Efficacy of bezafibrate for chronic GVHD of the liver after allogeneic hematopoietic stem cell transplantation.

Chronic GVHD (cGVHD) of the liver is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-SCT). It is characterized by the destruction of bile duct epithelium followed by progressive cholestasis, which resembles primary biliary cirrhosis (PBC) clinically and histologically. Bezafibrate (BF) is a widely used agent for hyperlipidemia that is also effective in ursodeoxycholic acid (UDCA)-resistant PBC patients. The putative mechanism in cholestasis is that BF upregulates the expression of phosphatidylcholine flippase on bile canaliculi, facilitates phospholipid output into bile and relieves bile duct damage caused by hydrophobic bile salts. Therefore, the effects of BF in patients with cGVHD of the liver were investigated. Of 87 patients with cGVHD who survived more than 100 days after SCT, 8 were given BF to treat liver cGVHD because of a poor therapeutic response to UDCA and immunosuppressants. The serum alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (gamma-GTP) levels decreased significantly within 1 month after initiation of BF therapy compared with those before BF therapy in all patients (ALP, 964.9.0+/-306.9 to 597.8+/-102.5 IU/l, P=0.012; gamma-GTP, 528.8+/-299.0 to 269.0+/-119.9 IU/l, P=0.012). BF was effective in patients with liver cGVHD, including UDCA-resistant patients. BF could be a novel therapeutic option for liver cGVHD that helps to preserve normal immunity with the antileukemic effect of cGVHD.

Hepatitis viral status affects the pattern of intrahepatic recurrence after resection for hepatocellular carcinoma.

AIM: To define whether the patterns of intrahepatic recurrence after resection for hepatocellular carcinoma differ according to hepatitis viral status. METHODS: One hundred and eleven patients undergoing a curative resection for hepatocellular carcinoma were divided into three groups: the C-viral group (n=55), which tested positive for hepatitis C antibody; the B-viral group (n=32), which tested positive for hepatitis B surface antigen; and the non-B non-C (NBNC) group (n=24), which tested negative for both hepatitis B surface antigen and hepatitis C antibody. The long-term outcomes were analyzed retrospectively. RESULTS: The pattern of development of intrahepatic recurrence differed between the NBNC group and the other groups: the cumulative probability of intrahepatic recurrence reached a plateau at 2.4 years after resection in the NBNC group, while it continued to increase steadily in the hepatitis viral groups. The C-viral group showed a higher incidence of intrahepatic recurrence than the other groups by univariate (P=0.0306) and multivariate (relative risk=1.69, P=0.0429) analyses. Multiple intrahepatic recurrent lesions were more common in the C-viral group (P=0.0457). CONCLUSIONS: Multicentric carcinogenesis in the remnant liver was less common in the NBNC group than in hepatitis viral groups. Hepatitis C virus infection is a significant risk factor for intrahepatic recurrence after resection and is also associated with multiple intrahepatic recurrent lesions.

Computed tomographic features of hepatocellular carcinoma predict long-term survival after hepatic resection.

AIM: To evaluate the potential of computed tomographic features of hepatocellular carcinoma as prognostic factors. METHODS: Medical records for 112 patients who had undergone a partial hepatectomy for hepatocellular carcinoma were retrospectively analyzed. The largest hepatic tumour in each patient was classified by pre-operative computed tomographic features as lobular configurations with indentations showing an acute angle, or non-lobular configuration without such indentations. RESULTS: Twenty-six tumours were lobular and 86 were non-lobular. The outcome after hepatectomy was significantly worse in patients with lobular tumours (cumulative 5-year survival rate of 19.9%) than with non-lobular ones (that of 75.2%) (P<0.001). Cox's proportional hazards model showed computed tomographic features (P=0.0025), cirrhosis (P=0.0033), and tumour size (P=0.0412) to be independent prognostic factors. A lobular configuration was associated with satellite nodules (P<0.001), portal vein invasion (P=0.021), and extrahepatic tumour relapse (P=0.006). CONCLUSIONS: Computed tomographic features represent a strong prognostic factor in patients undergoing partial hepatectomy for hepatocellular carcinoma, and are likely to accurately reflect the tumour biology. Configuration, size of the hepatic tumour and presence of cirrhosis are the most important prognostic imaging findings in these patients.

Computed tomographic features of colorectal carcinoma liver metastases predict posthepatectomy patient survival.

PURPOSE: The gross appearance of colorectal carcinoma liver metastases reflects the biologic behavior of the tumor, yielding prognostic information. The aims of this retrospective study were to determine whether preoperative computed tomographic features of colorectal carcinoma liver metastases reflect the gross appearance of resected specimens and whether these computed tomographic hepatic features predict survival after hepatectomy. METHODS: Eighty-five patients underwent curative partial hepatectomy for colorectal carcinoma liver metastases. Preoperative computed tomographic features of the largest hepatic deposit were classified by the contour of advancing margin of the tumor into two types: lobular tumors with indentations with an acute angle and nonlobular tumors without such indentations. The correlation between computed tomographic features and 18 other clinicopathologic factors was examined. RESULTS: The overall five-year survival rate was 34.1 percent. Of 85 hepatic tumors examined, 49 were lobular and 36 were nonlobular. Computed tomographic features correlated significantly with gross appearance (P = 0.007). Univariate analysis revealed that computed tomographic features (P < 0.0001), gross appearance (P = 0.0063), size of the largest hepatic deposit (P = 0.0075), age (P = 0.0140), and satellite lesions (P = 0.0443) were significant prognosticators. The five-year survival rates in patients with lobular and nonlobular tumors were 10.4 and 66.1 percent, respectively. By multivariate analysis, computed tomographic features (P < 0.0001) and size of the largest hepatic deposit (P = 0.0419) were independently significant. CONCLUSIONS: Computed tomographic features of colorectal carcinoma liver metastases correlate with their gross appearance. The computed tomographic characterization of liver metastases is the most important independent prognostic factor in patients undergoing curative hepatectomy.

Simultaneous detection of colorectal carcinoma liver and lung metastases does not warrant resection.

BACKGROUND: Recent evidence suggests that metastasectomy is efficacious for selected patients with hepatic and pulmonary metastases from a colorectal primary. The aim of this study was to identify a subgroup of patients who best benefit from hepatic and pulmonary metastasectomy among those with colorectal carcinoma metastases. STUDY DESIGN: We analyzed retrospectively a total of 136 patients who underwent resection of hepatic or pulmonary metastases of colorectal origin at Niigata University Medical Hospital between 1982 and 2000. The median follow-up period was 94 months. Eighty-four patients underwent hepatectomy alone, 25 underwent pulmonary resection alone, and 27 underwent both hepatic and pulmonary resection. The 27 patients undergoing hepatic and pulmonary resection were divided into two groups: 17 patients with sequentially detected hepatic and pulmonary metastases and 10 patients with simultaneously detected metastases. Survival time was determined from the date of initial metastasectomy. Differences in cumulative survival were evaluated using the log-rank test. Sixteen factors were assessed for their influence on the survival of the 27 patients undergoing resection of hepatic and pulmonary metastases; univariate and multivariate analyses were used in this evaluation. RESULTS: Patient survival after hepatic and pulmonary resection was comparable with that after hepatectomy alone (p = 0.536) and that after pulmonary resection alone (p = 0.294). Among the 27 patients undergoing hepatic and pulmonary resection, the outcomes after resection were significantly better in patients with sequentially detected metastases (cumulative 5-year survival of 44%) than in those with simultaneously detected ones (cumulative 5-year survival of 0%) (p < 0.001). On multivariate analysis sequential detection of hepatic and pulmonary metastases was the strongest independent favorable prognostic factor (p <0.001). CONCLUSIONS: Patients with sequentially detected hepatic and pulmonary metastases from a colorectal primary are good candidates for aggressive metastasectomy. Simultaneous detection of these metastases does not warrant resection.

Clinical significance of lymph node micrometastasis in gallbladder carcinoma.

BACKGROUND: This retrospective study was intended to define the clinical significance of lymph node micrometastasis in gallbladder carcinoma. METHODS: A total of 1136 regional lymph nodes taken from 63 consecutive patients undergoing radical resection were examined histologically. Micrometastasis was defined as a metastasis missed on routine histologic examination with hematoxylin-and-eosin but detected by immunohistochemical examination with an antibody against cytokeratins 8 and 18. RESULTS: None of 9 patients (0%) with pT1 disease and 19 of 54 patients (35%) with pT2-4 disease had nodal micrometastases. Univariate analysis identified nodal micrometastasis, type of radical resection, M classification, pT classification, perineural invasion, pTNM stage, timing of radical resection, lymphatic vessel invasion, and pN classification as significant variables. Multivariate analysis revealed that nodal micrometastasis (P =.0003) and type of radical resection (P=.0044) were independent prognostic factors. Nodal micrometastasis affected survival adversely, despite the absence (P=.0002) or presence (P <.0001) of overt nodal metastasis. Nodal micrometastasis correlated significantly with invasive characteristics: lymphatic vessel invasion, perineural invasion, and distant metastasis. CONCLUSIONS: Lymph node micrometastasis is the strongest independent predictor of worse survival regardless of the overt nodal status and may indicate aggressive tumor biology among patients undergoing curative resection for gallbladder carcinoma.

Early gallbladder carcinoma does not warrant radical resection.

BACKGROUND: This study was designed to address whether gallbladder cancer invading the muscle layer (stage pT(1b)) is a local disease and whether radical resection is necessary. METHODS: A retrospective analysis of 25 patients with pT(1b) gallbladder tumours, 13 of whom underwent simple cholecystectomy and 12 radical resection with regional lymph node dissection, was performed. A total of 147 regional lymph nodes was examined for metastasis. The median follow-up time was 95 months. RESULTS: No patient had blood vessel or perineural invasion on histology. Lymphatic vessel invasion was seen in one patient. Both overt metastasis and micrometastases were absent in all lymph nodes examined. Overall 10-year survival was 87 per cent. The outcome after simple cholecystectomy was comparable to that after radical resection (P = 0.16). Two patients who underwent radical resection died from tumour relapse in distant sites. CONCLUSION: Most pT(1b) gallbladder carcinomas spread only locally. Additional radical resection is not necessary when the depth of invasion of gallbladder carcinoma is limited to the muscle layer after simple cholecystectomy.

Two cases showing clonal progression with full evolution from aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome to myelodysplastic syndromes and leukemia.

We report 2 paroxysmal nocturnal hemoglobinuria (PNH) patients who were initially diagnosed with aplastic anemia and sequentially developed PNH, myelodysplastic syndromes (MDS), and leukemia. Flow cytometry and cytogenetic analysis showed the initial appearance and expansion of PNH clones, gradual replacement of PNH clones by MDS clones with monosomy 7, and then expansion of MDS clones or their subclones with additional chromosomal abnormalities. In relation to these developments, expression increased of the Wilms' tumor gene WT1, a marker for leukemic progression. These patients not only shared bone marrow failure but also might have harbored a hematopoietic environment favorable for the emergence of abnormal clones leading to leukemogenesis.

Pseudo-Meigs' syndrome caused by secondary ovarian tumors from gastrointestinal cancer. A case report and review of the literature.

BACKGROUND: Pseudo-Meigs' syndrome is a condition characterized by nonmalignant ascites and/or pleural effusion caused by pelvic tumors other than solid benign ovarian tumors. This syndrome has only rarely occurred in association with gastrointestinal cancers. METHOD: We treated a 53-year-old woman who developed this syndrome due to ovarian metastasis from colon cancer. Diagnostic work-up for abdominal distension disclosed a sigmoid colon cancer and bilateral ovarian masses. Ultrasonography demonstrated massive ascites and a right pleural effusion. Repeated cytologic examinations of both effusions revealed no malignant cells. Laparotomy disclosed no peritoneal dissemination. A radical sigmoidectomy and hysterectomy with bilateral salpingo-oophorectomy were performed. RESULTS: Histologic examination confirmed ovarian metastases from the colonic primary tumor. After resection, both effusions disappeared promptly, confirming a diagnosis of pseudo-Meigs' syndrome caused by sigmoid colon cancer. The patient remains alive with disease after 52 months. CONCLUSION: Among 6 reported occurrences with gastrointestinal tumors including our case, the primary site was the colon or rectum in 5 and the stomach in 1. Two cases were due to Krukenberg tumors. Three patients with documented outcomes were alive 108, 52, and 12 months after resection. Clinicians should note that gastrointestinal cancers, especially colorectal tumors, rarely may cause pseudo-Meigs' syndrome and resection may provide long-term palliation.

Domain configurations of the "incommensurate" structures of 2H-TaSe2 and Bi2Sr2(Ca1-xLn(x))Cu2O8+delta studied by HRTEM

High-resolution transmission electron microscopy (HRTEM) images of the "incommensurate" structures of 2H-TaSe2 and Bi2Sr2Ca1-xLnx Cu2O8+delta (Ln: rare earth metal) are shown. They were taken from a wide specimen area with homogeneous thickness. For the former, a configuration of two domains was found by a scrutiny of HRTEM images. For the latter, many configurations of two domains were extracted from the photometric density distribution in the one-dimensional contrast modulations in HRTEM images. One domain of the two in both configurations is created by a phase slip occurring in the primary atomic displacement longitudinal wave.

Atomic displacements in the modulated structure of Bi2Sr2(Ca(1-x)Pr(x))Cu2O(8+delta) and their effect on HRTEM reverse contrast image

The amplitude of transverse atomic displacement wave along the direction of incident electron beam exerts a significant effect on the brightness of spots in a high-resolution transmission electron microscope (HRTEM) reverse contrast image. The bright spot is associated with the projection of the modulated atomic chain along the beam direction. In general, the spot brightness is roughly inversely proportional to the amplitude of the displacement wave in an appropriate region of defocus, specimen thickness and amplitude. Monotonic decrease in the spot brightness with increasing amplitude can be attributed to the decrease in the degree of interference between scattered electrons. A complicated domain configuration has been found by the analysis of the spot brightness modulation observed in a [0 0 1] HRTEM reverse contrast image.

Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem-cell disorder in which the affected cells are deficient in glycosylphosphatidylinositol (GPI)-anchored proteins. Paroxysmal nocturnal hemoglobinuria is frequently associated with aplastic anemia, although the basis of this relation is unknown. OBJECTIVE: To assess the PNH status of patients with diverse marrow failure syndromes. DESIGN: Correlation of cytofluorometric data with clinical features. SETTING: Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland. PATIENTS: 115 patients with aplastic anemia, 39 patients with myelodysplasia, 28 patients who had recently undergone bone marrow transplantation, 18 patients with cancer that was treated with chemotherapy, 13 patients with large granular lymphocytosis, 20 controls who had received renal allografts, and 21 healthy participants. INTERVENTION: Patients with aplastic anemia, myelodysplasia, or renal allografts received antithymocyte globulin. MEASUREMENTS: Flow cytometry was used to assess expression of GPI-anchored proteins on granulocytes. RESULTS: Evidence of PNH was found in 25 of 115 (22%) patients with aplastic anemia. No patient with normal GPI-anchored protein expression at presentation developed PNH after therapy (n = 16). Nine of 39 (23%) patients with myelodysplasia had GPI-anchored protein-deficient cells. Abnormal cells were not detected in patients with constitutional or other forms of bone marrow failure or in renal allograft recipients who had received antithymocyte globulin. Aplastic anemia is known to respond to immunosuppressive therapy; in myelodysplasia, the presence of a PNH population was strongly correlated with hematologic improvement after administration of antithymocyte globulin (P = 0.0015). CONCLUSIONS: Flow cytometric analysis is superior to the Ham test and permits concomitant diagnosis of PNH in about 20% of patients with myelodysplasia (a rate similar to that seen in patients with aplastic anemia). The presence of GPI-anchored protein-deficient cells in myelodysplasia predicts responsiveness to immunosuppressive therapy. Early emergence of GPI-anchored protein-deficient hematopoiesis in a patient with marrow failure may point to an underlying immune pathogenesis.

Calcification in mucinous cholangiocellular carcinoma.

Calcification is rarely seen in cholangiocellular carcinoma. We herein report the case of a 53 year-old man with calcification in a cholangiocellular carcinoma. Because imaging studies had revealed coarse calcified foci, hepatolithiasis was suspected pre-operatively. The patient underwent a laparotomy in which intra-operative cholangioscopy revealed no gallstones but did reveal an unsuspected tumor with abundant mucin. A left hepatic lobectomy with resection of the extrahepatic bile duct was performed. The tumor histology was mucinous adenocarcinoma with calcification. In the English language literature, we found 9 cases of cholangiocellular carcinoma with macroscopic calcification. Six of these cases were mucinous adenocarcinomas. Roentgenologic examination revealed coarse calcification in 7 cases and fine calcification in 2 cases. Clinicians should note that cholangiocellular carcinoma, especially the mucinous variant, may be accompanied by coarse calcification.

Tumor necrosis factor-alpha and CD95 ligation suppress erythropoiesis in Fanconi anemia C gene knockout mice.

Fanconi anemia (FA) is a genetic syndrome predisposing to hematopoietic failure. Little is known about the pathophysiology of FA, except that tumor necrosis factor-alpha (TNF-alpha) is overexpressed in patients. FA group C (Fac) gene knockout mice have been developed in order to model the human disease, but the mice do not spontaneously exhibit aplasia. To investigate secondary influences on hematopoiesis in the Fac-null mice, we studied the sensitivity of hematopoietic progenitor cells (HPC) to death receptor triggering by TNF-alpha and Fas receptor (CD95) ligation. Previously we had found that overexpression of a human FAC transgene protects hematopoietic progenitors from Fas-mediated apoptosis (Wang et al., 1998, Cancer Res 58:3538-3541). In the present experiments with Fac-null mice, growth of erythroid burst-forming units (BFU-E) was significantly inhibited by TNF-alpha and CD95 ligation. Flow cytometric analysis revealed that CD95 was induced more readily in the Fac-null CD34+ cell fraction. Apoptosis induced by TNF-alpha alone or with CD95 ligation also occurred more frequently in null mouse HPC. We then bred null mice against transgenic mice overexpressing TNF-alpha (at serum levels in the range of 100 pg/ml). Resultant Fac-null mice that overexpressed TNF-alpha not only yielded decreased numbers of BFU-E but also expressed higher levels of CD95 in the CD34+ fraction. We conclude that mutation in the Fac protein induces heightened sensitivity to TNF-alpha and Fas receptor ligation, results that may explain the mechanism of anemia in FA-C patients.

Apoptosis resistance of blood cells from patients with paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome.

Bone marrow (BM) hypoplasia is a major cause of death in paroxysmal nocturnal hemoglobinuria (PNH). However, little is known about the molecular events leading to the hypoplasia. Considering the close pathologic association between PNH and aplastic anemia (AA), it is suggested that a similar mechanism operates in the development of their BM failure. Recent reports have indicated apoptosis-mediated BM suppression in AA. It is thus conceivable that apoptosis also operates to cause BM hypoplasia in PNH. If this is the case, PNH clones need to survive apoptosis and show considerable expansion leading to clinical manifestations. We report here that granulocytes obtained from 11 patients with PNH were apparently less susceptible than those from 20 healthy individuals to both spontaneous apoptosis without any ligands and that induced by anti-FAS (CD95) antibody in vitro. The patients' BM CD34+ cells were also resistant to apoptosis induced by treatment with tumor necrosis factor-alpha, interferon-gamma, and subsequently with anti-FAS antibody. In lymphocytes, the pathologic resistance was not discriminated from inherent resistance to apoptosis. Granulocytes from 13 patients with AA and 12 patients with myelodysplastic syndrome (MDS) exhibited similar resistance to apoptosis. CD34+ cells from MDS-BM also showed similar tendency. Thus, the comparative resistance to apoptosis supports the pathogenic implication of apoptosis in marrow injury of PNH and related stem cell disorders.

Differential glycosylation of Bence Jones protein and kidney impairment in patients with plasma cell dyscrasia.

Although Bence Jones protein (BJP) is generally accepted to be critically involved in the pathogenic process of kidney impairment in patients with myeloma, patients with BJP do not always have kidney dysfunction. As proteins often undergo glycosylation and alter their molecular nature, it is expected that the heterogeneity in kidney dysfunction can be explained at least partly by the differential affinity to the kidneys of BJP dependent on its glycosylation. Accordingly, we analyzed the structures of carbohydrates of urine BJP biochemically to correlate the structure with kidney function. BJP was obtained from 16 patients with myeloma, 2 patients with light chain amyloidosis, a patient with plasma cell leukemia, and a patient with Waldenstrom's macroglobulinemia. All BJP had five forms of oligosaccharides: three forms of biantennary oligosaccharides and two forms of triantennaries. The three biantennaries correspond to previously reported oligosaccharides on only lambda-type BJP, whereas the triantennaries are novel oligosaccharides found on BJP. Among the five oligosaccharides, the triantennary oligosaccharide Gal(beta)1-4GlcNAc(beta)1-2Man(alpha)1-6 [Gal(beta)1-GlcNA(beta)1-4(Gal(beta)1-4GlcNAc(beta) 1-2)Man(alpha)1-3]Man(beta)1-4GlcNAc(beta)1-4GlcNAc showed a significant negative correlation with the serum creatinine level (p = 0.015 by Spearman's correlation test, R = 0.744). Thus determination of BJP glycosylation may be useful for the evaluation of kidney impairment in patients with BJP.