Advanced moderately differentiated neuroendocrine carcinoma of the rectum with favorable prognosis by postoperative chemoradiation.

Rectal neuroendocrine carcinoma is rare with poor prognosis. We report herein a case of advanced moderately differentiated neuroendocrine carcinoma of the rectum with relatively favorable prognosis treated by postoperative adjuvant chemoradiation therapy. A 58-year-old Japanese female was referred and colonofiberscopy revealed an easy-bleeding irregular tumor in the lower rectum, which was pathologically diagnosed as a neuroendocrine carcinoma. Surgical treatment consisted of abdominoperineal resection and lymph node dissection. The tumor invaded deeply into perirectal tissues, and 9 of 11 lymph node metastases were observed. Immunohistochemically, chromogranin A showed diffuse and strong staining, and the MIB-1 labeling index was 18.3 +/- 5.6, supporting the high proliferation of the tumor. Some nucleus of the tumor showed positive staining for p21/WAF1. A total dose of 46 Gy of radiotherapy was delivered with 800 mg of daily oral doxifluridine. At 5 years post-surgery, the patient demonstrated no clinical evidence of intrapelvic recurrence or distant metastases.

Neuroendocrine differentiation in stage D2 prostate cancers.

OBJECTIVES: Chromogranin A (CgA) and neuro-specific enolase (NSE) are gaining acceptance as markers of several types of neuroendocrine tumors and the concentration of CgA and NSE have been reported to be elevated in relation to neuroendocrine differentiation of prostate cancer. The aim of the present study was to examine the correlation between the immunohistochemical (IHC) findings and serum value for CgA and NSE in untreated stage D(2) prostate cancer patients. METHODS: Immunohistochemistry was carried out using antibodies against CgA and NSE in 58 patients and, pretreatment serum CgA and NSE levels were measured by monoclonal immunoradiometric assay in 18 patients with stage D(2) prostate cancer treated by androgen ablation. We examined the relationship of the pretreatment serum level to IHC findings for CgA and NSE in prostate cancer patients to clinicopathological parameters, and prognosis. Also, we evaluated the correlation of IHC findings to serum levels for CgA and NSE. RESULTS: There was a statistically significant correlation between CgA positivity and serum CgA level (P = 0.0421). However, there was no statistically significant correlation between NSE positivity and serum NSE level (P > 0.05). We divided stage D(2) patients into three groups according to IHC positivity of CgA and NSE. The cause-specific survival was significantly poorer in patients with strongly positive (++) patients for independent CgA and combined CgA with NSE (P = 0.0379). Multivariate analysis of cause-specific survivals in patients with stage D(2) prostate cancer demonstrated that strong IHC stain was considered as independent variable associated with greater risk of death (P = 0.0142). CONCLUSION: Neuroendocrine differentiation in stage D(2) prostate cancer has attracted considerable attention as a potentially findings prognosis. Thus, CgA had a stronger relationship between serum levels and IHC positivity in contrast to NSE, suggesting clinical usefulness as a tumor marker in predicting the extent of neuroendocrine differentiation in prostate cancer.

Pim-3, a proto-oncogene with serine/threonine kinase activity, is aberrantly expressed in human pancreatic cancer and phosphorylates bad to block bad-mediated apoptosis in human pancreatic cancer cell lines.

Pancreatic cancer still remains a serious health problem with <5% 5-year survival rate for all stages. To develop an effective treatment, it is necessary to identify a target molecule that is crucially involved in pancreatic tumor growth. We previously observed that Pim-3, a member of the proto-oncogene Pim family that expresses serine/threonine kinase activity, was aberrantly expressed in human and mouse hepatomas but not in normal liver. Here, we show that Pim-3 is also expressed in malignant lesions of the pancreas but not in normal pancreatic tissue. Moreover, Pim-3 mRNA and protein were constitutively expressed in all human pancreatic cancer cell lines that we examined and colocalized with the proapoptotic protein Bad. The ablation of endogenous Pim-3 by small hairpin RNA transfection promoted apoptosis, as evidenced by increases in a proportion of cells in the sub-G(1) fraction of the cell cycle and in phosphatidyl serine externalization. A proapoptotic molecule, Bad, was phosphorylated constitutively at Ser(112) but not Ser(136) in human pancreatic cancer cell lines and this phosphorylation is presumed to represent its inactive form. Phosphorylation of Bad and the expression of an antiapoptotic molecule, Bcl-X(L), were reduced by the ablation of endogenous Pim-3. Thus, we provide the first evidence that Pim-3 can inactivate Bad and maintain the expression of Bcl-X(L) and thus prevent apoptosis of human pancreatic cancer cells. This may contribute to the net increase in tumor volume or tumor growth in pancreatic cancer.

Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancer cells.

AFP-producing gastric carcinoma (AFPGC) is a highly malignant variant of gastric cancer. An effective chemotherapy is needed to improve on the poor outcome of this disease. Survival signals activated by intracellular kinase networks could be involved in chemoresistance in malignant tumors. We investigated the role of a pivotal kinase pathway, the mammalian target of rapamycin complex 1 (mTORC1) pathway, in the effectiveness of chemotherapeutic agents in three AFPGC cell lines (GCIY, FU97 and Takigawa) as well as in four cell lines of conventional-type gastric carcinoma (CGC). AFPGC cells were generally resistant to multiple chemotherapeutic agents, including cisplatin, while CGC cells were generally sensitive. Downstream targets of mTORC1, including p70S6K and 4EBP1, were phosphorylated in all cell lines. Interestingly, cisplatin virtually abolished phosphorylation of p70S6K and 4EBP1 in CGC cells, while phosphorylation was maintained in cisplatin-treated AFPGC cells. The addition of rapamycin, an inhibitor of mTORC1, diminished the remaining activity of mTORC1 and significantly intensified the cytotoxic action of cisplatin in AFPGC cells. These results suggested that persistent activity of mTORC1 signals in cisplatin-treated AFPGC cells is involved in the mechanisms of cisplatin resistance in AFPGC. Finally, combined treatment of rapamycin and cisplatin significantly suppressed the subcutaneously implanted GCIY cells. In conclusion rapamycin may be a potential supplemental agent for the treatment of AFPGC when used in combination with cisplatin.

Serum p53 antibody as a diagnostic marker of high-risk endometrial cancer.

OBJECTIVE: The purpose of this study was to investigate the diagnostic impact of preoperative serum p53 antibody (S-p53 Ab) in patients with endometrial cancer. STUDY DESIGN: A hospital-based series of 67 patients, comprising 58 endometrioid adenocarcinomas (EA) and 9 serous adenocarcinomas (SA) between 1998-2002 were included. First, preoperative pathology was compared with final pathology in terms of histologic classification and tumor grade. Second, S-p53 Ab and CA125 were measured using preoperative serum samples, and immunohistochemical staining for p53 protein was assessed using hysterectomy specimens. RESULTS: There were discrepancies between preoperative and final pathology in terms of histologic classification (7%) and tumor grade in EAs (30%); other objective tests, therefore, were needed to minimize the diagnostic problems. S-p53 Ab titers varied from 0.27-786 (mean, 124) in SAs and from 0.1-7.47 (mean, 0.46) U/mL in EAs, respectively, and were positive in 6 (67%) SAs and in 3 (6%) EAs using 1.3 U/mL as cut-off. S-p53 Ab-positive rate was significantly correlated with SA histology and grade 3 EA tumor (odds ratio, 40; P = .005; 95% confidence interval, 3.04-525.43) with higher sensitivity and higher specificity than p53 staining and CA125, respectively. CONCLUSION: S-p53 Ab could conveniently and specifically identify high-risk endometrial cancer.

Down-regulation of CD9 in human ovarian carcinoma cell might contribute to peritoneal dissemination: morphologic alteration and reduced expression of beta1 integrin subsets.

Peritoneal dissemination is one of the main causes of death in cancer patients. Pathophysiology of metastasis has been well investigated, but the mechanism of diffuse spread of tumor colonies in the peritoneal cavity is not fully understood. CD9 is a member of tetraspanin and its down-regulation is known to be involved in poor prognosis. To investigate the significance of the down-regulation of CD9, HTOA, an ovarian carcinoma cell line that highly expressed CD9, was transiently transfected with small interfering RNA (siRNA) against CD9, and CD9-negative cells (HTOA(CD9-)) were purified. HTOA(CD9-) showed altered adhesion patterns on Matrigel, collagen, fibronectin, and laminin compared with those of control siRNA-transfected HTOA (control-HTOA). Flow cytometry and fluorescence cytostainings revealed that the expression levels of integrins beta1, alpha2, alpha3beta1, alpha5, and alpha6 were lower in HTOA(CD9-) than those of control-HTOA. HTOA(CD9-) showed altered expression of junctional and cytoskeletal molecules. By time-lapse video microscopy, control-HTOA showed solid adhesion to extracellular matrix and formed cobblestone pattern, whereas HTOA(CD9-) showed weaker adhesion and were distributed as diffuse spots. To examine whether the expression level of CD9 change during tumor dissemination, HTOA-P, a highly disseminative subclone of HTOA, was established. HTOA-P showed distinctive down-regulation of CD9 at mRNA and protein levels, and showed similar morphologic alteration as HTOA(CD9-) did. These findings indicate that the down-regulation of CD9 may be an acquired event in the process of tumor dissemination. Down-regulated CD9 may attenuate the expression of several integrins and rearrange junctional and cytoskeletal molecules that might contribute to dissemination of ovarian carcinomas.

Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia.

BACKGROUND: Maternal viral infection is associated with increased risk for schizophrenia. It is hypothesized that the maternal immune response to viruses may influence fetal brain development and lead to schizophrenia. METHODS: To mimic a viral infection, the synthetic double strand RNA polyriboinosinic-polyribocytidilic acid (poly I:C) was administered into pregnant mice. Behavioral evaluations (thigmotaxis, methamphetamine [MAP]-induced hyperactivity, novel-object recognition test [NORT]), sensorimotor gating (prepulse inhibition [PPI]), and biochemical evaluation of the dopaminergic function of the offspring of phosphate-buffered saline (PBS)-treated dams (PBS-mice) and that of poly I:C-treated dams (poly I:C-mice) were examined. RESULTS: In juveniles, no difference was found between the poly I:C-mice and PBS-mice. However, in adults, the poly I:C-mice exhibited attenuated thigmotaxis, greater response in MAP-induced (2 mg/kg) hyperlocomotion, deficits in PPI, and cognitive impairment in NORT compared with the PBS-mice. Cognitive impairment in the adult poly I:C-mice could be improved by subchronic administration of clozapine (5.0 mg/kg) but not haloperidol (.1 mg/kg). Increased dopamine (DA) turnover and decreased receptor binding of D2-like receptors, but not D1-like receptors, in the striatum were found in adult poly I:C-mice. CONCLUSIONS: Prenatal poly I:C administration causes maturation-dependent increased subcortical DA function and cognitive impairment in the offspring, indicating a neurodevelopmental animal model of schizophrenia.

Sonic Hedgehog-Gli1 signaling pathway might become an effective therapeutic target in gastrointestinal neuroendocrine carcinomas.

Gastrointestinal neuroendocrine carcinomas (NECs) are extremely aggressive and poorly prognostic. We showed previously that human achaete-scute homologue gene 1 (hASH1), a basic helix-loop-helix transcription factor regulated by Notch, was aberrantly expressed in NECs. To date, no effective therapeutic strategies for NECs have been investigated. Notch, Wnt and Hedgehog (Hh) signalings are important for stem cell self-renewal and carcinogenesis in the gastrointestinal epithelium. In this study, we showed that Hh signaling was clearly upregulated in NECs in Gli1-dependent manner. Specific therapeutic effects of cyclopamine on NECs were also demonstrated. RT-PCR showed that among eight frozen samples (three NECs, one carcinoid tumor, three adenocarcinomas and one normal mucosa), the band intensities of Gli1 were the strongest in NECs, moderately strong in a carcinoid tumor, very weak in adenocarcinomas and undetectable in a normal mucosa. In real-time RT-PCR, the expression levels of Gli1 in NECs were 108.4, 28.6 and 16.3 times higher than that in an adenocarcinoma. In immunohistochemistry using 25 paraffin-embedded tissues, all twelve NECs and three of six carcinoid tumors showed positive stainings for Gli1, whereas six of seven adenocarcinomas were negative. In vitro, RT-PCR showed that NEC cell lines expressed Gli1 mRNA significantly. Administration of cyclopamine suppressed cell proliferation and invasion, and induced apoptosis in NECs. In cyclopamine-treated NECs, downregulation of Gli1, Ptch1, Snail and hASH1, and upregulation of E-cadherin were demonstrated at mRNA levels. Such effects were not observed in a Gli1-negative colonic adenocarcinoma cell line or in control alkaloid-treated NECs. Hh signaling may play a crucial role in the pathophysiology of NECs. Blockade of Hh pathway using cyclopamine or its synthetic derivatives might open an effective therapeutic strategy to NECs, not only by suppressing tumor viability but also by altering tumor cell nature.

The expression of hepatocyte nuclear factor-4alpha, a developmental regulator of visceral endoderm, correlates with the intestinal phenotype of gastric adenocarcinomas.

AIMS: Hepatocyte nuclear factor (HNF)-4alpha is a developmental regulator of the visceral endoderm, which is expressed in the embryonic gut and later in the adult intestine and colon. However, adult gastric mucosa does not express HNF-4alpha. We investigated the possible involvement of HNF-4alpha in intestinal metaplasia and the intestinalisation of gastric adenocarcinomas. METHODS: Thirty-five cases of adenocarcinomas and 46 cases of adjacent non-neoplastic mucosa with (22 lesions) or without (24 lesions) intestinal metaplasia were immunostained for HNF-4alpha. The gastric or the intestinal phenotype was also examined using immunohistochemistry for MUC5AC, MUC2, CD10, and gastric-type mucin (GTM). Adenocarcinomas were classified into the gastric type (G-type, 42.9%), the mixed gastric and intestinal type (GI-type, 31.4%), and the intestinal type (I-type, 25.7%). RESULTS: The HNF-4alpha expression was exclusively seen in glandular cells with intestinal metaplasia, which was correlated with MUC2 expression (p<0.05) and inversely correlated with MUC5AC expression (p<0.05). All adenocarcinomas more or less expressed HNF-4alpha, with an intense expression being seen in the I-type (p<0.01) and in well-differentiated adenocarcinomas (p<0.03). CONCLUSIONS: HNF-4alpha expression is associated with the intestinal phenotype of non-neoplastic and neoplastic gastric glandular cells, suggesting a possible involvement in the establishment and/or maintenance of the intestinal phenotype of the gastric mucosa and adenocarcinomas.

Aberrant expression of human achaete-scute homologue gene 1 in the gastrointestinal neuroendocrine carcinomas.

PURPOSE: Gastrointestinal neuroendocrine carcinoma (NEC) is extremely aggressive, but its pathophysiologic features remain poorly understood. There have been no biologically specific markers for this disease. In this study, distinctive up-regulation of human achaete-scute homologue 1 (hASH1) in gastrointestinal NECs was clarified. EXPERIMENTAL DESIGN: Expression of hASH1 in NECs (n=10), carcinoid tumors (n = 10), other tumors (10 adenocarcinomas, 2 squamous cell carcinomas and 1 malignant lymphoma), and the corresponding normal mucosa were investigated by in situ hybridization, reverse transcription-PCR (RT-PCR), real-time RT-PCR, and immunohistochemistry. RESULTS: By in situ hybridization, mild to intense signals of hASH1 mRNA were detected in 9 of 10 NECs, but not in other tumors or normal mucosa, except for focally weak signals in one carcinoid tumor. RT-PCR showed strong expression of hASH1 in a small cell NEC, followed by a moderately differentiated NEC, and a carcinoid tumor, whereas it is undetectable in adenocarcinomas or normal mucosa. By real-time RT-PCR, the amounts of hASH1 mRNA in a small cell NEC were 16,600 times higher than those in adenocarcinomas and 110 times higher than those in a carcinoid tumor. Immunohistochemically, mammalian homologue of hASH1 was positive in 7 of 10 NECs but was negative in the other tumors. Pan-endocrine markers chromogranin A and synaptophysin were positive in almost all carcinoid tumors, in 4 and 7 of the 10 NECs, respectively. CONCLUSIONS: These findings revealed that hASH1 is distinctly up-regulated in gastrointestinal NECs. hASH1 may be used as a more sensitive and specific marker than conventional pan-endocrine markers for clinical diagnosis of gastrointestinal NECs.

Molecular classification and survival prediction in human gliomas based on proteome analysis.

The biological features of gliomas, which are characterized by highly heterogeneous biological aggressiveness even in the same histological category, would be precisely described by global gene expression data at the protein level. We investigated whether proteome analysis based on two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry can identify differences in protein expression between high- and low-grade glioma tissues. Proteome profiling patterns were compared in 85 tissue samples: 52 glioblastoma multiforme, 13 anaplastic astrocytomas, 10 atrocytomas, and 10 normal brain tissues. We could completely distinguish the normal brain tissues from glioma tissues by cluster analysis based on the proteome profiling patterns. Proteome-based clustering significantly correlated with the patient survival, and we could identify a biologically distinct subset of astrocytomas with aggressive nature. Discriminant analysis extracted a set of 37 proteins differentially expressed based on histological grading. Among them, many of the proteins that were increased in high-grade gliomas were categorized as signal transduction proteins, including small G-proteins. Immunohistochemical analysis confirmed the expression of identified proteins in glioma tissues. The present study shows that proteome analysis is useful to develop a novel system for the prediction of biological aggressiveness of gliomas. The proteins identified here could be novel biomarkers for survival prediction and rational targets for antiglioma therapy.

MR imaging of normal perivascular space expansion at midbrain.

BACKGROUND AND PURPOSE: A previous investigation of the MR imaging findings in the midbrain reported expanded perivascular (PV) spaces in only the ponto-mesencepalic junction (PMJ) in 20% of healthy subjects, whereas pathologically expanding PV spaces have been reported at the mesencephalo-diencephalic junction (MDJ) as multi-lobulated, cystic lesions with signal intensity compatible with that of CSF that cause aqueductal stenosis. To clarify the anatomical distinctions between normally expanded and pathologically expanding PV spaces, we defined their distribution in the normal midbrain by using high-spatial-resolution MR imaging. METHODS: Heavily T2-weighted MR imaging was performed in 115 adult subjects with neurologic complaints without cerebral disease. Histologic studies were performed from two normal midbrain blocks. RESULTS: Expanded PV spaces were visible at the PMJ in 87% of subjects and at the MDJ in 63% of subjects. On axial images, ovoid or linear lesions with signal intensity compatible to CSF were present behind the cerebral peduncle at both the PMJ and MDJ. These areas varied from less than 1 mm to 5 mm (maximum diameter on coronal sections). Histologic studies confirmed the distribution of expanded PV spaces, as noted on MR images. CONCLUSION: This study, by using high-spatial-resolution MR imaging, revealed that expanded PV spaces were visible at the PMJ and MDJ. Our finding of expanded PV spaces normally present at the MDJ may be related to pathologically expanding PV spaces, which should be kept in mind as a differential diagnosis for intraparenchymal cystic lesions in the midbrain with signal intensity compatible to CSF.

Evidence for hepatocellular differentiation in alpha-fetoprotein-negative gastric adenocarcinoma with hepatoid morphology: a study with in situ hybridisation for albumin mRNA.

AIM: Hepatoid adenocarcinoma, a putative chemosensitive tumour, is defined as a tumour with aberrant hepatocellular differentiation occurring in extrahepatic organs such as the stomach, usually in the gastrointestinal tract. Differentiation in the hepatocellular direction is usually supported by the production of alpha-fetoprotein (AFP) and, more recently, albumin (ALB) mRNA. We investigated ALB mRNA to address whether adenocarcinoma with hepatoid morphology, regardless of AFP production, can be diagnosed solely by morphological criteria as a hepatoid adenocarcinoma. METHODS: We performed in situ hybridisation (ISH) and immunohistochemistry (IH) for ALB mRNA on AFP-negative gastric adenocarcinomas with hepatoid morphology. AFP-positive hepatoid adenocarcinomas and AFP-negative conventional gastric adenocarcinomas were also investigated as positive and negative controls, respectively. RESULTS: All three gastric adenocarcinomas with hepatoid morphology with no evidence of AFP production stained positive for ALB mRNA, thus providing evidence of differentiation in the hepatocellular direction. Three of five cases of AFP-positive hepatoid adenocarcinoma of the stomach were positive for ALB mRNA, while 11 cases of AFP-negative conventional gastric adenocarcinoma were negative. CONCLUSION: The present study demonstrates that, irrespective of AFP production, gastric adenocarcinoma with morphological patterns suggestive of hepatoid differentiation should be diagnosed as hepatoid adenocarcinoma with important prognostic implications.

Pathophysiology of tumor neovascularization.

Neovascularization is essential to the process of development and differentiation of tissues in the vertebrate embryo, and is also involved in a wide variety of physiological and pathological conditions in adults, including wound repair, metabolic diseases, inflammation, cardiovascular disorders, and tumor progression. Thanks to cumulative studies on vasculature, new therapeutic approaches have been opened for us to some life-threatening diseases by controlling angiogenesis in the affected organs. In cancer therapy, for example, modulation of factors responsible for tumor angiogenesis may be beneficial in inhibiting of tumor progression. Several antiangiogenic approaches are currently under preclinical trial. However, the mechanisms of neovascularization in tumors are complicated and each tumor shows unique features in its vasculature, depending on tissue specificity, angiogenic micromilieu, grades and stages, host immunity, and so on. For better understanding and effective therapeutic approaches, it is important to clarify both the general mechanism of angiogenic events and the disease-specific mechanism of neovascularization. This review discusses the general features of angiogenesis under physiological and pathological conditions, mainly in tumor progression. In addition, recent topics such as contribution of the endothelial progenitor cells, tumor vasculogenic mimicry, markers for tumor-derived endothelial cells and pericytes, and angiogenic/angiostatic chemokines are summarized.

Squamous predominance in mixed-epithelial papillary cystadenomas of borderline malignancy of mullerian type arising in endometriotic cysts: a study of four cases.

Mixed-epithelial papillary cystadenoma of borderline malignancy of mullerian type (MEBMM) is composed of a mixture of mullerian epithelial types, such as mucinous, serous, endometrioid, and squamous. Four cases of MEBMM with squamous overgrowth (MEBMMSO) were reviewed. The patients' median age was 56 years, and all cases were unilateral. The clinical stages were Ia (two cases), Ic (one case), and IV based on the presence of tumor cells in pleural fluid (one case). No recurrence was seen in three of the cases. In one of those three cases, there was no recurrence after undergoing surgery only; in the other two of those three cases, there was no recurrence after undergoing surgery and receiving postoperative chemotherapy. In the single case that was at stage IV at initial presentation, a recurrent MEBMMSO nodule was found at a second look 17 months after the initial surgery. In terms of gross findings, all of the tumors were cystic with intracystic papillary fronds. In addition, old endometriotic lesions lined the cysts. The tumors were mainly composed of a proliferation of squamous-type epithelium, with minor foci containing a mixture of other mullerian-type epithelia, especially mucinous. Intraepithelial infiltration by neutrophilic leukocytes was prominent. The differential diagnosis of MEBMMSO includes proliferating Brenner tumors.

Value of expression of p21WAF1/CIP1 as a prognostic factor in advanced middle and lower rectal cancer patients treated with preoperative radio-chemotherapy.

Recent molecular biological studies suggested certain molecular markers might be useful as prognostic factors in patients with colorectal cancer. The purpose of this study was to investigate whether cyclin dependent inhibitor kinase p21WAF1/CIP1 (p21), p53 expression, and/or the presence of apoptosis had prognostic value in predicting survival in patients with advanced middle and lower rectal cancer who were treated with preoperative radio-chemotherapy. We examined the immunohistochemical expression of p21 and p53, and determined the degree of apoptosis in resected middle and lower rectal cancers from patients who received preoperative radio-chemotherapy (irradiation group, n=40) and from those who did not receive treatment (control group, n=35). The preoperative total radiotherapy dose was 42.6 Gy and the chemotherapy tegafur suppository dose was 750 mg/day. Clinicopathological features, and tumor expression of p53 and p21 and degree of apoptosis were analyzed by means of multivariate analysis. In the irradiation group, tumors were positive for p53, p21 and apoptosis in 34 of 40 (85.0%), 23 of 40 (57.5%) and 25 of 40 (62.5%) cases, respectively. The expression of p21 and the apoptotic index were significantly higher in the irradiated group compared to controls (2.0 versus 1.2%, p=0.05; 8 versus 3%, p=0.03, respectively). There was a significant correlation between p21 immunoreactivity and the degree of muscularis propria invasion (p=0.004), as well as between p21 immunoreactivity and survival rate (p=0.03). Multivariate analysis revealed that p21 expression (RR, 0.09; 95% CI, 0.01-0.78; p=0.03) and lymph node metastasis (RR, 3.63; 95% CI, 1.06-12.37; p=0.04) were significant prognostic factors for patient survival. These data suggested that p21 expression has prognostic value in predicting patient survival in advanced middle and lower rectal cancer.

Apoptosis and apoptosis-associated gene products related to the response to neoadjuvant chemotherapy for gastric cancer.

To evaluate the effect of neoadjuvant chemotherapy on gastric cancer, we examined the correlation between induction of apoptosis and expression of p53, Bcl-2, and Bax. Eighty-five patients with advanced gastric cancer were retrospectively divided into the following two groups: 54 patients received 5-fluorouracil (5-FU) at 300 mg/body/day for 14 days and cisplatin (CDDP) at 15 mg/body/day for 2 days as group A; 31 patients without any preoperative chemotherapy as group B. According to histological changes in tumors due to neoadjuvant chemotherapy, the therapeutic effects on tumors were evaluated. The apoptotic index (AI) of group A was significantly higher than that of group B (1.12+/-0.40 vs. 0.67+/-0.24; p<0.01). In group A, the AI of p53-positive cases was significantly lower than that of negative cases (0.92+/-0.32 vs. 1.39+/-0.32; p<0.01). The AI of histological responders was significantly higher than that of non-responders (1.34+/-0.35 vs. 1.02+/-0.38; p<0.01). There was no significant correlation between AI and expression of Bcl-2 or Bax. In group A, histological responders, Bcl-2 positive, and high AI patients had better prognosis, respectively. In conclusion, neoadjuvant chemotherapy for gastric cancer enhanced induction of apoptosis, and AI might be useful to evaluate the effect of neoadjuvant chemotherapy.

Histologic characteristics of normal perivascular spaces along the optic tract: new pathogenetic mechanism for edema in tumors in the pituitary region.

BACKGROUND AND PURPOSE: Perivascular (PV) spaces are known to distend and cause edema along the optic tract (OT) in pituitary-region tumors. Interstitial fluid may be retained in PV spaces when tumors block their drainage outlets to subarachnoid spaces. However, these spaces and their outlets have not been anatomically elucidated. Our purpose was to evaluate how often large PV spaces are present along the OT and demonstrate their superficial communication points to adjacent subarachnoid spaces. METHODS: We examined serial histologic sections of 10 hemispheric blocks obtained from cadavers without cerebral abnormality. RESULTS: Large PV spaces, 0.5-1.5 mm in maximum height, were always present along the middle portion of the OT. Perforation points of the largest spaces were noted at the medial sulcus of the OT in seven hemispheres and through the OT in three. CONCLUSION: Large PV spaces are present along the middle portion of the OT. Their communication point to adjacent subarachnoid spaces was histologically demonstrated. The locations and variations of the outlet of large PV spaces explain the clinical features of edemas; these findings anatomically support the hypothesis that blockage of the outlets to subarachnoid spaces may play a role in distending the PV spaces and in causing edema in pituitary-region tumors. Only MR imaging has revealed this change; further pathologic investigations are awaited.

In vitro model of suicide gene therapy for alpha-fetoprotein-producing gastric cancer.

BACKGROUND: Gastric adenocarcinoma producing alpha-fetoprotein (AFP) has a very poor prognosis. In search of new therapeutic strategies against AFP-producing gastric cancer, we examined the efficacy of suicide gene therapy, which has been effective on AFP-producing hepatoma. MATERIALS AND METHODS: The herpes simplex virus thymidine kinase (HSVtk) gene was transduced into an AFP-producing gastric adenocarcinoma cell line, FU97, using adenovirus vectors carrying the constructed AFP enhancer/promoter element, followed by ganciclovir (GCV) administration. RESULTS: Expression of the transgene was evident in FU97 but not in an AFP-nonproducing gastric adenocarcinoma cell line, MKN28, which meant that AFP enhancer/promoter-specific transcriptional targeting was achieved by the vectors. The viability of FU97 but not of MKN28 significantly decreased after the suicide gene therapy in vitro. CONCLUSION: Therapeutic application of the AFP enhancer/promoter-specific transfer of the HSVtk gene followed by GCV administration against AFP-producing gastric cancer deserves attention and further research.

Further evidence of hepatic transdifferentiation in hepatoid adenocarcinomas of the stomach: quantitative analysis of mRNA for albumin and hepatocyte nuclear factor-4alpha.

AIMS: To assess the production of a liver-specific protein, albumin, and of a master transcriptional factor, hepatocyte nuclear factor (HNF)-4alpha, in hepatoid adenocarcinoma tissue. METHODS: Standard and quantitative RT-PCR, using five cases of hepatoid and three cases of non-hepatoid gastric adenocarcinoma. RESULTS: Hepatoid adenocarcinomas expressed similarly large amounts of albumin mRNA as those expressed in hepatocellular carcinoma and normal liver tissues. The observed amounts were several hundred times more than those in non-hepatoid adenocarcinoma and normal stomach tissues. HNF-4alpha mRNA was expressed in all stomach samples examined, and the levels of expression did not quantitatively differ between hepatoid and non-hepatoid adenocarcinomas of the stomach. CONCLUSIONS: These results provide further support of a relationship between hepatic transdifferentiation in hepatoid adenocarcinomas and albumin mRNA expression. Furthermore, transdifferentiation to the hepatocytic phenotype in hepatoid adenocarcinoma tissue was not directly associated with HNF-4alpha expression, thus suggesting that transdifferentiation proceeds by a complicated mechanism.