[Tumoral disease of mice transmissible by cell-free material. II. Evolution of the disease toward a form of cytemic or acytemic tumoral reticulosis].
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Animals↗
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Modeling non-random deletions in cancer.
Chromosome deletions do abound in cancer and are detected in certain regions in a non-random manner. Although their relevance remains elusive, it is a general agreement that segmental losses provide the cell with selective growth advantage. Consequently these may contain genes and/or regulatory sequences that control normal growth and inhibit malignancy. We have developed a monochromosomal hybrid based experimental model for the generation and functional analysis of deletions, that is called "elimination test" (Et). Focused on human chromosome 3 - that was known to carry multiple 3p deletions - the Et was expected to restrict a 3p tumor suppressor region to a sufficiently small segment that permits the selection of a critically important candidate gene. Surprisingly, we detected three regions that were lost in all or majority of tumors: CER1 (3p21.3, Mb: 43.32-45.74), CER2 (3p22, Mb: 37.83-39.06) and FER (3p14.3-p21.2, Mb: 50.12-58.03). In contrast a 3q26-qter region (CRR) was regularly retained. CER1 - our main focus - contains multiple genes that may inhibit tumor growth, but 3 genes, RIS1, LF (LTF) and LIMD1 have already the necessary experimental support to be considered bona fide tumor suppressors. Tumor suppressor region borders display instability features including: (1) they break in evolution and in tumors, (2) they evolve horizontally, and (3) they are enriched with pseudogene insertions. The most remarkable features at the breakpoint cluster regions were segmental duplications that drive horizontal evolution and contribute to cancer associated instability.
Animals↗
[Malignant non-Hodgkin's lymphoma associated with a serum monoclonal immunoglobulin].
Among the 394 non-Hodgkin's lymphomas (NHL) observed at our hospital over a thirteen year period, we have found 17 associated monoclonal gammopathies (4.3%). Fourteen gammopathies could be correlated to the lymphoid tumor due to a study of immunological membrane markers and to the comparative evolution of the disease and the monoclonal gammopathy. Two different groups could be distinguished: Six patients out of the fourteen studied (43%) had a gammopathy similar to the surface immunoglobulins of the tumour lymphoid cells. Seven of the seventeen showed, after treatment, a parallel evolution between the tumor and the gammopathy. This originates directly from the tumoral secretion and deserves to be classified among the B lymphoid excretory tumors. Six were IgM and one was IgG. Eight of the fourteen patients studied (57%) did not show any immunological relation between the lymphoma and the monoclonal gammopathy. The evolutions (10 of the 17 patients) of the tumor and of the gammopathy were independent. Among the eleven gammopathies (1 double gammopathy), 5 were IgG, 4 were IgA and 2 were IgM. The incidence of these gammopathies related to the total group tf lymphomas is 2.5%. Given the age of these patients, the association seems fortuitous.
Adult↗
Cystic smooth-muscle tumor of the liver and spleen associated with Epstein-Barr virus after renal transplantation.
Immunosuppression is known to favor the development of various types of tumors. After organ transplantation, the risk of lymphoproliferative disease, whether clonal or not, is particularly increased and clearly associated with Epstein-Barr virus infection. We report a case of an unusual large cystic tumor of the liver with satellite hepatic and splenic nodules occurring 4 years after renal transplantation. Radiologic examination showed a rich vascularization of the tumor. Light and electron microscopy of a surgical liver biopsy, completed by an immunohistochemical study, demonstrated a well-differentiated tumor of smooth-muscle origin. Using in situ hybridization, we showed large amounts of Epstein-Barr virus messenger RNAs within the tumor cells. In addition, Southern blot analysis revealed that viral DNA was present in the form of a single monoclonal episome within the tumor. The polymerase chain reaction analysis of the genomic DNA of tumoral cells also indicated a monoclonal pattern. At last, the tumor was shown to be of host origin. Six months later, and despite three courses of chemotherapy, the tumoral lesions were unchanged. This case underlines the role of Epstein-Barr virus infection in the development of unusual and clonal smooth-muscle tumors after organ transplantation. The evolution of these rare tumors is uncertain.
Female↗
Challenges to the development of antigen-specific breast cancer vaccines.
Continued progress in the development of antigen-specific breast cancer vaccines depends on the identification of appropriate target antigens, the establishment of effective immunization strategies, and the ability to circumvent immune escape mechanisms. Methods such as T cell epitope cloning and serological expression cloning (SEREX) have led to the identification of a number target antigens expressed in breast cancer. Improved immunization strategies, such as using dendritic cells to present tumor-associated antigens to T lymphocytes, have been shown to induce antigen-specific T cell responses in vivo and, in some cases, objective clinical responses. An outcome of successful tumor immunity is the evolution of antigen-loss tumor variants. The development of a polyvalent breast cancer vaccine, directed against a panel of tumor-associated antigens, may counteract this form of immune escape.
Antigen-Antibody Reactions↗
[Smooth muscle mesentery associated with Epstein-Barr virus (EBV). Report of a case in a child with a liver transplant under FK506 regimen].
Smooth-muscle tumors, benign and malignant, are increasingly recognized in children who are immunocompromised because of HIV infection and organ transplantation. We report a case of an EBV-associated smooth-muscle tumor, of unusual location arising in a seven-year-old post-transplant patient who was previously treated for a lymphoproliferative disease. Five years after liver transplantation, a mesenteric tumor was diagnosed. The tumor was composed of spindle cells with smooth-muscle features. Immunohistochemical analysis was positive for muscle-specific actin and desmin, negative for EBV latent membrane protein (LMP-1). In situ hybridization revealed nuclear EBV sequences. This case underlines the role of EBV infection in the development of unusual smooth-muscle tumors after organ transplantation. The evolution of these rare tumors is uncertain.
Child↗
Allelic loss of chromosomal arm 8p in breast cancer progression.
Loss of heterozygosity (LOH) of chromosomal arm 8p has been reported to occur at high frequency for a number of common forms of human cancer, including breast cancer. The objectives of this study were to define the regions on this chromosomal arm that are likely to contain breast cancer tumor suppressor genes and to determine when loss of chromosomal arm 8p occurs during breast cancer progression. For mapping the tumor suppressor gene loci, we evaluated 60 cases of infiltrating ductal cancer for allelic loss using 14 microsatellite markers mapped to this chromosomal arm and found LOH of 8p in 36 (60%) of the tumors. Whereas most of these tumors had allelic loss at all informative markers, five tumors had partial loss of 8p affecting two nonoverlapping regions. LOH for all but one of the tumors with 8p loss involved the region between markers D8S560 and D8S518 at 8p21.3-p23.3, suggesting that this is the locus of a breast cancer tumor suppressor gene. We then studied LOH of 8p in 38 cases of ductal carcinoma in situ (DCIS) with multiple individually microdissected tumor foci evaluated for each case. LOH of 8p was found in 14 of the DCIS cases (36%), including 6 of 16 cases of low histological grade and 8 of 22 cases of intermediate or high histological grade. In four of these DCIS cases, 8p LOH was seen in some but not all of the multiple tumor foci examined. These data suggest that during the evolution of these tumors, LOH of 8p occurred after loss of other chromosomal arms that were lost in all tumor foci. Thus, LOH of 8p, particularly 8p21.3-p23, is a common genetic alteration in infiltrating and in situ breast cancer. Although 8p LOH is common even in low histological grade DCIS, this allelic loss often appears to be preceded by loss of other alleles in the evolution of breast cancer.
Breast Neoplasms↗
Contribution of the activation of the ras oncogene to the evolution of aldosterone- and renin-secreting tumors.
The possible point-mutational activation of the ras oncogene, which probably contributes to the evolution of aldosterone-producing adenomas and ectopic reninoma, was evaluated. Chromosomal DNA was extracted from six aldosterone-producing adenomas and one renin-secreting liver carcinoma, using the standard method with phenol:chloroform:isoamyl alcohol. One microgram of sample DNA, forward and reverse primers, Taq I polymerase and deoxyribonucleotide triphosphates (dNTPs) were mixed and the ras gene was amplified by the polymerase chain reaction. Point mutations at ras-12 or ras-61 sites of amplified DNA were tested by dot-blotting, using H-, N- and K-ras oligonucleotide probes with mutations at codons 12 or 61. However, there were no point mutations at amino acid codons 12 or 61 of c-Hi-ras, c-Ki-ras and N-ras oncogenes in all aldosterone-producing adenomas and the one ectopic reninoma. These results indicate that point-mutational activation of ras oncogenes does not contribute, at least in this series, towards the evolution of aldosterone-producing adenomas and the reninoma.
Adenoma↗
Depression secondary to tumors in patients who underwent surgery for mammary carcinoma: psycho-pharmaceutical and psychotherapeutic care.
The Authors repeated a pilot psycho-social research they had already undertaken in this University in 1986-1987, with an increased number of patients, administering a psycho-therapeutic treatment to patients who had undergone surgery for mammary carcinoma and correlating the evolution of the tumoral disease with the role of depression and the immune system. These 50 patients were compared to another randomly chosen control-group of 50 patients. Both groups were homogeneous as regards medical-surgical and psycho-social parameters and had routine oncological care. Only the patients of the study-group were submitted to individual psychotherapy and treated psychopharmacologically. At the end of the study, the two groups showed a statistically significant difference as regards the evolution of the tumoral disease in favour of the study-group. In addition, a relevant improvement from depression was recorded in the study-group along with a normalization and a boost of the immunological measurements.
Aged↗
Assessment of stage T1 (TNM 1997) for renal cell carcinoma: is recommended the subdivision in T1a and T1b?
INTRODUCTION: Classification TNM 1997 defines renal cell carcinoma smaller than 7 cm and confined to the kidney as stage T1. Our goal is to discuss if tumors smaller than 4 cm have the same behavior characteristics then tumors between 4 and 7 cm, to compose the same stage of the disease. MATERIALS AND METHODS: Retrospective assessment of 138 patients in stage T1 (TNM - 97), divided into 2 groups; group-1: composed of 65 patients (47%) with tumors < 4 cm, and group-2: composed of 73 patients (53%) with tumors between 4 and 7 cm. The following prognostic factors were assessed in the recurrence of the disease and survival of patients: nuclear degree, microvascular invasion, sarcomatous degeneration, and involved lymph nodes. Statistical evaluation has been accomplished through the log rank test, chi-square test, and Fisher's exact text. RESULTS: Average tumor size was 2.5 cm for group-1, and 5.3 cm for group-2. In group-2, there was the predominance of worse prognostic factors, with high-grade tumors (p = 0.01) and presence of microvascular invasion (p = 0.001). Sarcomatous tumors and involvement of lymph nodes did only happen in group-2. Disease-free survival for group-1, analyzed in the median period of 36 months, was 100%, and for group 2, in the median period of 31 months, was 81% (p = 0.008). CONCLUSION: The results obtained allow the conclusion that the present stage T1 for renal cell carcinoma gathers tumors of different evolution, being therefore recommendable the stratification in T1a for tumors smaller than 4 cm, and T1b for tumors between 4 and 7 cm.
Journal Article↗
Microsatellite alteration at chromosome 3p loci in neuroendocrine and non-neuroendocrine lung tumors. Histogenetic and clinical relevance.
Although chromosome 3p regions are the most frequent site for genetic alterations in small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC), the extent of such abnormality in carcinoid tumors remained to be investigated. Moreover, the histogenetic and biological implications of these findings in non-carcinoid lung tumors remain unclear. We studied eight microsatellite loci on chromosome 3p regions by multiplex polymerase chain reaction in paired normal and tumor DNA from 17 carcinoid tumors, 5 SCLCs, and 38 NSCLCs to determine the histogenetic and the clinical significance of their alterations in these neoplasms. Our results revealed a lack of microsatellite abnormalities at all loci tested in both typical and atypical carcinoid tumors. SCLCs and NSCLCs showed loss of heterozygosity in 100% (5/5) and 58.0% (22/38), respectively. Loss of heterozygosity at more than two loci correlated significantly with poor histological differentiation and were preponderantly found in high proliferative index and DNA aneuploid NSCLCs. Microsatellite instability was noted in only one (1.7%) of the lesions. Our study suggests that 1) the difference in chromosome 3p alterations between carcinoid tumors and SCLCs favors a stochastic rather than linear evolution of these tumors, 2) 3p alterations may constitute an initial event in the development of small cell carcinomas, and 3) loss of heterozygosity at 3p loci is associated with aggressive tumor characteristics in non-small-cell carcinomas.
Adult↗
Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors.
Although mechanisms for chromosomal instability in tumors have been described in animal and in vitro models, little is known about these processes in man. To explore cytogenetic evolution in human tumors, chromosomal breakpoint profiles were constructed for 102 pancreatic carcinomas and 140 osteosarcomas, two tumor types characterized by extensive genomic instability. Cases with few chromosomal alterations showed a preferential clustering of breakpoints to the terminal bands, whereas tumors with many changes showed primarily interstitial and centromeric breakpoints. The terminal breakpoint frequency was negatively correlated to telomeric TTAGGG repeat length, and fluorescence in situ hybridization with telomeric TTAGGG probes consistently indicated shortened telomeres and >10% of chromosome ends lacking telomeric signals. Because telomeric dysfunction may lead to formation of unstable ring and dicentric chromosomes, mitotic figures were also evaluated. Anaphase bridges were found in all cases, and fluorescence in situ hybridization demonstrated extensive structural rearrangements of chromosomes, with terminal transferase detection showing fragmented DNA in 5-20% of interphase cells. Less than 2% of cells showed evidence of necrosis or apoptosis, and telomerase was expressed in the majority of cases. Telomeric dysfunction may thus trigger chromosomal fragmentation through persistent bridge-breakage events in pancreatic carcinomas and osteosarcomas, leading to a continuous reorganization of the tumor genome. Telomerase expression is not sufficient for completely stabilizing the chromosome complement but may be crucial for preventing complete genomic deterioration and maintaining cellular survival.
Adolescent↗
Tumor-host interaction in non-random metastatic pattern distribution.
In the clinical evolution of malign tumors, prognosis depends on whether metastasis develops or not. Biologically speaking, the formation of metastasis implies the existence of tumor cells capable of successfully performing all the steps in the metastatic process: local invasion, lymphatic or hematogenous dissemination, arrest in the microvascular bed of an organ, extravasation and growth of a secondary colony. Clinical observations have demonstrated that for each primary tumor there is a colonization pattern determined by the characteristics of the microvascular endothelium and the functional environment of the target organ. Moreover, the formation of metastasis depends on at least two additional factors: a) tumor cell-tumor cell and tumor cell-host cell relations modulated by intercellular contact and/or soluble paracrine or autocrine growth factors; b) the antitumor efficiency of the immune system, mediated primarily by the action of NK/LAK cells, macrophages and cytolytic T-lymphocytes, whose activity is in turn regulated by a complex of cytokines, including interferons, tumor necrosis factors and interleukins. In this work, we first review certain aspects of tumor biology that are specifically involved in tumor cell-host cell interactions determining non-random metastatic pattern distribution, and then review the implication of certain cytokines in the regulation of tumor proliferation.
Animals↗
Recent advances in the treatment of skull base tumors using radiation.
The evolution of technology has led to dramatic advances in the ability to treat tumors of the skull base, and the future of these devices seems bright. Only with time, however, will we be certain of their true role in the management of tumors of the skull base.
Cranial Irradiation↗
Mutually compensatory mutations during evolution of the tetramerization domain of tumor suppressor p53 lead to impaired hetero-oligomerization.
We have measured the stability and stoichiometry of variants of the human p53 tetramerization domain to assess the effects of mutation on homo- and hetero-oligomerization. The residues chosen for mutation were those in the hydrophobic core that we had previously found to be critical for its stability but are not conserved in human p73 or p51 or in p53-related proteins from invertebrates or vertebrates. The mutations introduced were either single natural mutations or combinations of mutations present in p53-like proteins from different species. Most of the mutations were substantially destabilizing when introduced singly. The introduction of multiple mutations led to two opposite effects: some combinations of mutations that have occurred during the evolution of the hydrophobic core of the domain in p53-like proteins had additive destabilizing effects, whereas other naturally occurring combinations of mutations had little or no net effect on the stability, there being mutually compensating effects of up to 9.5 kcal/mol of tetramer. The triple mutant L332V/F341L/L344I, whose hydrophobic core represents that of the chicken p53 domain, was nearly as stable as the human domain but had impaired hetero-oligomerization with it. Thus, engineering of a functional p53 variant with a reduced capacity to hetero-oligomerize with wild-type human p53 can be achieved without any impairment in the stability and subunit affinity of the engineered homo-oligomer.
Animals↗
Modeling multi-drug chemotherapy: tailoring treatment to individuals.
BACKGROUND: Predicting and tailoring optimal cancer treatments presents a major challenge. METHODS: A computational model (kinetically tailored treatment, or KITT model) is developed to predict drug combinations, doses, and schedules likely to be effective in reducing tumor size and prolonging patient life. Treatment strategies may be tailored to individuals based on tumor cell kinetics. The model incorporates intra-tumor heterogeneity and evolution of drug resistance, apoptotic rates, and cell division rates. Tumor growth may follow an exponential or a Gompertzian trajectory. Drug pharmacodynamic and pharmacokinetic models are used. Toxicity is modeled in several ways. RESULTS: A key prediction of KITT is that including cytostatic drugs like tamoxifen and herceptin during treatment with cytotoxic drugs substantially increases the probability of cure and prolongs patient life. Results also suggest that altering drug scheduling may be more effective but not more toxic than dose escalation. CAF chemotherapy (cyclophosphamide, adriamycin, and 5-fluorouracil) is predicted to be more effective than CMF (cyclophosphamide, methotrexate, and 5-fluorouracil). KITT also suggests that tumors with a high proliferative index (PI) may respond better to drug combinations incorporating two cell-cycle phase-specific drugs than do tumors with a low PI. Tumors with a low PI, in contrast, are predicted to respond better to regimens involving two cell-cycle phase-non-specific drugs than do tumors with a high PI. These predictions are borne out by clinical trial results published in the literature, which are discussed. Simulated predictions of the model match well with results from a clinical trial by Silvestrini et al. (2000. Int. J. Cancer 87, 405). The results of simulating the growth of 26896 tumors are used to construct a decision tree for prognosis to identify the key tumor and treatment variables. CONCLUSION: Additional tests of the model are needed in which physicians collect information on apoptotic and proliferative indices, cell-cycle times, and drug resistance from biopsies of each individual's tumor. Computational models may become important tools to help optimize and tailor cancer treatments.
Antineoplastic Combined Chemotherapy Protocols↗
Pattern visual evoked potentials represent an early index for the evolution of optic chiasma syndrome of tumoral etiology.
The use of visual evoked potentials in the detection of optic chiasma syndrome of tumoral etiology has been controversial in the literature. In our study the pattern visual evoked potentials (PVEP) were recorded in 22 healthy free volunteers and in 32 patients with optic chiasma syndrome (OCS) produced by tumors of the hypothalamic-pituitary area, mainly pituitary adenomas with suprasellar extension, proved by CT scan. The PVEP were recorded bilateral after monocular photic stimulation of each atropinized eye, in parallel with a complete ophthalmologic exam consisting in visual field, visual acuity and optic fundus. The main results showed that the latencies P100 recorded bilateral were correlated (p < 0.01) with the types of visual field deficiency, in each hemifield. The changes in P100 latency are more sensitive than the evolution of visual field deficiency by campimetry. The same correlation was observed between the "W" form of P wave with the visual field defect. A significant decrease (p < 0.05) of the amplitude of P100 was observed only if the visual acuity was less than 1/2. It is suggested that the PVEP is a reliable index of diagnosis and evolution for the optic chiasma syndrome aside the usual ophthalmologic exam.
Adolescent↗
How to starve a tumor.
The formation of new blood vessels, termed angiogenesis, is a central process in the evolution of a tumor and its subsequent metastasis. Angiogenesis is potently inhibited by the fumagillins, a family of epoxide-containing natural products. The recent identification of a protein target for these compounds may help decipher the mechanisms underlying endothelial cell growth. The fact that binding is irreversible may inspire the design of electrophilic inhibitors of other, poorly understood cellular processes.
Aminopeptidases↗