Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK): Co-expression in metastatic serous ovarian carcinoma

Activation or suppression of intracellular signaling via the mitogen-activated protein kinase (MAPK) family has been linked to expression of matrix metalloproteinases (MMP) in experimental models, but this association has not been demonstrated in clinical material. The objective of this study was to investigate the possible association between expression and activity of MMP, expression of the MMP inducer EMMPRIN, and the expression (level) and phosphorylation status (activity) of the extracellular-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK) and high osmolarity glycerol response kinase (p38) in effusions from patients diagnosed with serous ovarian carcinoma. MAPK level and activity were studied in 55 effusions using immunoblotting. MMP-1, MMP-2, MMP-9 and EMMPRIN expression was studied using immunocytochemistry (ICC) and mRNA in situ hybridization (ISH). The gelatinolytic activity of MMP-2 and MMP-9 was measured by zymography. ERK and phospho-ERK (p-ERK) were detected in 54/55 (98%) and 50/55 (91%) specimens, respectively. JNK and p-JNK were detected in 53/55 (96%) and 38/55 (69%) specimens, respectively. p38 was expressed in 54/55 (98%) specimens, and its phosphorylated form was found in 51/55 (92%). MMP-2 mRNA expression (P=0.048), protein expression (P=0.046) and gelatinolytic activity (P=0.039) correlated with ERK phosphorylative activity. MMP-2 activity also correlated with p38 activity (P=0.017). MMP-9 protein expression correlated with phosphorylation of p38 (P=0.046), but enzyme activity showed inverse relationship with both p-ERK (P=0.05) and p-p38 (P=0.033) expression. EMMPRIN expression correlated with MMP-1 (P<0.001), MMP-2 (P=0.042) and MMP-9 (P=0.029) expression, as well as with ERK activity (P=0.001). Our results present the first evidence of a possible link between MAPK signaling and MMP expression and activity in vivo. These data may expand our understanding regarding the mechanisms by which MMP synthesis is regulated in effusions and possibly affect treatment strategies for this form of malignancy. This revised version was published online in July 2006 with corrections to the Cover Date.     

Fine-needle aspiration cytology of lobular carcinoma in situ

Fine-needle aspiration cytology (FNAC) plays a key role in the preoperative diagnosis of breast carcinoma but is less reliable in the diagnosis of in situ lesions. The objective of the present study was to investigate the cytological features of lobular carcinoma in situ (LCIS), regarding which little data is available to date. Cytological features of FNAC of the breast from 21 patients with histology-proven LCIS were described and compared with surgical specimens. Aspirates from 8/21 cases had cell groups diagnostic for or compatible with LCIS. Aspirates from an additional two cases demonstrated hypercellular, dissociated, and more pleomorphic tumor cells, which were originally diagnosed as invasive lobular carcinoma (ILC). The remaining 11 aspirates were diagnosed as benign or nondiagnostic. FNAC from the eight diagnostic specimens were characterized by loosely cohesive cell groups composed of uniform cells with occasional intracytoplasmic lumina, slightly irregular and eccentric nuclei. We conclude that the main difficulty in diagnosing LCIS by FNAC is sampling rather than recognition of the lesions. However, one should be aware of the cytological features of LCIS in order to reach a correct diagnosis. There are no reliable cytological criteria that help in differentiating pleomorphic and dissociated LCIS from ILC.     

Differential expression of CD44s and CD44v3-10 in adenocarcinoma cells and reactive mesothelial cells in effusions

The detection of malignant cells in serous effusions obtained from patients diagnosed with cancer marks the presence of metastatic disease and is associated with a poor outcome. The purpose of this study was to evaluate the role of CD44s and CD44v isoforms in the distinction between mesothelial cells and malignant epithelial cells in effusions. Fifty-nine fresh pleural and peritoneal effusions were studied. These consisted of 41 specimens from patients with known gynecological neoplasms, 9 from patients diagnosed with breast adenocarcinoma, and 9 effusions from patients with various nongynecological malignancies or tumors of unknown origin. Forty-three effusions contained malignant/atypical epithelial cells, and 16 effusions were diagnosed as reactive. Three effusions contained exclusively malignant cells. Specimens were stained with anti-CD44s, v3, v5, v6, v7 and v3-10. The presence of staining in cancer cells, benign mesothelial cells and lymphocytes was evaluated. CD44s immunoreactivity was seen in 10 of 43 (23%) cases in malignant/atypical epithelial cells and in 53 of 56 (94%) cases in benign cells. In contrast, CD44v3-10 was seen in 23 of 43 (55%) cases in malignant/atypical epithelial cells and in 3 of 56 (6%) cases in benign cells. We advocate the use of CD44s and CD44v3-10 immunostaining in diagnostic evaluation of difficult serous effusions. Received: 30 August 1999 / Accepted: 8 November 1999     

Molecular definition of a small amplification domain within 3q26 in tumors of cervix, ovary, and lung

A common amplification target encompassing chromosome region 3q25 to q27 has been identified by comparative genomic hybridization analyses in tumors of the cervix, ovary, endometrium, lung, and head and neck. Because this segment spans at least 30 megabases, we undertook a molecular analysis of copy number to more precisely define the amplification domain. Our Southern blot and fluorescence in situ hybridization results with the use of 17 markers confirmed the presence of low-level 3q amplification events in cervical, ovarian, and variant SCLC tumors. Most of the tumor types studied appeared to have similar, broad amplification domains centered within 3q26.2, suggesting that the same target is being affected in all. The ovarian carcinoma cell line NIH:OVCAR3 had a highly restricted amplification domain spanned by four overlapping YAC clones, suggesting a small target. The region of highest amplification included the gene for the RNA component of telomerase (hTR), supporting it as a potential target. Although the importance of low-level amplification is unknown, the consistent and reproducible nature of this event in a variety of carcinomas suggests that 3q26.2 harbors an oncogene whose low-level amplification has a significant influence on tumor biology.     

Lateral Differences in the Latency Between Finger Tapping and the Heart Beat

Based upon suggestions that the two cerebral hemispheres may be differentially involved in the perception and regulation of autonomic activity, three studies were designed to explore differences in the relationship between left versus right hand finger tapping and the heartbeat. In each study, right-handed subjects were asked to tap with either their left versus right forefingers regularly at the rate of approximately once per second. When the time from the R-spike immediately preceding their tap to the tap was examined, a significant difference between the two hands was obtained in two of the studies, with the left hand tapping closer to the last R-spike compared with the right. A variety of additional conditions in the experiments suggest that this effect may depend upon tapping rhythmically. The implications of these findings for the differential role of the left and right hemispheres in the perception and regulation of cardiac activity are considered.     

Primary primitive neuroectodermal tumor of the cauda equina

Primitive neuroectodermal tumors (PNETs) are aggressive neoplasms composed predominantly of undifferentiated cells that show evidence of neural differentiation. Although their classification has been controversial, PNETs are well recognized primary tumors of both central and peripheral nervous systems. PNETs must be distinguished from other round-cell tumors, including Ewing's sarcoma, lymphoma, rhabdomyosarcoma, and small cell carcinoma. Intraspinal PNETs are rare neoplasms that are usually metastatic in origin. We describe the eighth reported primary PNET of the cauda equina that developed in a 52-year-old man with no significant medical history. The tumor was characterized by Homer-Wright rosettes and immunoreactivity for CD99, glial fibrillary acidic protein, neuron-specific enolase S100, and synaptophysin. The anatomic location of primary intrathecal PNETs is important as those arising in the spinal cord develop in the central nervous system, whereas those arising in the cauda equina develop in the peripheral nervous system. The histogenesis of intrathecal PNETs may be multifactorial.