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H van Dekken

Publications and source records attributed to H van Dekken.

At least 19 recordsLinked to original sources
PubMed2006

Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study.

This study was performed to assess the efficacy and safety of preoperative chemoradiation consisting of carboplatin and paclitaxel and concurrent radiotherapy for patients with resectable (T2-3N0-1M0) oesophageal cancer. Treatment consisted of paclitaxel 50 mg m(-2) and carboplatin AUC=2 on days 1, 8, 15, 22 and 29 and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by oesophagectomy. All 54 entered patients completed the chemoradiation without delay or dose-reduction. Grade 3-4 toxicities were: neutropaenia 15%, thrombocytopaenia 2%, and oesophagitis 7.5%. After completion of the chemoradiotherapy 63% had a major endoscopical response. Fifty-two patients (96%) underwent a resection. The postoperative mortality rate was 7.7%. All patients had an R0-resection. The pathological complete response rate was 25%, and an additional 36.5% had less than 10% vital residual tumour cells. At a median follow-up of 23.2 months, the median survival time has not yet been reached. The probability of disease-free survival after 30 months was 60%. In conclusion, weekly neoadjuvant paclitaxel and carboplatin with concurrent radiotherapy is a very tolerable regimen and can be given on an outpatient basis. It achieves considerable down staging and a subsequent 100% radical resection rate in this series. A phase III trial with this regimen is now ongoing.

Adenocarcinoma↗
PubMed2006

[Incidental cystic structures in the upper abdomen: to remove or not to remove?].

An abdominal cystic structure was diagnosed incidentally in two women aged 44 and 52 years, respectively. The first patient had a mesenteric cyst that was removed because of its malignant potential. The second had a duodenal duplication cyst which was not removed due to the minor risk of complications. Two other patients, a man aged 19 years and a woman aged 40 years, were referred with mechanical complaints due to a splenic cyst and a hepatic cyst, respectively. The splenic cyst was removed surgically and the hepatic cyst was treated by sclerotherapy. Cysts are fluid-filled cavities that can develop throughout the abdomen. They are often discovered by coincidence. These four patients show that cysts in the upper abdomen may be due to various disorders and that the decision to treat is based on the risk of complications, such as bleeding, rupture or malignant potential, as well as the symptoms related to the size ofthe cyst.

Adult↗
PubMed2006

Does CDX2 expression predict Barrett's metaplasia in oesophageal columnar epithelium without goblet cells?

BACKGROUND: Intestinal metaplasia (Barrett's oesophagus), but not cardiac-type mucosa in columnar-lined oesophagus, is regarded as premalignant. As intestinal metaplasia and cardiac-type mucosa are endoscopically indiscernible, it is difficult to take targeted samples from columnar-lined oesophagus with consequently a risk of having undetected intestinal metaplasia. AIM: To investigate whether the intestinal markers CDX2, MUC2 and villin can predict the presence of undetected intestinal metaplasia in columnar-lined oesophagus. Methods Presence of intestinal metaplasia or cardiac-type mucosa was identified in 122 biopsy sets of columnar-lined oesophagus from 61 patients, collected at two subsequent follow-up upper endoscopies. CDX2, MUC2 and villin expression were determined by immunohistochemistry. RESULTS: All intestinal metaplasia samples (55) were positive for CDX2 and MUC2 and 32 of 55 for villin. CDX2 expression was detected in 23 of 67 (34%) samples with only cardiac-type mucosa. Detection of CDX2 in cardiac-type mucosa increased the likelihood of finding intestinal metaplasia in another biopsy set of columnar-lined oesophagus (odds ratio 3.5, 95% CI = 1.2-10, P = 0.02). MUC2 was positive in 13 of 23 (57%) of CDX2-positive cardiac-type mucosa samples, whereas villin was detected in seven of 23 (30%). CONCLUSIONS: CDX2 expression in cardiac-type mucosa might be able to predict the presence of undetected intestinal metaplasia in columnar-lined oesophagus, and thus may be a putative marker for the presence of intestinal metaplasia in the absence of goblet cells.

Adult↗
PubMed2005

Expression of apoptosis related proteins during malignant progression in chronic ulcerative colitis.

BACKGROUND: Chronic ulcerative colitis (CUC) is associated with increased risk of developing colon cancer through a dysplasia (intraepithelial neoplasia)-carcinoma sequence. AIMS: To investigate the expression of apoptosis and inflammatory related proteins in CUC. METHODS: The expression of proteins involved in apoptosis and inflammation (inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Bcl-xl, Fas, and active caspase 3) was investigated and compared with that seen in sporadic colon carcinoma. RESULTS: COX-2 was negative in the epithelium of all samples. iNOS was clearly present in inflammatory areas in CUC epithelium, weakly expressed in dysplasia, and absent or weakly expressed in tumour cells. Bcl-xl was absent in CUC, increased in dysplasia, and highly expressed in most carcinomas. Fas expression was positive in the surface epithelium of CUC, dysplasia, and most tumour cells. Activated caspase 3 was weakly positive in all samples, indicating limited apoptosis. Compared with CUC associated carcinoma, iNOS was consistently expressed in sporadic colon carcinoma cells, whereas Bcl-xl was almost absent in these tumour cells and Fas was only weakly expressed. Activated caspase 3 was present in normal mucosal samples and some tumour cells. CONCLUSION: Apoptosis related proteins--particularly iNOS, Bcl-xl, and Fas-show a distinct pattern of expression in the CUC to carcinoma sequence, which differs from that seen in sporadic carcinoma, but bears a striking resemblance to that seen during neoplastic progression in Barrett's oesophagus. These results support a causal role for chronic inflammation in cancer development in CUC, and treatment of ulcerative colitis should aim to minimise inflammation.

Adenocarcinoma↗
PubMed2004

Oesophageal cancer incidence and mortality in patients with long-segment Barrett's oesophagus after a mean follow-up of 12.7 years.

BACKGROUND: Data on cancer risk in patients with long-segment Barrett's oesophagus (BO) from older studies are often difficult to interpret, since the definition of BO has evolved from an endoscopical to a histological diagnosis. In this work the diagnoses in the Rotterdam BO cohort on current standards was redefined to obtain more accurate data on cancer risk in patients who had not undergone standard endoscopic surveillance. In addition, it was determined which patient factors present at index endoscopy were associated with neoplastic progression in BO. METHODS: The Rotterdam BO cohort comprises all patients with > or =3 cm BO, diagnosed at endoscopy between 1973 and 1984. In the present study, only patients with intestinal metaplasia were included (n = 105). Follow-up data were obtained by questionnaires and/or interviews with patients or treating physicians. A Kaplan-Meier analysis was used to estimate 20-year risks. RESULTS: The mean length of the BO was 7.1 cm (range: 3-15 cm). Cancer in BO developed in 6/105 (6%) patients, and high-grade dysplasia (HGD) in 5/105 (5%) patients during 1329 patient-years of follow-up, which equals one cancer case per 221 patient-years and one HGD case per 266 patient-years. After a mean follow-up of 12.7 years, 72 (69%) patients had died; only 4 of them died of oesophageal cancer or its treatment. A longer length of BO was associated with an increased risk of progression to HGD or cancer (P < 0.02). Six of 24 patients who ever had low-grade dysplasia progressed to HGD or cancer 2-16 years after a diagnosis of BO. CONCLUSIONS: The annual risk of developing HGD or adenocarcinoma in patients with long-segment BO is 0.83%. Death due to adenocarcinoma is, however, uncommon, even in a cohort of patients with long-segment BO.

Adenocarcinoma↗
PubMed2004

5-aminolevulinic acid photodynamic therapy versus argon plasma coagulation for ablation of Barrett's oesophagus: a randomised trial.

BACKGROUND: Photochemical and thermal methods are used for ablating Barrett's oesophagus (BO). The aim of this study was to compare 5-aminolevulinic acid induced photodynamic therapy (ALA-PDT) with argon plasma coagulation (APC) with respect to complete reversal of BO. METHODS: Patients with BO (32 no dysplasia and eight low grade dysplasia) were randomised to one of three treatments: (a) ALA-PDT as a single dose of 100 J/cm(2) at four hours (PDT100; n = 13); (b) ALA-PDT as a fractionated dose of 20 and 100 J/cm(2) at one and four hours, respectively (PDT20+100; n = 13); or (c) APC at a power setting of 65 W in two sessions (APC; n = 14). If complete elimination of BO was not achieved by the designated treatment, the remaining BO was treated by a maximum of two sessions of APC. RESULTS: Mean endoscopic reduction of BO at six weeks was 51% (range 20-100%) in the PDT100 group, 86% (range 0-100%) in the PDT20+100 group, and 93% (range 40-100%) in the APC group (PDT100 v PDT20+100, p<0.005; PDT100 v APC, p<0.005; and PDT20+100 v APC, NS) with histologically complete ablation in 1/13 (8%) patients in the PDT100 group, 4/12 (33%) in the PDT20+100 group, and 5/14 (36%) in the APC group (NS). Remaining BO was additionally treated with APC in 23/40 (58%) patients. Histological examination at 12 months revealed complete ablation in 9/11 (82%) patients in the PDT100 group, in 9/10 (90%) patients in the PDT20+100 group, and in 8/12 (67%) patients in the APC group (NS). At 12 months, no dysplasia was detected. Side effects (that is, pain (p<0.01), and nausea and vomiting (p<0.05)) and elevated liver transaminases (p<0.01) were more common after PDT than APC therapy. One patient died three days after treatment with PDT, presumably from cardiac arrhythmia. CONCLUSION: APC alone or ALA-PDT in combination with APC can lead to complete reversal of Barrett's epithelium in at least two thirds of patients when administered in multiple treatment sessions. As the goal of treatment should be complete reversal of Barrett's epithelium, we do not recommend these techniques for the prophylactic ablation of BO.

Aged↗
PubMed2004

MUC4 is increased in high grade intraepithelial neoplasia in Barrett's oesophagus and is associated with a proapoptotic Bax to Bcl-2 ratio.

BACKGROUND: Patients with Barrett's oesophagus (BO) are at risk of oesophageal adenocarcinoma. Because the pattern of mucosal mucins changes during neoplastic progression, it may serve as a marker of intraepithelial neoplasia. AIMS: To determine the expression pattern of mucins in neoplastic BO epithelium (high grade dysplasia) and correlate it with the expression of apoptosis markers Bax and Bcl-2. METHODS: Thirty seven patients with BO were studied: 16 without intraepithelial neoplasia, six with high grade intraepithelial neoplasia (HGN), and 15 with infiltrating adenocarcinoma. Biopsies were obtained from squamous epithelium, Barrett's epithelium, and (when present) foci of suspected HGN or adenocarcinoma. MUC1-4, MUC5AC, MUC5B, MUC6, Bax, and Bcl-2 mRNA were determined by semiquantitative RT-PCR. MUC2, MUC5AC, and MUC6 protein was determined by immunoblotting. RESULTS: Mucin expression varied between neoplastic progression stages in BO. Mucin mRNA levels were low in squamous epithelium, except for MUC4, and were at least four times higher in BO and HGN (p<0.001), but less so in adenocarcinoma. MUC4 expression was significantly lower in BO than in normal squamous epithelium, whereas in HGN and adenocarcinoma, levels were significantly higher than in BO (p = 0.037). The Bax:Bcl-2 ratio was increased in HGN compared with BO (p = 0.04). MUC2, MUC5AC, and MUC6 protein values correlated with mRNA data. CONCLUSIONS: Mucin expression varies during the development of oesophageal adenocarcinoma in BO. MUC4 could serve as a tumour marker in this process. In contrast to animal studies, upregulation of MUC4 in HGN is associated with increased apoptosis, suggesting that MUC4 plays a minor role in apoptosis regulation in BO.

Adenocarcinoma↗
PubMed2002

[The malignant side of chronic inflammatory bowel disease].

Patients with chronic inflammatory bowel disease (IBD) have a higher risk of colorectal carcinoma, and present with this malignancy at a younger age than non-IBD individuals. In three patients, two men aged 20 and 36 years and one woman aged 34 years, colorectal cancer developed at a young age, following a long history of ulcerative colitis. Surveillance for colorectal cancer in IBD patients needs to be performed by regular colonoscopy with extensive biopsy sampling for the detection of dysplasia, regarded by many as predictive for colon carcinoma. Whenever a dysplasia-associated lesion or mass or a highgrade dysplasia is identified, there is a strong indication for colectomy. When low-grade dysplasia is found, the findings should be discussed with the patient and it should be decided whether the patient should resume surveillance or opt for colectomy.

Adenocarcinoma↗
PubMed2001

Genomic alterations in malignant transformation of Barrett's esophagus.

The incidence of adenocarcinoma in Barrett's esophagus has been increasing rapidly over the past decades. Neoplastic progression is characterized by three well-defined premalignant stages: metaplasia, low-grade dysplasia, and high-grade dysplasia. A genome-wide overview, based on comparative genomic hybridization, was performed, evaluating 30 Barrett's adenocarcinomas and 25 adjacent precursors, i.e., 6 metaplasias, 9 low-grade dysplasias, and 10 high-grade dysplasias. The frequency of losses and gains significantly increased in the subsequent stages of malignant transformation. Losses of 5q21-q23, 9p21, 17p12-13.1, 18q21, and Y were revealed in low-grade dysplasias. This was followed by loss of 7q33-q35 and gains of 7p12-p15, 7q21-q22, and 17q21 in high-grade dysplasias along with high-level amplification (HLA) of 7q21 and 17q21. In the invasive cancers, additional losses of 3p14-p21, 4p, 4q, 8p21, 13q14-q31, 14q24.3-q31, 16q21-q22, and 22q as well as gains of 3q25-q27, 8q23-24.1, 12p11.2-12, 15q22-q24, and 20q11.2-q13.1 were distinguished along with HLAs of 8p12-p22 and 20q11.2-q13.1. Approximately one-third of the alterations in the dysplasias were also found in the adjacent adenocarcinomas, illustrating that multiple clonal lineages can be present in Barrett's esophagus. Novel findings include loss on 7q, gain on 12p, and the observation of several HLAs in high-grade dysplasias. Furthermore, loss of 7q33-q35 was found to represent a significant distinction between low-grade and high-grade dysplasia (P = 0.01), whereas loss of 16q21-q22 and gain of 20q11.2-q13.1 were disclosed to significantly discriminate between high-grade dysplasia and adenocarcinoma (P = 0.02 and P = 0.03, respectively). This inventory of genetic aberrations increases our understanding of malignant transformation in Barrett's esophagus and might provide useful biomarkers for disease progression.

Adenocarcinoma↗
PubMed2001

Spatial variability of genomic aberrations in a large glioblastoma resection specimen.

In the present study, the distribution of genetic aberrations in a glioblastoma resection specimen of unusually large size (9x8x2 cm) was investigated using comparative genomic hybridization (CGH). CGH was performed on 20 samples taken from the specimen, and the genetic aberrations found were compared with the regional histology. The samples were histopathologically graded according to WHO criteria, and a division in high- and low-grade areas and infiltration rims was made. In high-grade areas, low-grade areas as well as infiltration rims, gains on 10p11.2-pter (14/20), 11q12-q22 (6/20) and losses on 4q13-qter (9/20), 10q22-qter (8/20), 11p14-pter (5/20), 13q12-qter (7/20) were revealed. Gains on 1q21-32 (2/4) and losses on 7p21-pter (3/4) were exclusively found in the high-grade areas. In the low-grade tumor samples and in the infiltration rim, gains on 16p11.2-pter (6/16), 17p11.2-pter (6/16), 17q11.2-qter (5/16), 20q11.2-q13 (3/16) and deletions on 5q31-qter (4/16) were detected. Gains on 7q21-qter (8/11) and 8q11.2-qter (6/11), and loss of chromosome 9 (4/11) and the Y-chromosome (4/11) were found in the high-grade and low-grade samples, not in the infiltration rims. The finding of a set of identical chromosomal aberrations throughout the resection specimen, most of which have been previously reported in gliomas, confirms a mechanism of clonal tumor proliferation operative in gliomas. The previously unreported genetic alterations which were predominantly traced in the tumor rims, might reflect either selection for properties related to infiltrating behavior, or genomic instability of subclones. The findings illustrate the importance of searching for high-grade genetic aberrations in low-grade tumor samples taken from cases in which sampling error is suspected.

Brain Neoplasms↗
PubMed2001

Molecular cytogenetic analysis of prostatic adenocarcinomas from screening studies : early cancers may contain aggressive genetic features.

No objective parameters have been found so far that can predict the biological behavior of early stages of prostatic cancer, which are encountered frequently nowadays due to surveillance and screening programs. We have applied comparative genomic hybridization to routinely processed, paraffin-embedded radical prostatectomy specimens derived from patients who participated in the European Randomized Study of Screening for Prostate Cancer. We defined a panel consisting of 36 early cancer specimens: 13 small (total tumor volume (Tv) < 0.5 ml) carcinomas and 23 intermediate (Tv between 0.5-1.0 ml) tumors. These samples were compared with a set of 16 locally advanced, large (Tv > 2.0 ml) tumor samples, not derived from the European Randomized Study of Screening for Prostate Cancer. Chromosome arms that frequently (ie, > or = 15%) showed loss in the small tumors included 13q (31%), 6q (23%), and Y (15%), whereas frequent (ie, > or = 15%) gain was seen of 20q (15%). In the intermediate cancers, loss was detected of 8p (35%), 16q (30%), 5q (26%), Y (22%), 6q, and 18q (both 17%). No consistent gains were found in this group. In the large tumors, loss was seen of 13q (69%), 8p (50%), 5q, 6q (both 31%), and Y (15%). Gains were observed of 8q (37%), 3q (25%), 7p, 7q, 9q, and Xq (all 19%). Comparison of these early, localized tumors with large adenocarcinomas showed a significant increase in the number of aberrant chromosomes per case (Rs = 0.36, P = 0.009). The same was true for the number of lost or gained chromosomes per case (Rs = 0.27, P: = 0.05; Rs = 0.48, respectively; P < 0.001). Interestingly, chromosomal alterations that were found in previous studies to be potential biomarkers for tumor aggressiveness, ie, gain of 7pq and/or 8q, were already distinguished in the small and intermediate cancers. In conclusion, our data show that chromosomal losses, more specifically of 6q and 13q, are early events in prostatic tumorigenesis, whereas chromosomal gains, especially of 8q, appear to be late events in prostatic tumor development. Finally, early localized tumors, as detected by screening programs, harbor cancers with aggressive genetic characteristics.

Adenocarcinoma↗
PubMed2001

Molecular cytogenetic evaluation of gastric cardia adenocarcinoma and precursor lesions.

Analyses of cancer incidence data in the United States and Western Europe revealed steadily rising rates over the past decades of adenocarcinomas of the esophagus and gastric cardia. Genetic information on gastric cardia adenocarcinoma and its preneoplasias is sparse. We have used comparative genomic hybridization to obtain a genome-wide overview of 20 archival gastric cardia adenocarcinomas and 10 adjacent preneoplastic lesions (4 metaplasias, 1 low-grade dysplasia, 5 high-grade dysplasias). Multiple genetic alterations were discriminated in all adenocarcinomas. Frequent loss (> or =25% of all tumors) was detected, in decreasing order of frequency, on 5q, 18q, 4q, 3p, 9p, 2q, 11q, 14q, 21q, 4p, 9q, 16q, 1p, and 8p. Frequent gain (> or =25% of all tumors) was disclosed, in decreasing order of frequency, on 20q, 7p, 8q, 1q, 7q, 20p, 17q, 13q, Xp, 6q, 8p, 19q, 5p, 6p, and Xq. Loss of the Y chromosome was found in 60% of male cases. High level amplification was frequently (>10% of all tumors) detected on 7q21, 8p22, 12p11.2, 17q12-q21, and 19q13.1-q13.2. The precursor lesions showed multiple aberrations in all high-grade dysplasias, whereas few genetic changes were discerned in LGD and metaplasias. High level amplifications were also found in high-grade dysplasias, ie, on 7q21, 8p22, and 17q12-q21. Moreover, the percentage of aberrations was not significantly different for invasive carcinomas or high-grade dysplasias. Approximately 70% of the precursor aberrations were also present in the adjacent carcinoma. Minimal overlapping regions in the preneoplasias included loss on 18q12-q21 and gains on 8q23 and 17q12-q21, suggesting involvement of genes residing in these regions. In conclusion, we have (i) created a map of genetic alterations in gastric cardia adenocarcinomas and (ii) provided evidence for the presence of a metaplasia-dysplasia-carcinoma sequence in this poorly understood type of cancer.

Adenocarcinoma↗
PubMed2001

Evaluation of oncogene amplification in intact and truncated cell nuclei of gastro-esophageal cancer cell lines by DNA in situ hybridisation.

Adenocarcinoma arising around the gastro-esophageal junction (GEJ) is a highly malignant form of cancer. Its incidence is rising sharply. The study of oncogenes in these carcinomas may give information concerning treatment and prognosis. In the present study, the fluorescence in situ hybridisation (FISH) technique was optimised for genetic characterisation of oncogenes in archival cancer specimens. Three cell lines derived from GEJ adenocarcinomas were investigated, i.e. JROECL 19, JROECL 33 and OACM5.1C, both in fresh and paraffin-embedded preparations. Furthermore, paraffin-embedded material of three xenografts was studied, i.e. JROECL 19, JROECL 33, and OACM4.1X. We focussed on the oncogenes MYC and HER2/neu, since they are frequently involved in intestinal cancers. Firstly, our results indicate that it is feasible to detect oncogene-specific probes with the FISH technique in formalin-fixed, paraffin-embedded material. Secondly, it appeared that the optimal section thickness for analysis was 2 microm. This thickness resulted in minimal nuclear overlap, which facilitates counting of FISH spots. Due to the truncation phenomenon, however, the sensitivity of the technique is less than FISH on intact nuclei. Importantly, (high level) oncogene amplifications were easily recognised in 2 microm thick sections. Finally, counting of the individual copy number of the MYC and HER2/neu oncogenes was feasible enabling an arbitrary assessment of low- and high-level amplification. In conclusion, FISH is an accurate technique for detecting amplification of oncogenes in paraffin-embedded patient material.

Adenocarcinoma↗
PubMed2000

Molecular cytogenetic evaluation of virus-associated and non-viral hepatocellular carcinoma: analysis of 26 carcinomas and 12 concurrent dysplasias.

The worldwide incidence of hepatocellular carcinoma (HCC) is approximately one million cases a year. This makes HCC one of the most frequent human malignancies, especially in Asia and Africa, although the incidence is increasing also in the western world. HCC is a complication of chronic liver disease, with cirrhosis as the most important risk factor. Viral co-pathogenesis makes cirrhosis due to hepatitis B (HBV) and hepatitis C virus (HCV) infection a very important factor in the development of HCC. As curative therapy is often ruled out due to the late detection of HCC, it would be attractive to find parameters which predict malignant transformation in HBV- and HCV-infected livers. This study has used comparative genomic hybridization (CGH) to analyse 26 HCCs (11 non-viral, nine HBV, six HCV) and 12 concurrent dysplasias (five non-viral, five HBV, two HCV). Frequent gain (> or =25% of all tumours) was detected, in decreasing order of frequency, on 8q (69%), 1q (46%), 17q (46%), 12q (42%), 20q (31%), 5p (27%), 6q (27%), and Xq (27%). Frequent loss (> or =25% of all tumours) was found, in decreasing order of frequency, on 8p (58%), 16q (54%), 4q (42%), 13q (39%), 1p (35%), 4p (35%), 16p (35%), 18q (35%), 14q (31%), 17p (31%), 9p (27%), and 9q (27%). Minimal overlapping regions could be determined at multiple locations (candidate genes in parentheses). Minimal regions of overlap for deletions were assigned to 4p14-15 (PCDH7), 8p21-22 (FEZ1), 9p12-13, 13q14-31 (RB1), 14q31 (TSHR), 16p12-13.1 (GSPT1), 16q21-23 (CDH1), 17p12-13 (TP53), and 18q21-22 (DPC4, DCC). Minimal overlapping amplified sites could be seen at 8q24 (MYC), 12q15-21 (MDM2), 17q22-25 (SSTR2, GH1), and 20q12-13.2 (MYBL2, PTPN1). A single high level amplification was seen on 5q21 in an HBV-related tumour. Aberrations appeared more frequent in HBV-related HCCs than in HCV-associated tumours (p=0.008). This was most prominent with respect to losses (p=0.004), specifically loss on 4p (p=0.007), 16q (p=0.04), 17p (p=0.04), and 18q (p=0.03). In addition, loss on 17p was significantly lower in non-viral cancers than in HBV-related HCC (p<0.001). Furthermore, loss on 13q was more prevalent in HCCs in non-cirrhotic livers (p=0.02), thus suggesting a different, potentially more aggressive, pathway in neoplastic progression. A tendency (p=0.07) was observed for loss on 9q in high-stage tumours; no specific changes were found in relation to tumour grade. A subset of the HCC-associated genetic changes was disclosed in the preneoplastic stage, i.e. liver cell dysplasia. This group of dysplasias showed frequent gain on 17q (25%) and frequent loss on 16q (33%), 4q (25%), and 17p (25%). The majority of the dysplasias with alterations revealed genetic changes that were also present in the primary tumour. In conclusion, firstly, this study has provided a detailed map of genomic changes occurring in HCC of viral and non-viral origin, and has suggested candidate genes. Loss on 17p, including the TP53 region, appeared significantly more prevalent in HBV-associated liver cancers, whereas loss on 13q, with possible involvement of RB1, was distinguished as a possible genetic biomarker. Secondly, CGH analysis of liver cell dysplasia, both viral and non-viral, has revealed HCC-specific early genetic changes, thereby confirming its preneoplastic nature. Finally, genes residing in these early altered regions, such as CDH1 or TP53, might be associated with hepatocellular carcinogenesis.

Adult↗
PubMed2000

Identification of genetic markers for prostatic cancer progression.

Despite the high incidence of prostate cancer, only limited data are available on genes or chromosomes specifically involved in its initiation and progression. We have applied comparative genomic hybridization to routinely processed, paraffin-embedded, tissues at different times in prostatic tumor progression to screen the tumor genome for gains and losses. Our panel included specimens derived from 56 different patients: 23 patients with primary, prostate-confined carcinomas; 18 patients with regional lymph node metastases; and 15 patients with distant metastases. Chromosome arms that most frequently showed losses, included 13q (55%), 8p (48%), 6q (43%), 5q (32%), 16q (25%), 18q (20%), 2q (18%), 4q (18%), 10q (18%), and Y (16%). Gains were often seen of chromosome arms 8q (36%), 17q (23%), Xq (23%), 7q (21%), 3q (18%), 9q (18%), 1q (16%), Xp (16%). Furthermore, specific high-level amplifications, eg, of 1q21, 1q25, and Xq12 to q13, were found in metastatic cancers. A significant accumulation of genetic changes in distant metastases was observed, eg, loss of 10q (p = 0.03) and gain of 7q (p = 0.03) sequences. In addition, investigation of a potential biomarker identified in previous studies by our group, ie, extra copies of #7 and/or #8, revealed a high prevalence of 7pq and/or 8q gain in the distant metastases (p = 0.02). Importantly, gains were observed more frequently in tumors derived from progressors after radical prostatectomy, than in nonprogressors (mean time of follow-up, 74 months). Specifically, gain of chromosome 7pq and/or 8q sequences appeared an accurate discriminator between the progressors and nonprogressors. Multivariate analysis showed a significant correlation between progressive disease and the number of chromosomes with gains. This correlation also held true when stage (p = 0.007) or grade (p = 0.002) were taken into account. Likewise, this applied for gain of chromosome 7pq and/or 8q sequences (p = 0.03 and p = 0.005 for stage or grade, respectively). Additionally, an increase in the number of chromosomes with gains per case was related to a decrease in biochemical progression-free survival (Ptrend <0.001). More specifically, the gain of 7pq and/or 8q sequences markedly reduced the biochemical progression-free survival (p < 0.001). In conclusion, this study has, firstly, documented the spectrum of chromosomal alterations in subsequent stages of prostate cancer, a number of which had not been described previously. It allowed us to identify chromosomal regions related to advanced tumor stage, ie, loss of 10q24 and gain of 7q11.2 and/or 7q31 sequences. Secondly, gain of 7pq and/or 8q was identified as a potential genetic discriminator between progressors and nonprogressors after radical surgery.

Chromosome Aberrations↗
PubMed2000

Porphyrin biosynthesis in human Barrett's oesophagus and adenocarcinoma after ingestion of 5-aminolaevulinic acid.

5-Aminolaevulinic acid (ALA)-induced porphyrin biosynthesis, which is used for ALA-based photodynamic therapy (ALA-PDT), was studied in tissues of 10 patients with Barrett's oesophagus (BE) and adenocarcinoma of the oesophagus (AC) undergoing oesophagectomy at a mean time interval of 6.7 h after the ingestion of ALA (60 mg kg(-1)). In BE, AC, squamous epithelium (SQ) and gastric cardia, the activities of the haem biosynthetic enzymes porphobilinogen deaminase (PBG-D) and ferrochelatase (FC) and the PDT power index--the ratio between PBG-D and FC in BE and AC in comparison with SQ--were determined before ALA ingestion. Following ALA administration, ALA, porphobilinogen, uroporphyrin I and PPIX were determined in tissues and plasma. The PDT power index did not predict the level of intracellular accumulation of PPIX found at 6.7 h. In BE, there was no selectivity of PPIX accumulation compared to SQ, whereas in half of patients with AC selectivity was found. Higher haem biosynthetic enzyme activities (i.e. PBG-D) and lower PPIX precursor concentrations were found in BE and AC compared to SQ. It is therefore possible that PPIX levels will peak at earlier time intervals in BE and AC compared to SQ.

Adenocarcinoma↗
PubMed2000

Cytogenetic analysis of gemistocytic cells in gliomas.

Gemistocytes are glial cells characterized by voluminous, eosinophilic cytoplasm and a peripherally positioned, often flattened nucleus. Gemistocytes, usually present in anoxic-ischemic brains, are regularly encountered in glial neoplasms. The presence of gemistocytes in gliomas has been associated with an unfavorable clinical course, notwithstanding the low proliferative potential of these cells. It is not known whether gemistocytes residing in gliomas are dormant tumor cells, or alternatively, represent interspersed reactive glial cells. Whereas gemistocytic astrocytomas have been subject to various genetic investigations, no genomic analysis comparing individual cells in gliomas has been reported so far. In the present study, 3 astrocytomas, 3 oligodendrogliomas, and 3 mixed oligoastrocytomas, all harboring gemistocytic cells, were genetically analyzed by DNA in situ hybridization to paraffin-embedded, formalin-fixed tissue samples with optimal preservation of cellular morphology. To this end, probes for the centromeric regions of chromosome 7 and 10, known to show copy number aberrations in gliomas, were used. In addition, probes for centromeric regions of chromosomes 1 and 17 were used for the ploidy status of the tumors. The spot counts for the various chromosomes were statistically compared. Gains of chromosome 7 were found in 1 anaplastic astrocytoma, 1 anaplastic oligodendroglioma, and 1 anaplastic oligoastrocytoma. Loss of chromosome 10 was seen in 2 anaplastic astrocytomas, in 1 anaplastic oligodendroglioma, and in 1 anaplastic oligoastrocytoma. In 3 cases, significant differences in spot distributions between gemistocytes and non-gemistocytes were found, but the other cases showed no difference in spot distribution. It is concluded that, although many gemistocytic cells in gliomas may be considered reactive cells, in a subset of tumors, part of the gemistocytic cells should be considered neoplastic.

Adult↗