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PubMedDate not supplied

High levels of sFas and PBMC apoptosis before and after excision of malignant melanoma--case report.

In our study we investigated the level of apoptosis in PBMCs and the serological level of sFas (CD95/APO-1) in 22 patients with malignant melanoma (12 patients with unique cutaneous primary tumour and 10 patients with unique brain metastasis). The first determination was performed before tumour excision and the second at 6-7 months after excision. Results in patients with primary tumour in the first determination: 6 patients with over normal values in PBMCs apoptosis and 5 patients with increased values of sFas. In the second determination: apoptosis was increased in 5 patients and sFas level was increased in 4 cases. In patients with metastases in the first determination apoptosis of PBMC was increased in 7 cases and sFas in 5 cases. In the second determination apoptosis was increased in 4 cases and sFas was increased in 4 cases. Our results show that half of the investigated patients presented elevated values of PBMCs apoptosis and Fas receptor both before and 6-7 months after tumour excision. Apoptosis values for PBMCs and sFas values were with 1/4 higher than normals. There was no difference in clinical evolution of the patients with normal or increased values for studied parameters. Clinical evolution was performed for 1 year. The presence of increased values for PBMCs and sFas after tumour excision, primary or metastasis is surprising and hard to explain. It is possible that tumoral evolution induces a disregulation at PBMCs level or other cells level that persists unexpectedly, after tumour excision or apoptotic processes, in a certain level to be independent and anterior to tumour development.

Apoptosis↗
PubMed2004

Oligoclonality in bladder cancer: the implication for molecular therapies.

PURPOSE: There is conflicting evidence in the published literature regarding the clonal or oligoclonal origin of bladder cancer. MATERIALS AND METHODS: A MEDLINE search of articles on the clonality, genetic, epigenetic and tumor microenvironment of bladder cancer cells was done. Laboratory and clinical studies were included and relevant articles were selected if tumor cell clonality was part of the study. We reviewed this published evidence. RESULTS: Current thinking proposes 2 main theories. 1) In the clonogenic theory multifocal and recurrent tumors evolve from a single transformed cell and, hence, all progeny share a number of identical genetic mutations. 2) The field change theory assumes a global change in the urothelium with multiple transformed cells evolving into mature tumors independently. The evidence for and against each theory is compelling. Of equal importance are the parallel epigenetic modifications and changes in the cellular microenvironment that permit tumor evolution. CONCLUSIONS: The presence of oligoclonality has implications for the potential efficacy of novel molecular therapeutic agents for bladder cancer. The molecular targets for such therapies must be widely sampled in a tumor population to assess expression in separate clones.

Carcinoma, Transitional Cell↗
PubMedDate not supplied

Xeroradiographic evaluation of murine osteosarcoma.

Xeroradiography, a method of X-ray imaging based upon selenium photoconductivity, was used for the study of experimental osteosarcoma induced by MSV-M virus in rats. Due to the peculiar features of xeroradiographic image (enhancement of details and lowering of the overall contrast) good pictures of osseous structures together with soft tissues were obtained even in very young animals. Serially perfomred xeroradiographies gave a permanent representation of tumor evolution with time. Advantages and drawbacks of this method are discussed, particularly with respect to radiation dosage. Xeroradiography is proposed for the study of the response to antiblastic chemotherapy of experimental bone tumors.

Animals↗
PubMed1997

Chromosome 11q13 gene amplifications in oral and oropharyngeal carcinomas: no correlation with subclinical lymph node invasion and disease recurrence.

Gene amplifications in the q13 band of chromosome 11 are among the most frequent genetic alterations in head and neck squamous cell carcinomas. Previous studies have suggested that such amplification is a marker of aggressive tumor evolution. Their potential for predicting subclinical lymph node invasion or disease recurrence was investigated in a prospective series of 50 oral and oropharyngeal carcinomas. Cell DNA content was also measured in 32 tumors of this series. Gene amplifications affecting the 11q13 band were detected in 11 of 50 (20%) patients, a relatively low frequency in comparison with data reported previously for other carcinomas of the upper aerodigestive tract, especially hypopharyngeal carcinomas. These gene amplifications were preferentially associated with aneuploidy. Cervical lymph nodes of 26 clinically N0 (Tumor-Node-Metastasis staging) patients were surgically explored. The frequency of 11q13 amplifications was very similar in the presence or in the absence of histological invasion, 3 of 15 (20%) and 2 of 11 (18%), respectively. Thus, 11q13 amplifications do not appear to be a reliable marker for prediction of subclinical lymph-node invasion in oral and oropharyngeal carcinomas. The detection of 11q13 amplifications was also not associated with a higher risk of disease recurrence. These data suggest that not only the prevalence but also the prognostic significance of 11q13 amplifications varies between tumors at different sites in the upper aerodigestive tract.

Adult↗
PubMed2004

Value of Hu antibody determinations in the follow-up of paraneoplastic neurologic syndromes.

The long-term evolution of Hu antibody (Hu-Ab) titers in patients with paraneoplastic neurologic syndromes (PNSs) is not known. Described is the evolution of Hu-Ab titers in 35 patients with PNS with a median follow-up of 32 months (range 6 to 108 months). No correlation was observed between Hu-Ab titers and neurologic outcome, tumor evolution, or type of treatment. Serial Hu-Ab determinations are not useful for monitoring the clinical outcome of patients with PNS.

Adult↗
PubMed2025

MIF as an oncogenic driver of low-heterogeneity melanomas.

Identifying targets involved in tumor evolution and immune escape is an active area of research in oncology. Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory cytokine that promotes transformed cell proliferation and survival, and generates a tumor-permissive immune landscape of immunosuppressive myeloid and T cells. Shvefel and colleagues have identified a key role for MIF in tumor progression in melanoma clones with low tumor heterogeneity. These findings provide important insights into the potential therapeutic utility of MIF antagonists and support ongoing research to utilize MIF pathway inhibitors for improved therapeutic outcomes.

Animals↗
PubMed1981

Effect of cyclophosphamide on serum ceruloplasmin oxidase activity in sarcoma bearing rats.

High levels of serum ceruloplasmin oxidase activity were detected in U strain isogenic male rats bearing a syngeneic sarcoma in all phases of tumoral evolution. Normal levels of ceruloplasmin were only observed after a single i.p. dose of cyclophosphamide (100 mg/kg). However subsequent weekly administration of the drug did not prevent the return of hyperceruloplasminemia in the tumor hosts. Normal rats treated similarly with cyclophosphamide presented a fall in the enzyme activity after the 1st dose.

Animals↗
PubMed1988

In vivo 31P MRS in new antineoplastic agents evaluation on experimental tumor models.

Two new antineoplastic agents, a nitrosourea and a DNA-bis-intercalator have been studied in vivo by 31P magnetic resonance spectroscopy on a rat glioma and Walker carcinoma. On rat glioma, spectra are modified when the tumor is treated by the nitrosourea, showing the depletion of high-energy phosphates. On Walker carcinoma both drugs delay the tumor evolution to necrosis, showing important levels of high-energy phosphates on NMR spectra. There appears to be a great dependence upon energy metabolism during chemotherapy, depending on the nature and physiology of the observed tumor.

Animals↗
PubMed2002

Connective tissue growth factor gene expression alters tumor progression in esophageal cancer.

The ability of cancer cells to initiate specific fibroblast reactions may subsequently determine tumor evolution. In the present study we examined the coordinated expression of transforming growth factor-beta-1 (TGF-beta1), its signaling receptors, and its downstream mediator-connective tissue growth factor (CTGF)--and their impact on tumor progression and fibrogenesis in esophageal carcinomas. Messenger ribonucleic acid (mRNA) expression of TGF-beta1, CTGF, TGF-beta receptor subtype I ALK5 (TbetaR-IALK5), and TGF-beta receptor type II (TbetaR-II) was studied by Northern blot analysis in esophageal cancer and the normal esophagus. By means of immunohistochemistry and Western blot analysis, the respective proteins were localized in the tissue samples and the protein content was quantitated. Northern blot analysis revealed 3-fold and 4-fold increases (p < 0.05) in TGF-beta1 and CTGF mRNA levels, respectively, in esophageal cancer in comparison with normal controls, whereas TbetaR-I mRNA levels were significantly decreased and TbetaR-II mRNA levels were unchanged in the cancer samples. Immunostaining revealed results similar to those seen on the RNA level. TGF-beta1 and CTGF immunoreactivity were increased, TbetaR-II was unchanged, and TbetaR-IALK5 immunoreactivity was decreased. CTGF immunoreactivity was mainly present in the stroma surrounding the cancer cells but was also present in the cancer cells. The degree of fibrosis was different in squamous and adenocarcinomas and was significantly related to CTGF mRNA expression levels. The presence of CTGF in squamous cell carcinomas was associated with longer survival, whereas in adenocarcinomas it influenced survival negatively. The findings indicate that TGF-beta signaling is disturbed in esophageal cancer. CTGF, a downstream effector of TGF-beta action, differentially influences the composition of tumor microenvironment and distinct cell-matrix interactions in the two histological types of esophageal carcinoma, resulting in differences in tumor progression and patient survival.

Adenocarcinoma↗
PubMed2026

Personalized medicine strategy for MPNSTs: using precision oncology on PDOX models to inform tumor boards.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are a heterogeneous group of aggressive soft tissue sarcomas with poor prognosis. Currently there is a lack of effective treatments for MPNSTs. Here, we propose a personalized medicine approach that integrates a precision oncology strategy guided by MPNST genomic analysis, with a functional validation of treatment response in an orthotopic xenograft model (PDOX) derived from the same MPNST. METHODS: Comprehensive whole genome sequencing analysis was performed in primary MPNSTs, relapses and (in one case) metastases, following disease progression in two independent individuals. Matched MPNST PDOX models were generated by orthotopically implanting tumor fragments near the sciatic nerve of immunodeficient mice. Candidate targeted combination therapies were prioritized based on genomic alterations and tested in vivo in the PDOX models. RESULTS: The feasibility of the developed strategy is illustrated for two MPNST patients, one Neurofibromatosis type 1 (NF1) individual that developed two independent MPNSTs and another sporadic MPNST case with multiple metastatic relapses. Genomic analysis revealed a remarkable degree of genomic stability across primary MPNSTs and their successive relapses in each patient, and even metastases in one individual. While based on a small number of cases requiring additional analyses, this finding aligns with previous evidence suggesting a fair genomic conservation throughout tumor evolution. This stability supports the identification of consistent therapeutic vulnerabilities throughout disease progression. Among the therapies tested, co-treatment of MEK inhibitor (MEKi) plus bromodomain inhibitor (BETi) elicited the highest antitumor activity, resulting in approximately 60% tumor volume reduction in the sporadic MPNST PDX model, whose patient has been receiving this therapy for eight months with sustained remission. CONCLUSIONS: This study demonstrates the feasibility and clinical utility of integrating genomic-driven precision oncology with PDOX-based functional testing for MPNSTs. This strategy may support molecular tumor boards (MTBs) in their treatment decisions. The observed genomic stability supports the use of longitudinal tumor profiling to guide treatment, and the success of MEKi+BETi highlights its potential as a combination therapy for MPNSTs.

Precision Medicine↗
PubMed1994

c-k-ras and p53 mutations occur very early in adenocarcinoma of the lung.

The topographical distribution of a mutation provides insight into past patterns of tumor evolution. This approach was applied to two loci commonly mutated in adenocarcinoma of the lung--p53 and c-K-ras. In 41 primary adenocarcinomas, c-K-ras codon 12 point mutations were detected in 8 (19.5%) tumors and p53 point mutations were detected in 10 (24.4%) tumors, with one tumor harboring both mutations. These mutations were only detected in malignant cells and with a homogeneous topographical distribution throughout 16 tumors, including metastasis. Intratumor heterogeneity was detected in only one tumor in which a small portion lacked the specific p53 mutation. Based on this topographical analysis, it is likely that when these mutations occur in adenocarcinoma of the lung, they are usually acquired during the very earliest phases of tumor formation before the bulk of clonal expansion, and in very small precursor lesions.

Adenocarcinoma↗
PubMed1993

p53 protein expression in mammary ductal carcinoma in situ: relationship to immunohistochemical expression of estrogen receptor and c-erbB-2 protein.

The immunohistochemical expression of the p53 gene protein was examined in a consecutive series of 143 cases of pure ductal carcinoma in situ (DCIS) of the breast. Expression of wild-type and/or mutant p53 protein was detected in 36 (25.2%) of the cases examined, as evidenced by positive nuclear staining with the monoclonal antibody DO 7. Thirty-four (35.8%) of the large cell cases showed p53 protein expression compared with two (4.1%) of the small cell cases (chi 2 = 15.3 [df = 1], P < .001). p53 Protein expression also was associated with an increased histologic degree of necrosis, with a nearly significant association of negative tumor estrogen receptor status and p53 protein expression. No significant association of p53 protein expression and c-erbB-2 protein expression was seen. Immunohistochemical expression of p53 protein is present in approximately 25% of DCIS cases and is confined almost exclusively to large cell DCIS, a morphologic subtype of in situ breast carcinoma thought to be more biologically aggressive. Expression of p53 protein may be important in the neoplastic progression of DCIS, reflecting the acquisition of p53 gene mutations in large cell DCIS cases. Therefore, p53 may be implicated in mammary tumor evolution from in situ to invasive disease.

Biomarkers, Tumor↗
PubMedDate not supplied

Transplantable melanomas in gerbils (Meriones unguiculatus). I. Origin, morphology and growth rate.

A family of serially transplanted melanomas in gerbils is described. These tumors were derived from the cutaneous melanotic melanoma that arose in 1 of 44 gerbils injected postnatally with N-ethyl-N-nitrosourea. It consists of a slow growing heavily melanotic parental line and two fast growing melanotic (FGM) and amelanotic (A-FGM) lines that appeared abruptly during serial transplantation of the parental tumor. The FGM melanotic line originated after a sudden acceleration of growth of the parental line during the 4th in vivo passage that was accompanied by a decrease in both pigmentation and metastasizing potential. The A-FGM derived from the depigmented tissue of the 7th in vivo passage of the FGM line and has been characterized by an amelanotic phenotype, an increased metastasizing potential and similar growth rate to that of the FGM. Once established, both lines expressed considerable phenotypic stability during serial transplantation in gerbils. Thus, the Zeman UJ melanomas represent the first established family of transplantable melanomas in gerbils, which serve as a model for pigmented cell and melanoma research and as a subject for a retrospective analysis of the phenomenon of tumor evolution.

Animals↗
PubMed2006

Clinical, etiological and progression factors of hearing in sudden deafness.

UNLABELLED: Out of the many forms of therapy for sudden deafness, some require hospitalization and present significant risks. AIM: This prospective study analyzes etiology and evolution in cases of sudden deafness (SD) where outpatient oral treatment was used. STUDY DESIGN: Clinical with transversal cohort. MATERIAL AND METHOD: Forty cases of sudden hearing loss were followed for at least one year. All were submitted to initial clinical evaluation, auditory tests, routine blood analysis, and magnetic resonance imaging. All received initial treatment with pentoxifylline and prednisone. RESULTS: 45% (n=18) presented normal auditory thresholds, 40% (n=16) showed some improvement in hearing, 15% (n=6) maintained initial hearing level. Nine cases (22.5%) presented clinical conditions possibly implicated in hearing loss (viral infection, immunomediated hearing loss, vascular disorders, and so on); three (7.5%) had cerebellopontine tumors. Evolution of hearing in these 12 cases with presumed etiology presented no differences from hearing in the 28 cases without any known etiological factor. Clinical treatment within the first seven days was the only statistically significantly different condition in patients who improved hearing. CONCLUSIONS: An objective search for etiological bases should be conducted in any case of acute sensorineural hearing loss. The presence of cerebellopontine tumors in 7.5% of cases of SD, among other treated causes, justifies a thorough clinical investigation in these patients. Overall good evolution of hearing was observed in 67.5% of cases of SD, regardless of its etiology. Therapy within the first seven days of SD was significantly related to better outcomes in hearing.

Adolescent↗
PubMed2004

Competition and natural selection in a mathematical model of cancer.

A malignant tumor is a dynamic amalgamation of various cell phenotypes, both cancerous (parenchyma) and healthy (stroma). These diverse cells compete over resources as well as cooperate to maintain tumor viability. Therefore, tumors are both an ecological community and an integrated tissue. An understanding of how natural selection operates in this unique ecological context should expose unappreciated vulnerabilities shared by all cancers. In this study I address natural selection's role in tumor evolution by developing and exploring a mathematical model of a heterogenous primary neoplasm. The model is a system of nonlinear ordinary differential equations tracking the mass of up to two different parenchyma cell types, the mass of vascular endothelial cells from which new tumor blood vessels are built and the total length of tumor microvessels. Results predict the possibility of a hypertumor-a focus of aggressively reproducing parenchyma cells that invade and destroy part or all of the tumor, perhaps before it becomes a clinical entity. If this phenomenon occurs, then we should see examples of tumors that develop an aggressive histology but are paradoxically prone to extinction. Neuroblastoma, a common childhood cancer, may sometimes fit this pattern. In addition, this model suggests that parenchyma cell diversity can be maintained by a tissue-like integration of cells specialized to provide different services.

Humans↗
PubMed2001

Tumor suppression and potentiation by manipulation of pp32 expression.

Alternative use of genes of the closely-related pp32 family is a common occurrence in human prostate cancer. pp32r1 and pp32r2, the oncogenic members of the pp32 family, are expressed in prostatic adenocarcinoma, while adjacent benign prostate continues to express pp32. This study focuses upon the role of pp32 in tumor suppression. We demonstrate that antisense inhibition of pp32 in NIH3T3 cells leads to a variety of phenotypic changes associated with transformation including reduced serum dependence and loss of contact inhibition. NIH3T3 cells with antisense-inhibited pp32 are not tumorigenic, but are markedly more susceptible to oncogenic stimuli such as ras. In contrast, constitutive expression of pp32 abolishes ras mediated transformation in vitro and tumorigenesis in vivo. These data demonstrate, from the functional aspect, that pp32 acts as a tumor suppressor. Furthermore, inactivation of pp32 function through alternative gene use may be a critical event in tumor evolution and progression.

3T3 Cells↗
PubMed1986

Activation of malignant B-lymphocytes: pathophysiologic and clinical importance.

Recent advances in clarifying the activation mechanisms of the normal immune system have provided the basis for successful experiments concerning the activation of malignant lymphocytes. Such studies with malignant cells, freshly sampled from patients with lymphoproliferative diseases, can be used for pathophysiological considerations, analysis of tumor evolution, classification of malignant subsets, and karyotyping. Of particular interest is the possibility of abrogating the maturation arrest in some clonally-restricted cells. This might lead to therapeutical implications, since the differentiation blockage plays a fundamental role in the clonal expansion and pathogenesis of tumors. Recently, it has been shown that interferon (IFN) can be a potent inducer of various degrees of transformation, differentiation and even proliferation in different subsets of normal and malignant B cells. This may be important in explaining the divergent results of IFN treatment in various malignant B-cell disorders.

B-Lymphocytes↗
PubMed1980

Autologous bone marrow infusion following high dose chemotherapy of the canine transmissible venereal tumor (TVT).

The present study was undertaken to evaluate infusion of cryopreserved autologous bone marrow following supralethal chemotherapy in canines bearing a solid tumor thought to be moderately sensitive to cytotoxic agents. Initial studies in 5 dogs established a combination of busulfan (Bu) 3 mg/kg X 2 days and cyclophosphamide (Cy) 50 mg/kg on day 3 to produce bone marrow lethality within 14 days (high dose regime). Bu 1 mg/kg, Cy 20 mg/kg produced tolerable toxicity (low dose regime). Eight pairs of dogs were challenged with 3 X 10(8) transmissible venereal tumor cells. Measurable progressive tumor growth occurred in all instances. Marrow aspirated from the femoral shafts of the animals was cryopreserved in 10% DMSO. One dog of each pair received the high dose Bu + Cy regime followed in 30 h by marrow infusion and his partner received the low dose regime without marrow. Tumors were measured serially for at least 2 months. Infusion of marrow resulted in evidence of hematologic recovery within 2 weeks following the high dose regime. Tumor responses occurred in both groups when compared to 8 untreated tumor challenged controls. High dose animals had greater initial responses than low dosed dogs but long term responses were not significantly different. Eight dogs rechallenged with tumor cells after initial successful therapy failed to develop tumors. It was concluded that: a) cryopreserved autologous bone marrow infusion was effective in protecting tumor bearing canines from otherwise lethal chemotherapy; b) the transmissible venereal tumor of canines responded to both high and low dose regimes; c) the rescue of dogs by stored autologous marrow did not offer additional benefits in tumor control over a standard regime; d) chemotherapy treated dogs resisted tumor rechallenge. This model may offer a large animal system to study the autologous marrow rescue concept during controlled periods of tumor evolution.

Anemia, Aplastic↗