Reversible Acceleration of Disease Progression Following Cyclosporin A Treatment in a Patient With Myelodysplastic Syndrome

A 38-year-old Japanese man with myelodysplastic syndrome (MDS), whose bone marrow smears demonstrated hypercellularity, was treated with oral cyclosporin A (CsA) therapy. During the course of this therapy, the numbers of peripheral blood and bone marrow blasts increased and the level of serum lactate dehydrogenase increased. After discontinuation of CsA treatment, all of these levels rapidly decreased. We consider that CsA might accelerate disease progression in certain MDS cases.     

Effect of sodium nitroprusside and 8-bromo cyclic GMP on nerve-mediated and acetylcholine-evoked secretory responses in the rat pancreas

The effects of sodium nitroprusside (SNP) and 8-bromo-guanosine 3'5' cyclic monophosphate (8-Br-cyclic GMP) on nerve-mediated and acetylcholine (ACh)-evoked amylase secretion, tritiated choline ([3H]-choline) release and on intracellular free calcium concentration ([Ca2+]i) in the isolated rat pancreas were investigated. Electrical field stimulation (EFS; 10 Hz) and ACh (1 x 10(-5) M) caused large increases in amylase output from pancreatic segments. The response to ACh was blocked by atropine (1 x 10(-5) M) whereas the EFS-evoked response was markedly reduced but not abolished. In contrast, pretreatment with tetrodotoxin (1 x 10(-6) M) abolished the secretory effect of EFS. Either SNP (1 x 10(-3) M) or 8-Br-cyclic GMP (1 x 10(-4) M) inhibited amylase secretion compared to basal. Combining either SNP or 8-Br-cyclic GMP with EFS resulted in a marked decrease in amylase output compared to EFS alone. In contrast, either SNP or 8-Br-cyclic GMP had no significant effect on the amylase response to ACh. When extracellular Ca2+ concentration ([Ca2+]o) was elevated from 2.56 mM to 5.12 mM, SNP failed to inhibit the response to EFS. EFS stimulated the release of 3H from pancreatic segments preloaded with [3H]-choline. Either SNP or 8-Br-cyclic GMP had no effect on basal 3H release but significantly reduced the EFS-evoked response. In fura-2 loaded acinar cells, SNP elicited a small decrease in [Ca2+]i compared to basal and had no effect on the ACh-induced [Ca2+]i peak response. Nitric oxide may modulate the release of endogenous neural ACh in response to EFS in the rat pancreas.     

Weekly continuous infusion of 5-fluorouracil with oral leucovorin in metastatic breast cancer patients with primary resistance to doxorubicin

Doxorubicin-resistant metastatic breast cancer (MBC) is a very poor prognosis scenario, where only taxanes have shown activity, often at the expense of severe toxicity that compromises palliation. This study was undertaken to test the antitumor activity and tolerability of infusional 5-fluorouracil (5-FU) modulated with low-dose oral leucovorin (LV), in heavily pretreated patients with stringent criteria of primary resistance to doxorubicin, visceral involvement, and suboptimal performance status. Twenty-six patients with measurable MBC and primary resistance to anthracyclines received a weekly outpatient 48-hour infusion of high-dose 5-FU with low dose oral leucovorin. All patients were assessable for response and toxicity. Eight partial responses were seen (30% response rate) in soft tissue and visceral sites, with a median response duration of eight months (5 + to 12). 98% of the cycles were minimally toxic or non-toxic. Toxicities included mucositis, diarrhea, and plantar-palmar-syndrome. Our results suggest that this schedule of LV-modulated infusional 5-FU can produce a substantial number of long-lasting responses and meaningful palliation to this very poor prognosis population.     

Phase I and pharmacokinetic study of gemcitabine administered at fixed-dose rate, combined with docetaxel/melphalan/carboplatin, with autologous hematopoietic progenitor-cell support, in patients with advanced refractory tumors.

The purpose of this trial was to define the maximum tolerated duration (MTD), dose-limiting toxicity (DLT), regimen-related toxicities (RRT), and pharmacokinetics of gemcitabine infused at a fixed dose rate (FDR) of 10 mg/m2/min, combined with docetaxel/melphalan/carboplatin, using autologous stem cell transplantation (ASCT). The duration of gemcitabine infusion was incrementally escalated as a single treatment on day -6 or as 4 daily infusions on days -5 to -2. Gemcitabine was followed by docetaxel (300 or 350 mg/m2) on day -5, and then melphalan (50 mg/m2/day) and carboplatin (333 mg/m2/day) on days -4 to -2. Fifty-two patients with refractory tumors were accrued with a median age of 40 (range: 6-66), a median of 3 (1-6) prior chemotherapy regimens, and 3 (1-7) organs involved. The gemcitabine MTD was defined at 20 hours (total dose 12,000 mg/m2) on both schedules. The DLT was enteritis. Three patients died from aspiration, catheter-related sepsis, and enteritis, respectively. The tumor response rate was 91%, with 50% complete responses. At current 2-year median follow-up, the event-free and overall survival (EFS, OS) rates are 54% (median 26 months) and 79% (median not reached), respectively. Gemcitabine area under the curve (AUC), but not clearance, increased linearly with infusion duration, and correlated with grade 3 RRT. Docetaxel showed a linear increase of its AUC and similar clearance compared with prior reports at lower doses. In conclusion, ASCT-supported infusions of gemcitabine at FDR could be prolonged up to 20 hours. The resulting gemcitabine/docetaxel/melphalan/carboplatin combination was highly active in refractory cancers and should be further tested in disease-specific trials.     

Stem-cell transplantation for the treatment of advanced solid tumors

Over the past two decades, high-dose chemotherapy (HDC) with autologous stem-cell transplantation (ASCT) has been explored for a variety of solid tumors in adults, particularly breast cancer, ovarian cancer and non-seminomatous germ-cell tumors. The results of prospective phase II studies seemed superior in many cases to the outcome expected with standard-dose chemotherapy (SDC). The value of HDC for adult solid tumors remains, in most instances, a controversial issue, currently under the scrutiny of randomized phase III trial evaluation. ASCT pursuing an immune graft-versus-tumor effect has been evaluated in recent years for patients with advanced and refractory solid malignancies. This article reviews the results of the main phase II and III studies of HDC with ASCT, as well as the preliminary experience using allogeneic transplantation for solid tumors.     

Epitope selection in major histocompatibility complex class I-mediated pathway is affected by the intracellular localization of an antigen

We analyzed the mode of antigen presentation of an endogenous antigen localized in the cytoplasm or in the mitochondria. Pseudomonas aeruginosa PAO leucine-, isoleucine-, valine-binding protein (LIVAT-BP) encoded by the braC gene was used as a model antigen. Using mouse BALB/3T3 cells, we established two LIVAT-BP transfectants by transfection of a plasmid harboring the intact braC or braC gene fused with the mitochondrial transport signal derived from the yeast COXIV gene. One of the resulting transfectants, BC-15, expressed LIVAT-BP in the cytoplasm, while YZ-710 cells expressed LIVAT-BP in the mitochondria. The splenic effector cells derived from BALB/c mice primed with BC-15 cells exhibited cytotoxic T lymphocyte (CTL) activity against BC-15 cells, but not against YZ-710 cells, whereas splenic effector cells primed with YZ-710 cells exhibited CTL activity against YZ-710 cells, but not against BC-15 cells. Neither group of splenic effector cells showed CTL activity against parental BALB/3T3 cells. These CTL belonged to the CD8⁺ αβ T cell subset. Furthermore, we observed that the CTL activity against BC-15 cells or YZ-710 cells was blocked with anti-H2-K^d mAb, but not with anti-H2-D^d or H2-L^d mAb. The CTL against BC-15 or YZ-710 cells could kill parental BALB/3T3 cells in the presence of peptides produced by alkali lysis of the LIVAT-BP. suggesting that these CTL indeed recognized the peptide(s) derived from LIVAT-BP. We determined that the epitope for the CTL against BC-15 cells was QYGEGIATEV, corresponding to residues 162–171, and that the epitope recognized by the CTL against YZ-710 cells was GYKLIFRTI, corresponding to residues 123–131 of LIVAT-BP, respectively. Thus, we show here that epitope selection for MHC class I expression is affected by the intracellular localization of the antigenic protein.     

A case of systemic sclerosis complicated by Takayasu's arteritis]

We report a case of systemic sclerosis complicated by Takayasu's arteritis. A 68-year-old woman had been treated for hypertension since 1984. She also had Raynaud's phenomenon and noticed vertigo and dizziness. In January 1992, she was diagnosed with back bruit. In April 1994, she was complicated by vertigo and diagnosed with asymmetrical blood pressure. In October 1998, she consulted our hospital because of neck bruit, abdominal bruit, back bruit and stenosis of descending aorta bifurcation on chest computed tomography. Her blood pressure was asymmetrical, being recorded as 190/101 on the right and 140/90 on the left. Scleroderma was observed from the finger to forehand, precordia, and face. Telangiectasia was observed on the precordia. Laboratory studies revealed the presence of anti-nuclear antibody (x 1280, discrete speckled.), anti-centromere antibody but anti-topoisomerasel antibody was negative. Skin biopsy from the left forehand detected proliferation of collgen fibers and perivascular inflammatory cell infiltration. A diagnosis of systemic sclerosis was made according to the American Rheumatism Association criteria. We suspected complication by Takayasu's arteritis because of asymmetrical blood pressure and bruit. Chest-abdominal angiography detected stenosis of the right brachiocephalic trunk, celiac artery, and left renal artery. We diagnosed Takayasu's arteritis. This is the second case report of a patient with systemic sclerosis complicated by Takayasu's arteritis.