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PubMed2004

Clonal evolution as pathogenetic mechanism in relapse of primary CNS lymphoma.

Comparative investigation of immunoglobulin (Ig) heavy chain gene rearrangements and DNA sequence analyses of a primary lymphoma of the CNS (PCNSL) and its recurrence revealed that both tumors used the same Ig gene segment. In addition to shared somatic mutations, the primary and the recurrent PCNSLs harbored somatic mutations unique to each tumor. Clonal evolution rather than subclone selection appears to underlie the development of tumor recurrence in this case.

Aged↗
PubMedDate not supplied

Tumor-specific immune responsiveness of the tumor-bearing host.

In vitro lymphocyte stimulation by mitomycin-C-blocked tumor cells has been used to demonstrate tumor-specific antigens in methylcholanthrene-induced sarcomas and in syngeneic murine systems, and to follow the evolution of tumor immunity in the tumor-bearing state. Lymphocytes from normal mice, from mice bearing small methylcholanthrene-induced tumors (less than 1 cm in diameter) and from tumor-immunized mice (which had been sensitized by tumor cell inoculation and subsequent tumor (removal) were stimulated by mitomycin-C-blocked tumor cells to undergo increased DNA synthesis in culture. However, lymph node cells from mice with large methylcholanthrene-induced tumors (greater than 1 cm in diameter) had quite different characteristics. The background DNA-synthetic activity of lymph node cells from tumor-bearing mice was much higher than that of lymph node cells from normal mice or from preimmunized, non-tumor-bearing mice, and progressively increased with the duration of tumor-bearing and the size of the tumor. Lymph node cells from mice bearing large tumours appeared to be maximally stimulated by the tumor in vivo and were incapable of further stimulation by the same tumor cells in vitro, but exhibited normal responses to other antigens and nonspecific mitogens. Lymph node cells from mice bearing large tumors depleted of the adherent cells had lower background levels of DNA synthetic activity per 10(6) cells and underwent stimulation similarly to lymphoid cells from preimmunized, non-tumor-bearing mice. Spleen cells from mice bearing large tumors also had increased background levels of DNA synthetic activity, but contrary to the observations made with the lymph node cells, they were able to undergo further stimulation when cultured with the same tumor cells. Studies on the background incorporation of tritiated thymidine by lymph node cells from tumor-bearing mice revealed that the spontaneous uptake of reconstituted populations was nearly that of the original population and more than twice that of the arithmetical sum of the nonadherent and the adherent subpopulations. This was not found with normal lymph node cells or with spleen cells from normal or tumor-bearing mice. The differential effects observed with lymph node cells compared to spleen cells from tumor-bearing mice are emphasized and possible explanations for these findings are discussed.

Animals↗
PubMed2001

Multivariate analyses of genomic imbalances in solid tumors reveal distinct and converging pathways of karyotypic evolution.

A total of 3,016 malignant solid tumors (kidney, colorectal, breast, head and neck, ovarian, and lung carcinomas, neuroglial tumors, malignant melanoma, and testicular germ cell tumors) were selected for statistical analyses regarding karyotypic evolution. Genomic imbalances, i.e., net gains and losses, present in more than 5% of each tumor type were identified. Individual tumors were then classified with respect to absence or presence of these imbalances. To analyze for possible patterns of correlated imbalances, principal component analyses (PCA) were performed. Furthermore, algorithms were developed to analyze the temporal order of the imbalances, as well as the possible selection for early or late appearance in the karyotypic evolution. By analyzing the temporal order of imbalances common to many tumor types, a general order for nine of these emerged, namely, +7, -3p, -6q, -1p, -8p, -17p, -9p, -18, and -22. The distributions of the number of imbalances per case revealed a geometrical distribution, ranging from one to nine imbalances per tumor, in the majority of the tumor types. In tumor types in which cases with a high number of imbalances per case were frequent, notably head and neck, ovarian, and lung carcinomas, the overall distributions were bimodal, indicating the presence of two modes of chromosome evolution. By combining data from the PCA with the temporal analyses, it was possible to identify karyotypic pathways. It was found that the majority of the tumor types displayed more than one cytogenetic route, but, as the karyotypic evolution continued, these converged to a common pathway.

Allelic Imbalance↗
PubMed2004

Multilineage progression of genetically unstable tumor subclones in cutaneous T-cell lymphoma.

Molecular analysis of solid malignant tumors has suggested multilineage progression of genetically unstable subclones during early stages of tumorigenesis as a common mechanism of tumor cell evolution. We have investigated whether multilineage progression is a feature of cutaneous T-cell lymphoma (CTCL). To identify individual tumor cell subclones, we determined the pattern of mutations within microsatellite DNA obtained from multiple histomorphologically confined tumor cell nests of mycosis fungoides (MF) and lymphomatoid papulosis (LyP) lesions. Tumor cells were isolated by laser microdissection, and allelotypes were determined at microsatellite markers D6S260, D9S162, D9S171, D10S215, TP53.PCR15, and D18S65. Nine cases of MF and one patient with anaplastic large cell lymphoma (ALCL) originating from LyP were analyzed at 277 different microdissected areas obtained from 31 individual lesions. Three specimens of cutaneous lichen planus microdissected at 26 areas served as the control tissue. Microsatellite instability in microdissected tissue [MSI(md-tissue)] was detected in tumor tissues of all CTCL patients. One hundred and fifty-seven of 469 analyzed polymerase chain reaction (PCR) amplifications contained mutated microsatellite alleles (34%). In lichen planus, MSI(md-tissue) was seen in only four of 76 PCR products (5%) (P < 0.0001). The distribution of allelotypes in tumor cells from different disease stages was consistent with multilineage progression in five MF cases, as well as in the LyP/ALCL patient. Our results suggest that CTCL may evolve by multilineage progression and that tumor subclones in MF can be detected in early disease stages by mutation analysis of microsatellite DNA obtained from multiple microdissected areas.

Alleles↗
PubMed2003

Dysregulation of cytokines in acute Q fever: role of interleukin-10 and tumor necrosis factor in chronic evolution of Q fever.

Q fever manifests as primary infection or acute Q fever and may become chronic in patients with underlying valvulopathy. Because Coxiella burnetii infection depends on host response, we measured tumor necrosis factor (TNF), interleukin (IL)-6, IL-12, and IL-10 in patients with different clinical presentations of acute Q fever. Compared with control subjects, patients with uncomplicated acute Q fever exhibited increased release of the 4 cytokines. Their amounts were higher in patients with hepatitis than in patients with fever or pneumonia. In patients with valvulopathy, who exhibited the highest risk of chronic evolution, the amounts of TNF and IL-10 were higher than in patients without valvulopathy. TNF production was specifically enhanced in patients who developed Q fever endocarditis. These results show that acute Q fever is associated with cytokine overproduction. Persistent TNF amounts were associated with the occurrence of endocarditis in patients with valvulopathy, and that may be a marker of chronic evolution of Q fever.

Adolescent↗
PubMed1996

Molecular and cellular biomarkers for field cancerization and multistep process in head and neck tumorigenesis.

One way to explain the development of head and neck cancer is through the theories of field cancerization, i.e., the exposure of an entire field of tissue to repeated carcinogenic insult, and multistep process, i.e., development of multiple cancers in a predisposed filed through a series of recognizable stages. Recent molecular genetic studies of histologically normal and premalignant epithelia of high-risk subjects and studies of malignant tumors in aerodigestive tract epithelia have identified a continuum of accumulated specific genetic alterations that possibly occur during the clonal evolution of tumors, namely, during the multistep process. Second primary or multiple primary tumors arise in the same fields as independent clones, with similar but unique molecular genetic and/or cellular alterations. Consequently, the assessment of these genetic and phenotypic alterations has been integrated into clinical chemoprevention trials in an effort to identify biomarkers that are also risk predictors and intermediate end points. This review covers candidate biomarkers of the processes of field cancerization and multistep tumor development in aerodigestive tract epithelia, including general and specific genetic markers, proliferation markers, and squamous differentiation markers.

Biomarkers, Tumor↗
PubMedDate not supplied

Fine needle aspiration biopsy of anaplastic thyroid carcinoma developing from a Hürthle cell tumor: a case report.

BACKGROUND: Anaplastic thyroid carcinoma is a highly malignant tumor in elderly people with a long history of multinodular goiter and is usually associated with a rapidly fatal clinical evolution. The tumor often develops as a result of anaplastic transformation of a slowly growing papillary carcinoma or follicular neoplasm. CASE: An 85-year-old woman had a multinodular goiter and had been asymptomatic, with a normal white blood cell count and chest radiograph three months prior to her hospital admission for the treatment. The tumor presented with low grade fever, leukocytosis, multiple metastatic lung nodules and enlargement of the intrathoracic thyroid in a period of three months, causing compression of the esophagus and trachea. Despite a total thyroidectomy, the tumor recurred within one month and caused dysphagia and death. CONCLUSION: FNAB permitted the diagnosis of an anaplastic thyroid carcinoma arising from an intrathoracic Hürthle cell tumor.

Aged↗
PubMed1994

Cytogenetic intratumor heterogeneity in soft tissue tumors.

Multiple (two to seven) samples, obtained from the same surgical specimen or at different occasions, were analyzed in 54 benign and malignant soft tissue tumors, to investigate cytogenetic clonal evolution. In 28 tumors only normal karyotypes were found. Ten tumors had abnormal karyotypes, but were noninformative, most often due to a high level of karyotypic complexity or great cell-to-cell variation. Sixteen tumors were informative: four (leiomyosarcoma, liposarcoma, malignant Schwannoma, and a benign mesenchymal tumor, probably leiomyoma) had identical karyotypes in different samples, whereas the remaining 12 tumors (seven malignant fibrous histiocytomas [MFH], two leiomyosarcomas, two liposarcomas, and one synovial sarcoma) displayed intersample heterogeneity. Also, intrasample heterogeneity was detected; more than one clone was found in 21 of 73 samples with aberrations from 26 tumors. The different clones were related in all cases except two. In seven cases, samples from different occasions were studied, and clonal evolution could be evidenced in five of them, whereas in two cases the karyotypes remained unchanged. The results indicate that the acquisition of ring chromosomes is an early event in the development of MFH and possibly also pleomorphic liposarcoma. The findings, together with previous data, also indicate that rearrangements of 19p13 are late events in the progression of pleomorphic sarcomas. The overall conclusion from this study is that cytogenetic heterogeneity is common in soft tissue tumors, and that this might influence the evaluation of cytogenetic and molecular genetic findings.

Adult↗
PubMed2004

Effect of anesthesia on the signal intensity in tumors using BOLD-MRI: comparison with flow measurements by Laser Doppler flowmetry and oxygen measurements by luminescence-based probes.

BOLD-contrast functional magnetic resonance imaging (MRI) was used to assess the evolution of tumor oxygenation and blood flow after administration of four different anesthetics: pentobarbital (60 mg/kg), ketamine/xylazine (80/8 mg/kg), fentanyl/droperidol (0.078/3.9 mg/kg), and isoflurane (1.5%). Gradient echo sequences were carried out at 4.7 Tesla in a TLT tumor model implanted in the muscle of NMRI mice. In parallel experiments, tumor blood flow and tumor pO2 were measured using the OxyLite/OxyFlo probe system. A comparison was made with the changes occurring in the skeletal muscle (host tissue). The signal intensity was dramatically decreased in tumors after administration of anesthetics, except isoflurane. These results correlated well with measurements of oxygenation and blood perfusion. Isoflurane produced constant muscle pO2 and blood perfusion although large transient fluctuations in pO2 and blood flow were reported in some tumors. Our results emphasize the need for careful monitoring of the effects of anesthesia when trying to identify new therapeutic approaches that are aimed at modulating tumor hemodynamics.

Anesthetics↗
PubMed1993

[Programmed death of cells (apoptosis)].

Apoptosis is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. During apoptosis the cell decrease in size, loose contact with neighboring cells, and loose specialized surface elements such as microvilli and cell-cell junctions. A shift of fluid out of the cells causes cytoplasm condensation, which is followed by convolution of the nuclear and cellular outlines. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells. Apoptosis is associated with prostate atrophy after castration or atrophy of the adrenal cortex and thymus after administration of glucocorticoids. Apoptosis is involved in elimination of CD4 T lymphocytes in the course of HIV infection. The interest in apoptosis in oncology stems from the fact that it occurs in tumors, spontaneously as well as triggered by different antitumor drugs, radiation or after withdraw of growth factors. Spontaneous apoptosis may play a role in evolution of tumor malignancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Apoptosis↗
PubMed1991

[Neoplasms of the major and minor salivary glands. The diagnostic and therapeutic approaches and case presentations].

Between January 1982 and December 1988, 37 patients with neoplasm of salivary glands have been treated in our Division of Surgical Oncology. The sites of tumors were: parotid 26, submandibular gland 4, minor salivary gland 7. The preoperative diagnostic procedures were: sialogram, ultrasonogram, fine needle aspiration. Malignant tumors were 16:5 adenoca., 4 metastases, 3 adenoid cystic, 2 mucoepidermoid, 1 acinic cells, 1 lymphoma. Twenty-one patients affected by neoplasms and 5 by malignant tumors were treated with surgery only. Nine patients affected by malignant tumors were treated with surgery and RT. Two patients were treated with RT only. The first therapeutic step is surgery; in order to control local evolution of tumor, postoperative irradiation is recommended. Possible indications of preoperative diagnostic procedures and the therapeutic choices are discussed.

Adult↗
PubMedDate not supplied

[Biological behavior of untreated bladder carcinoma in situ].

The biological behaviour of initially untreated carcinoma in situ of the bladder was studied in 20 patients. A 35.4-month follow-up revealed a heterogeneous behaviour of this disease entity. Diffuse tumors were clearly distinct from focal tumors. The evolution of the former appeared to be more aggressive: no spontaneous remission was observed, 58.3% remained as such while 41.6% progressed to muscle layer infiltration. Focal tumors evolved more favourably: only 1 (12.5%) developed into diffuse carcinoma in situ, 2 (25%) continued to be positive for cytology, while 4 (50%) remitted spontaneously. We therefore consider that both patient groups must be treated upon diagnosis. Intravesical treatment, which achieves a high rate of complete response, is advocated.

Adult↗
PubMed1995

[Bilateral tumors of the testis: the role of the diagnosis of carcinoma in situ in early detection].

In a series of 540 patients with testicular germ cell tumors, the diagnosis of bilateral tumor was observed nine times. Two patients presented a simultaneous bilateral tumor and for seven others a second tumor occurred after an interval varying from 1 to 16 years. The often late discovery of the contralateral cancer sometimes requires a prolonged follow up for patients with unilateral testicular malignancy. Incidence, risk factors and therapy are discussed, in particular the anomalies in testicular migration, hypofertility, testicular atrophy and carcinoma in situ. Prevention of bilateral consecutive tumors depends on the research of carcinoma in situ thanks to testicular biopsy. A slight radiotherapy allows eradication of this tumor, whose evolution towards invading cancer is particularly high. A rigorous watch of these patients can be considered. With the absence of early detection, the treatment of the simultaneous tumor needs taking into consideration the treatment of the initial tumor. In case of a diagnosis at stage 1, observation after orchidectomy is possible without further treatment.

Adult↗
PubMed2005

Emerging roles of centrosomal amplification and genomic instability in cancer.

The carcinogenic process is multistep in terms of its etiology and multifactor in terms of its evolution. In this context, the temporal accumulation of multiple genetic changes during multistage carcinogenesis that can be mediated at least in part by genomic instability may represent crucial components of tumor cell evolution. Evidence is accumulating indicating a close link between genomic instability and cancer initiation and progression. Neoplastic cells typically possess numerous genomic lesions, which may include sequence alterations (point mutations, small deletions, and insertions) and/or gross structural abnormalities in one or more chromosomes (large-scale deletions, rearrangements, gene amplifications). Furthermore karyotypic alterations, including whole chromosome loss or gain, ploidy changes (aneuploidy and polyploidy) and a variety of chromosome aberrations are common in tumor cells. Genomic instability also involves mitotic defects associated with centrosome abnormalities. However, the question of whether abnormal centrosomes cause genomic instability or develop secondary to other changes has not been conclusively resolved. In this review, the recent studies investigating genomic instability and aneuploidy in human cancer, centrosome amplification and the role of centrosomal duplication in chromosomal mis-segregetion, and genes implicated in regulating chromosome segregation, centrosomal amplification and progression in cancer cells are discussed.

Aneuploidy↗
PubMed2005

Current imaging paradigms in radiation oncology.

The technological revolution in imaging during recent decades has transformed the way image-guided radiation therapy is performed. Anatomical imaging (plain radiography, computed tomography, magnetic resonance imaging) greatly improved the accuracy of delineating target structures and has formed the foundation of 3D-based radiation treatment. However, the treatment planning paradigm in radiation oncology is beginning to shift toward a more biological and molecular approach as advances in biochemistry, molecular biology, and technology have made functional imaging (positron emission tomography, nuclear magnetic resonance spectroscopy, optical imaging) of physiological processes in tumors more feasible and practical. This review provides an overview of the role of current imaging strategies in radiation oncology, with a focus on functional imaging modalities, as it relates to staging and molecular profiling (cellular proliferation, apoptosis, angiogenesis, hypoxia, receptor status) of tumors, defining radiation target volumes, and assessing therapeutic response. In addition, obstacles such as imaging-pathological validation, optimal timing of post-therapy scans, spatial and temporal evolution of tumors, and lack of clinical outcome studies are discussed that must be overcome before a new era of functional imaging-guided therapy becomes a clinical reality.

Humans↗
PubMedDate not supplied

[Surgical treatment of gastric, enteric pancreatic endocrine tumors. Part 2. treatment of hepatic metastases].

The development of hepatic metastases (HM) marks a turning point in the evolutionand prognosis of well-differentiated endocrine tumors (ET). Management is usually multicisciplinary (chemotherapy, arterial chemo-embolization, percutaneous ablation, somatostatin analogs, biotherapy, and surgery). A thorough pre-operative work-up is neecessary to exclude extrahepatic disease and to detect tiny HM's. Complete resection (RO) is the only curative treatment for well-differentiated ET with HM. The type of resection is specific to each case and may range from wedge resection of a metastasis to complex hepatectomy with simultaneous resection of the primary ET. Cytoreductive surgery may be indicated for palliation when medical therapy fails to control endocrine symptoms. Operative mortality is low (0-6%) and global survival is 60-70% afterafter R) resection of HM of well-differentiated ET's. After resection of HM involving only one hepatic lobe, 5 year survival is better than 90%. When HM are multiple, bilobar and synchronous, the prognosis is very poor--only 10% of such patients can have a complete resection and this often requires a long prologue of ancillary procedures (chemotherapy, chemoembolization, portal vein ligation, percutaneous ablation). Hepatic transplantation (HT) has only a limited rôle in the treatment of HM for ET; mortality is high when HT is associated with large and complex resections, i.e. pancreaticoduodenectomy. Although there is no consensus in the literature, HT should be limited to the most optimal cases (young, good general health, well-differentiated tumor, slow evolution, complete resection of the primary rumor, and unresectable liver metastases). Global survival for HT in patients with ET is 60% at 2 years, 47% at 5 years; tumor-free survival at 5 years is 24%. HT for HM has better survival results for ET's of intestinal origin (carcinoids) than for duodenopancreatic ET's.

Embolization, Therapeutic↗
PubMedDate not supplied

The canine p53 gene is subject to somatic mutations in thypoid carcinoma.

In many different types of tumors in man and mouse, p53 is the tumor suppressor gene most frequently affected by a combination of somatic mutation and loss of the wildtype allele. In order to develop a molecular tool to study the genetic evolution of tumors in the dog, we have cloned an evolutionary conserved part of the canine homologue of p53. The isolated genomic segment, 534 bp in length, contains the 3' half of exon 5, the complete exon 6 and the 5' half of exon 7, as well as the intronic intervening sequences. The gene organization of this segment shows strong homology to that published earlier for a number of other species, including man, mouse, and Xenopus laevis. This conservation is apparent at the DNA sequence level, as well as at the deduced aminoacid sequence level. mRNA expression can be detected at low levels in normal tissues with increased mitotic activity, and in the Madin-Darby canine kidney cell line. A-->G T transversion was found in 1 out of 23 investigated primary thyroid carcinomas at a position corresponding to codon 174 in the human p53, and was predicted to give rise to an aminoacid substitution in the protein. These results suggest that p53 plays a role in the development of malignancy in the dog, in a way comparable to that in man.

Amino Acid Sequence↗
PubMed1995

Malignant rhabdoid tumors: a clinicopathologic review and conceptual discussion.

The malignant rhabdoid tumor (MRT) has been a controversial lesion since its seminal description. There is no consensus as to whether it represents a distinctive clinicopathological entity or, alternatively, a phenotypic pattern that is potentially common to several disparate neoplasms. MRT of the kidney is a childhood tumor that is associated with uniformly aggressive behavior, but it shows a wide spectrum of histologic, immunophenotypic, and cytogenetic findings. Malignant extrarenal rhabdoid tumors (MERTs) have been observed in pure form over a broader range of patient ages and anatomic locations, but they show substantial morphological and biological homology with renal MRT. Lastly, "composite" extrarenal rhabdoid tumors (CERTs)--in which recognizable "parent" neoplasms are admixed with MERTs--also have been recognized in several topographic sites. In aggregate, these observations suggest that "rhabdoid tumors" are a heterogeneous group of lesions with dissimilar lineages of differentiation. Particularly in CERTs, it is likely that the rhabdoid phenotype represents a common end point of clonal evolution in tumors of clearly different origins. Despite these caveats, the authors do support retention of the diagnosis of "rhabdoid tumor," because the affiliated morphological pattern is uniformly attended by aggressive biological behavior despite potential dissimilarities at a subcellular level.

Abdominal Neoplasms↗