Germ cell tumor in the hypothalamo-neurohypophysial region: clinical features and treatment

Twenty-one patients with germ cell tumors (17 germinomas and 4 teratomas) involving the hypothalamic-neurohypophysial (HN) region were reviewed retrospectively. Eleven patients were males and 10 females, and their ages ranged from 7 to 45 years (average 18.5 years). Diabetes insipidus was the initial and the most prominent symptom in most germinomas; in teratomas the most prominent symptom was visual disturbance. Fifteen patients with germinomas were treated by radiotherapy, and 4 with teratomas were treated by surgical resection alone. Two recent germinoma patients with extensive CSF dissemination were treated with systemic chemotherapy consisting of anticancer platinum drugs and etoposide, which resulted in a complete disappearance of the tumors. Patients with germinoma treated after the introduction of CT scanning had a greatly improved mortality rate, and their actual survival rate was 87.5% over 10 years. On the basis of this review, the authors consider that diagnosis at an early stage of the disease and chemotherapy, which can be an effective therapeuric alternative to radiation therapy, may improve not only the mortality rate but also the quality of life of patients with HN germ cell tumors.     

Long-term follow-up study of 268 diabetic patients undergoing haemodialysis, with special attention to visual acuity and heterogeneity

We studied the long-term outcome of 268 patients suffering fromdiabetic end-stage renal disease (DM-ESRD) treated with long-termhaemodialysis between 1978 and 1991, with special emphasis onvisual acuity as well as the heterogeneity of DM-ESRD The 50%patient survival on haemodialysis was 60 months. Visual disturbanceswere found in 73.1% (392/536) of eyes at the start of haemodialysis.Chronological assess ment of visual acuity demonstrated thestabilization of visual acuity and 87.1% (364/418) of eyes werestable, 4.8% (20/418) were improved, and 8.1% (34/418) wereaggravated in the long term respectively. The change of visualacuity was frequently seen in the short term, and rapid shiftsof body fluid to correct overhydration induced abrupt changesof glycaemic control as well as retraction of macular oedema.Hence it might be one of the factors affecting rapid changeof visual acuity in the short term. Meanwhile, long-term deterioration of visual acuity resulted from either hyperten sionunresponsive to medical treatment or poor glycaemic control.Some DM-ESRD patients had only background retinopathy at thestart of haemodialysis and these were likely to have the nephroscleroticglomerular lesion. They were old, not nephrotic and had a milddegree of diabetes during the predialysis stage. Thus, DM-ESRDpatients seem to have some heterogeneity in their clinical characteristics,and old DM-ESRD patients with only background retinopathy havethe appearance of diabetic macroangiopathy rather than microangiopathy.     

Biliary cystadenoma with mesenchymal stroma of the liver: Correlation between unusual MR appearance and pathologic findings

We reported a case of the biliary cystadenoma of the liver. The cystic mass had labulation and septation and showed marked hyperintensity on T1-weighted images and hypointensity on T2-weighted images; MR findings were very unusual for cystadenoma. The content of the cystic mass was jelly-like, thick mucinous fluid without intracystic hemorrhage. We concluded that these unusual signal intensities of the cyst were due to hyperproteinous mucinous fluid.     

Correlation between vibration-induced white finger and symptoms of upper and lower extremities in vibration syndrome

Summary The correlation was investigated between the frequency of attacks of vibration-induced white finger (VWF) and numbness or coldness of the fingers and legs in patients with vibration syndrome. Some 1687 patients with vibration syndrome were examined and of these 342 chain-saw operators and 277 rock-drill operators had no disease other than vibration snydrome. Then subjects were matched by age and period of treatment within three years. In the last analysis, 20 in the VWF almost everyday group or in the never group, and 40 in the occasionally group were selected from the chain-saw operators, and from the rock-drill operators 32 in the VWF everyday or the never group and 64 in the occasionally group. The present study showed that, with the frequency of VWF attacks, patients had a higher prevalence of coldness not only in the fingers but also in the legs. These findings suggest a correlation between the severity of circulatory disturbances of the upper extremities and that of the lower ones in patients with vibration syndrome. Further studies on circulatory disturbances in the leg are required.     

Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients

Classical citrullinemia (CTLN1), a rare autosomal recessive disorder, is caused by mutations of the argininosuccinate synthetase (ASS) gene, localized on chromosome 9q34.1. ASS functions as a rate-limiting enzyme in the urea cycle. Previously, we identified 32 mutations in the ASS gene of CTLN1 patients mainly in Japan and the United States, and to date 34 different mutations have been described in 50 families worldwide. In the present study, we report ASS mutations detected in 35 additional CTLN1 families from 11 countries. By analyzing the entire coding sequence and the intron-exon boundaries of the ASS gene using RT-PCR and/or genomic DNA-PCR, we have identified 16 novel mutations (two different 1-bp deletions, a 67-bp insertion, and 13 missense) and have detected 12 known mutations. Altogether, 50 different mutations (seven deletion, three splice site, one duplication, two nonsense, and 37 missense) in 85 CTLN1 families were identified. On the basis of primary sequence comparisons with the crystal structure of E. coli ASS protein, it may be concluded that any of the 37 missense mutations found at 30 different positions led to structural and functional impairments of the human ASS protein. It has been found that three mutations are particularly frequent: IVS6-2A>G in 23 families (Japan: 20 and Korea: three), G390R in 18 families (Turkey: six, U.S.: five, Spain: three, Israel: one, Austria: one, Canada: one, and Bolivia: one), and R304W in 10 families (Japan: nine and Turkey: one). Most mutations of the ASS gene are "private" and are distributed throughout the gene, except for exons 5 and 12-14. It seems that the clinical course of the patients with truncated mutations or the G390R mutation is early-onset/severe. The phenotype of the patients with certain missense mutations (G362V or W179R) is more late-onset/mild. Eight patients with R86H, A118T, R265H, or K310R mutations were adult/late-onset and four of them showed severe symptoms during pregnancy or postpartum. However, it is still difficult to prove the genotype-phenotype correlation, because many patients were compound heterozygotes (with two different mutations), lived in different environments at the time of diagnosis, and/or had several treatment regimes or various knowledge of the disease.     

Development of a high-level expression system for deuterium-labeled human serum albumin

We have developed an expression system for recombinant human serum albumin (rHSA) using methylotrophic yeast Pichia pastoris Mut(+) transformants together with the multiple cross-over integration of the vector containing human serum albumin (HSA). After 86 h of methanol induction, the secreted rHSA reached levels of approximately 320 mg/l in 100% H(2)O medium and approximately 180 mg/l in 70% D(2)O/30% H(2)O (v/v) medium in a fed-batch fermenter. The structures of the obtained rHSA and plasma-derived HSA (pHSA) were virtually identical as viewed from various physicochemical techniques such as HPLC, SDS gel electrophoresis, and CD. NMR peaks of the partially deuterium (D)-labeled rHSA (DrHSA) were quite sharp compared to those of pHSA due to suppression of the intramolecular nuclear Overhauser effect, promising further structural studies of the whole HSA molecule in the solution state using the recent NMR techniques.     

CD44 variant 6 in endometrioid carcinoma of the uterus: its expression in the adenocarcinoma component is an independent prognostic marker

The expression of variant isoforms of CD44 (CD44v) correlates with the metastatic potential of various carcinomas. In endometrial cancer, however, the significance of CD44v-expression as a prognostic indicator has not been fully investigated, nor has it been compared with that of p53, estrogen receptor or Ki67. Surgical material consisted of 14 atypical endometrial hyperplasias (AEH) and 163 endometrial carcinomas (EC). Expression of CD44s, v3 and v6 in carcinoma tissue, and other prognostic markers were immunohistochemically evaluated. The expression in the squamous differentiation was strictly excluded for the evaluation of immunohistochemistry, because the significance was different from that in the adenocarcinoma component. CD44s was frequently expressed in AEH and EC. On the other hand, CD44v3- and v6-positivities were rare or nonexistent in AEH, but were observed in 8 and 35% of EC, respectively. CD44v3-expression correlated significantly with histologic grade and lymph node metastasis. However, there was no correlation between CD44v6 expression and any clinicopathologic factor, nor were other prognostic markers expressed. Univariate analysis revealed that each CD44 was a prognostic determinant in the patients with EC. However, employing multivariate analysis, there were only three independent factors: p53 overexpression, CD44v6 expression and myometrial invasion. CD44v6 expression in the adenocarcinoma component may directly affect the behavior of carcinoma and the prognosis of patients with EC.     

Genomic alterations in primary cutaneous melanomas detected by metaphase comparative genomic hybridization with laser capture or manual microdissection: 6p gains may predict poor outcome

To clarify the correlation of genomic alterations with clinical and histological features, we performed metaphase comparative genomic hybridization analysis on 20 primary cutaneous melanomas, which were obtained by laser capture or manual microdissection, and 16 melanoma cell lines. There were no differences in the average number of aberrations between acral melanomas (AM) and non-AM, although gains of 5q and 11q13 were more frequent (P=0.05) and 10q loss was less frequent (P=0.01) in AM than in non-AM. Although tumor thickness is considered a measurable estimate of clinical expression, there were no differences in the average number of aberrations among 4 groups, classified by thickness of the tumor. While the majority of aberrations were equally distributed among the 4 groups, 6p gains were found only in the thickest tumors. Patients with 6p or 1q gains had a lower overall survival rate than those without them (P=0.0002 or P=0.013). While gains of 1q, 2q, 3p, 3q, 7q, 20p, and 20q were more frequent in the cell lines than in the primary tumors (P<0.01), losses of 6q, 9p, 10p, and 10q were equally found in both cell lines and primary tumors. The present study showed that chromosomal aberrations had already occurred in the thinner tumors, and that 6p and 1q gains may be a prognostic factor.     

Two Cases of Peritoneal Serous Papillary Adenocarcinoma

Two cases of peritoneal papillary carcinoma are reported. The patient in the first case was a 71-year-old woman with symptoms of obstructive ileus. Laparotomy revealed a tumor in the omentum involving the transverse colon, and several small tumors in the peritoneum and pelvic wall. However, no primary site of the tumor was seen in the ovary, pancreas, or gastrointestinal tract. The patient in the second case was a 44-year-old woman with carcinomatous peritonitis. Postmortem examination revealed multiple tumors in the peritoneum, omentum, and pelvic wall. Tumors were also found in the cortex with mild invasion of the underlying parenchyma of the bilateral ovaries, although these lesions were thought to be metastatic. The histologic features of the tumor in both cases were those of tubulopapillary adenocarcinoma containing scattered psammoma bodies. The cells were positive with the PAS D technique, but negative with alcian blue staining. In both cases, the serum levels of CA-125 were considerably elevated, and the tumor cells showed positivity for CA-125, S 100 protein, cytokeratin and EMA by im-munohistochemistry. The present cases were most likely peritoneal serous papillary adenocarcinoma derived from extraovarian peritoneal mesothelium with miillerian potential, being different from the usual type of diffuse malignant mesothelioma. Acta Pathol Jpn 41: 642-646, 1991.     

Frequent co-localization of Cox-2 and laminin-5 gamma2 chain at the invasive front of early-stage lung adenocarcinomas

Laminin-5 is an extracellular matrix protein that plays a key role in cell migration and tumor invasion. Cox-2 is an induced isoform of cyclooxygenases that plays an important role in carcinogenesis, suppression of apoptosis, angiogenesis, and metastasis of colon cancer. We report frequent co-expression of cox-2 and laminin-5 at the invasive front of early-stage lung adenocarcinomas. We investigated the expression of cox-2 and laminin-5 immunohistochemically in 102 cases of small-sized lung adenocarcinoma (maximum dimension, 2 cm or less). Cox-2 and laminin-5 were expressed in 97 (95.1%) and 82 (80.4%) cases, respectively. Both were preferentially localized in cancer cells at the cancer-stroma interface, although cox-2 tended to show a diffuse staining pattern in some cases. A comparison of their staining patterns revealed a striking similarity in their distribution in 24 cases, and a partial overlap between their localization in another 20 cases. Moreover, an overall correlation was found between the expression levels of cox-2 and laminin-5 (P = 0.018). To gain insight into the mechanisms that regulate the expression of these proteins, we additionally studied their expression in 58 cases of stage I lung adenocarcinoma, in which p53 status was determined by immunohistochemistry, polymerase chain reaction-single strand conformation polymorphism analysis, and direct sequencing. The results showed that tumors with mutant p53 tended to express more cox-2 than those with wild-type p53 (P = 0.080). Also, tumors that overexpressed p53 had higher levels of cox-2 and laminin-5 than those without p53 overexpression (P = 0.032 and 0.047, respectively). Further immunohistochemical analysis showed that tumors that overexpressed both epidermal growth factor receptor (EGFR) and erbB-2 had higher levels of cox-2 and laminin-5 than those without concomitant overexpression of these proteins (P = 0.014 and P = 0.018, respectively). To see whether EGFR signaling is involved in cox-2 and laminin-5 expression, we further conducted in vitro analyses using six lung adenocarcinoma cell lines (A549, HLC-1, ABC-1, LC-2/ad, VMRC-LCD, and L27). Western blot analyses showed that cox-2 mRNA levels, and to a lesser extent laminin-5 gamma2 mRNA levels, correlated with the expression levels of erbB-2 and the phosphorylated form of MAPK/ERK-1/2 protein. The addition of transforming growth factor-alpha increased both cox-2 and laminin-5 gamma2 mRNA levels in A549, ABC-1, and L27 with different kinetics; the induction of cox-2 occurred earlier than that of laminin-5 gamma2. Finally, the migration of ABC-1 cells was inhibited by MAP kinase kinase inhibitor PD98059 and a selective cox-2 inhibitor NS-398. In contrast, the migration of A549 cells was inhibited by PD98059, but much less effectively by NS-398. These results suggest that co-stimulatory mechanisms may exist that increase the expression of cox-2 and laminin-5 at the invasive front of lung adenocarcinomas and that EGFR signaling could be one of the mechanisms. Further investigations are warranted concerning the role of cox-2 and laminin-5 in cancer cell invasion and the significance of p53 and EGFR signaling in the regulation of cox-2 and laminin-5 expression.