The effects of dexmedetomidine on inflammatory mediators after cardiopulmonary bypass.

Cardiac surgery with cardiopulmonary bypass is associated with the development of a systemic inflammatory response that can often lead to dysfunction of major organs. We hypothesised that the highly selective α2-adrenergic agonist, dexmedetomidine, attenuates the systemic inflammatory response. Forty-two patients were randomly assigned to receive dexmedetomidine or saline after aortic cross-clamping). The mean (SD) levels of the nuclear protein plasma high-mobility group box 1 increased significantly from 5.1 (2.2) ng ml(-1) during (16.6 (7.3) ng ml(-1) ) and after (14.3 (8.2) ng ml(-1) ) cardiopulmonary bypass in the saline group. In the dexmedetomidine group, the levels increased significantly only during cardiopulmonary bypass (4.0 (1.9) ng ml(-1) baseline vs. 10.8 (2.7) ng ml(-1) ) but not after (7.4 (3.8) ng ml(-1) ). Dexmedetomidine infusion also suppressed the rise in mean (SD) interleukin-6 levels after cardiopulmonary bypass (a rise of 124.5 (72.0) pg ml(-1) vs. 65.3 (30.9) pg ml(-1)). These suppressive effects of dexmedetomidine might be due to the inhibition of nuclear factor kappa B activation and suggest that intra-operative dexmedetomidine may beneficially inhibit inflammatory responses associated with ischaemia-reperfusion injury during cardiopulmonary bypass.

Effects of epidural anaesthesia on surgical stress-induced immunosuppression during upper abdominal surgery.

BACKGROUND: Previously, we have demonstrated that surgical stress rapidly induced transient hyporesponsiveness of blood cells to endotoxin and that monocyte mCD14 and HLA-DR expression decreased soon after the start of surgery under general anaesthesia. This study was designed to investigate the effects of epidural anaesthesia on surgical stress-induced immunosuppression in patients undergoing upper abdominal surgery. METHODS: After having obtained informed consent, patients were randomly allocated to receive general anaesthesia (Group G) or general anaesthesia with epidural anaesthesia (Group E). Perioperative changes in neutrophil phagocytic activity, neutrophil respiratory burst activity, monocyte mCD14 and HLA-DR expression, plasma IL-10 concentration, and the LPS-induced TNF-alpha production in whole blood were measured. RESULTS: Surgical stress rapidly depressed neutrophil phagocytic activity, monocyte mCD14 and HLA-DR expression, and LPS-induced TNF-alpha production ex vivo (P < 0.05 vs preoperation) in both Group G and Group E. In contrast, the plasma IL-10 concentration increased significantly 2 h after the start of surgery (P < 0.05) in both groups. There were no significant differences between the two groups. The neutrophil respiratory burst activity did not change during the operation in either group. CONCLUSION: This study showed that the innate immune system is suppressed from the early period of upper abdominal surgery. Subgroup analysis suggested that epidural anaesthesia to T4 dermatome as well as general anaesthesia may not protect patients from this immunosuppression. These results in part explain the impairment of host-defense mechanisms seen in the perioperative period.

Non-HTLV-1-associated primary gastric T-cell lymphomas show cytotoxic activity: clinicopathological, immunohistochemical characteristics and TIA-1 expression in 31 cases.

AIMS: Most primary gastrointestinal lymphomas are of B-cell origin and T-cell origin is very rare. Recent studies have suggested that human T-cell lymphotrophic virus type 1 (HTLV-1) may be involved in the development of primary gastric T-cell lymphoma. We analysed 31 patients with primary gastric T-cell lymphoma in south-west Japan, an area endemic for HTLV-1, and determined their phenotypes, genotypes, and HTLV-1 status. METHODS AND RESULTS: Here we present 31 cases of primary gastric T-cell lymphoma in a HTLV-1-endemic area in Japan and analyse the clinical status, histology, phenotype and virus status. The median age at onset of primary gastric T-cell lymphoma was 57 years with a gender ratio of M:F = 1.58:1. Six of the 31 primary gastric T-cell lymphoma cases had HTLV-1 proviral DNA (five males, one female), nine of the 31 cases were positive for anti-adult T cell leukaemia antibody, without examination of HTLV-1 proviral DNA (five males, four females), eight were non-HTLV-1-associated primary gastric T-cell lymphoma (four males, four females) and the other eight cases were unknown. Primary gastric T-cell lymphoma usually presented as a large ulcerated tumour at the corpus to the antrum and histologically consisted of anaplastic large cell type (n = 2), pleomorphic large cell type (n = 3), pleomorphic medium and large cell type (n = 14), pleomorphic medium cell type (n = 11), and angioimmunoblastic T-cell lymphoma type (n = 1). There were no clear macroscopic and microscopic differences between HTLV-1-associated and non-HTLV-1-associated primary gastric T-cell lymphoma. Most patients died within 2 years of diagnosis, and both types of primary gastric T-cell lymphoma (with and without HTLV-1) were associated with poor prognosis. Cytotoxic marker analysis showed that HTLV-1-associated lymphomas were negative for TIA-1, while non-HTLV-1-associated lymphomas were positive for TIA-1. CONCLUSIONS: Our results suggest that in HTLV-1-endemic areas, patients with HTLV-1-associated primary gastric T-cell lymphoma should be managed carefully and that TIA-1 seems to be useful for identifying the aetiology of this lesion.

Prognostic value of Bcl 10 rearrangement in diffuse large B-cell lymphoma.

The role of bcl 10, a recently cloned apoptosis-associated gene, in diffuse large B-cell lymphoma (DLBL) is unknown. Here we determined the role of bcl 10 gene rearrangement on prognosis. Bcl 10 rearrangement was examined by Southern blot. Bcl 10 rearrangement was detected in 20 of 137 (14.6%) samples of DLBL. The frequency of bcl 10 rearrangement was higher in extranodal (eight of 38 cases, 21%) than in nodal (12 of 99, 12%) DLBL. The survival rate in patients with bcl 10 rearrangement tended to be better than in those with germ-line bcl 10, albeit statistically insignificant probably due to the small population sample. The superior prognosis in patients with bcl 10 rearrangement might be due to bcl 10-induced enhanced apoptosis.

Apoptosis and prognostic factors in myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a group of disorders characterized by peripheral pancytopenia despite normo- or hyper-cellular bone marrow. This is thought to be due to apoptosis of hematopoietic bone marrow cells, resulting in ineffective hematopoiesis. Several studies have confirmed the presence of a high apoptotic rate and proliferative state in the bone marrow of MDS. However, MDS is a heterogeneous disease from the point of view of prognosis. Some patients develop only anemia and show long survival with or without maintenance therapy, while others develop fatal pancytopenia or leukemic changes and therefore show a poor prognosis. This review focuses on the relationship between prognosis and apoptotic or proliferative processes affecting hematopoietic cells in the bone marrow of patients with MDS.

Rearrangements of bcl-1, bcl-2, bcl-6, and c-myc in diffuse large B-cell lymphomas.

Diffuse large B-cell lymphoma (DLBL) is characterized by a marked degree of morphologic and clinical heterogeneity. We studied 137 patients with de novo DLBL for rearrangements of the bcl-1, bcl-2, bcl-6 and c-myc oncogenes by Southern blot analysis. Structural alterations of bcl-1, bcl-2, bcl-6, and c-myc were detected in 21 of 137 (15.3%), 8 of 137 (5.8%), 22 of 137 (16.1%), 14 of 137 (10.2%) patients, respectively. Two cases showed a combination of bcl-1 and bcl-6 rearrangements. Chromosomal analysis was performed in 31 cases of the 137 DLBL. 27 of these showed karyotypic abnormalities, and two had translocations 3q27 involving bcl-6. However, one of two cases had no rearrangement of bcl-6. Patients with rearranged bcl-6 and c-myc tended to have poorer survival than patients with germ-line. Furthermore, bcl-1 and bcl-2 rearrangements tended to have a better outcome, although the above differences were not statistically significant. Rearrangements of the bcl-1, 2, 6, and c-myc gene correlated with the clinical outcome in DLBL and may thus serve as prognostic markers in patients with this form of malignant lymphoma. However, other genetic factors are probably involved in determining prognosis.

Ketamine isomers suppress superantigen-induced proinflammatory cytokine production in human whole blood.

PURPOSE: To investigate the efficacy of S(+)-ketamine and R(-)-ketamine on staphylococcal enterotoxin B (SEB)-induced tumour necrosis factor (TNF)-, interleukin (IL)-6, and IL-8 production in human whole blood in vitro. METHODS: After Ethics Committee approval and informed consent, blood samples were obtained from ten healthy volunteers and diluted with five volumes of RPMI 1640. After adding different doses of ketamine isomers (0-1000 microM), the blood was stimulated with SEB (10 ng x mL(-1)). After a six-hour incubation period, the plasma TNF- activity was determined by the L929 cell cytotoxic assay and IL-6 and IL-8 concentrations were measured using an enzyme-linked immunoassay. RESULTS: Ketamine isomers significantly suppressed SEB-induced TNF- production at concentrations exceeding 50 microM. Ketamine isomers at concentrations exceeding 100 microM also significantly suppressed SEB-induced IL-6 production. Furthermore, ketamine isomers at concentrations exceeding 500 microM significantly suppressed SEB-induced IL-8 production. There were no significant differences between the suppressive effects of S(+)-ketamine and R(-)-ketamine on SEB-induced proinflammatory cytokine production. CONCLUSION: This study demonstrated that ketamine isomers suppressed SEB-induced TNF-, IL-6, and IL-8 production in human whole blood.

CD10 and Bcl10 expression in diffuse large B-cell lymphoma: CD10 is a marker of improved prognosis.

AIMS: Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically and pathologically heterogeneous. The Bcl10 gene was recently isolated from the breakpoint region of t(1;14)(p22;q32) in mucosa-associated lymphoid tissue (MALT) lymphomas, and is considered to be an apoptosis-associated gene. CD10 is considered to be a marker of follicular centre B-cell differentiation. To assess the clinical significance and roles of CD10 and Bcl10 in DLBCL, we analysed 138 cases, using immunohistochemical methods. METHODS AND RESULTS: CD10 expression was limited to the cytoplasm, whereas Bcl10 expression was detected in the cytoplasm and/or nuclei. CD10 expression was detected in 39 of 138 cases (28.2%), cytoplasmic Bcl10 in 68 cases (49.2%), and nuclear Bcl10 in 34 cases (24.6%). Nuclear Bcl10 was detected in 14 of 28 cases (50%) of extranodal DLBCL, but only 20 of 110 cases (18.2%) of nodal DLBCL. Cytoplasmic Bcl10 was detected in 19 of 28 cases (67.8%) of extranodal DLBCL and 49 of 110 cases (44.5%) of nodal DLBCL. CD10 expression closely correlated with improved survival (68% overall survival (OS) vs. 48% OS), but not with site of disease. A high International Prognostic Index (IPI) was considered to be a poor prognostic factor associated with a shorter OS. CD10 expression was detected in 27 of 84 cases (32.1%) with low-risk IPIs, and in 12 of 54 cases (22.2%) with high-risk IPIs. In the low-risk group, cases expressing CD10 carried a better prognosis than CD10- cases (93% OS vs. 71% OS), whereas this was not the case in the high-risk group (25% vs. 20%). CONCLUSIONS: Bcl10 expression was associated with extranodal DLBCL, but not with prognosis. CD10 expression was closely associated with improved survival, but not with risk as predicted by IPI. Overall, our results suggest that CD10 expression may be useful, in combination with clinical parameters, for determining the prognosis of DLBCL.

Bcl10 expression, rearrangement and mutation in MALT lymphoma: correlation with expression of nuclear factor-kappaB.

Mucosa-associated lymphoid tissue (MALT) lymphomas usually involve extranodal sites, especially the stomach, lung and salivary glands. The Bcl10 gene was recently isolated from the breakpoint region of t(1;14) (p22;q32) in MALT lymphomas, and considered to be an apoptosis-associated gene, and involves a caspase recruitment domain (CARD)-containing protein that activates NF-kappaB. We investigated the role of Bcl10 in MALT lymphoma by analyzing its expression, rearrangement and somatic mutation, by immunostaining, reverse transcriptase-polymerase chain reaction (RT-PCR), Southern blot and PCR in 20 cases of MALT lymphoma. Expression of NF-kappaB was studied by immunostaining. Five cases of reactive lymphadenitis (RLA) were used as the control. Bcl10 rearrangement was detected in 8 of 20 (40%) MALT lymphomas, but in none of RLA. Significant Bcl10 mutation was detected only in 1 case (5%) with MALT, but not in RLA. RT-PCR showed higher density bands of Bcl10 in MALT lymphomas than in RLA. Immunostaining showed a weak Bcl10 expression in the germinal center and very weak expression in the marginal zone B-cells in RLA, which was limited to the cytoplasm. In contrast, Bcl10 was strongly expressed in MALT lymphomas, and was mainly detected in the cytoplasm, as well as in the nuclei. Bcl10 expression did not correlate with Bcl10 mutation and re-arrangements. NF-kappaB was expressed in nuclei of MALT lymphoma cells, but not in RLA. Bcl10 expression in MALT lymphoma correlated closely with NF-kappaB expression. Our results suggest that activation of Bcl10 and NF-kappaB may be important in MALT lymphomagenesis, and that nuclear localization of Bcl10 may be important in the progression of MALT.

Expression of human tumor-associated antigen RCAS1 in Reed-Sternberg cells in association with Epstein-Barr virus infection: a potential mechanism of immune evasion.

RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is present in neoplastic cells, induces apoptosis of natural killer (NK)/T cells and plays a role in immune evasion. Fas ligand (FasL) is considered to have similar roles. The Epstein-Barr virus (EBV)-encoded latent membrane protein is expressed by malignant Hodgkin and Reed-Sternberg (H&RS) cells of EBV-associated Hodgkin's disease (HD) and considered to be a target of cytotoxic T lymphocytes (CTLs). However, CTL response is inadequate in HD. To determine whether RCAS1 and FasL are expressed in EBV-associated HD and participate in immune evasion, tissues of 20 EBV(-) and 15 EBV(+) HD cases were immunohistochemically stained for RCAS1, FasL and HLA classes I and II, whose deficiencies could explain CTL escape. Lymphocytes surrounding H&RS cells tended to be CD4(+) cells and rarely CD8(+), TIA-1(+) (cytotoxic marker) or NK cells. HLA class I and/or II were expressed in all EBV(+) HD cases, and RCAS1-expressing H&RS cells were found in 14/15 (93%) EBV(+) HD cases but only 8/20 (40%) EBV(-) HD cases (p < 0.05). FasL was detected in 9/15 (60%) and 7/20 (35%) EBV(+) and EBV(-) HD cases, respectively. ssDNA-positive (apoptotic) lymphocytes, surrounding H&RS cells, were rarely seen but were present in RCAS1(+) cases (20/22 cases, 91%) rather than negative cases (0/13 cases, 0%) (p < 0.005). Our findings suggest that EBV(+) H&RS cells might evade the host immune response by expressing RCAS1 rather than FasL.

Chromosome 16q deletion and loss of E-cadherin expression in Hodgkin and Reed-Sternberg cells.

Hodgkin and Reed-Sternberg (H&RS) cells are generally considered to be the neoplastic cells of Hodgkin's disease (HD); however, such H&RS cells are a few in number due to the numerous reactive cells. Very few data have so far been published on the cytogenetic abnormalities in HD. We have previously used the analysis of comparative genomic hybridization (CGH), employing sorted H&RS cells. The most commonly observed genetic aberrations were a loss on 16q11/21, a gain on 1p13 and a gain on 7q35/36. To confirm the loss of 16q, we analyzed the loss of heterozygosity (LOH) using the regions D16S3075 (16p13), D16S3068 (16q11), D16S3136 (16q12), D16S503 (16q13), D16S515 (16q21), D16S3091 (16q23) and D16S520 (16q24). A total of 100 sorted H&RS cells were compared with a similar number of sorted reactive T cells in 15 cases with HD, including 5 cases with nodular sclerosis (NS) type and 10 cases with mixed cellularity (MC) type. LOHs of 16q, especially 16q21-23, were frequently detected, but 16p deletions were infrequent. Analysis of 16q21 showed LOH in 12 of 15 cases with HD (80%), including 9 cases with MC type (90%) and 3 cases with NS type (60%). 16q23 showed LOH in 9 of 15 cases with HD (60%), including 5 cases with MC type (50%) and 4 cases with NS (80%). On the other hand, 16p13 showed LOH in 3 of 15 cases with HD (20%). Immunohistochemical staining showed that H&RS cells rarely expressed E-cadherin, which is located on 16q. Our findings suggest that 16q deletion, especially 16q21-23, is probably involved in H&RS giant cell formation and tumorigenesis.

Possible immortalization of Hodgkin and Reed-Sternberg cells: telomerase expression, lengthening of telomere, and inhibition of apoptosis by NF-kappaB expression.

Telomerase, an enzyme associated with cellular immortality, is expressed on malignant tumor cells. Deregulation of telomerase is thought to facilitate tumorigenesis and cellular immortality by providing cancer cells with unlimited proliferation capacity. Hodgkin and Reed-Sternberg (H&RS) cells are generally considered as neoplastic cells in Hodgkin's disease (HD), however, such cells are only found in a minority of HD lesions. In addition, H&RS cells with mitotic features are rare and mummified forms are occasionally encountered. There are no available data on the relationship between telomerase activity and apoptosis in HD. We studied 14 cases with Hodgkin's disease (mixed cellularity type, nine cases; nodular sclerosis type, five cases) to clarify the relationship between telomerase activity and apoptosis using in situ hybridization of human telomerase reverse transcriptase (hTERT), reverse transcriptase-polymerase chain reaction (RT-PCR) of hTERT, using extracted RNA and immunohistochemistry of nuclear factor-?B (NF-?B), and TdT-mediated dUTP-digoxigenin nick end-labeling (TUNEL) technique for apoptosis. We also analyzed the telomere length, using sorted H&RS cells. TUNEL showed a few apoptotic H&RS cells, but the cells frequently expressed hTERT, as confirmed by ISH and RT-PCR. Lengthening of the telomere of H&RS cells was noted in ten cases. In addition, H&RS cells frequently expressed NF-?B, which is known as an inducible transcription factor and inhibitor of apoptosis. Our findings of telomerase activity in H&RS cells indicate that these cells are neoplastic and are potentially immortal. In addition, NF-?B expression on H&RS cells suggests its possibility in inhibition of apoptosis of these cells.

Surgical stress induces endotoxin hyporesponsiveness and an early decrease of monocyte mCD14 and HLA-DR expression during surgery.

UNLABELLED: It is generally accepted that major surgery is associated with severe alterations of the host-defense mechanisms. We investigated the effect of surgical stress on the immune system. Specifically, we studied the relationship between perioperative lipopolysaccharide (LPS) hyporesponsiveness and monocyte human leukocyte antigen-DR (HLA-DR) and CD14 expression during the perioperative period in 20 patients who underwent partial gastrectomy. This study demonstrated that surgical stress rapidly depressed monocyte mCD14 and HLA-DR expression in comparison with preanesthesia levels. Monocyte mCD14 expression recovered to preoperative levels on the first postoperative day, and monocyte HLA-DR expression recovered by the seventh postoperative day. Consistent with our previous study, LPS-induced tumor necrosis factor (TNF)-alpha production ex vivo was significantly suppressed from the beginning of the operation. On the contrary, the plasma interleukin-10 concentration started to increase after the surgical incision was made. LPS hyporesponsiveness was least at the end of the operation and returned to preoperative levels on the first postoperative day. In conclusion, the present study demonstrated that LPS responsiveness, plasma interleukin-10 concentration, and monocytes mCD14 and HLA-DR expression altered from the early period of surgery. These alterations may be related to the impairment of the immune system during the perioperative period. IMPLICATIONS: Recent studies demonstrate that surgical stress induces immune dysfunction. We found that surgical stress rapidly decreased monocyte mCD14 and human leukocyte antigen-DR expression, and endotoxin responsiveness. These findings suggest that early changes of the immune system caused by surgical stress contribute to postoperative complications such as sepsis and multiple organ failure.

Developmental assessment-based surgical intervention for intractable epilepsies in infants and young children.

PURPOSE: To define the most appropriate time for surgery for medically intractable epilepsies in infants and young children. METHODS: First we examined retrospectively the changes in developmental quotients (DQs) during the clinical course and the clinical factors affecting the DQ in 39 consecutive patients younger than 15 years, who underwent surgical treatment for intractable epilepsy. Second, we examined prospectively five new patients for early detection of developmental arrest or regression by periodic developmental assessments and whether this could lead to early surgical intervention, eventually resulting in minimal developmental defects. RESULTS: Retrospective studies revealed that the DQ progressively decreased with age and that the reduction of DQ was related to continuing frequent seizures in many patients. The prospective studies demonstrated that periodic developmental assessments could detect the reduction of DQ at 5 months or later after onset of frequent seizures in three patients. In two other patients, operations were performed before reduction of DQs, and their postoperative DQ levels were normal. The post-operative recovery of DQ was complete in one patient whose operation was performed 3 months after reduction of DQ, whereas it was incomplete in two others whose operations were carried out at 12 and 14 months after reduction, respectively. Furthermore, three patients with normal developmental outcome had shorter periods between the onset of frequent seizures and the operation (< or = 7 months) than those of two patients with developmental delay (> or = 17 months). CONCLUSIONS: To minimize the developmental defects, periodic developmental assessments should be initiated when frequent seizures have occurred, and surgery should be considered as soon as possible when DQ reduction is recognized.

Amplification and expression of a decoy receptor for fas ligand (DcR3) in virus (EBV or HTLV-I) associated lymphomas.

The recently identified decoy receptor 3 (DcR3) binds to FasL and inhibits FasL-induced apoptosis, and is considered to play a role in the immune escape system of neoplastic cells. To examine the involvement of DcR3 in the immune evasions of virus-associated lymphoma, we analyzed the amplification and expression of DcR3, using dot blot and in situ hybridization (ISH), in 45 cases, which included 17 cases with Epstein-Barr virus (EBV)-associated lymphoma (seven pyothorax-associated B-cell lymphomas (PAL); ten natural killer lymphoma (NKL)), seven cases with adult T-cell leukemia lymphoma (ATLL), 13 Hodgkin's disease (eight EBV-associated cases; five non-EBV-associated cases), and eight control cases (three reactive lymphadenopathy; five non-EBV-associated-B-cell lymphoma). EBV-associated PAL and NKL exhibited DcR3 amplification and expression in lymphoma cells. ATLL also showed DcR3 expression and amplification. The cases with DcR3 amplification showed DcR3 expression; however, the expression was confined in the neoplastic cells, but not in the reactive cells. In Hodgkin's disease (HD), DcR3 was expressed only in Hodgkin and Reed-Sternberg giant (H-RS) cells. However, DcR3 was not expressed or amplified in reactive lymphadenopathy. Non-EBV-associated B-cell lymphoma also rarely expressed DcR3, and showed no amplification except in two cases, in which rare expression was present. Our results suggest that EBV and HTLV-I probably use DcR3 to escape from the immune system during lymphomagenesis, or virus-infected lymphoma cells with DcR3 expression might be selected in the multistep tumorigenesis.

Inhibition of disease flare with diethylstilbestrol diphosphate and chlormadinone acetate administration for two weeks prior to slow-releasing leuprolide acetate in prostatic cancer patients.

To determine whether administration of estrogen or gestagen prior to luteinizing hormone-releasing hormone (LH-RH) agonist prevents disease flare in prostate cancer patients, we pretreated the patients with either diethylstilbestrol diphosphate (DES-P) 300 mg daily (N = 17) or chlormadinone acetate (CMA) 100 mg daily (N = 16) or none (N = 16) for two weeks before the initial injection of leuprolide acetate (L). Blood samples for prostatic specific antigen (PSA), testosterone (T), and luteinizing hormone were collected before CMA and DES-P administration, before and at 2, 7, 14, 28, 56, and 84 days after the first administration of leuprolide. The treatment with DES-P and CMA prior to LH-RH agonist induced an early decline of PSA. The mean PSA level showed no significant secondary rise in those patients with pretreatment after L administration. In the patients pretreated with DES-P or CMA, the mean serum T level never exceeded the pretreatment baseline after L administration. On the other hand, in the patients without DES-P or CMA, both serum T and PSA levels increased after the first administration of L. These results clearly demonstrate that pretreatment with DES-P 300 mg daily or CMA 100 mg daily for 2 weeks is quite effective to prevent disease flare after the first administration of L in patients with prostatic cancer.

Chromophobe renal cell carcinoma with sarcomatoid change. A case report.

Chromophobe renal cell carcinoma (RCC) is a newly established entity of renal neoplasm with histological and molecular biological features different from those of common RCCs. Chromophobe RCC shows characteristically cloudy and reticular cytoplasm and cellular features resembling distal nephron. Its prognosis has been reported to be more favorable than that of common RCCs. Recently, however, several cases have been reported which showed sarcomatoid change to present poor prognosis. Here we present a case of chromophobe RCC with sarcomatoid change which was once resected surgically. The surgically resected tumor was histologically composed of chromophobe epithelial cell sheets and sarcomatoid elements. The former showed positivity for colloid iron staining, and was immunohistochemically positive for E-cadherin and epithelial membrane antigen (EMA), whereas the latter was positive for vimentin instead of colloid iron and E-cadherin. EMA was focally positive in the sarcomatoid element. The patient died with systemic metastases 14 months after the operation. Histologically, the metastatic tumors were composed only of sarcomatoid element lacking epithelial element. Based on these findings and previous reports, this case supports the existence of a tumor progression pathway from chromophobe to sarcomatoid RCC. It is necessary to perform careful postoperative investigation of chromophobe RCC due to its possible histological progression to the sarcomatoid subtype.

Evaluation of apoptosis as a prognostic factor in myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a group of disorders characterized by peripheral pancytopenia despite normo- or hypercellular bone marrow. This is thought to be as a result of the apoptosis of haematopoietic bone marrow cells resulting in ineffective haematopoiesis. To clarify the relationship between prognosis and apoptosis and/or cell proliferation in the bone marrow, we studied 51 cases with MDS. Bone marrow biopsies were stained immunohistochemically for MIB-1 (marker for proliferating cells) and CD34 (marker for stem cells). Apoptosis was visualized by detection of DNA fragmentation using TdT incorporation of nucleotides on 3' ends of DNA (TUNEL technique) and expressed as the apoptotic rate. MDS patients included 32 with refractory anaemia (RA), one RA with ringed sideroblasts (RARS) patient, seven RA with excess of blasts (RAEB) patients, eight patients with RAEB in transformation (RAEB-t) and three patients with chronic myelomonocytic leukaemia (CMMoL). In addition, we also studied six cases with acute myeloid leukaemia (AML) arising from MDS (AML-MDS) and ten control subjects. Fatal pancytopenia was the cause of death in 19 out of 51 patients. The apoptotic rate was higher in MDS patients (5.5%) than in control subjects (0.6%) and AML-MDS patients (0.4%). The percentage of MIB-1 positive cells was higher in MDS and AML-MDS than in control. The percentage of CD34-positive cells was higher in AML-MDS, RAEB, RAEB-t and CMMoL patients than control subjects and RA patients. Our findings indicate the activation of both the proliferative and apoptotic rates in MDS. Poor prognosis correlated significantly with higher apoptotic rates, but not with percentages of MIB-1 and CD34-positive cells. Our results suggest that apoptosis might be a useful prognostic factor and inhibition of apoptotic mechanisms may induce leukaemic transformation in MDS.

Gastrointestinal T cell lymphoma: predominant cytotoxic phenotypes, including alpha/beta, gamma/delta T cell and natural killer cells.

Gastrointestinal T cell lymphoma (TCL) is a rare subset of peripheral TCL, presenting with or without cytotoxic phenotype, a history of coeliac disease (CD) and enteropathy. However, CD is rare in Japan. Here, we describe the clinicopathological features of 18 Japanese cases. Lesions were found in the small intestine (n=13), stomach (n=3) and colon (n=2). Seven patients presented with enteropathy but none had a history of CD. Lymphomas appeared as ulceration (n=11), tumour formation (n=6), or polypoid growth (n=1). Histologically (REAL classification), neoplastic lesions were composed of intestinal type T cell lymphoma (ITCL, n=13, including one case with NK type), anaplastic large cell (ALCL, n=2), adult T cell leukaemia/lymphoma (ATLL, n=2), and lymphoblastic type (n=1). Epstein Barr virus infection was detected by EBER-1 in situ hybridization in 6 of 11 cases with ITCL but not in the other types. ALCL expressed CD30. CD56 was expressed in 3 of 11 cases of ITCL but not in other types. Among the 10 examined cases, 8 were alphabeta T cell type [CD2+, CD3+, T cell receptor (TCR)delta-1-, betaF1+], one was gammadelta T cell type [CD2+, CD3+, TCRdelta-1+, betaF1-], and the remaining case expressed natural killer (NK) cell type [CD2+, CD3-, CD56+, TCRdelta-1-, betaF1-]. Among the 8 examined cases, 3 expressed CD103 molecule, which was associated with extrathymic T cells of intraepithelial lymphocytes. All cases except ATLL expressed the cytotoxicity-associated molecule of TIA-1, and 11 of 14 TIA-1 positive cases expressed activated cytotoxic molecules of perforin, granzyme B, and/or Fas ligand. Despite the morphological, genetic and phenotypic heterogeneity, prognosis was poor, and 11 of 13 patients with small intestinal lesions died albeit appropriate treatment, but 3 of 4 patients with gastric or colonic lesions were still alive. The main cause of death was intestinal perforation. The latter might be due to the site specificity of small intestine and tumour cytotoxicity.