Images in clinical medicine. Hydatidiform mole.
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Adult↗
Biomedical subjects
V T Smit
Publications and source records attributed to V T Smit.
Loss of heterozygosity mapping at chromosome arm 16q in 712 breast tumors reveals factors that influence delineation of candidate regions.
Loss of heterozygosity (LOH) at the long arm of chromosome 16 occurs in at least half of all breast tumors and is considered to target one or more tumor suppressor genes. Despite extensive studies by us and by others, a clear consensus of the boundaries of the smallest region of overlap (SRO) could not be identified. To find more solid evidence for SROs, we tested a large series of 712 breast tumors for LOH at 16q using a dense map of polymorphic markers. Strict criteria for LOH and retention were applied, and results that did not meet these criteria were excluded from the analysis. We compared LOH results obtained from samples with different DNA isolation methods, ie., from microdissected tissue versus total tissue blocks. In the latter group, 16% of the cases were excluded because of noninterpretable LOH results. The selection of polymorphic markers is clearly influencing the LOH pattern because a chromosomal region seems more frequently involved in LOH when many markers from this region are used. The LOH detection method, i.e., radioactive versus fluorescence detection, has no marked effect on the results. Increasing the threshold window for retention of heterozygosity resulted in significantly more cases with complex LOH, i.e., several alternating regions of loss and retention, than seen in tumors with a small window for retention. Tumors with complex LOH do not provide evidence for clear-cut SROs that are repeatedly found in other samples. On disregarding these complex cases, we could identify three different SROs, two at band 16q24.3 and one at 16q22.1. In all three tumor series, we found cases with single LOH regions that designated the distal region at 16q24.3 and the region at 16q22.1. Comparing histological data on these tumors did not result in the identification of a particular subtype with LOH at 16q or a specific region involved in LOH. Only the rare mucinous tumors had no 16q LOH at all. Furthermore, a positive estrogen content is prevalent in tumors with 16q LOH, but not in tumors with LOH at 16q24.3 only.
Breast Neoplasms↗
An uncommon cause of stroke in young adults.
We describe a previously healthy 48-year-old man who presented with clinical characteristics suggestive of internal carotid artery dissection, confirmed by magnetic resonance imaging. He developed a massive infarction of the left cerebral hemisphere and died after 3 days of transtentorial herniation. Post-mortem examination identified a dissection of the thoracic aorta caused by Erdheim-Gsell cystic medionecrosis, with the characteristic degeneration of the elastic fibers of the lamina media. The dissection showed an unusually large extension not only distally into both iliac arteries, but also proximally into both carotid arteries. To our knowledge, such an extensive dissection has not been described previously. Underlying vessel wall disorders of the aorta, such as Erdheim Gsell cystic medionecrosis, should be considered in young patients with spontaneous arterial dissection.
Aortic Dissection↗
Molecular genetic evidence for the conversion hypothesis of the origin of malignant mixed müllerian tumours.
The origin of malignant mixed Müllerian tumours (MMMTs) has long been debated, due to the indefinite relationship between epithelial and mesenchymal malignant cells. In order to obtain insight into the clonal relationship between the two components of these tumours, molecular genetic changes were investigated at the level of loss of heterozygosity (LOH) in both cells types. LOH was studied in a series of six cases with 74 polymorphic microsatellite markers mapping to 19 different chromosomes. The epithelial and the mesenchymal neoplastic cells were separately microdissected from formalin-fixed, paraffin-embedded tissue, prior to DNA isolation. LOH was observed for 35 different markers mapping to chromosomes 3, 6, 8, 11, 15, 16, 17, 18, 21, and X. The most frequently involved chromosomes were 17p, 17q, 11q, 15q, and 21q. LOH was observed in five out of six cases and identical alleles were lost in the epithelial and in the mesenchymal cells. No genetic differences were observed between the two cell types for any of the informative markers. Immunohistochemistry (IHC) and TP53 mutation analysis revealed involvement of TP53 in all cases. Mutations were identified in five MMMTs. In four tumours, of which three had a missense mutation, strong nuclear staining for p53 was observed. In the remaining two cases, the mutation resulted in a stop codon, with no nuclear staining for p53 by IHC. The results support a monoclonal origin of MMMTs, with the absence of genetic changes uniquely associated with either of the phenotypes. The latter finding is compatible with current opinion that these neoplasms should be considered as metaplastic carcinomas and supports the conversion hypothesis.
Aged↗
Surgical/pathologic-stage migration confounds comparisons of gastric cancer survival rates between Japan and Western countries.
PURPOSE: Possible causes underlying the substantial differences in gastric cancer survival rates observed between Japan and the West were examined in a randomized trial comparing the Western R1 resection with limited lymphadenectomy and the Japanese R2 resection with extended lymphadenectomy. PATIENTS AND METHODS: The effect of four factors associated with lymphadenectomy on microscopic tumor-node-metastasis (TNM) staging, and on stage-specific survival rates was assessed in 473 curatively resected patients. RESULTS: After application of extended lymphadenectomy, additional information on N status was available, only in R2 resections with up-staging to N2 status in 30% of patients. The calculated effect of this stage migration on known 5-year survival rates was as follows: an increase of 1% in TNM stage Ia, 2% in Ib, 7% in II, 15% in IIIa, and 15% in IIIb. A further increase in survival was observed by stage migration to N3 or N4 status, due to selective extension of lymphadenectomy to clinically overt metastases located outside the allocated level of clearance (contamination). Incomplete lymphadenectomy of N1- or N2-level stations indicated for dissection (noncompliance) demonstrates that more migration can occur when strictly adhering to the protocol. Examining more nodes per N level (diligence) induces even more migration, since the number of nodes that were histologically examined per N level correlated significantly with nodal status (lymph node-negative [N-] or lymph node-positive [N+]). CONCLUSION: These factors explain, at least partially, superior stage-specific survival rates after R2 compared with R1 resections, without a real survival benefit in individual patients.
Emigration and Immigration↗
Establishment and characterization of 7 ovarian carcinoma cell lines and one granulosa tumor cell line: growth features and cytogenetics.
The characteristics of 7 newly established ovarian carcinoma cell lines and one granulosa tumor cell line obtained from tumor samples of 7 patients with varying histology of the primary tumor are reported. The cell lines were isolated from 5 serous carcinomas, a mucinous carcinoma, an endometrioid carcinoma and a granulosa cell tumor. All cell lines were passaged at least 25 times and showed stable growth rates. Colony-forming efficiency varied on plastic from 2 to 57% and in agar from 0.01 to 9.30%. The DNA index of the granulosa tumor cell line was diploid, while the ovarian carcinoma cell lines were all aneuploid. In 2 cell lines polyploidisation occurred during culturing. A thorough cytogenetic analysis of 7 cell lines revealed that the granulosa tumor cell line has only minor cytogenetic abnormalities (+5, 22q+). In contrast, the epithelial ovarian-cancer cell lines gave very complex karyotypes with numerous markers and structurally rearranged chromosomes. The chromosomes most often in excess were 15 and 20. Structural rearrangements of chromosomes 1, 3, 7 and 11 were prominent in all ovarian cell lines. In addition, we found changes in chromosomes X, 5, 8 and 13 that have rarely been described before.
Carcinoma↗
Alpha satellite DNAs on chromosomes 10 and 12 are both members of the dimeric suprachromosomal subfamily, but display little identity at the nucleotide sequence level.
We have investigated the organization and complexity of alpha satellite DNA on chromosomes 10 and 12 by restriction endonuclease mapping, in situ hybridization (ISH), and DNA-sequencing methods. Alpha satellite DNA on both chromosomes displays a basic dimeric organization, revealed as a 6- and an 8-mer higher-order repeat (HOR) unit on chromosome 10 and as an 8-mer HOR on chromosome 12. While these HORs show complete chromosome specificity under high-stringency ISH conditions, they recognize an identical set of chromosomes under lower stringencies. At the nucleotide sequence level, both chromosome 10 HORs are 50% identical to the HOR on chromosome 12 and to all other alpha satellite DNA sequences from the in situ cross-hybridizing chromosomes, with the exception of chromosome 6. An 80% identity between chromosome 6- and chromosome 10-derived alphoid sequences was observed. These data suggest that the alphoid DNA on chromosomes 6 and 10 may represent a distinct subclass of the dimeric subfamily. These sequences are proposed to be present, along with the more typical dimeric alpha satellite sequences, on a number of different human chromosomes.
Base Sequence↗
Flow cytometric analysis of DNA stemline heterogeneity in primary and metastatic breast cancer.
Flow cytometric DNA-ploidy analysis was used to investigate intratumor DNA stemline heterogeneity in primary breast carcinomas and lymph node metastases (LNM). The study was done in tumor specimens from 44 patients 35 of whom had LNM. In all, measurements were done in 214 different samples of primary tumors and 211 lymph nodes. Sixty-one percent (27/44) of the primary tumors were found to have multiple DNA aneuploid stemlines when the data of the separate samples per tumor (mean 4.9) were compared. Only five of 44 (11%) primary tumors were DNA diploid; two of these had DNA aneuploid metastases. Statistical analysis of these results indicated that, on average, four samples are needed for reliable determination of the DNA ploidy status of primary tumors by flow cytometry. In the majority of the cases (26/35), distinct tumor DNA stemlines found in LNM were also present in the primary tumor, which suggests that the generation of DNA ploidy diversity may have taken place prior to metastasis. Multiploidy was not related to tumor size but, particularly for LNM, was significantly correlated with age (r = 0.40, P = 0.02). The results of this study support the view that breast cancer is an extremely heterogeneous disease and that underestimation of this factor might account for the disagreement in literature about the prognostic value of DNA ploidy determinations.
Adenocarcinoma, Mucinous↗
Improved interpretation of complex chromosomal rearrangements by combined GTG banding and in situ suppression hybridization using chromosome-specific libraries and cosmid probes.
Chromosome aberrations of a hypodiploid ovarian carcinoma cell line (modal chromosome number 38) having a complex karyotype were analyzed using biotinylated DNA library probes that specifically hybridize to chromosomes 3, 6, 7, 8, 11, 13, and 16 from telomere (pter) to telomere (qter). A series of cosmid probes localized to the short arm of chromosome 16 were used to further investigate one of the two aberrant chromosomes 16 present in this cell line. The competitive in situ suppression (CISS) hybridization of DNA-libraries was mostly performed subsequent to GTG-banding of the same metaphase cell in order to interpret the hybridization signals optimally. This combined approach made it possible to detect the origin of chromosomal material that could not be identified using GTG-banding. Furthermore, the in situ hybridization techniques appeared to be helpful in the characterization of complex translocations and for accurate breakpoint determination.
Adenocarcinoma↗
Flow cytometric DNA-ploidy analysis of synchronously occurring multiple malignant tumors of the female genital tract.
In this study the authors applied flow cytometric DNA-ploidy analysis to multiple female genital tract malignant tumors in 43 patients, most of whom (n = 37) had bilateral ovarian cancer. An algorithm was developed for calculation of the likelihood ratio of the probabilities that measured DNA index differences between multiple tumor localizations within the same patient could be attributed to measurement variation or to true biologic DNA content differences. The results of this statistical analysis show that in 72% of the cases (31 of 43) this probability ratio exceeded 1. Because the probability that two independent tumors will have a near-identical aneuploid DNA content is very low, this finding supports a metastatic process rather than the occurrence of multiple primary tumors in these patients. Thus, flow cytometric DNA-ploidy analysis can be helpful in the identification of metastatic disease in patients with multiple female genital tract malignant tumors.
Adenocarcinoma↗
Localization and polymorphism of a chromosome 12-specific alpha satellite DNA sequence.
The isolation and localization of a chromosome 12-specific alpha satellite DNA sequence, p alpha 12H8, is described. This clone contains a complete copy of the 1.4-kb HindIII higher-order repeat present within the alpha satellite array on chromosome 12. The specificity of p alpha 12H8 was demonstrated by in situ hybridization and Southern blot analysis of a somatic cell hybrid mapping panel, both performed under high-stringency conditions. Polymorphic restriction patterns within the alpha satellite array, revealed by the use of the restriction enzymes BglII and EcoRV, were demonstrated to display Mendelian inheritance. These properties make p alpha 12H8 a valuable genetic marker for the centromeric region of chromosome 12.
Centromere↗
Combined GTG-banding and nonradioactive in situ hybridization improves characterization of complex karyotypes.
Nonradioactive in situ hybridization (ISH) using biotinylated centromere probes for chromosomes 1, 6, 7, 10, 16, 17, 18, and the X, respectively, was combined with GTG-banding to study cytogenetic changes in two different ovarian cancer cell lines. ISH was performed after GTG-banding on the same metaphase. The use of a low trypsin concentration (0.01%) in the banding procedure was essential for subsequent ISH. This combined approach allows the detection of subtle chromosomal rearrangements and appears to aid the identification of marker chromosomes.
Adult↗
Analysis of tumor heterogeneity in a patient with synchronously occurring female genital tract malignancies by DNA flow cytometry, DNA fingerprinting, and immunohistochemistry.
A case of a patient with bilateral ovarian cancer and a uterine malignant mesodermal mixed tumor with ascites and metastatic disease is presented. Flow cytometry, DNA fingerprinting, and immunohistochemistry were performed to assess the origin of these malignancies. Ploidy analysis showed that both ovarian tumors had different aneuploid stemlines (DNA index [DI] = 1.64, 1.85, right ovary and DI = 1.73, left ovary) indicating independent origins. One of the stemlines in the right ovary (DI = 1.64) was also present in the ascites cells, whereas omentum metastases showed the same stemline (DI = 1.73) as the left ovarian tumor. The uterine malignancy contained three aneuploid stemlines. The highest stemline was associated with epithelial differentiation, but a metastatic origin from the left ovarian tumor seems unlikely. DNA fingerprinting analysis revealed a common change in restriction fragment length pattern in the DNA from all tumor localizations as compared with the patient's constitutional DNA. These results indicate that DNA flow cytometry can be helpful in discriminating intragenital metastatic disease from multiple primary tumors.
Aged↗
KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas.
DNAs from human pancreatic adenocarcinomas were analyzed for the presence of mutations in codons 12, 13 and 61 of the NRAS, KRAS and HRAS gene. Formalin-fixed and paraffin-embedded tissue was used directly in an in vitro amplification reaction to expand the relevant RAS sequences. The mutations were detected by selective hybridization using mutation-specific synthetic oligonucleotides. In 28 of the 30 patients we found a mutation in codon 12 of the KRAS gene. This result confirms the findings of Almoguera et al. [Cell 53 (1988) 549-554] that KRAS mutations occur frequently in adenocarcinomas of the exocrine pancreas. The mutations are predominantly G-T transversions, in contrast to the KRAS mutations in colon tumors which are mainly G-A transitions. Furthermore, in a portion of the tumors the mutation appears to be homozygous.
Adenocarcinoma↗
Immunohistology of a sarcomatous mural nodule in an ovarian mucinous cystadenocarcinoma.
Mucinous tumors of the ovary are incidentally associated with ovarian sarcoma. Several cases of sarcoma-like mural nodules in ovarian mucinous tumors have been described previously, but only two well-documented cases of true sarcoma were reported. The purpose of this article is to report a case of sarcoma occurring in ovarian mucinous neoplasm, which differs histologically from the two cases described earlier. This case is the first of its kind with immunohistochemical characterization.
Adult↗
Acute pancreatitis in systemic lupus erythematosus.
Lethal acute pancreatitis developed in a 16-year-old Caucasian woman suffering from systemic lupus erythematosus. Until the time of onset of pancreatitis, the patient's medications included prednisone, furosemide, ethacrynic acid and chlorthalidone, all of which have been related to pancreatitis. At autopsy, no specific signs of autoimmune activity were found in the diseased pancreatic tissue. A review of the literature shows that information on the association of pancreatitis and SLE is scarce. This case illustrates the dilemma of pathogenesis and therapy of acute pancreatitis in SLE and the need for further investigation.
Acute Disease↗
Rheumatoid vasculitis presenting as appendicitis.
Appendicitis was diagnosed in a 38-year-old patient with seropositive rheumatoid arthritis. Despite appendectomy the patient's clinical condition deteriorated. Thorough microscopical evaluation of the pathological anatomical specimens from the appendix made possible a diagnosis of necrotizing vasculitis. The systemic nature of the vasculitis was confirmed with a muscle biopsy. A complete remission was induced with immunosuppressive treatment. The case exemplifies a rare but serious manifestation of rheumatoid vasculitis.
Adult↗