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The authors describe a case of intra-spinal epidermoid cyst and recall the scarcity of the symptoms of such tumors and their slow evolution and emphasize the very likely part taken by spinal punctures in the genesis of a number of them.
We have approached the question of the reliability of the thymidine labeling index (TLI) of breast carcinoma by comparing paired samples. Because the distribution of the TLI is approximately lognormal, comparisons were made after transformation to the natural logarithm. For 38 paired samples from the primary carcinoma (biopsy versus residual tumor in mastectomy specimen), r, 0.89, p less than 0.0001. For 68 primary carcinomas versus their axillary metastases, r, 0.90, p less than 0.0001. Substantial correlation was also observed between the TLIs of 18 primary breast carcinomas and their recurrent or metastatic lesions studied after relapse (r, 0.75, p less than 0.0003), and between 14 pairs of first and second primary carcinomas recovered from the same breast (r, 0.72, p less than 0.003). Good agreement was achieved among three observers in measuring the TLI from a set of breast carcinoma autoradiographs. We conclude that the TLI is sufficiently reliable for semiquantitative use as a means of separating breast carcinomas into groups with slow, moderate, and rapid rates of proliferation. The substantial similarities between the TLIs of breast carcinoma samples from different sites of the primary tumor, between primary tumor and axillary metastases, and between primary tumor and subsequent samples of relapsed tumor suggest that clonal evolution either is infrequent or does not usually affect the cell kinetics of the carcinoma. The similarity of the TLIs of synchronous dual primary carcinomas is an additional interesting finding.
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Out of a total of 360 cases compiled of testicle tumours obtained from numerous Spanish urologists, the authors analyse their distribution according to the age at the onset, in decades, in the 232 patients in which it became known to them, observing the greatest incidence between 21 and 50 years of age. They then compare the age-type of tumour parameters, in 115 of the cases of which they received the data. In the second part of the study, they make a brief study of the methods of therapy: orchidectomy, with or without lymphadenectomy, radio or cobaltotherapy, antiblastic chemotherapy or the combination of several means of treatment, summing up in the form of a general chart, the results obtained in the 275 observations known to this end and they conclude with another diagram comparing the cases of survival (117 out of the above-mentioned 275) with those obtained by other foreign observers.
The primary mesothelioma of the spermatic cord is a very rate tumor, histologically benign. Its evolution, because of the possibility of recurrence, is uncertain. We have found only six cases in the literature. Our observation relate the very quick apparition by a young Italian, 19 years old, of a left hydrocele under tension ascending into the inguinal fold. At operation, we discovered a mesothelioma in the spermatic cord and in the tunica vaginalis, covering both testicle and epididymis. Ten months after a left enlarged hemicastration, without scrotectomy, no recurrence has been reported.
Twenty-eight rats were given weekly injections of 1,2-dimethylhydrazine (DMH) for periods of 1-10 weeks. The preneoplastic changes occurring in the descending colon were monitored by transmission electron microscopy. Marked uniformity was observed in the time period of lesion development in the colon induced by the carcinogen especially at the epithelialstromal junction in preneoplastic lesions. Little changes were observed after 3 weeks treatment with the DMH. The greatest changes occurred after 6 weeks treatment, resulting in epithelium and mesenchyme. It has been confirmed that 3 weeks treatment with DMH is subcarcinogenic, whereas 10 weeks treatment results in a high incidence of tumors. These findings are compatible with the hypothesis that a carcinogen may act by inducing alterations in a small number of enterocytes and that colonic tumors arise through stepwise evolutional changes in these cells.
Mucin is a viscous secretion of glycoproteins secreted by epithelial cells of normal and cancerous tissues. Excessive and abnormal mucin synthesis has been observed in a number of cancers. The conformation and configuration of the surface carbohydrates play a key role in generating multiple forms of mucins in different cancers. The epitopes on the surface of mucin are recognized by antibodies present in different cancer cells. The primary structure of some of the cancer-associated mucins has been determined by molecular cloning of their complementary DNAs. The detection methods for cancer-associated mucins and their clinical applications are discussed.
Chromogranin A (CgA) is the major member of the granin family of acidic secretory glycoproteins that are expressed in all endocrine and neuroendocrine cells. Granins have been proposed to play multiple roles in the secretory process. Intracellularly, granins play a role in targeting peptide hormones and neurotransmitters to granules of the regulated pathway by virtue of their ability to aggregate in the low-pH, high-calcium environment of the trans-Golgi network. Extra-cellularly, peptides formed as a result of proteolytic processing of granins regulate hormone secretion. Some conserved features of the mature CgA protein are polyglutamic acids, calcium-binding sites, and several pairs of basic amino acids. The first 2 features are important for its intracellular functions, and the latter characteristic suggested that peptides could be released from the molecule by precursor processing enzymes. Several biologically active peptides encoded within the CgA molecule, such as vasostatin, beta-granin, chromostatin, pancreastatin, and parastatin act predominantly to inhibit hormone and neurotransmitter release in an autocrine or paracrine fashion. The biosynthesis of CgA is regulated by many different factors, including steroid hormones and agents that act through a variety of signalling pathways. CgA biosynthesis and that of the resident hormone or neurotransmitter can be regulated differentially. The widespread distribution of CgA has made the measurement of circulating immunoreactive CgA a valuable tool in the diagnosis of neuroendocrine neoplasia, and CgA immunohistochemistry can help to identify the neuroendocrine nature of tumours. Recent molecular biology studies are identifying those elements in the CgA gene promoter responsible for its specific neuroendocrine cell expression.
The authors report a case of congenital epulis in the lower gum of a new born female. This rare benign tumor of the newborn is histologically characterized by the granular aspect of its cells. It occurs more frequently in females than in males. Differential diagnosis mainly concerns Abrikossoff tumor whose histogenesis and evolution are different. The distinctive features of epulis are the presence of a fusiform cell component and the negativity of the granular cells for PS100.
A new human myeloma cell line, ANBL-6, was established and characterized at the genotypic and phenotypic levels. The cells exhibit a clonally rearranged immunoglobulin gene locus and resemble plasma cells morphologically. The ANBL-6 cells also exhibited an absolute dependence on exogenous interleukin 6 for growth. Of interest, DNA ploidy analysis suggested the existence of a near-diploid as well as a near-tetraploid population in this cell line. Cytogenetic studies confirmed the existence of two aneuploid karyotypes and further revealed a clonal relationship between the two karyotypes, as evidenced by numerous shared structural abnormalities. To determine whether the near-diploid cells functioned as stem cells for the near-tetraploid population, the near-diploid population was separated via flow cytometry and recultured prior to ploidy analysis. This population was observed to remain predominantly near-diploid over time, suggesting that these cells did not function as stem cells for the near-tetraploid population. However, the near-tetraploid cells did exhibit a growth advantage in vitro. Moreover, sequential ploidy analysis performed retrospectively on fresh bone marrow cells from the patient also suggested that there was an expansion of the near-tetraploid population during clinical relapse. These results suggest that both populations are self-regenerating and reflect the consequences of clonal evolution in the myeloma tumor. The coexistence of clonally related subclones with shared chromosomal abnormalities, however, suggests that the near-tetraploid subclone was derived from the near-diploid subclone at an unknown time during tumorigenesis.
Fifty percent of intracranial epidermoid cysts are located in the cerebral posterior fossa. Clinical presenting features are not specific and vary according to cyst topography and mass effect on neighbouring structures. In CT, the lesion is hypodense as related to the cerebral tissue, but with no specificity. In MRI, the typical form shows quasi-pathognomonic morphologic characters with polyedric contours, a marble aspect, a reduced mass effect as compared to the tumor volume and an evolution signal close to that of cerebrospinal fluid, with no increase after contrast agent injection. Some primary cholesteatomas have a different radiological aspect. They can be hyperdense in CT and have a spontaneous hyperintense signal in T1-weighted MRI sequence. They correspond to complicated epidermoid cysts associated with hemorrhages and granulomatous meningeal reaction whose constitution is very very close to that of cholesterine granulomas.
Rat pancreatitis-associated protein (PAP) mRNA is barely detectable in normal pancreas and overexpressed during acute pancreatitis (Iovanna, J., Orelle, B., Keim, V., and Dagorn J.-C. (1991) J. Biol. Chem. 266, 24664-24669). RNA amplification by reverse-transcriptase-coupled polymerase chain reaction showed that PAP mRNA was constitutively expressed in duodenum, jejunum, and ileum, at similar levels as in pancreas during the acute phase of pancreatitis. A weak expression was also detected in several other tissues. The rat PAP gene was isolated from a genomic library and characterized over 3.2 kilobases of gene sequence and 1.2 kilobases of 5'-flanking sequence. The 5' end of the coding sequence was determined by primer extension of the PAP transcript. Several potential regulatory elements were identified in the promoter region, including a pancreas-specific consensus sequence, two Pan1 (pancreas-specific) transcription activators, two IL-6 response elements, and one glucocorticoid response element. The PAP coding sequence spanned over six exons. The first three exons encoded the 5'-untranslated region of the mRNA, the signal peptide, and 39 amino acids of the NH2-terminal end of the mature protein, respectively. The other three exons encoded a domain of the protein with significant homology to the carbohydrate-recognition domain of animal lectins. Sequence comparison of the PAP gene with 13 carbohydrate-recognition domain-containing genes revealed that they derived from the same ancestor gene. Position of introns within the carbohydrate-recognition domain were different, however, suggesting that PAP belongs to a new group of lectins. These results support the hypothesis that genes encoding PAP and other lectins evolved from a common ancestor gene by intron gain.
The authors present a study of 50 patients with adenocarcinomas of the colon and rectum, patients with gastric adenocarcinomas, and 30 healthy individuals as a control group. In all subjects the following parameters were determined: total number of lymphocytes in the peripheral blood, T lymphocytes, T-active lymphocytes, and B lymphocytes. A study of the test for lymphoblastic transformation (TTL) with phytohemagglutinin (PHA) stimulation and the determination of alpha-fetoprotein (AFP) and carcino-embryonic antigen (CEA) were also carried out. In patients with gastric adenocarcinoma the results revealed a lymphopenia, especially at the expense of T and T-active lymphocytes, as well as a depression (in 73 per cent) of the lymphocytic response to the PHA stimulation. Patients with carcinoma of the colon showed significant results in the T-active lymphocyte population. In both neoplastic situations the determination for alpha-fetoprotein was negative, while the CEA presented a clear correlation with the evolutive stage of the tumor, being more demonstrative in the tumors located in the colon and rectum.
An attempt to reconstruct the chromosome evolution in 19 primary retinoblastoma tumors was made, taking into consideration the frequencies of the rearrangements for each case. The rearrangements were classified as early or late according to their frequency. Early chromosome rearrangements were +1q, +6p, -13/del(13q), -16/del(16q), -17/del(17p), and late rearrangements were (in decreasing order) -8, -17/del(17p), -22, +3/+3q, -4, -19, +1q, +7/+7q, -14, +21. Chromosome evolution was reconstructed by the analysis of parsimony using programs of phylogenetic inference, which belong to the computer package PHYLIP. Results of the reconstruction of chromosome evolution suggest that there are two types of retinoblastoma tumors which can be distinguished based on chromosome imbalance, and correlate with the presence or absence of additional copies of the short arm (p) of chromosome 6. Tumors with additional 6p chromosome had marked heterogeneity, with a high frequency of early as well as late chromosome changes. By contrast, tumors with a normal 6p complement had the fewest chromosome changes and, in particular, a lower frequency of late changes.
The tumor suppressor p53 is conformationally unstable at physiological temperature. Even the activated p53delta30 variant, which lacks the self-inhibiting carboxy terminal domain, has a half-life of only 8 min at 37 degrees C in vitro. We have developed a genetic approach to identify p53 variants that stabilize the active conformation. The human p53delta30 gene was randomly mutated, and the resulting library was expressed in Escherichia coli under conditions that apparently denatured the parental protein. Stable p53 variants were identified based on their ability to specifically bind a p53 consensus site. The initial thermostable variants were randomly recombined by DNA shuffling, and substitutions that were functionally additive or synergistic were identified in a second more stringent round of screening. The DNA binding activity of N239Y/N268D/E336V p53delta30 variant has a half-life of 100 min at 37 degrees C, 12 times longer than that of the parental protein. The thermostable variants should be more amenable to crystallographic studies and more effective in gene therapies than the wild-type protein.
Androgen replacement therapy in the aging male with partial androgen deficiency improved quality of life. However, such treatment is prohibited for men with a preexisting prostate cancer. The possibility of an increased risk of prostate cancer for healthy men has also been suggested on theoretical basis but recent experimental data showed that androgens may act in prevention of prostate cancer. In this review, we try to evaluate benefits and risks associated to a hormonal replacement therapy in regard to recent data. Several studies analyzing the role of testosterone for prostatic epithelial cells evidenced that testosterone acts in prostatic cell differentiation but does not have a direct role for induction of cell proliferation. Moreover, clinical studies have shown that low free testosterone levels in serum is associated with aggressive prostate cancer, like that has been observed in men with prostate cancer under prostate cancer chemoprevention by finasteride. These data suggest that an androgen pathway disruption in prostate is responsible of cell deregulations that may be associated not only with apoptosis of differentiated prostatic cells but also with potential cell transformation. The effects of androgens withdrawal for prostate cancer therapy induced in a short time the tumor arrest growth. However with time, cells adapt to low levels of androgens leading to the evolution of an androgen-independent tumor, which is more aggressive and most often fatal. The molecular mechanisms of this evolution begin to merge. A hypothesis is that such mechanisms could be initiated in elderly men with an androgen deficiency. The question is raised of whether hormonal replacement therapy could prevent prostate cancer. An encouraging recent study performed on rats demonstrated a protective effect of DHEA for prostate cancer. However, the putative role of the normalization of DHEA or other androgen levels in prevention of prostate cancer should be evaluated in clinical trials.
This review illustrates the evolution in the clinical use of prostate specific antigen as a prostate cancer tumour marker. Because PSA lacks specificity, several new PSA parameters have been investigated such as the age-referenced PSA and the PSA density of the transition zone. We discuss also the molecular forms of PSA and the complexed PSA and new tumour markers which could be of interest in the future such as the HK2.
Comparative genome analysis may provide novel insights into gene evolution and function. To investigate the von Hippel-Lindau (VHL) disease tumor suppressor gene, we sequenced the VHL gene in seven primate species. Comparative analysis was performed for human, primate, and rodent VHL genes and for a putative Caenorhabditis elegans VHL homologue identified by database analysis. The VHL gene has two translation initiation sites (at codons 1 and 54); however, the relative importance of the full-length translation product (pVHL30) and that translated from the second internal translation initiation site (pVHL19) is unclear. The N-terminal sequence of pVHL30 contains eight copies of a GXEEX acidic repeat motif in human and higher primates, but only three copies were present in the marmoset, and only one copy was present in rodent VHL genes. Evolutionary analysis suggested that the N-terminal repetitive sequence in pVHL30 was of less functional importance than those regions present in both pVHL30 and pVHL19. The VHL gene product is reported to form complexes with various proteins including elongin B, elongin C, VBP-1, fibronectin, Spl, CUL2, and HIF-1. Although most of the regions in pVHL that had been implicated in binding specific proteins demonstrated evolutionary conservation, the carboxy-terminal putative VBP-1 binding site was less well conserved, suggesting that VBP-1 binding may have less functional significance. Although an amino acid substitution (K171T) close to the pVHL elongin binding region was found in baboon, analysis of the structure of human pVHL suggested that this substitution would not interfere with pVHL/elongin C interaction. In general, there was a good correlation between the pVHL domains that demonstrated most evolutionary conservation and those that were most frequently mutated in tumors. Analysis of human/C. elegans conservation and human germline and somatic mutation patterns identified a highly conserved mutation cluster region between codons 74 and 90. However, this region is likely to be important for the structural integrity of pVHL rather than representing an additional protein binding domain.