsychological and neuroradiological studies, are essential prerequisites to successful BMT in X-ALD.

Ataxia telangiectasia associated with B-cell lymphoma: the effect of a half-dose of the drugs administered according to the acute lymphoblastic leukemia standard risk protocol.

Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, and variable degrees of humoral and cellular immunodeficiency. Affected individuals are known to exhibit a high incidence of lymphoma and leukemia. Because of increased chemosensitivity, the treatment of A-T patients with malignancies requires extremely careful planning and caution with respect to the use of chemotherapy. The authors report on a 12-year-old boy with A-T who developed B-cell lymphoma. He received a half-dose of the drugs administered according to the acute lymphoblastic leukemia (ALL) protocol issued by our children's cancer study group (9104 Standard Risk Protocol, Tokai Pediatric Oncology Study Group). As a result, he continues to be in complete remission and free of treatment complications 32 months after the diagnosis of B-cell lymphoma.

[Clinical efficacy of post-TUR prophylactic chemotherapy for superficial bladder cancer--the result of co-operative prospective randomized trial].

We have performed a prospective randomized clinical trial of post-operative prophylactic therapy for superficial bladder cancer since October in 1991. The criteria were as follows; age < or = 80 y.o., Ta/T1, TCC G1/G2, without CIS lesion and resectable cancer by TUR. The therapeutic arm was divided into three as follows: arm A intracystic instillation with Epirubicin; arm B: oral administration with 5-FU; arm C: combination of arm A and arm B. The number of registered patients were 20 in arm A, 18 in arm B, and 18 in arm C. The patient characteristics in every group were not significantly different. The prophylactic efficacy of arm A was superior to that in the other two groups.

[Clinical investigation of prostatic cancer patients who underwent radical prostatectomy: analysis of patients in the Tokai Urological Cancer Registry].

Between 1989 and 1991, 815 cases of prostatic carcinoma were registered in the Tokai Urological Cancer Registry. We investigated the clinical features and prognosis of 69 patients who underwent radical prostatectomy. The median age and clinical stage, were 65.9 +/- 4.7 years and A in 7 patients, 66.3 +/- 5.8 years and B in 31, 68.2 +/- 2.7 years and C in 26, 63.4 +/- 13.5 years and N(+) in 5. Neoadjuvant therapy consisting of endocrine therapy and chemoendocrine therapy was administered to 28 and 14 patients, respectively. In comparison to the clinical stage, pathologically, 4 cases (9.5%) showed downstaging or overstaging, 15 (35.7%) understaging and 23 (54.8%) accurate staging in the neoadjuvant therapy group, and, respectively, 2 (7.4%), 12 (44.4%) and 13 (48.2%) in the non-neoadjuvant therapy group. There was a significant difference in the pretreatment prostatic antigen (PA) value between pT0 and pT3 (p < 0.05), between pT0 and pN(+) (p < 0.01) and between pT2 and pN(+) (p < 0.05). In addition, the pretreatment PA value in the recurrence group was higher than that in the non-recurrence group in both neoadjuvant and non-neoadjuvant groups, with a significant difference (p < 0.01) in the neoadjuvant group. Cancer recurrence was noticed in 2 patients given non-neoadjuvant therapy and 3 given neoadjuvant therapy. There was no significant difference in the non-recurrence rate with the pathological stage either with or without neoadjuvant therapy. However, the non-recurrence rate in the neoadjuvant therapy group was higher than that in the non-neoadjuvant therapy group.

Marinesco-Sjögren syndrome associated with acute myeloblastic leukemia.

Marinesco-Sjögren syndrome is a rare autosomal recessive disorder characterized by cerebellar atrophy, ataxia, cataracts, short stature and varying degrees of mental retardation. A high incidence of malignant disease associated with this syndrome has not so far been reported. We report the case of a 6-year-old girl affected with Marinesco-Sjögren syndrome, who developed acute myeloblastic leukemia (AML, M2), and whose karyotype was 46,XX,t(8;21),(q22;q22) in bone marrow blasts. This is the first report of Marinesco-Sjögren syndrome associated with malignant disorders.

[A study on predicting factors of the effect of intra-arterial infusion chemotherapy in patients with bladder cancers: the usefulness of in-vitro chemisensitivity test measuring intracellular ATP contents (ATP assay)].

We studied a relationship between in vitro sensitivity of the tumors to anti-cancerous drugs and histopathological effectiveness of an intra-arterial infusion chemotherapy in 15 patients with bladder cancers. The in vitro sensitivity test was performed by measuring intra-cellular ATP contents (ATP assay). The intra-arterial chemotherapy were performed by injecting methotrexate (MTX), adriamycin (ADM) and eisplatin (CDDP) from the internal iliac artery. When the intra-cellular ATP contents of the tumor cells treated with an anti-cancerous drug decreased to less than 50% of the untreated tumor cells, the tumor was evaluated as sensitive to the drug. The effectiveness of the chemotherapy were histopathologically evaluated by a pathologist according to the response criteria for bladder cancer treatment. When the histopathological responses of higher than grade 2 were observed in the tumor, the chemotherapy was evaluated as effective. In 8 of 9 tumors sensitive to ADM, chemotherapy were effective histopathologically and in all 6 tumors resistant to ADM, histopathological response of the chemotherapies were poor. The overall coincidence ratio between sensitivity to ADM and the histopathological effectiveness of the chemotherapy was 93%, showing statistically significant correlation. In 7 of 12 tumors sensitive to CDDP, the chemotherapies were effective and in 2 of 3 tumors resistant to CDDP, the chemotherapies were ineffective. Although the overall coincidence ratio between the sensitivities to CDDP and chemotherapeutic effectiveness was 60%, there was no significant correlation between them. In 7 of 8 tumors sensitive to both of ADM and CDDP, the chemotherapies were effective and in 6 of 7 tumors resistant to at least one of them, the chemotherapies were ineffective. (ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the synthesis of sesquiterpene lactones, 14. Syntheses of (-)-arbusclin D and (+)-4-EPI-arbusclin D: the stereochemical assignment of arbusclin D.

Efficient syntheses of (-)-arbusclin D and (+)-4-epi-arbusclin D are reported. By these syntheses the C-4 stereochemistry of arbusclin D and the absolute configuration of (-)-arbusclin D have been determined to be a s shown in structure 1. The biological activities, such as cytotoxic activity toward P-388 lymphocytic leukemia, plant growth regulating activity, and antimicrobial activity of compounds 1, 3, 7, 9, 12, and 14 were also studied.

Intra-arterial administration of methotrexate, adriamycin, and cisplatin as neoadjuvant chemotherapy for bladder cancer.

As neoadjuvant chemotherapy for advanced bladder cancer, the intra-arterial administration of methotrexate (MTX), Adriamycin (ADM), and cisplatin (CDDP; IA-MAC) was evaluated. A total of 48 patients with bladder cancer (greater than or equal to T2 or CIS) were selected and received 30.1 mg MTX, 34.5 mg ADM, and 89.1 mg CDDP as an average course. The mean tumor-regression rate after 2 or 3 weeks was 52.3%, and patients with grade 3 transitional-cell carcinoma showed the best results, achieving a 69.6% regression rate. In 30 cases (63%), downstaging was observed. Among the 46 patients who underwent subsequent surgical therapy, the bladder could be preserved in 26 cases by transurethral resection or segmental resection. According to the criteria of the Japanese Association of Cancer Therapy, a histological effect of GIII or better was obtained in 15 cases (29%). The histological effect correlated well with the tumor-regression rate. As compared with intravenous therapy with MTX, vinblastine, ADM, and CDDP (M-VAC), IA-MAC treatment was well tolerated due to its lower degree of bone marrow suppression, and it resulted in a longer disease-free interval and better survival. In addition, the period prior to surgical therapy was shortened in this study. These results suggest that IA-MAC chemotherapy can be useful as an arm of multidisciplinary treatment of advanced bladder tumors.

Studies on the synthesis of sesquiterpene lactones, 12. Synthesis of (+)-colartin, (+)-arbusculin A, and their C-4 epimers and their biological activities.

Colartin [9] and arbusculin A [11] have been synthesized from alpha-santonin [1] in 14.5% (11 steps) and 9.3% (13 steps) overall yields, respectively. Arbusculin A [11] and compounds 20, 21, and 22, which were derived from intermediate 2, showed significant cell growth inhibitory activity against murine lymphocytic leukemia (P-388) in vitro. Plant growth regulating activity of 11 and its synthetic intermediates 4, 5, 8, and 9 was also studied.

[Endoscopic and fluoroscopic pyeloureterotomy for ureteropelvic junction obstruction and ureteral stricture].

Endoscopic or fluoroscopic pyeloureterotomy was performed in a total of 32 patients (34 ureters) with ureteropelvic junction obstruction (UPJO) or ureteral stricture from March 1985. Cold incision was performed, using a flexible knife over a guidewire, endoscopically on 23 ureters and fluoroscopically on 11 ureters. The mean operation time was 98.9 +/- 48.3 minutes. Twenty-five (74%) of the 34 ureters showed relief of subjective symptoms, normalized urinalysis and radiographical improvement of hydronephrosis with a mean follow-up period of 11.7 +/- 10.0 months (range: 3-43). The clinical results by etiology were as follows: primary UPJO, 13/16 (81%); secondary UPJO, 4/4 (100%); ureteral stricture, 6/7 (85%); obliteration of ureteral implantation, 2/7 (29%). No major complication was noted with this endourological technique. This endourological technique might be clinically useful for the treatment of UPJO and ureteral strictures.

[An advanced gastric cancer with varied histopathologic features including a choriocarcinoma: report of a case].

A 77-year-old male, complaining of epigastralgia, was admitted to hospital. An upper GI series revealed a hemispheric filling defect at the greater curvature of the lower gastric body and two submucosal tumor-like lesions of the antrum. Closer inspection revealed a tumor measuring 60 x 42 mm, with an irregular ulcer, and two submucosal tumor-like lesions with bridging folds, measuring 42 x 28 mm and 20 x 14 mm, respectively. Histologically, the microscopic features in the ulcerated tumor showed a variety of tumor cells with clear PAS-positive cytoplasms and marked atypical nuclei forming glandular structures that predominated. Additionally, a clear cell carcinoma, a papillary adenocarcinoma, a signet-ring cell carcinoma, and a choriocarcinoma were partially seen. Finally, in the submucosal tumor-like lesions, diffuse small tumor cells with scanty PAS-positive cytoplasms without granular structures were seen.

[Carcinoma of the renal pelvis and ureter. An investigation of 384 registered cases in the Tokai Urological Cancer Registry].

Registration of renal pelvic and ureteral tumor was done from 1980 through 1986, in the Tokai Urological Tumor Registry. Among the 404 cases of the carcinoma, 384 cases (210 renal pelvis, 174 ureter) were subjected to the present study. A total of 319 cases (83.1%) showed a complete cure, while 20 cases (5.2%) were considered as partial cure, and 45 cases (11.7%) were classified to progressive disease group. Chemotherapy was performed on 151 patients including systemic administration to 141 patients (33.9%) and 11 patients received combined intravesical instillation therapy. Irradiation was performed on 49 patients (12.8%). Degree of histological and morphological differentiation of renal pelvis and ureter tumor were studied in 341 cases of transitional cell carcinoma (88.8%); G0, 0.3%, G1, 12.9%, G2, 49.3%, Gx, 5.2%. Stage of the tumor were T1, 33.6%; T2, 12.5%; T3, 14.6%; T4, 13.3%; Tis, 0.3%; Tx, 24.7%. Five-year relative survival for carcinoma of the renal pelvis was 46.6%, and for the ureter it was 53.1%. Five-year survival according to histological differentiation of transitional cell carcinoma and according to the stage of the tumor were as follows; G1, 91.6%; G2, 58.5%; G3, 27.2%; Ta, 84.6%; T1. 74.2%; T2, 48.5%; T3, 24.1%, T4, 7.3%. The rate of survival was correlated with histological differentiation of the tumor cells. The survival was poor in cases who had the components of squamous cell carcinoma and/or adenocarcinoma. Overall survived case were 177, 122 patients died of cancer, 20 patients died of other causes than cancer, and 1 patient died from immediate surgical effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Metastatic renal tumor from the lung with regional lymph node involvement: a case report.

We report a case of metastatic renal tumor from lung cancer. A 53-year-old man presented with gross hematuria 2 years after treatment of the primary lesion. Investigations suggested a metastatic tumor in the right kidney from the lung which was accompanied with regional lymph node metastasis. Surgical treatment was not performed because of his poor condition and the lymph node involvement. Therefore, the combination chemotherapy of 5-fluorouracil, vincristine and doxorubicin, OK-432 was applied. Although this conservative management was effective, he died of progression 6 months later and an autopsy confirmed the diagnosis of metastatic renal tumor.