Significance of uterine corpus tumor invasion in early-stage cervical cancer.

OBJECTIVE: To examine characteristics and survival outcomes of women with surgically-treated cervical cancer exhibiting uterine corpus tumor invasion. METHODS: We utilized The Surveillance, Epidemiology, and End Results Program to identify cervical cancer patients who underwent hysterectomy between 1973 and 2003. Logistic regression models were used to identify risk factors for uterine corpus tumor invasion on multivariable analysis. Association of uterine corpus tumor invasion and cause-specific survival (CSS) from cervical cancer was examined with Cox proportional hazard regression models on multivariable analysis. RESULTS: We identified 837 (4.9%) cases of uterine corpus invasion and 16,237 (95.1%) cases of non-invasion. Median follow-up time was 14.0 years. There were 1642 deaths due to cervical cancer. Uterine corpus invasion was independently associated with older age, non-squamous histology, high-grade tumors, large tumor size, and nodal metastasis on multivariable analysis (all, P < 0.001). On univariable analysis, uterine corpus tumor invasion was significantly associated with decreased CSS compared to the non-invasion (5-year rates, 79.0% versus 94.5%, P < 0.001). After controlling for other significant prognostic factors, uterine corpus tumor invasion remained an independent prognostic factor for decreased CSS (adjusted-hazard ratio 1.45, 95% confidence interval 1.21-1.74). Among stage T1b cases (n = 6730), uterine corpus tumor invasion remained an independent prognostic factor for decreased CSS (adjusted-hazard ratio 1.95, 95%CI 1.47-2.60). Uterine corpus tumor invasion was significantly associated with decreased CSS in stage T1b1 disease (74.5% versus 90.7%, P < 0.001) and in stage T1b2 disease (67.0% versus 79.5%, P = 0.01). CONCLUSION: Uterine corpus tumor invasion is an independent prognostic factor for decreased survival of women with early-stage cervical cancer.

Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma.

BACKGROUND: To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma. PATIENTS AND METHODS: A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes. RESULTS: Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001). CONCLUSION: Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

Impact of multimodal therapy on the survival of patients with newly diagnosed uterine carcinosarcoma.

PURPOSE: To investigate treatment outcomes of uterine carcinosarcoma (CS) patients who underwent complete surgical resection of all visible disease and platinum-based adjuvant chemotherapy (multimodal therapy). MATERIALS AND METHODS: The authors reviewed 127 uterine CS patients treated at this institution from 1990 to 2010. They operated 123 patients in clinical Stages 1-3, 97 of which underwent complete resection and systemic lymphadenectomy. RESULTS: A total of 97 patients (FIGO 2008: Stage 1 in 50 patients, Stage 2 in six, Stage 3 in 37, and Stage 4 in four) underwent surgical staging, 74 of which were administered five cycles (median) of platinum-based adjuvant chemotherapy. The median overall survival (OS) associated with multimodal therapy 50.6 months compared with 34.9 months incomplete multimodal therapy. After multimodal treatment, 32.9% (32/97) patients showed recurrence (24/32 hematogenous). CONCLUSION: Multimodal therapy increased survival among uterine CS patients, but the recurrence rate remained high. Further consideration of treatment options for uterine CS is required.

[Rib-originated fibrous dysplasia: report of a case].

The incidence of fibrous dysplasia (FD) is not frequent in the case of benign bone tumors of the chest wall, and differential diagnosis between FD and the malignancy on the basis of imaging findings is difficult. We report a case of a painful FD lesion (size, 9×8 cm) that originated from the 5th rib of a 52-year-old man and was surgically resected. His symptoms improved after the operation. Painful and large FD lesions should be resected because of a difficulty in differential diagnosis from malignant tumors.

Locoregional mitomycin C injection for esophageal stricture after endoscopic submucosal dissection.

This prospective study aimed to evaluate the feasibility and safety of locoregional mitomycin C (MMC) injection to treat refractory esophageal strictures after endoscopic submucosal dissection (ESD) for superficial esophageal carcinoma. Patients with dysphagia and strictures that were refractory to repeated endoscopic balloon dilation (EBD) were eligible. After EBD, MMC was injected into the dilated site. Between June 2009 and August 2010, five patients were recruited. The treatment was performed once in two patients and twice in three patients with recurrent dysphagia or restenosis. In all patients, passing a standard endoscope through the site was easy and the dysphagia grade improved (grade 3→1 in 3 patients, grade 4→2 in 2 patients). No serious complications were noted. During the observation period of 4.8 months, neither recurrent dysphagia nor re-stricture appeared in any of the patients. The combination of locoregional MMC injections and EBD is feasible and safe for the treatment of esophageal strictures after ESD.Recently, endoscopic submucosal dissection (ESD) has been developed and accepted as a new endoscopic treatment for gastrointestinal tumors. ESD is a promising treatment for superficial esophageal carcinoma (SEC), and it has a reliable en bloc resection rate. However, the application of ESD for widespread lesions is challenging because of the high risk of the development of severe strictures, which lead to a low quality of life after ESD. Although endoscopic balloon dilation (EBD) is effective for benign strictures, it needs to be performed frequently until the dysphagia disappears 1. Mitomycin C (MMC), which is a chemotherapeutic agent derived from some Streptomyces species 2, reduces scar formation when topically applied to a surgical lesion. MMC has been applied to treat strictures in a variety of anatomical locations, including a variety of organs 3. The aim of this study was to prospectively evaluate both the feasibility and the safety of locoregional MMC injection therapy in patients with refractory esophageal strictures after ESD for SEC.

Narrow-band imaging in the diagnosis of colorectal mucosal lesions: a pilot study.

BACKGROUND AND STUDY AIMS: A newly developed narrow-band imaging (NBI) technique, in which modified optical filters were used in the light source of a video endoscope system, was applied during colonoscopy in a clinical setting. This pilot study evaluated the clinical feasibility of the NBI system for evaluating colorectal lesions. PATIENTS AND METHODS: A total of 43 colorectal lesions in 34 patients were included in the study. The quality of visualization of colorectal lesions and the accuracy of differentiation between neoplastic and non-neoplastic lesions using the NBI system were evaluated in comparison with results from conventional colonoscopy and with chromoendoscopy. RESULTS: For pit pattern delineation, NBI was superior to conventional endoscopy (P < 0.001), but inferior to chromoendoscopy (P < 0.05). NBI achieved better visualization of the mucosal vascular network and of the hue of lesions than conventional endoscopy (P < 0.05). However there was no significant difference between NBI and chromoendoscopy in differentiating neoplastic from non-neoplastic lesions (both techniques had a sensitivity of 100 % and a specificity 75 %). This was better than the results of conventional colonoscopy (sensitivity 83 %, specificity 44 %; P < 0.05 for specificity). CONCLUSIONS: These results suggest that in the examination of colonic lesions the NBI system provides imaging features additional to those of both conventional endoscopy and chromoendoscopy. For distinguishing neoplasms from non-neoplastic lesions, NBI was equivalent to chromoendoscopy.

In-situ visualization and quantification of mineralization of cultured osteogenetic cells.

An osteoblastic cell line (HOS cells) produces a prominent osteoid matrix with mineralization. Fibroblasts, on the other hand, do not exhibit this mineralization. To evaluate the degree of mineralization, we added calcein to the culture medium and then observed the culture wells by using an image analyzer. The calcein uptake into the cell/matrix layer was detected in the HOS cells but not in the fibroblasts. The calcein uptake was also quantified in situ by using an image analyzer, which revealed high levels in the HOS cells, which correlated well with the calcium content of the mineralized matrix. Rat marrow cells were also cultured in media containing calcein, fetal bovine serum, beta-glycerophosphate, L-ascorbic acid 2-phosphate, and with or without dexamethasone. With the dexamethasone, the cells exhibited osteogenic differentiation that resulted in mineralized matrix formation after about 10 days. The matrix formation coincided with the appearance of calcein uptake into the cell/matrix layer, with the amount of calcein uptake increasing with time. By contrast, the culture without the dexamethasone did not exhibit matrix formation and the calcein uptake was negligible. In the case of both HOS cell and rat marrow cell cultures in vitro, calcein did not affect expressions of their alkaline phosphatase activity or osteocalcin production. Furthermore, histologic observation revealed that rat marrow cells subcultured with calcein could show osteogenic ability after in vivo implantation. These results suggest that the current method of detecting calcein uptake in a culture allows the monitoring of the osteogenic capacity of cultured cells, as well as the measurement of the amount of mineralization produced by the osteogenic cells. Given that osteogenic cultured cells/mineralized matrices are used in bone reconstruction surgery, the in situ monitoring method is invaluable in that it allows us to evaluate the osteogenic capacity of in vitro constructs.

Geldanamycin, an inhibitor of Hsp90, sensitizes human tumour cells to radiation.

PURPOSE: The effects of the heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) were examined on the radiosensitivity and signal transduction pathways in human tumour cell lines. MATERIALS AND METHODS: Two human cell lines, SQ-5 and DLD-1, derived from lung carcinoma and colon adenocarcinoma, respectively, were incubated for 16 h at 37 degrees C in medium containing 0.2 microM GA. The cells were then irradiated with X-rays and incubated with GA for a further 8 h. Radiation sensitivity was determined by clonogenic assays and protein levels were examined by Western blotting. RESULTS: GA radiosensitized both cell lines, but potentiated X-ray sensitivity more in SQ-5 than in DLD-1 cells. It was found that GA depleted EGFR and ErbB-2 in DLD-1 cells and depleted only ErbB-2 in SQ-5 cells. GA also reduced the expression of Akt and phosphorylated Akt (pAkt) expression in SQ-5 cells. In addition, the ratio (%) of apoptotic cells and poly [ADP-ribose] polymerase cleavage increased in SQ-5 but not in DLD-1 cells after exposure to GA and X-ray irradiation. The findings suggest that GA enhances the radiation sensitivity of human tumour cells by inhibiting the EGFR signal transduction system and the Akt signalling pathway. CONCLUSION: Targeting Hsp90 with GA provides a promising experimental strategy for radiosensitization of carcinoma.

A morphologic study of Carpentier-Edwards pericardial xenografts in the mitral position exhibiting primary tissue failure in adults in comparison with Ionescu-Shiley pericardial xenografts.

OBJECTIVE: We sought to investigate the durability and mechanism of the Carpentier-Edwards pericardial xenograft in the mitral position in comparison with that of the Ionescu-Shiley pericardial xenograft. METHODS: A total of 284 patients who received the Ionescu-Shiley pericardial xenograft in the mitral position between 1980 and 1984 and 84 patients who received the Carpentier-Edwards pericardial xenograft in the mitral position between 1984 and 1999 were included in the study. The freedom from reoperation rates for both graft types were determined. For morphologic study, the pathologic findings of 23 valves of 123 explanted Ionescu-Shiley pericardial xenografts with structural valve deterioration, nonstructural valve deterioration, or both were determined and compared with those of 20 explanted Carpentier-Edwards pericardial xenografts with structural valve deterioration, nonstructural valve deterioration, or both. Each pathologic finding was graded and assigned a score. Both types were matched for age at reoperation (50-75 years) and duration of valve function (8-11 years). RESULTS: Freedom from reoperation caused by structural valve deterioration, nonstructural valve deterioration, or both was significantly better for Carpentier-Edwards pericardial xenografts than for Ionescu-Shiley pericardial xenografts at 8 years after the operation (Carpentier-Edwards pericardial xenografts: 91.3% vs Ionescu-Shiley pericardial xenografts: 71.9%, P =.0061), but it was similar for both types at 12 years (Carpentier-Edwards pericardial xenografts: 43.6% vs Ionescu-Shiley pericardial xenografts: 43.6%, P =.2865). No severe leaflet tears were seen among Carpentier-Edwards pericardial xenografts. The mean area percentage of tissue overgrowth was 15.3% in Carpentier-Edwards pericardial xenografts and 3.4% in Ionescu-Shiley pericardial xenografts (P =.0001). The mean calcification area percentage was 13.6% in Carpentier-Edwards pericardial xenografts and 31.5% in Ionescu-Shiley pericardial xenografts (P =.0001). CONCLUSIONS: Tissue overgrowth on the atrial surface, ventricular surface, or both was the cause of structural valve deterioration, nonstructural valve deterioration, or both of Carpentier-Edwards pericardial xenografts in adults. This was different from Ionescu-Shiley pericardial xenograft failure, which resulted from severe calcification and leaflet tears. Organized thrombi on cusps, in addition to valve design, may have contributed to such tissue overgrowth on Carpentier-Edwards pericardial xenografts.

Identification of sequence polymorphisms in two sulfation-related genes, PAPSS2 and SLC26A2, and an association analysis with knee osteoarthritis.

Osteoarthritis (OA) is one of the most common musculoskeletal disorders and is characterized by degeneration of articular cartilage. Sulfation of extracellular matrix proteins in articular cartilage is an important step in maintaining normal cartilage metabolism. Two sulfation-related genes have been reported as the causal genes of severe chondrodysplasias: mutations in PAPSS2 (3'-phosphoadenosine 5'-phosphosulfate synthase 2) cause spondylo-epimetaphyseal dysplasia (SEMD), and mutations in SLC26A2 (solute carrier family 26, member 2) cause diastrophic dysplasia. Given their critical roles in cartilage metabolism and the severe phenotypes that result from mutations in these genes, we examined PAPSS2 and SLC26A2 as candidate susceptibility loci for OA. We identified sequence polymorphisms in the coding and core promoter regions of these genes and analyzed their potential association with knee OA within the Japanese population. Ten sequence polymorphisms were detected in PAPSS2 and five in SLC26A2. An association analysis showed suggestive association of one minor polymorphism in the promoter region of SLC26A2. This 4-bp adenine deletion allele, del4A, was over-represented in knee OA (P = 0.043, odds ratio = 3.43) and is thought to confer a minor susceptibility to knee OA within the Japanese population. Haplotype analysis showed no evidence of association with the two genes, however, excluding them as major susceptibility loci for knee OA.

Prognostic significance of carcinoembryonic antigen levels in peritoneal washes in patients with gastric cancer.

BACKGROUND: Peritoneal metastasis is the most frequent cause of death in patients with gastric cancer. Detection of free cancer cells in the peritoneal cavity at the time of surgery, therefore, is considered to be of great value in predicting the peritoneal recurrence and accordingly in the prognosis in patients with gastric cancer. This study examined the clinical significance of intraoperative determination of carcinoembryonic antigen (CEA) levels in peritoneal washes (pCEA) in patients with gastric cancer. METHODS: CEA levels in peritoneal washes were correlated retrospectively with several clinicopathologic factors including clinical outcome in 56 patients with resectable gastric cancer. RESULTS: Among several clinicopathologic factors, the depth of tumor invasion significantly and independently correlated with pCEA levels as revealed by multivariate stepwise logistic regression analysis. A significant difference in overall survival rates was observed between pCEA-positive and pCEA-negative groups: 5-year survival rates were 95.7% in pCEA-negative and 20% in pCEA-positive patients (P <0.0001). Multivariate analysis indicated that pCEA level is a statistically significant independent prognostic factor for the survival of patients with gastric cancer, and is an important factor for predicting peritoneal recurrence. CONCLUSIONS: pCEA could be a potential predictor of a poor prognosis as well as peritoneal recurrence in patients with gastric cancer. We believe that this information could contribute to determining the optimal intraoperative and postoperative therapeutic plan including adjuvant chemotherapy of gastric cancer.

mRNA expression of type I and type II receptors for activin, transforming growth factor-beta, and bone morphogenetic protein in the murine erythroleukemic cell line, F5-5.fl.

OBJECTIVE: Intracellular signaling of activin and transforming growth factor-beta (TGF-beta) is thought to be mediated by the same molecules (Smad2/3 and Smad4). Although differentiation of murine erythroleukemia F5-5.fl cells is induced by activin, it is not induced by TGF-beta, suggesting that at some point TGF-beta signaling is defective. The aim of this study was to investigate the unresponsiveness of F5-5.fl cells to TGF-beta. DESIGN: mRNA expression of ligands, receptors, and signal mediators for the TGF-beta family was examined in F5-5.fl cells using RT-PCR. RESULTS: Activin induced erythrodifferentiation of F5-5.fl cells in a dose-dependent manner. Neither TGF-beta1 nor bone morphogenetic protein (BMP)-4 affected the differentiation of F5-5.fl cells in the presence or absence of activin. Although mRNAs of TGF-betas (TGF-beta1, TGF-beta2 and TGF-beta3) were detected, those of inhibin/activin (alpha-, betaA- and betaB-subunits) and BMPs (BMP-2, BMP-4 and BMP-7) could not be detected in the cells, suggesting that neither activins nor BMPs are produced in F5-5.fl cells. The expression of both type I (ALK-4/ActRIB) and type II (ActRII) receptors for activin was detected in F5-5.fl cells. In contrast, while the expression of type I receptor for TGF-beta (ALK-5/TbetaRI) was detected, that of type II receptor (TbetaRII) was not. The mRNA of all Smads examined was detected in F5-5.fl cells. CONCLUSIONS: A defect in the type II receptor might cause unresponsiveness to TGF-beta in F5-5.fl cells. An erythrodifferentiation assay using F5-5.fl cells would be useful for measuring net activin activity because it would not be necessary to consider endogenous activins and BMPs.

Synthesis and biological activities of 2'-deoxy-2'-fluoro-4'-thioarabinofuranosylpyrimidine and -purine nucleosides.

As part of our ongoing investigation of the synthesis of biologically interesting 2'-modified-4'-thionucleosides, we synthesized 2'-deoxy-2'-fluoro-4'-thioarabinofuranosylpyrimidine and -purine nucleosides, and evaluated their antiviral and antitumor activities. In the pyrimidine series, beta-anomers of 5-ethyluracil, 5-iodouracil, 5-chloroethyluracil, and 5-iodocytosine derivatives showed potent and selective anti-HSV-1 and HSV-2 activities in vitro. In the purine series, guanine and 2,6-diaminopurine derivatives showed prominent antiviral activities with slight cytotoxicity. On the other hand, the 5-fluorocytosine derivative (5F-4'-thioFAC) showed potent antitumor activity against both leukemia and solid tumor. Its antitumor spectrum against 14 human solid tumor and one leukemic cell lines was compared with that of 4'-thioFAC. The results showed that 5F-4'-thioFAC had an antitumor spectrum similar to that of 4'-thioFAC. However, 5F-4'-thioFAC was about 10 times less active than 4'-thioFAC.

Constitutional t(3;11)(p21;q23) in a family, including one member with lymphoma: establishment of novel cell lines with this translocation.

We describe a family with an inherited constitutional chromosome translocation (3;11) (p21;q23). Of three proven translocation carriers, one had duodenal malignant lymphoma (B-cell diffuse lymphoma, medium-sized cell type). The t(3;11)(p21;q23) was detected not only in hematopoietic cells including the patient's lymphoma cells, non-pathological bone marrow, and phytohemagglutinin-stimulated peripheral blood, but also in fibroblasts of the skin. We have successfully established an Epstein-Barr virus-transformed B-cell line and a Herpesvirus saimiri-transformed T-cell line from the patient, and found that both cell lines also carried this translocation. The patient's asymptomatic mother and sister had the same chromosomal abnormality. Chromosomal abnormalities of the 11q23 band occur frequently in various hematopoietic malignant disorders, and 3q21 has been linked to the pathogenesis of several solid tumors including carcinomas of the kidney, lung, and breast. Although 11q23 is known to recombine with many different chromosomal segments, t(3;11)(p21;q23) has not been reported to our knowledge. Further assessment is warranted to clarify if this constitutional translocation predisposes to certain malignancies. Our cell lines carrying the novel chromosome translocation would be useful for the molecular analysis of the rearranged genes involving both 3p21 and 11q23.

Mutations of the E2F4 gene in hematological malignancies having microsatellite instability.

Mutations of coding repeats within the E2F4, TGF-betaRII, BAX, IGFIIR, and hMSH3 are critical targets of microsatellite instability (MSI) in many kinds of cancers. We analyzed 9 childhood acute lymphoblastic leukemia (ALL) samples, 5 acute myelocytic leukemia (AML) samples, and 10 adult T-cell leukemia (ATL) samples having MSI to determine whether they had mutations of the E2F4, TGF-betaRII, BAX, IGFIIR, and hMSH3 genes. Frameshift mutations were found at trinucleotide repeats within a coding exon of the E2F4 gene in 2 of 10 (20%) ATL samples and 1 of 9 (11%) childhood ALL samples. No mutations were found in the TGF-betaRII, BAX, IGFIIR, and hMSH3 genes. E2F4 is a transcription factor that influences the cell-cycle progression. These results suggest that mutations of the E2F4 gene, presumably caused by an abnormality of one of the DNA repair genes, may play an important role in development of ATL and childhood ALL. (Blood. 2000;95:1509-1510)

Acridone derivatives are selective inhibitors of HIV-1 replication in chronically infected cells.

In our extensive screening of anti-HIV-1 agents in chronically infected cell lines, we have found acridone derivatives to be selective inhibitors of HIV-1 replication. Among the acridone derivatives, 1-hydroxy-10-methyl-9,10-dihydroacrid-9-one (RD6-5071) suppressed tumor necrosis factor (TNF)-alpha-induced HIV-1 expression in the latently infected cell line OM-10.1, U1, and ACH-2. Its 50% effective concentration for HIV-1 p24 antigen production was 2.0 microg/ml in OM-10.1 cells, while its 50% cytotoxic concentration was 18 microg/ml. The compound also inhibited phorbol 12-myristate 13-acetate (PMA)-induced HIV-1 expression in these cell lines. Furthermore, RD6-5071 was inhibitory to HIV-1 replication in acutely infected U937 and peripheral blood mononuclear cells. The compound was found to suppress TNF-alpha-induced HIV-1 long terminal repeat-driven gene expression. An inhibition assay for protein kinase C (PKC) revealed that RD6-5071 could reduce the enzyme activity. Furthermore, the compound was a moderate inhibitor of PMA-induced nuclear factor kappaB (NF-kappaB) activation, as determined by a gel mobility shift analysis. These results suggest that the acridone derivatives suppress HIV-1 replication at the transcriptional level primarily through a mechanism of PKC inhibition.

Comparison of 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosine with gemcitabine in its antitumor activity.

The antitumor activity of a novel nucleoside, 1-(2-deoxy-2-fluoro-4-thio-beta-D arabinofuranosyl)cytosine (4'-thio-FAC) was compared with that of 2'-deoxy-2',2'-difluorocytidine (gemcitabine). 4'-Thio-FAC showed potent antitumor effects against various solid cancer cell lines in vitro. Also, gemcitabine showed remarkable in vitro antitumor effects, even more potent than 4'-thio-FAC. However, 4'-thio-FAC inhibited tumor growth more strongly than gemcitabine did at the same dose against human cancer cells implanted s.c. in nude mice. In addition, 4'-thio-FAC suppressed the tumor growth by oral administration. The toxicity of 4'-thio-FAC was weaker than that of gemcitabine in nude mice in both consecutive and intermittent administration. Accordingly, clinical usefulness of 4'-thio-FAC is expected.

[A case of non-Hodgkin's lymphoma presenting with acute renal failure diagnosed by renal biopsy].

We report a case of non-Hodgkin's lymphoma (NHL) presenting with acute renal failure. A-56-year-old male was admitted to our hospital on October, 1997 with fever and renal dysfunction. Physical examination showed no abnormality except for hepatomegaly. Body surface lymphadenopathy was not observed. Computed tomography (CT) of the abdomen showed markedly enlarged kidneys bilaterally and a mass of soft tissue density, which was considered as a swelling lymph node, around the aortic artery. The renal biopsy revealed parenchymal involvement of the NHL cells without normal tubulo-interstitial structure, but the glomeruli were almost intact. Our case rapidly fell into oliguria and acute renal failure, hence needed hemodialysis. After chemotherapy was performed, his renal function gradually improved and the kidney became smaller on subsequent CT. Unfortunately, the patient happened to suffer from methicillin-resistant staphylococcus aureus (MRSA) infection in a neutropenic state and died. Necropsy revealed recovery of the renal interstitium without residual NHL cells. Renal lymphoma without any other organ or nodal involvement is a rare type of NHL, which considered primary renal lymphoma (PRL). However, we believe this case to have been a result of lymphomatous infiltration of the kidneys in disseminated lymphoma.

The effect of flow on the neutrophil-mediated Ca2+ responses in human vascular endothelial cells stimulated by endotoxin.

Leukocyte-vascular endothelial cell (EC) interactions which promote inflammatory and immune reactions involve bidirectional signaling between two cell types. We investigated the effects of flow on neutrophil-mediated changes in endothelial intracellular Ca2+ levels ([Ca2+]i). Cultured human umbilical vein ECs stimulated by endotoxin were labeled with Fura-2 and exposed to fluid flow with neutrophils. The individual changes in [Ca2+]i were monitored. The application of flow with neutrophils to stimulated ECs led to an increase in [Ca2+]i although either flow without neutrophils or neutrophils without flow rarely induced a rise in [Ca2+]i. Furthermore, flow application with neutrophils to unstimulated ECs also rarely promoted a rise in [Ca2+]i. These findings suggest that the flow might thus induce or enhance the inflammatory process by the induction of Ca2+ signaling in endotoxin-stimulated endothelium facing neutrophils in the blood flow.