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Shwachman-Diamond syndrome with Shwachman-Bodian-Diamond syndrome (SBDS) biallelic variants is a rare disorder that predisposes the carrier to malignant hemopathies but solid-cancer predisposition is poorly known. Among 155 cases entered in the French Registry for Severe Chronic Neutropenia, three were identified with malignant solid tumors (ovary, breast, and esophagus). All cancers occurred during the fifth decade and, despite being localized at diagnosis, were rapidly fatal thereafter. No cancer was observed post transplantation in the 14 HSCT survivors. Based on the literature and our patient data, we can merely advance that this complication is predominantly diagnosed in adults.

Although anal cancer remains a relatively uncommon tumour its frequency is rising, especially in high-risk groups. It is now well recognized that anal squamous cell carcinoma, the largely predominant tumour type, shares many similarities with cancer of the uterine cervix, with a major role for oncogenic human papilloma viruses in both tumours. Anal squamous precancerous lesions have now to be classified with the same criteria and terminology as their cervical counterparts, by using the Lower Anogenital Squamous Terminology (LAST) proposal. Only p16 protein is a useful marker in this setting at the present time. As most cases of anal cancer are treated by non-surgical procedures, pathology has a limited role in the staging of the disease, except for early lesions treated by local excision, and when the sentinel lymph node procedure is undertaken that is still under evaluation. A variety of other tumour types can occur more rarely, with difficult diagnostic issues, solved in most cases by immunohistochemistry.

Aims: The human equilibrative nucleoside transporter 1 (hENT1) expression level in pancreatic ductal adenocarcinoma (PDAC) may predict survival in gemcitabine-treated patients after resection. These results have been obtained with a murine anti-hENT1 antibody (10D7G2) that is not commercially available. Another antibody, which is rabbit-derived (SP120), appears to have no predictive value in local, advanced or metastatic PDAC. We aimed to study whether the two antibodies are equivalent. Methods and results: We compared hENT1 expression with both antibodies in resected PDAC. The results were correlated with overall survival (OS) following gemcitabine treatment. Tissues from two sets of patients (n = 147 each) were stained with SP120 by the use of different equipment, with an amplification technique being used for set 2. The rate of 'hENT1 high' cases was lower with SP120 (set 1, 7% versus 48%; set 2, 11% versus 38%). With the amplification technique, the rate of hENT1 high cases was globally similar between both antibodies. However, concordance between the antibodies was found in only 50% of cases. High hENT1 expression was predictive of OS only with 10D7G2 (hazard ratio 0.49; 95% confidence interval 0.24-0.98; P = 0.045). Conclusions: The two antibodies are not equivalent. Further prospective studies seem to be warranted before hENT1 testing for PDAC is used in daily practise.

Aim Duodenal adenomas occur in about 90% of patients with familial adenomatous polyposis (FAP) and are the second cause of death of patients who have had a prophylactic proctocolectomy. Studies suggest that biliary acids have a role in the development of duodenal adenomas. The aim of this study was to evaluate the impact of ursodesoxycholic acid (UDCA) on duodenal adenoma formation in patients with FAP. Method A randomized, double-blinded, placebo-controlled study was carried out of 71 patients (20–65 years) who already had a restorative proctocolectomy. Subjects received either 10 mg/kg of UDCA orally per day or a placebo tablet for 24 months. The Spigelman severity score was determined after duodenal axial and lateral view endoscopy at 12 and 24 months. Results At 2 years 55 patients had completed the entire period of treatment. At the end of the follow-up period, nine (25%) patients in the UDCA group and seven (20%) in the placebo group had a decrease in the Spigelman score (P = 0.6142). Patients receiving UDCA had no side-effects (0%) compared with four (14%) in the placebo group (P = 0.0392). Conclusion UDCA had no effect on the development of duodenal adenomas in FAP patients (NCT: 00134758).

Two main colorectal polyposis syndromes have been described, familial adenomatous polyposis and MUTYH-associated polyposis syndromes. Some polyposis remains unexplained: 20% of adenomatous polyposis and serrated polyposis. The aim of this study was to evaluate in a cohort of patients with unexplained polyposis whether a genetic defect could be detected. Individuals presenting polyposis with more than 40 adenomas or more than 20 serrated polyps (hyperplastic, sessile serrated and mixed), without causative mutation identified, were included. Complementary explorations on APC or MUTYH were performed: search for APC mosaicism, splicing-affecting mutations, large genomic rearrangement of MUTYH. Four genes of Wnt pathway (AXIN2, PPP2R1B, WIF1, SFRP1) and two genes of transforming growth factor-β (TGF-β) pathway (SMAD4, BMPR1A) were screened for germline mutation. Twenty-five patients had an unexplained adenomatous polyposis (familial or sporadic). Five pathogenic mutations were found: four in APC gene (with one case of mosaicism) and one in BMPR1A gene. The exploration of APC mosaicism was better performed from adenoma DNA with high-resolution melting. The screening of the candidate genes did not find any causative mutation. Thirteen individuals had an unexplained serrated polyposis and a frameshift on SMAD4 gene was identified. All mutations were identified in familial cases of polyposis. After new pathological examination, both BMPR1A and SMAD4 cases were found to be associated with a juvenile polyposis while the polyposis was initially described as adenomatous or undetermined. In 17% (6/38) of the patients the causative mutation of the polyposis was identified. Genetic causes were heterogeneous. Sporadic polyposis patients must be considered as potential APC mosaicism. The histological classification of polyposis is strongly important in direct genetic exploration.

V. Hofman, E. Long, M. Ilie, C. Bonnetaud, J. M. Vignaud, J. F. Flejou, S. Lantuejoul, E. Piaton, N. Mourad, C. Butori, E. Selva, C. H. Marquette, M. Poudenx, S. Sibon, S. Kelhef, N. Venissac, J. P. Jais, J. Mouroux, T. J. Molina, P. Vielh and P. Hofman Morphological analysis of circulating tumour cells in patients undergoing surgery for non-small cell lung carcinoma using the isolation by size of epithelial tumour cell (ISET) method Background and objective: Recurrence rates after surgery for non-small cell lung cancer (NSCLC) range from 25 to 50% and 5-year survival is only 60–70%. Because no biomarkers are predictive of recurrence or the onset of metastasis, pathological TNM (pTNM) staging is currently the best prognostic factor. Consequently, the preoperative detection of circulating tumour cells (CTCs) might be useful in tailoring therapy. The aim of this study was to characterize morphologically any circulating non-haematological cells (CNHCs) in patients undergoing surgery for NSCLC using the isolation by size of epithelial tumour cell (ISET) method. Methods: Of 299 blood samples tested, 250 were from patients with resectable NSCLC and 59 from healthy controls. The presence of CNHCs was assessed blindly and independently by 10 cytopathologists on May-Grunwald–Giemsa stained filters and the cells classified into three groups: (i) malignant cells, (ii) uncertain malignant cells, and (iii) benign cells. We assessed interobserver agreement using Kappa (κ) analysis as the measure of agreement. Results: A total of 123 out of 250 (49%) patients showed CNHCs corresponding to malignant, uncertain malignant and benign cells, in 102/250 (41%), 15/250 (6%) and 6/250 (2%) cases, respectively. No CNHCs were detected in the blood of healthy subjects. Interobserver diagnostic variability was absent for CNHCs, low for malignant cells and limited for uncertain malignant and benign cells. Conclusion: Identification of CTCs in resectable NSCLC patients, using ISET technology and according to cytopathological criteria of malignancy, appears to be a new and promising field of cytopathology with potential relevance to lung oncology.

The hyperfucosylation of a number of glycoconjugates observed in liver diseases involves the action of several specific fucosyltransferases (F.T.) notably responsible for synthesizing histo-blood group antigens. We determined the activities of alpha 3, alpha 2 and alpha 3/4 F.T. in 35 liver biopsy samples from patients with fatty liver, alcoholic or post-hepatic liver cirrhosis, primary or secondary biliary cirrhosis, acute hepatitis or a normal liver. F.T. activities were measured by transfer of GDP [14C] fucose to asialotransferrin for alpha 3 F.T., to phenyl beta-D-galactoside for alpha 2 F.T. and to 2' fucosyllactose for alpha 3/4 F.T. The diseased liver extracts showed an early increase in non-Le gene-associated alpha 3 F.T. activity (p = 0.001), which was related to the number of steatosic hepatocytes and the degree of intralobular inflammatory infiltration. Overexpression of this alpha 3 F.T. provides an explanation for the strong expression of 3-fucosyl lactosamine structures described in several hepatobiliary diseases. alpha 2 F.T. levels were significantly elevated in the two groups of liver cirrhosis and acute hepatitis (p = 0.05), but not enough to consider alpha 2 F.T. as a sensitive feature of mesenchymal cell injury. All Lewis-positive biopsies displaying biliary alterations showed increased Le gene-encoded alpha 3/4 F.T. activity (p = 0.001), which was related to the intensity of neoductular proliferation. Elevated levels of alpha 3/4 F.T. may be a very early sign of biliary regeneration.

While a certain degree of structural and functional intra-lobular heterogeneity of sinusoidal endothelial cells has been observed in rodents, little information is available about the zonal characteristics of sinusoidal endothelial cells in the human liver acinus. We have therefore examined the intra-acinar distribution of a panel of endothelial markers in the normal human liver, including: (a) structural markers of continuous and sinusoidal endothelia (PECAM-1, CD-34 protein, VE-cadherin, 1F10 antigen), (b) functional markers specific for sinusoidal endothelial cells, as previously determined in the laboratory (CD4 protein, the lipopolysaccharide-binding protein receptor (CD 14), aminopeptidase N, ICAM-1, receptors II and III for the Fc fragment of immunoglobulins G), (c) endothelial cell-matrix adhesion proteins and leukocyte-endothelial cell adhesion molecules. We observed a heterogeneous distribution for: (a) the 1F10 antigen, whose distribution in the human liver acinus was restricted to vessels situated along the axis of acinar zone 1, (b) the lipopolysaccharide-binding protein receptor and the receptor III for the Fc fragment of IgG, not expressed or only barely expressed in acinar zone 1. The distribution of the other markers tested did not display significant intra-lobular variation. Our in situ results suggest the existence of a degree of zonal heterogeneity in the structural and functional characteristics of sinusoidal endothelial cells in the human liver acinus. This might contribute to the constitution of distinct microenvironments within the human liver parenchyma.

Summary Aim : To compare the efficacy of different regimens in patients in whom previous Helicobacter pylori eradication therapy has failed. Methods : In this study named StratHegy patients (n = 287) were randomized to receive one of three empirical triple therapy regimens or a strategy based on antibiotic susceptibility. The empirical regimens were omeprazole, 20 mg b.d., plus amoxicillin, 1000 mg b.d., and clarithromycin, 500 mg b.d., for 7 days (OAC7), clarithromycin, 500 mg b.d., for 14 days (OAC14) or metronidazole, 500 mg b.d., for 14 days (OAM14). In the susceptibility-based strategy, patients with clarithromycin-susceptible strains received OAC14, whilst the others received OAM14. The 13C-urea breath test was performed before randomization and 4–5 weeks after eradication therapy. Results : In the intention-to-treat analysis, the eradication rates for empirical therapies were as follows: OAC7, 47.4% (27/57); OAC14, 34.5% (20/58); OAM14, 63.2% (36/57); it was 74.3% (84/113) for the susceptibility-based treatment (P

Aims: To establish the prevalence of cyclooxygenase-2 (COX-2) expression in a large series of resected Barrett's adenocarcinoma and associated preneoplastic lesions and to correlate this expression with clinicopathological data and prognosis. Methods: COX-2 expression was assessed by immunohistochemistry in resected surgical specimens of 66 Barrett's adenocarcinomas and 32 cases of Barrett's mucosa (with dysplasia in 17 cases). Results: Epithelial expression of COX-2 protein was increased in Barrett's mucosa compared with normal oesophagus. Epithelial expression of COX-2 was found in 91% of Barrett's specialized mucosa negative for dysplasia, 94% of Barrett's mucosa with dysplasia, and 97% of Barrett's adenocarcinoma. COX-2 expression was significantly higher in the well-differentiated adenocarcinomas when compared with the poorly differentiated tumours. There was no significant correlation between COX-2 expression and the other pathological features of the tumours. Survival analysis showed no significant prognostic value for COX-2. Conclusion: Our results confirm up-regulation of COX-2 in Barrett's oesophagus—metaplastic and dysplastic—and in Barrett's adenocarcinoma. Increased COX-2 expression did not differ during the progression from Barrett's oesophagus negative for dysplasia to Barrett's adenocarcinoma and is related to adenocarcinoma whose histology is well differentiated. This suggests that enhanced expression of COX-2 may occur early during Barrett's-associated neoplastic transformation.

Mixed ductal–pancreatic polypeptide-cell carcinoma of the pancreas Aims: Mixed ductal-endocrine carcinomas of the pancreas are rare tumours with 10 cases reported in the English literature. We report the first case with a polypeptide-cell component. Methods and results: The tumour was fortuitouslydiscovered in a 72-year-old woman during the exploration of an endometrial adenocarcinoma. It measured 100 mm and was located in the tail of the pancreas. On microscopic examination two intermingled endocrine and exocrine components were present. The endocrine component consisted of trabeculae and solid nests composed of cells immunoreactive for chromogranin A, synaptophysin and pancreatic polypeptide, but negative for p53 and Bcl-2 proteins. The exocrine component was composed of tubules lined by atypical cylindrical cells immunoreactive for CK19, CEA, p53 and Bcl-2. The stroma of the endocrine component contained amyloid deposits. Conclusion: Mixed ductal–endocrine carcinomas of the pancreas are often described in middle-aged patients. The tumours are usually large and located in the head of the pancreas. An endocrine syndrome is rare and the prognosis is often unfavourable. We report the first case of mixed endocrine–exocrine carcinoma of the pancreas with a pancreatic polypeptide-cell component. The histogenesis of mixed carcinoma of the pancreas is still uncertain but the over-expression of p53 and Bcl-2 could play a major role in the neoplastic progression of the ductal component.

Intraductal papillary-mucinous tumours (IPMTs) of the pancreas are heterogeneous proliferations characterized by a malignant potential. The molecular mechanisms underlying the tumourigenesis process are not well understood. Recently, it has been shown that IPMTs secreting the mucin antigen MUC2 have a better prognosis, but the complete pattern of MUC gene expression has not yet been established. The aims of this study were to evaluate the mucin gene expression in 57 IPMTs and eight related lesions surgically resected and to relate MUC gene expression to the histological diagnosis. In situ hybridization (ISH) was performed in 28 cases with probes specific for the MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC6, and MUC7 genes. An immunohistochemical analysis was carried in all 65 cases and in 90 conventional ductal adenocarcinomas of the pancreas using MUC1, MUC2, and MUC5AC antibodies. IPMTs of adenoma (dysplasia) type exhibited high expression of MUC2 (93%), MUC5AC (97%), and, to a lesser extent, of MUC4 (71%), all of which were also observed in colloid carcinomas associated with IPMTs. In contrast, IPMTs with simple hyperplasia, intraductal oncocytic papillary neoplasms, and pyloric glandular adenomas exhibited little or no expression of MUC2. The mucin expression profile supports the existence of two types of invasive tumour associated with IPMTs: a colloid and an ordinary form. The latter shows a pattern similar to the conventional ductal adenocarcinomas with a loss of MUC2 and a gain of MUC1 and has a greater tendency to metastasize. In conclusion, the altered expression of mucin, characteristic of IPMT of adenoma type and of colloid carcinomas, may contribute to the better clinical outcome of these neoplasms, compared to conventional pancreatic ductal adenocarcinomas.

Background : The relationship between Helicobacter pylori infection and non-ulcer dyspepsia is not established. Aim : To determine whether eradication of H. pylori might be of benefit in non-ulcer dyspepsia patients. Methods : We randomly assigned 129 H. pylori infected patients with severe epigastric pain, without gastro-oesophageal reflux symptoms, to receive twice daily treatment with 300 mg of ranitidine, 1000 mg of amoxicillin, and 500 mg of clarithromycin for 7 days and 124 such patients to receive identical-appearing placebos. Results : Treatment was successful (decrease of symptoms at 12 months) in 62% of patients in the active-treatment group and in 60% of the placebo group (N.S.). At 12 months, the rate of eradication of H. pylori was 69% in the active-treatment group and 18% in the placebo group (P

Aims (i) To investigate and compare the numerical aberrations of chromosomes 7, 8, 11, 17 and Y in a series of 60 adenocarcinomas of the oesophagus, gastric cardia and gastric antrum; and (ii) to specify the sequence of chromosomal aberrations occurring during the neoplastic progression of Barrett's oesophagus. Methods and results: Chromosomal in-situ hybridization was performed on deparaffinized tissue sections from 20 Barrett's adenocarcinomas, 20 adenocarcinomas of the cardia and 20 adenocarcinomas of the antrum, with centromeric alpha satellite DNA probes specific for chromosomes 7, 8, 11, 17 and Y, labelled with digoxigenin. Signals were detected by immunoperoxidase staining. The copy number for each chromosome was counted in 200 tumour cells nuclei and 100 lymphocytes as controls. In parallel, the DNA content of the nuclear suspensions was measured by flow cytometry. Numerical abnormalities of the five chromosomes (loss of the Y chromosome, monosomy, trisomy, and tetrasomy) were frequently observed in the three groups of adenocarcinomas (from 40% to 65% of the cases). Sixty per cent to 75% of oesophagus and gastric adenocarcinomas were DNA-aneuploid. Chromosomal aberrations progressively increased with advancing degrees of dysplasia in Barrett's mucosa, with an increasing frequency of trisomy and loss of the Y chromosome from non-dysplastic Barrett's mucosa to invasive adenocarcinoma, and with monosomy and tetrasomy present only in invasive cancers. Conclusions: Our study confirms the high frequency of chromosomal numerical aberrations in oesophageal and gastric adenocarcinomas, without differences between adenocarcinomas of the gastric cardia and antrum. We have shown that these alterations occur early during the neoplastic transformation of Barrett's mucosa.

Esophageal carcinoma includes squamous cell carcinoma and Barrett's adenocarcinoma. The latter usually develops from a premalignant lesion named Barrett's esophagus. MUC genes are known to be specifically expressed in the normal, premalignant and malignant epithelia of various tissues. The aim of this study was to establish the pattern of MUC gene expression in the esophageal mucosa under normal conditions, and under pathological conditions such as squamous cell carcinoma, Barrett's esophagus and adenocarcinoma. Samples of esophageal control mucosa, metaplastic and malignant tissues were obtained from 40 patients undergoing esophagectomy for squamous cell carcinoma (n = 17), or Barrett's esophagus with adenocarcinoma (n = 23). In situ hybridization and northern blot were used with probes specific for the MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC6 and MUC7 genes to assess their expression in these samples. Submucosal glands of control esophageal mucosa expressed MUC5B, whereas MUC1 and MUC4 were found in both control epithelium and squamous cell carcinoma. MUC4 expression correlated with squamous cell differentiation. Barrett's adenocarcinoma exhibited various patterns of MUC gene expression, the strongest being in the well-differentiated mucinous adenocarcinomas. Barrett's metaplasia was also associated with a specific MUC gene expression pattern, since the gastric apomucin mRNAs, MUC5AC and MUC6, were expressed in gastric metaplasia, and the intestinal apomucin mRNAs, MUC3, MUC4 and mostly MUC2, in intestinal metaplasia. Residual expression of gastric apomucin mRNAs was found in intestinal metaplasia. From these results, we conclude that MUC genes can be considered reliable phenotypic markers of the esophageal cell differentiation, thus providing new insight into the development of Barrett's esophagus.

Several somatic genetic alterations have been described in colorectal carcinoma (CRC). Recurrent chromosomal deletions have suggested the presence of tumor suppressor genes (TSG) specifically involved in colorectal carcinogenesis. For one of them, two non-overlapping regions have been proposed on the short arm of chromosome 8, encompassing the LPL and NEFL genes. The short arm of chromosome 8 has been extensively studied in colorectal cancer and in other cancer types. Both regions have been reported as candidate loci for a TSG. In order to delineate a reliable region of deletional overlap on chromosome arm 8p in CRC, a series of 365 CRC samples was selected for the absence of microsatellite instability (RER, replication error); tumor and normal matched DNAs were studied for 54 microsatellite polymorphisms distributed on 8p using multiplex-PCR amplification. After purification of tumor nuclei by flow cytometry based on either the abnormal DNA index or the presence of a high expression of cytokeratin, complete allelic losses on 8p were observed in 48% of cases. Measurement of the DNA index showed that 88% of RER tumors were hyperploid. Complete allelic losses of only part of the short arm were observed on 26 occasions. These data allowed us to define a 1 cM interval of common deletion, flanked by the loci D8S1771 and NEFL, where a putative TSG may be localized. Genes Chromosomes Cancer 25:147–153, 1999. © 1999 Wiley-Liss, Inc.

Microsatellite instability (MI) characterizing tumors with replication errors (RER+ tumors) was first described in colorectal tumors from hereditary non-polyposis colorectal cancer (HNPCC) patients as well as in sporadic cases. It has also been observed in subgroups of extracolonic sporadic tumors, but there is no consensus as to the number of microsatellite loci to examine, and the threshold percentage of unstable loci required to classify a tumor as RER+. We have recently shown that BAT-26, a mononucleotide repeat microsatellite, was quasi-monomorphic in DNA from normal individuals and from colorectal RER- samples, and showed important size variations in RER+ samples. In the present work, we analyzed BAT-26 allelic profiles in tumors of the breast (n = 107), brain (n = 78), stomach (n = 59), prostate (n = 49), esophagus (n = 36), thyroid (n = 31), endometrium (n = 12), and cervix (n = 10) whose RER status was already known, thus extending BAT-26 analysis to a total of 542 human solid tumors. BAT-26 alleles were quasi-monomorphic in RER- samples (475/481) and shortened in RER+ tumors (57/61), including four tumors shown to have been misclassified on the basis of dinucleotide repeat microsatellite analysis. In 3/481 RER- and 4/61 RER+ cases, BAT-26 size variation was important enough to attract attention, but not sufficient to establish the RER status of the corresponding tumors. In these cases, the analysis of BAT-25 and BAT-34C4, two other mononucleotide repeat microsatellites, was necessary to resolve the ambiguity. There were only 3 false positive cases. In conclusion, BAT-26 was able to identify the RER status of 539 out of 542 tumors from various origins (99.5% efficiency) in a single-step experiment without the requirement for matching normal DNA.

Aims: To establish the prevalence of CD44 protein expression in a large surgical series of Barrett's adenocarcinoma and associated preneoplastic lesions and to correlate this expression with clinicopathological data and prognosis. Methods and results: CD44H and variants (V4/V5,V6) expression was detected by immunohistochemistry in formalin-fixed, paraffin wax tissue samples of Barrett's mucosa (50) and Barrett's adenocarcinoma (73) obtained from surgical resections from 73 patients. This expression was correlated with pathological features of the tumour and prognosis. CD44H and V6 expression was found in 62% and 55% of Barrett's specialized mucosa negative for dysplasia and in 70% and 63% of Barrett's adenocarcinoma, respectively. CD44H and V6 expression was restricted to the lower part of the crypts in Barrett's specialized mucosa negative for dysplasia and reached the upper part of the crypts in high-grade dysplasia. A significant relation was found between CD44V6 expression and depth of tumour invasion in the oesophageal wall (P = 0.05), neoplastic vascular invasion (P = 0.0001), neoplastic perineural invasion (P = 0.0004) and stage in Rosenberg's classification (P = 0.02). Cancers with CD44V6 expression had a significantly poorer prognosis (5-year survival: 17%) than those without (5-year survival: 44%) (P = 0.02) in univariate analysis. However, multivariate analysis showed that CD44V6 expression had no independent prognostic value when tumour invasion and lymph node involvement were taken as explanatory variables. Conclusion: CD44H and V6 are frequently expressed in Barrett's oesophagus. The pattern of expression that we observed from mucosa negative for dysplasia to adenocarcinoma suggests that CD44H and V6 may be involved in the carcinogenesis of Barrett's mucosa. CD44V6 expression in adenocarcinoma is correlated to aggressive pathological features.

Loss of heterozygosity on chromosome 9 has been reported in a variety of human cancers. The cyclin-dependent kinase inhibitor p16 gene, mapped on chromosome 9p21, is presumed to be the tumor-suppressor gene localized in this chromosome. The aim of our study was to determine, in 26 Barrett's adenocarcinomas and 20 squamous-cell carcinomas of the esophagus, the prevalence of loss of heterozygosity on chromosome 9 by typing of microsatellite loci and mutation of p16 by direct sequencing of exons 1 and 2. Allelic losses were found in 69% of adenocarcinomas, but only a microdeletion in exon 1 of p16 occurred in 1 tumor. Among squamous-cell carcinomas, 65% had allelic losses and 5 tumors were mutated on the p16 gene (1 deletion, 3 nucleotide substitutions and 1 insertion). The relatively low rate of p16 mutation observed here coupled with the high frequency of loss of heterozygosity on chromosome 9 suggests that one or several tumor-suppressor gene(s) distinct from p16 may be the target(s) of allelic deletion in most esophageal cancers or that p16 is inactivated in another way.

Mucinous cystic tumors of the pancreas must be distinguished from other cystic lesions because of their potential malignancy. Our purpose was to assess the reliability of gastric M1 mucin analysis in the fluid of cystic lesions of the pancreas in comparison or association with carcinoembryonic antigen. M1 mucin and carcinoembryonic antigen were measured in cyst fluid obtained preoperatively by fine-needle aspiration. The lesions consisted of 12 serous cystadenomas, 9 mucinous cystadenomas, 8 cystadenocarcinomas and 6 intraductal mucinous hypersecreting neoplasms. Thirty pancreatic pseudocysts complicating well-documented chronic pancreatitis were also examined. In addition, M1 mucins were localized by immunoperoxidase staining in fetal and normal adult pancreas and in mucinous and serous tumors. Carcinoembryonic values of G20 ng/ml and M1 mucin values of G50 U M1/ml represented 82 and 78% sensitivity, respectively, as well as 100% specificity for distinguishing mucinous lesions from serous cystadenomas; the sensitivity for this purpose was 100% using these criteria in combination. Carcinoembryonic antigen values of G300 ng/ml and M1 mucin values of G1,200 U M1/ml represented 56 and 30% sensitivity, respectively, as well as 100% specificity for distinguishing mucinous lesions from pseudocysts; the sensitivity for this purpose was 60% using these criteria in combination. By immunohistology, M1 mucins were detected in the wall of mucinous lesions but not in fetal and normal adult pancreas and in serous cystadenomas. Measurement of M1 mucin antigen in cyst fluid could thus improve the diagnosis of mucinous cystic lesions of the pancreas.Int. J. Cancer74:286‐290, 1997. r 1997 Wiley-Liss, Inc.

Background. An important marker for hepatocellular carcinoma is the presence of des-γ-carboxy (abnormal) prothrombin. However, the molecular basis for the reduced carboxylation of prothrombin is unknown. Methods. Two groups of patients were defined according to the absence (Group I, n = 7) or presence (Group II, n = 8) of des-γ-carboxy prothrombin. The enzymatic activity of y-carboxylase and the total microsomal prothrombin concentration were determined in all tumors. The kinetic parameters for the synthetic peptide Phe-Leu-Glu-Glu-Leu (FLEEI.) were measured in eight tumors. The γ-carboxylase mRNA expression was evaluated by Northern blot analysis in 12 of 15 tumors. In addition, the total vitamin K content (K, K, epoxide, and menaquinones 4-10) in 10 tumors was investigated by high performance liquid chromatography. Results. Concentrations of menaquinones 4-10 were normal in the nontumorous part of the liver but significantly decreased (P = 0.02) in all the tumors (Groups I and II). This decrease was more severe in Group II (P = 0.02). The tumors in Group I had normal or increased γ-carboxylase activity and increased mRNA expression (P < 0.02) as compared with their nontumorous counterparts. The tumors in Group II were heterogeneous. Five tumors displayed low y-carboxylase activity, associated with low mRNA expression in two, whereas two others had high γ carboxylase activity and mRNA expression. The concentration of FLEEL at half-maximal velocity was normal in all the tumors examined (Groups I and II), and a relation was found between the level of expression of γ-carboxylase and the maximal velocity for FLEEL carboxylation in the tumors in Group II (r = 0.98; P < 0.01). The microsomal content of normal prothrombin was within normal limits in all tumors (Groups I and II). Conclusions. Tumor vitamin K content has a critical role in the synthesis of des-γ-carboxy prothrombin. Furthermore, the γ-carboxylase defect, which is observed in some secreting tumors, is the result of the defective gene expression of a normal enzyme and not the consequence of the presence of a competitive inhibitor. It is possible that a 75% reduction in γ-carboxylase gene expression could take a part in the secretion of des-γ-carboxy prothrombin, but this mechanism is not predominant.

Superficial adenocarcinoma of the oesophagus is defined as carcinoma limited to the mucosa or submucosa regardless of lymph node status. Columnar epithelium lined lower oesophagus, now generally referred to as Barrett's oesophagus, is probably the main cause of adenocarcinoma in the lower oesophagus. Twelve cases of superficial adenocarcinoma arising in Barrett's oesophagus are presented. They were observed over a 6 year period and taken from a series of 50 cases of patients with Barrett's oesophagus and adenocarcinoma, a prevalence of 24%. Endoscopic diagnosis of malignancy was made in six patients. The initial biopsies showed an adenocarcinoma in six patients and some degrees of dysplasia in the other six patients. Prior to surgery, a histological diagnosis of adenocarcinoma was made in all twelve patients. In four patients the adenocarcinoma was confined to the mucosa, and in eight it extended to the submucosa. One patient had a metastatic lymph node. Ten patients are alive without evidence of tumour spread after a mean follow-up of 30 months.