Monoclonality of composite large-cell neuroendocrine carcinoma and invasive intestinal-type mucinous adenocarcinoma of the cervix: a case study.

A rare case of mixed carcinoma of the cervix is reported, composed of a large-cell neuroendocrine carcinoma and an invasive intestinal-type mucinous adenocarcinoma. The large-cell neuroendocrine carcinoma was composed of solid nests, sheets, and trabeculae of medium-sized to large-sized cells, and was positive for chromogranin-A and CD56. The invasive intestinal-type mucinous adenocarcinoma showed sparsely scattered immunoreactivity for chromogranin-A. Using an X-chromosome clonality assay, these 2 components showed patterns of monoclonality. These results suggest that the large-cell neuroendocrine carcinoma may have arisen from the invasive mucinous adenocarcinoma.

Clinicopathological significance of podocalyxin and phosphorylated ezrin in uterine endometrioid adenocarcinoma.

BACKGROUND: Podocalyxin is an anti-adhesive glycoprotein that has been associated with highly aggressive forms of cancers. Podocalyxin increases the migration and invasive properties of cancer cells through its interaction with ezrin, which undergoes an increase in phosphorylation through podocalyxin. AIMS: To study the roles of podocalyxin and phosphorylated ezrin (pEzrin) in uterine endometrioid adenocarcinoma (UEA). METHODS: Using immunohistochemisty the authors investigated the expression of podocalyxin and pEzrin along with some well-known markers of tumour aggressiveness including p53, oestrogen receptor and Ki-67 in UEA. RESULTS: Podocalyxin and pEzrin expression levels were positive in 36.1% (22 of 61 patients) and 50.8% (31 of 61 patients) of UEA cases, respectively. Further, podocalyxin expression was correlated with tumour grade (p=0.0001), FIGO stage (p=0.0062), p53 expression (p=0.0050) and Ki-67 index (p=0.0069). In addition, pEzrin expression was associated with FIGO stage (p=0.0231), p53 expression (p<0.0001) and Ki-67 index (p=0.0010). The expression of podocalyxin was also correlated with that of pEzrin (p=0.0102). CONCLUSIONS: These results suggest that overexpression of podocalyxin and pEzrin may indicate a more aggressive phenotype; thus, evaluation of these proteins may be useful in prediction of disease progression in UEA cases.

Neuropilin-2 expression in papillary thyroid carcinoma: correlation with VEGF-D expression, lymph node metastasis, and VEGF-D-induced aggressive cancer cell phenotype.

CONTEXT: Neuropilin-2 (Nrp2) is a coreceptor for vascular endothelial growth factor-D (VEGF-D) that is expressed on the surface of endothelial cells. Recently, Nrp2 was shown to play a role in lymph node metastasis and promotion of cancer cell migration. VEGF-D also promotes lymphangiogenesis, which in turn promotes tumor metastasis. OBJECTIVE: The aim was to study the role of neuropilin-2 in lymph node metastasis in human papillary thyroid carcinoma (PTC). DESIGN: Expression of Nrp2 was studied by immunohistochemistry and the relationship between Nrp2 expression and lymph node metastasis, VEGF-D expression and other established clinicopathological variables were analyzed in PTC. The effects of neutralizing anti-Nrp2 antibody on VEGF-D-induced invasion and migration were assessed in PTC cell lines. RESULTS: Nrp2 expression was observed in 64.3% (36 of 56) of the PTC patients. Nrp2 expression was significantly correlated with lymph node metastasis (P = 0.0216) and VEGF-D expression (P = 0.0034). VEGF-D was shown to promote filopodia formation and cancer cell migration and invasion by K1 and B-CPAP cells. These responses were significantly blocked by neutralizing anti-Nrp2 antibody. CONCLUSION: Nrp2 expression was correlated with lymph node metastasis and VEGF-D expression in PTC. Our data also showed a role for Nrp2 in regulating VEGF-D-induced invasion and migration in vitro.

A rare case of xanthogranuloma of the stomach masquerading as an advanced stage tumor.

BACKGROUND: Xanthogranuloma of the stomach is an extremely rare disease, and this lesion has only been found to coexist with early gastric cancer in 2 cases in the literature. CASE PRESENTATION: We report a case of xanthogranuloma of the stomach combined with early gastric cancer that mimicked an advanced stage tumor. A 65-year-old female was referred to our hospital because of epigastralgia. During a physical examination, a defined abdominal mass was palpable in the region of the left hypochondrium. Imaging studies revealed an advanced gastric cancer, which was suspected of having infiltrated the abdominal wall. Total gastrectomy and resection of the regional lymph node and abdominal wall were performed. Histopathologic examination of the resected specimen demonstrated xanthogranuloma combined with early gastric cancer. CONCLUSION: Xanthogranuloma presenting as a form of SMT (submucosal tumor) of the stomach is an extremely rare disease, and diagnosing it preoperatively is difficult. Further accumulation and investigation of this entity is necessary.

Neuropilin-2 expression in breast cancer: correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression.

BACKGROUND: Neuropilin-2 (Nrp2) is a receptor for vascular endothelial growth factor-C (VEGF-C), which is a well-known lymphangiogenic factor and plays an important role in lymph node metastasis of various human cancers, including breast cancer. Recently, Nrp2 was shown to play a role in cancer by promoting tumor cell metastasis. CXC chemokine receptor 4 (CXCR4) also promotes tumor metastasis. In the previous studies, we demonstrated that VEGF-C and cytoplasmic CXCR4 expressions were correlated with poorer patient prognosis (BMC Cancer 2008,8:340; Breast Cancer Res Treat 2005, 91:125-132). METHODS: The relationship between Nrp2 expression and lymph node metastasis, VEGF-C expression, CXCR4 expression, and other established clinicopathological variables (these data were cited in our previous papers), including prognosis, was analyzed in human breast cancer. Effects of neutralizing anti-Nrp2 antibody on CXCR4 expression and chemotaxis were assessed in MDA-MB-231 breast cancer cells. RESULTS: Nrp2 expression was observed in 53.1% (60 of 113) of the invasive breast carcinomas. Nrp2 expression was significantly correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Survival curves determined by the Kaplan-Meier method showed that Nrp2 expression was associated with reduced overall survival. In multivariate analysis, Nrp2 expression emerged as a significant independent predictor for overall survival. Neutralizing anti-Nrp2 antibody blocks cytoplasmic CXCR4 expression and CXCR4-induced migration in MDA-MB-231 cells. CONCLUSION: Nrp2 expression was correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Nrp2 expression may serve as a significant prognostic factor for long-term survival in breast cancer. Our data also showed a role for Nrp2 in regulating cytoplasmic CXCR4 expression in vitro.

Coexistence of a clear cell adenocarcinoma and an adenosarcoma with a heterologous rhabdomyosarcoma in an endometriotic cyst of the ovary: a case study.

SUMMARY: A rare case of a clear cell adenocarcinoma and an adenosarcoma coexisting with a heterologous rhabdomyosarcoma in an endometriotic cyst of the ovary is reported. The tumor was composed of a cystic area and a solid area arising from the cyst wall. In the cystic lesion, a detached polypoid mass was also identified. The cyst wall was lined with a single layer of endometrial-type cells, whereas the solid area was composed of a clear cell adenocarcinoma. In the detached polypoid mass, an exophytic leaf-like pattern containing benign endometrial-type cells and squamous epithelial and rhabdomyosarcoma components, which were positive for desmin and myoglobin, was observed. Using X-chromosomal clonality assay, these clear cell adenocarcinoma and adenosarcoma components showed patterns of polyclonality. To the authors' knowledge, this is the first reported case of a clear cell adenocarcinoma and an adenosarcoma coexisting with heterologous rhabdomyosarcoma in an endometriotic cyst of the ovary.

[Histoculture drug response assay guided adjuvant chemotherapy in patients with ERCC1-positive non-small cell lung cancer].

PURPOSE: A previous large randomized control study(IALT)revealed that cisplatin(CDDP)-based adjuvant chemotherapy was not effective for patients with ERCC1-positive non-small cell lung cancer(NSCLC). We evaluated the chemosensitivity of surgically resected specimens of NSCLC using in vitro chemosensitivity test and searched for promising adjuvant chemotherapy protocols in the ERCC1-positive subgroup of NSCLC. PATIENTS AND METHODS: Chemosensitivities of 10 anticancer agents including cisplatin were evaluated by histoculture drug response assay(HDRA) using 28 surgically resected NSCLC specimens. ERCC 1 status was evaluated by immunohistochemistry. RESULTS: ERCC1 was positive in 22 and negative in 6 specimens. All ERCC1-negative specimens were sensitive for CDDP in HDRA, and all CDDP-resistant specimens in HDRA showed positive ERCC1 staining. ERCC1 status was significantly correlated with CDDP sensitivity(p=0.01). HDRA showed average 3(0-6)sensitive anticancer agents except for CDDP even in ERCC1-positive specimens. CONCLUSION: HDRA may provide effective non-platinum adjuvant chemotherapy protocols for patients with ERCC1-positive, i.e. CDDP resistant, NSCLC.

Monoclonality of composite large cell neuroendocrine carcinoma and mucinous epithelial tumor of the ovary: a case study.

A rare case of mixed carcinoma of the ovary is reported, composed of a large cell neuroendocrine carcinoma and a mucinous borderline endocervical tumor. The large cell neuroendocrine carcinoma was composed of solid nests, sheets, and trabeculae of medium to large-sized cells, and was positive for synaptophysin. The mucinous epithelial tumor varied in appearance from a borderline to an intraepithelial carcinoma, and showed sparsely scattered immunoreactivity for chromogranin-A. Using an X-chromosome clonality assay, these 2 components showed patterns of monoclonality. These results suggest that the large cell neuroendocrine carcinoma may have arisen from the mucinous epithelial tumor.

Cytoplasmic CXCR4 expression in breast cancer: induction by nitric oxide and correlation with lymph node metastasis and poor prognosis.

BACKGROUND: Lymph nodes constitute the first site of metastasis for most malignancies, and the extent of lymph node involvement is a major criterion for evaluating patient prognosis. The CXC chemokine receptor 4 (CXCR4) has been shown to play an important role in lymph node metastasis. Nitric oxide (NO) may also contribute to induction of metastatic ability in human cancers. METHODS: CXCR4 expression was analyzed in primary human breast carcinoma with long-term follow-up. The relationship between nitrotyrosine levels (a biomarker for peroxynitrate formation from NO in vivo) and lymph node status, CXCR4 immunoreactivity, and other established clinico-pathological parameters, as well as prognosis, was analyzed. Nitrite/nitrate levels and CXCR4 expressions were assessed in MDA-MB-231 and SK-BR-3 breast cancer cell lines after induction and/or inhibition of NO synthesis. RESULTS: CXCR4 staining was predominantly cytoplasmic; this was observed in 50%(56/113) of the tumors. Cytoplasmic CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis. Kaplan-Meier survival curves showed that cytoplasmic CXCR4 expression was associated with reduced disease-free and overall survival. In multivariate analysis, cytoplasmic CXCR4 expression emerged as a significant independent predictor for overall and disease-free survival. Cytoplasmic expression of functional CXCR4 in MDA-MB-231 and SK-BR-3 cells was increased by treatment with the NO donor DETA NONOate. This increase was abolished by L-NAME, an inhibitor of NOS. CONCLUSION: Our data showed a role for NO in stimulating cytoplasmic CXCR4 expression in vitro. Formation of the biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in vivo. In addition, cytoplasmic CXCR4 expression may serve as a significant prognostic factor for long-term survival in breast cancer.

CXCR4 expression in papillary thyroid carcinoma: induction by nitric oxide and correlation with lymph node metastasis.

BACKGROUND: Metastasis to regional lymph nodes is a common step in the progression of cancer. Recent evidence suggests that tumor production of CXCR4 promotes lymph node metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers. METHODS: Nitrite/nitrate levels and functional CXCR4 expression were assessed in K1 and B-CPAP papillary thyroid carcinoma (PTC) cells after induction and/or inhibition of NO synthesis. CXCR4 expression was also analyzed in primary human PTC. The relationship between nitrotyrosine levels, which are a biomarker for peroxynitrate formation from NO in vivo, CXCR4 expression, and lymph node status was also analyzed. RESULTS: Production of nitrite/nitrate and functional CXCR4 expression in both cell lines was increased by treatment with the NO donor DETA NONOate. The NOS inhibitor L-NAME eliminated this increase. Positive CXCR4 immunostaining was observed in 60.7% (34/56) of PTCs. CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis in human PTC. CONCLUSION: Our data indicate that NO stimulates CXCR4 expression in vitro. Formation of the NO biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in human PTC. NO may induce lymph node metastasis via CXCR4 induction in papillary thyroid carcinoma.

Nuclear localization of glyceraldehyde-3-phosphate dehydrogenase is not involved in the initiation of apoptosis induced by 1-Methyl-4-phenyl-pyridium iodide (MPP+).

Nuclear localization of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is implicated in the process of apoptosis. To study the function of GAPDH, we expressed GAPDH C-terminally fused with or without nuclear localization signal (NLS) in SH-SY5Y and NB41A3 cells using a retrovirus expression system. GAPDH carrying NLS (GAPDH-NLS) was expressed mainly in the nucleus. However, expression of GAPDH-NLS did not cause any difference in cell survival rate as compared to that of the vector alone or GAPDH without NLS. Treatment with 1-Methyl-4-phenyl-pyridium iodide (MPP+) caused no difference in the cell survival rate or in the pattern or extent of apoptosis among the three transductants. In the cells expressing GAPDH without NLS, MPP+ did not cause visible translocation of GAPDH into nucleus before the onset of apoptosis. Since GAPDH is known to comprise a CRM1-mediated nuclear export signal, we blocked the nuclear export of GAPDH by treatment with leptomycin B, an inhibitor of CRM1-mediated nuclear export. The treatment did not cause any difference in apoptosis among the three transductants. An additional treatment with MPP+ induced no apoptotic difference in these cells. Thus, we have concluded that a simple nuclear localization of GAPDH does not induce apoptosis, and that MPP+-induced apoptosis is not caused by nuclear translocation of GAPDH.

Cerebellar atrophy in a patient with anorexia nervosa.

UNLABELLED: Reversible cerebral atrophy (pseudoatrophy) is observable in patients with anorexia nervosa. However, it is extremely rare to see marked cerebellar atrophy. OBJECTIVES: We report on a patient who developed cerebellar atrophy after the severe deterioration of cardiac and respiratory functions resulting from undernutririon. RESULTS: A 30-year-old Japanese woman was admitted to the Wakayama Medical University Hospital (Wakayama, Japan) because of unsteadiness of gait. She had a 7-year history of anorexia nervosa and had been admitted to an emergency hospital because of asthenic shock resulting from severe undernutrition at the age of 28. On admission to our hospital, neurologic examination revealed dysarthria and cerebellar ataxia of the trunk and lower extremities without nystagmus. A brain magnetic resonance imaging scan demonstrated marked atrophy of the cerebellum. DISCUSSION: Because her cerebellar ataxia appeared during severe deterioration of her general condition, and there has been no subsequent progression, it is possible that her cerebellar atrophy was induced by undernutrition.

[Three patients with Parkinson's disease whose therapeutic levels were successfully improved after administration of quetiapine for suppression of psychosis].

Psychosis characterized by hallucination or delusion, which occurs during drug therapy of parkinsonian patients, is one of the limiting factors for the control of motor symptoms or complications. In the present study, we encountered three patients with Parkinson's disease (PD) at advanced stages; all three patients had severe psychosis and severe wearing-off phenomenon and one had severe orthostatic hypotension. Their psychotic symptoms were successfully treated by administration of quetiapine, resulting in the favorable control of motor fluctuations and elevation of therapeutic levels unless any aggravation of parkinsonism occurs. Although the measure against drug-induced psychosis is principally a reduction of the doses or withdrawal of causative drugs, the effective use of antipsychotic drugs, such as quetiapine, is helpful to suppress psychosis and allow the patient to adjust to antiparkinsonian drugs for the control of symptoms other than psychosis.