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Results for “tumor evolution”

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At least 343 records · Page 19Linked to original sources
PubMed2000

Dynamic optimization of a linear-quadratic model with incomplete repair and volume-dependent sensitivity and repopulation.

PURPOSE: The linear-quadratic model typically assumes that tumor sensitivity and repopulation are constant over the time course of radiotherapy. However, evidence suggests that the growth fraction increases and the cell-loss factor decreases as the tumor shrinks. We investigate whether this evolution in tumor geometry, as well as the irregular time intervals between fractions in conventional hyperfractionation schemes, can be exploited by fractionation schedules that employ time-varying fraction sizes. METHODS: We construct a mathematical model of a spherical tumor with a hypoxic core and a viable rim, which is most appropriate for a prevascular tumor, and is only a caricature of a vascularized tumor. This model is embedded into the traditional linear-quadratic model by assuming instantaneous reoxygenation. Dynamic programming is used to numerically compute the fractionation regimen that maximizes the tumor-control probability (TCP) subject to constraints on the biologically effective dose of the early and late tissues. RESULTS: In several numerical examples that employ five or 10 fractions per week on a 1-cm or 5-cm diameter tumor, optimally varying the fraction sizes increases the TCP significantly. The optimal regimen incorporates large Friday (afternoon, if 10 fractions per week) fractions that are escalated throughout the course of treatment, and larger afternoon fractions than morning fractions. CONCLUSION: Numerical results suggest that a significant increase in tumor cure can be achieved by allowing the fraction sizes to vary throughout the course of treatment. Several strategies deserve further investigation: using larger fractions before overnight and weekend breaks, and escalating the dose (particularly on Friday afternoons) throughout the course of treatment.

Algorithms↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed1989

[Use of systemic carboplatin in superficial tumors of the bladder. Preliminary phase II study (toxicity)].

The high recurrence rate of superficial bladder tumors, its frequent association with premalignant tumors, and its evolution into infiltrating tumors in 15% of the cases justify the use of tumoricidal agents as adjuvant therapy. For the past 20 years, several agents have been used intravesically with limited efficacy (+/- 40% recurrence/year), high local morbidity (cystitis, urethral stenosis), and excessively long duration of treatment (+/- 1 year). The efficacy of CDDP in the treatment of bladder tumors has been reported elsewhere. An objective response of +/- 50% (RC + RP) at a dose of 50-70 mg/m2 has been observed. The new generations of platinum, less toxic and easier to use, have raised hopes vis-à-vis its efficacy in the treatment of this tumor type. To date, we have evaluated 26 patients with superficial tumor of the bladder over a period of one year. These patients had been submitted to a treatment protocol with systemic carboplatinum following complete TUR and assessment of bone marrow; renal function, WHO, audiometry, urinary cytology, determination of tumor cell markers (CEA, çGT). Treatment consisted of 3 cycles of i.v. carboplatinum at a dose of 300 mg/m2 (1/30 days). We have corroborated the following features: ease of use, good patient tolerance and scant toxicity. However, its efficacy has as yet to be determined through the disease-free interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment.

Emergence of invasive behavior in cancer is life-threatening, yet ill-defined due to its multifactorial nature. We present a multiscale mathematical model of cancer invasion, which considers cellular and microenvironmental factors simultaneously and interactively. Unexpectedly, the model simulations predict that harsh tumor microenvironment conditions (e.g., hypoxia, heterogenous extracellular matrix) exert a dramatic selective force on the tumor, which grows as an invasive mass with fingering margins, dominated by a few clones with aggressive traits. In contrast, mild microenvironment conditions (e.g., normoxia, homogeneous matrix) allow clones with similar aggressive traits to coexist with less aggressive phenotypes in a heterogeneous tumor mass with smooth, noninvasive margins. Thus, the genetic make-up of a cancer cell may realize its invasive potential through a clonal evolution process driven by definable microenvironmental selective forces. Our mathematical model provides a theoretical/experimental framework to quantitatively characterize this selective pressure for invasion and test ways to eliminate it.

Adaptation, Physiological↗
PubMed2004

A model for karyotypic evolution in testicular germ cell tumors.

Testicular germ cell tumor karyotypes are characterized by near-triploidy, with chromosome numbers ranging from 50 to 70, and by the frequent appearance of i(12p). The high chromosome number has been attributed to the formation of tetraploid carcinoma in situ cells followed by chromosomal losses that ultimately lead to tumor forms that are more advanced. In the present investigation, we show by analysis of the accumulated cytogenetic data on testicular germ cell tumors and computer simulations that two distinct processes are operating in the karyotypic evolution of these tumors. The results suggest that whole-chromosome changes originate from a multipolar cell division of a tetraploid cell, whereas imbalances caused by structural changes accumulate in a stepwise manner.

Cell Division↗
PubMed2006

Heterogeneity of neoplastic cells in B-cell chronic lymphoproliferative disorders: biclonality versus intraclonal evolution of a single tumor cell clone.

BACKGROUND AND OBJECTIVES: B-cell chronic lymphoproliferative disorders (B-CLPD) are usually monoclonal expansions of a single B-cell clone. However in some cases, two unrelated B-cell clones co-exist. Additionally, cases with two B-cell subpopulations displaying a similar phenotype but distinct DNA contents exist, the exact nature of these cases remaining unknown. In order to gain insight into the characteristics of these complex B-CLPD we examined two cohorts of patients. MATERIAL AND METHODS: One cohort had two phenotypically distinct B-cell populations (group A; n= 9) and the other, two B-cell subsets showing different DNA contents and/or light scatter properties, but a similar immunophenotype (group B; n= 7). RESULTS: Fluorescent in situ hybridization studies revealed the presence of genetic abnormalities in six cases from group A, either in one (n=5) or the two co-existing B-cell populations (n=1); in all these cases the two B-cell populations showed unrelated IgH gene rearrangements. In all seven cases from group B, the B-cell population showing higher DNA contents had additional chromosomal abnormalities as compared to the other subset; molecular analysis confirmed the monoclonal nature of these cases. INTERPRETATION AND CONCLUSIONS: In summary, we show that in group A, two phenotypically/cytogenetically distinct, unrelated B-cell clones co-exist, while the two B-cell populations from group B appear to represent different stages of evolution of a single clone.

Base Sequence↗
PubMed2001

Extent of tumor-brain interface: a new tool to predict evolution of malignant gliomas.

OBJECT: Tumor size is one of the features commonly used in oncology to predict disease evolution. However, for most primary brain tumors it is not predictive of outcome. Taking advantage of a gene therapy trial in which recurrences of glioblastoma were targeted with suicide genes, the authors developed a new parameter: the extent of tumor-brain interface--also called surface of tumor volume (STV)--to better describe three-dimensional conformation and the relationship between tumors and the surrounding normal tissue. Correlations between the STV and the usual clinical parameters were analyzed. METHODS: Between 1995 and 1998, 16 patients presenting with recurrent glioblastomas were enrolled in this study. Preoperative magnetic resonance images were analyzed on a separate workstation; the interface between tumor and normal brain tissue was measured on each 3-mm-thick section to assess STV. The mean STV was 29.2 cm2, and the mean tumor volume (TV) was 23.8 cm3. The STV was significantly correlated with survival (Spearman test: r = -0.54, p = 0.03), but TV was not (Spearman test: r = -0.39, p = 0.15). A separate analysis of responding and nonresponding patients showed that, as expected, STV was negatively correlated with survival among nonresponding patients (p = 0.04), but that among responding patients there was a positive tendency between STV and survival. CONCLUSIONS: These findings indicate that STV may be a useful tool for predicting the evolution of malignant glioma. Moreover, in future gene therapy trials in which such in situ approaches are used, increasing density and improved distribution of transfer cells should be taken into consideration as an important issue for efficacy.

Adult↗
PubMedDate not supplied

[Small bowel tumors -- peculiarities of diagnosis and evolution].

The authors analyze 13 cases of small bowel tumors. There are emphasized the difficulties of diagnosis, which is rarely established before the laparotomy. In the same time, clinical features are few and operations are often performed too late, in emergency, due to tumors complications (perforation, bleeding, occlusion). There are also presented new etiopathogenic hypothesis, recently mentioned in literature. Surgical treatment is followed by many post-operative complications. Five-years survival is low, under 40% of patients.

Adenocarcinoma↗
PubMed1993

Evolution of mouse mammary tumor virus-related sequences in the human genome.

The human genome contains numerous copies of elements with sequence homology to the mouse mammary tumor virus (MMTV). We have been interested in whether these elements are still actively transposing in the germ lines, and investigated this question by looking at restriction fragment patterns. Genomic DNA from humans and selected animals were digested with three different restriction enzymes and hybridized with five probes representative of five subgroups of the human MMTV-related elements. Two polymorphisms as well as two cases of sexual dimorphism were discovered in human DNA. The latter indicate the presence of at least two elements of the MMTV family on the Y chromosome. DNA samples from non-primate mammals were all unreactive. Both chimpanzee and rhesus monkey had restriction patterns of roughly the same number of bands and total intensity as humans. The number of differences in patterns between humans, and between humans and chimpanzee or rhesus monkey, were compatible with being caused by point mutations. The data indicate that these elements were actively spreading in the genome some time before the split between apes and Old World monkeys, while being relatively inactive, at least as to transpositions in the germ line, in later ages.

Animals↗
PubMed2007

Chromosomal deletions in bladder cancer: shutting down pathways.

Bladder cancer is one of the most common cancers in the world, leading to approximately 145,000 deaths annually. Bladder cancer is typically managed by surgical removal of the tumor; however, the recurrence rate is disappointingly very high, often requiring systemic chemotherapy. Improvement in the diagnosis and prognosis of bladder cancer will only come from a comprehensive understanding of the genetic factors that lead to its development. In this review, we focus on the chromosomal deletions that contribute to the downregulation of tumor suppressor pathways in bladder cancer. Chromosomal deletions are not a random event, since bladder cancer progression has been associated with specific chromosomal deletions and this progression correlates with specific stages of tumor development. The most commonly found chromosomal deletion in all stages of bladder cancer involves deletions in chromosome 9, resulting in the loss of three genes encoding proteins that activate the Rb and p53 tumor suppressors. Additionally, chromosome 9 harbors the TSC1 tumor suppressor which downregulates the well-known anti-apoptotic Akt/mTOR pathway. Hence, deletions on one chromosome may have a crucial influence on the initial steps in tumor development. Other deletions targeting the tumor suppressors Rb, p53, FHIT and LZTS1 occur at later stages of tumor development. Considering the central importance of these tumor suppressor pathways in the formation and evolution of tumors, the time has come to evaluate available drugs in bladder cancer that target the positive regulators of these pathways.

Chromosome Deletion↗
PubMed2003

Changes in tumor vascularization after irradiation, anthracyclin, or antiangiogenic treatment in nitrosomethyl ureas-induced rat mammary tumors.

PURPOSE: Changes in tumor vascularization may be involved in tumor regression after anticancer treatments. We therefore studied the relationship between tumor vascularization and tumor response according to treatment by irradiation (RT), epirubicin (EPI), or antiangiogenic agent TNP-470 in a nitrosomethyl-ureas-induced rat mammary tumor model by measuring the changes in tumor blood flow using high-frequency Power-Doppler sonography. EXPERIMENTAL DESIGN: Mammary tumors were induced in female Sprague-Dawley rats by a single s.c. injection of nitrosomethyl-ureas. After tumor areas reached 2 cm(2), the animals received four weekly injections of epirubicin (EPI group), or a single fraction of 18 Gy (RT group), or six injections of TNP-470 within 12 days (TNP group), or both (RT combined with TNP-470, RT+TNP group). Power-Doppler sonography quantification of tumor vascularization (PDI) was performed before and 12 days after initiation of treatment. Tumor shrinkage was later evaluated and compared with the early changes in PDI values. RESULTS: Compared with the control group, EPI induced an arrest in tumor growth. A similar effect was obtained with TNP-470. There was a decrease in tumor area after RT, but administration of TNP-470 combined with RT did not further enhance this effect. Changes in tumor area paralleled changes in PDI in the EPI group. Furthermore, changes in PDI 7 days after RT were associated with further tumor change in the RT groups, whereas they were independent of the antitumor effect of TNP-470. CONCLUSIONS: Changes in functional tumor vascularization evolution appeared to be closely associated with tumor regression after anticancer treatment.

Animals↗
PubMed1991

Tumor cell progression and differentiation in metastasis.

The development and evolution of tumors is regulated by both genetic and epigenetic events. It is thought that these processes tend to drive neoplastic development in opposing directions so that tumor progression, predominantly as a consequence of mutational events, leads to increasing tumor aggression. Conversely the induction of differentiation, largely through epigenetic mechanisms, tends to cause tumors to evolve to a more benign phenotype. However, these generalizations are a simplistic view of a complex dynamic event where both processes can be overlaid within a single neoplasm. Using malignant melanoma as a model system the alterations in gene expression and their effects upon metastatic dissemination, that accompany some of these changes, both natural and induced, are described.

Animals↗
PubMed2005

p53 gain-of-function: tumor biology and bioinformatics come together.

p53 is typically viewed as a tumor suppressor. However, many missense somatic and germline mutations in the p53 gene cause gain-of-function whereby p53 acquires novel biochemical activities, such as the ability to transactivate transcription of new genes or to mediate new regulatory protein-protein interactions. Several recent studies show that at least some gain-of-function mutations of p53 are biologically relevant leading to a change in the tumor phenotype. Independent bioinformatic analysis of somatic mutation spectra of the p53 gene yields three lines of evidence supporting the notion that gain-of-function could be the prevalent mode of p53 evolution in tumors. (1) The hotspots in the p53 gene show signs of intensive positive selection. (2) The hotspots are located primarily in functionally important motifs of the DNA-binding domain of p53 which are highly conserved in interspecies evolution. (3) The spectra of hotspots significantly differ among various tumor types and the germline (Li-Fraumeni syndrome); in addition to the hotspots shared by the germline and some of the tumors, many are tumor-specific. The latter observation suggests an unexpected level of complexity of p53 evolution in tumors, with distinct novel function gained in different tumors.

Animals↗