RESUMO
BACKGROUND: The prognostic significance of the primary tumor site in breast cancers is not established with only a few studies having evaluated the issue. MATERIALS AND METHODS: The relevance of a primary tumor site with respect to systemic disease relapse was evaluated in 187 patients with breast cancer treated with primary surgery and adjuvant chemotherapy, in whom the location of primary tumor was classifiable in any one of the three sites, namely: outer, periareolar, and inner, quadrants. Data was obtained from prospectively maintained records of breast cancer patients treated at a single surgical unit in a tertiary care center. RESULTS: The three groups were comparable with regard to demographic, pathological tumor, and treatment characteristics. In the multivariate analysis, patients with inner and periareolar quadrant tumors had a higher hazard for systemic disease relapse, (2.53, 95% CI: 1.18-5.42; P = 0.02, and 2.73, 95% CI: 1.04-7.14; P = 0.04, respectively) as compared to outer quadrant tumors. The projected five-year survival estimates in Kaplan Meier were 87%, 61%, and 69%, respectively, for outer, periareolar, and inner quadrant. On further substratification the difference was particularly noted in high risk inner quadrant tumors: age 45, premenopausal patients, tumor size> 2 cms, positive nodes and intermediate or high grade histology, as also in patients treated with breast conservation and CMF, Cyclophosphamide, Methorexate, 5 Fluorouracil chemotherapy. CONCLUSION: The location of the primary tumor influences survival in breast cancer with inferior outcome for tumors in inner and periareolar quadrants, especially in high risk groups and those treated with conservative approaches. The role of aggressive therapies merits investigation in these patients.
Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalos de Confiança , Ciclofosfamida/uso terapêutico , Progressão da Doença , Feminino , Fluoruracila/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Falha de Tratamento , Resultado do TratamentoRESUMO
This study examined the pathological complete response (pCR) rate and safety of sequential gemcitabine-based combinations in breast cancer. We also examined gene expression profiles from tumour biopsies to identify biomarkers predictive of response. Indian women with large or locally advanced breast cancer received 4 cycles of gemcitabine 1200 mg m(-2) plus doxorubicin 60 mg m(-2) (Gem+Dox), then 4 cycles of gemcitabine 1000 mg m(-2) plus cisplatin 70 mg m(-2) (Gem+Cis), and surgery. Three alternate dosing sequences were used during cycle 1 to examine dynamic changes in molecular profiles. Of 65 women treated, 13 (24.5% of 53 patients with surgery) had a pCR and 22 (33.8%) had a complete clinical response. Patients administered Gem d1, 8 and Dox d2 in cycle 1 (20 of 65) reported more toxicities, with G3/4 neutropenic infection/febrile neutropenia (7 of 20) as the most common cycle-1 event. Four drug-related deaths occurred. In 46 of 65 patients, 10-fold cross validated supervised analyses identified gene expression patterns that predicted with >or=73% accuracy (1) clinical complete response after eight cycles, (2) overall clinical complete response, and (3) pCR. This regimen shows strong activity. Patients receiving Gem d1, 8 and Dox d2 experienced unacceptable toxicity, whereas patients on other sequences had manageable safety profiles. Gene expression patterns may predict benefit from gemcitabine-containing neoadjuvant therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Perfilação da Expressão Gênica , Adulto , Idoso , Neoplasias da Mama/metabolismo , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , GencitabinaRESUMO
1. Four types of yolk spheres with variable structure, chemical composition and frequency of occurrence in yolk plasma of hierarchical follicles (F(4), F(3), F(2) and F(1) with diameters of 10.0, 15.5, 20.0 and 35.0 mm, respectively) of the hen ovary were identified using histochemical methods for localising lipids, carbohydrates and proteins. 2. Yolk spheres of the first type (YS(1)) had a phospholipoprotein membrane surrounding fluid matrix which stained lightly for phospholipids, proteins and acidic mucopolysaccharides. Two types of droplets were observed in the matrix of YS(1). Spheres of the second type (YS(2)) had a lipoprotein- and acidic mucopolysaccharide-rich peripheral region and a single large droplet in its fluid matrix. Droplets of YS(2), unlike YS(1), showed three regions and metachromatic staining with ninhydrin-Schiff reagent. The third type of sphere (YS(3)) had a homogeneous matrix staining for proteins, neutral lipids and florescent yellow with alcian blue and differentially with ninhydrin-Schiff reagent; it was bounded by a phospholipids- and acidic mucopolysaccharide-containing thick peripheral region. Its fluid matrix also showed toluidine-blue-positive, densely packed granules and small droplets. The fourth type (YS(4)) was seen only in bromophenol blue and Nile blue preparations, revealing the presence of proteins and neural lipids in their matrix and peripheral regions. 3. Quantitative data on the relative abundance of yolk spheres in F(4) to F(1) follicles revealed more YS(3) (51.1 to 64.7%) than YS(1) (16.2 to 28.3%) and YS(2) (19.1 to 23.2%). The percentage of YS(1) increased and that of YS(3) decreased as follicle size increased.
Assuntos
Gema de Ovo/citologia , Ovário/fisiologia , Animais , Galinhas , Gema de Ovo/química , Feminino , Glicosaminoglicanos/análise , Histocitoquímica/métodos , Proteínas de Membrana/análise , Folículo Ovariano/citologia , Fosfolipídeos/análiseRESUMO
We were able to detect clinically normal carriers of xeroderma pigmentosum (XP) genes with coded samples of either peripheral blood lymphocytes or skin fibroblasts, using a cytogenetic assay shown previously to detect individuals with cancer-prone genetic disorders. Metaphase cells of phytohemagglutinin-stimulated T-lymphocytes from eight individuals who are obligate heterozygotes for XP were compared with those from nine normal controls at 1.3, 2.3, and 3.3 h after x-irradiation (58 R) during the G2 phase of the cell cycle. Lymphocytes from the XP heterozygotes had twofold higher frequencies of chromatid breaks or chromatid gaps than normal (P less than 10(-5)) when fixed at 2.3 or 3.3 h after irradiation. Lymphocytes from six XP homozygotes had frequencies of breaks and gaps threefold higher than normal. Skin fibroblasts from an additional obligate XP heterozygote, when fixed approximately 2 h after x-irradiation (68 R), had a twofold higher frequency of chromatid breaks and a fourfold higher frequency of gaps than fibroblasts from a normal control. This frequency of aberrations in cells from the XP heterozygote was approximately half that observed in the XP homozygote. The elevated frequencies of chromatid breaks and gaps after G2 phase x-irradiation may provide the basis of a test for identifying carriers of the XP gene(s) within known XP families.
Assuntos
Aberrações Cromossômicas , Triagem de Portadores Genéticos , Xeroderma Pigmentoso/genética , Adolescente , Adulto , Idoso , Ciclo Celular , Células Cultivadas , Criança , Pré-Escolar , Feminino , Fibroblastos/citologia , Humanos , Interfase , Linfócitos/patologia , Linfócitos/efeitos da radiação , Masculino , Metáfase , Pessoa de Meia-Idade , Valores de Referência , Pele/patologiaRESUMO
Oral administration of isotretinoin (13-cis retinoic acid) was shown previously (Kraemer, K. H., J. J. DiGiovanna, A. N. Moshell, R. E. Tarone, and G. L. Peck. 1988. N. Engl. J. Med. 318:1633-1637) to reduce the frequency of skin cancers in xeroderma pigmentosum (XP) patients. The mechanism of protection was unclear. In the present study, x-ray-induced chromatid damage in PHA-stimulated blood lymphocytes from five XP patients receiving isotretinoin was approximately half that in blood samples from the same patients before or subsequent to treatment. The x-ray-induced chromatid damage in blood lymphocytes from a normal control was reduced significantly by cocultivation with blood or plasma from an XP patient receiving isotretinoin or by addition of 10(-6) M isotretinoin to cultures 1 h before x-irradiation. A similar reduction in x-ray-induced chromatid damage was reported previously by adding to the culture medium, mannitol, a scavenger of the free hydroxyl radical, or catalase, which decomposes hydrogen peroxide; both of these products are generated during ionizing radiation. The present observations suggest that isotretinoin acts as a scavenger of such radiation products, thereby providing protection against x-ray-induced chromatid damage.
Assuntos
Cromátides/efeitos dos fármacos , Cromátides/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Isotretinoína/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/efeitos da radiação , Adulto , Idoso , Células Cultivadas , Feminino , Humanos , Linfócitos/ultraestrutura , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/prevenção & controle , Raios X , Xeroderma Pigmentoso/complicaçõesRESUMO
Food acceptance and toxic effects of feeding sodium selenite (Se) alone and in combination with monosodium glutamate (MSG), a taste enhancer were studied in the laboratory rat. Dose-dependent stimulation of daily food intake was observed with MSG offered in no-choice or bi-choice with the plain food. Consumption of pellets containing 0.05, 0.5 and 1.0% Se was significantly low than the plain or MSG containing pellets but their active ingredient was sufficient to cause mortality of rats. Food pellets containing both MSG and Se in no-choice feeding trial were not preferred by the rats, as their consumption remained low as compared to pellets containing only MSG. However, prior feeding on MSG containing pellets for two days increased the amount of intake of Se-containing pellets. No mortality of rats feeding on pellets containing different concentrations of MSG was recorded. Feeding on Se-containing pellets caused dose-dependent mortality on the third day of the trial. As compared to rats feeding on Se-containing pellets, the mortality rate was reduced in those provided Se in combination with MSG but the intake of active ingredient of Se in both these trials did not differ significantly. Decrease in death rate of rats feeding on Se in combination with MSG containing pellets suggested that addition of MSG to seleniferous food probably provide protection to some extent from the toxic effects of selenium. However, combination of excess doses of MSG and Se in food pellets caused mortality of all experimental animals.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Selênio/toxicidade , Glutamato de Sódio/farmacologia , Animais , Feminino , Aromatizantes/administração & dosagem , Aromatizantes/farmacologia , Masculino , Ratos , Selênio/administração & dosagem , Selênio/antagonistas & inibidores , Glutamato de Sódio/administração & dosagem , Selenito de Sódio/administração & dosagem , Selenito de Sódio/antagonistas & inibidores , Selenito de Sódio/toxicidadeRESUMO
Traditional examination has inherent deficiencies. Objective Structured Clinical Examination (OSCE) is considered as a method of assessment that may overcome many such deficits. OSCE is being increasingly used worldwide in various medical specialities for formative and summative assessment. Although it is being used in various disciplines in our country as well, its use in the stream of general surgery is scarce. We report our experience of assessment of undergraduate students appearing in their pre-professional examination in the subject of general surgery by conducting OSCE. In our experience, OSCE was considered a better assessment tool as compared to the traditional method of examination by both faculty and students and is acceptable to students and faculty alike. Conducting OSCE is feasible for assessment of students of general surgery.
RESUMO
Certain responses of mouse and hamster cells to polyoma virus were examined with respect to their specificity as "indicators" of neoplastic conversion in vitro. These responses included the development of transplantation antigens and changes in morphologic growth pattern, cytology, karyology, rates of proliferation, and glycolytic activities. Under limited conditions, i.e., in short-term, slow-growing cultures, the morphologic change in growth pattern and increases in glycolytic activity and proliferation rate induced by polyoma virus appeared to correlate with neoplastic conversion. However, in long-term or rapidly growing short-term cultures, similar morphologic patterns occurred in cells that subsequently tested as non-neoplastic. Also, such patterns could be induced by polyoma virus in cells already neoplastic. Cells that had undergone "spontaneous" neoplastic conversion frequently showed none of these morphologic features of virus-transformed cells. Prolonged culture of cells without added virus resulted in increased glycolytic activities and proliferation rates equivalent to those of virus-transformed cells. These changes occurred in at least one cell line long before evidence of neoplastic conversion. The cytologic changes in the virus-treated neoplastic cells were similar to those usually associated with neoplastic cells in vivo and may possibly serve as sensitive indicators of in vitro neoplastic conversion. From the observations of this study, the change in morphologic growth pattern is interpreted not as loss of "contact inhibition," but as a proliferative response accompanied by decreased adhesion of cells to the glass substrate.
Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Aberrações Cromossômicas , Cromossomos de Mamíferos , Polyomavirus , Animais , Linhagem Celular , Cricetinae , Humanos , Técnicas In Vitro , Camundongos , Fatores de TempoRESUMO
A line of normal human skin fibroblasts (KD) differed from its malignant derivative (HUT-14) in the extent of cytogenetic damage induced by X-irradiation during G2 phase. Malignant cells had significantly more chromatid breaks and gaps after exposure to 25, 50, or 100 rad. On the assumption that each chromatid contains a single continuous DNA double helix, chromatid breaks would represent unrepaired DNA double-strand breaks; the gaps may represent single-strand breaks. Results from alkaline elution of cellular DNA immediately after irradiation showed that the normal and malignant cells in asynchronous population were equally sensitive to DNA single-strand breakage by X-irradiation. Caffeine or beta-cytosine arabinoside (ara-C), inhibitors of DNA repair, when added directly following G2 phase exposure, significantly increased the incidence of radiation-induced chromatid damage in the normal cells. In contrast, similar treatment of the malignant cells had little influence. Ara-C differed from caffeine in its effects; whereas both agents increased the frequency of chromatid breaks and gaps, only ara-C increased the frequency of gaps to the level observed in the irradiated malignant cells. Addition of catalase, which destroys H2O2, or mannitol, a scavenger of the derivative free hydroxyl radical (.OH), to the cultures of malignant cells before, during, and following irradiation significantly reduced the chromatid damage; and catalase prevented formation of chromatid gaps. The DNA damage induced by X-ray during G2 phase in the normal KD cells was apparently repaired by a caffeine- and ara-C-sensitive mechanism(s) that was deficient or absent in their malignant derivatives.
Assuntos
Reparo do DNA/efeitos dos fármacos , Interfase/efeitos da radiação , 4-Nitroquinolina-1-Óxido , Cafeína/farmacologia , Catalase/farmacologia , Linhagem Celular , Transformação Celular Neoplásica , Aberrações Cromossômicas , Citarabina/farmacologia , Fibroblastos/ultraestrutura , Humanos , Manitol/farmacologia , Doses de RadiaçãoRESUMO
Visible light and oxygen enhanced both chromosome instability and malignant transformation of mouse cells in culture. Nine cell lines were initiated from 8 pools of 10- to 13-day C3H embryos. Each cell line was divided into sublines, which were either maintained shielded from light or were exposed for 3 or 24 hours to fluorescent light (approximately 150 foot-candles) two or three times weekly. Cultures of the sublines were also maintained with either a gaseous phase of 0-1% oxygen or atmospheric (18%) oxygen. Each line was monitored for cytologic manifestations of malignant neoplastic transformation, and 8 lines were monitored for chromosome alterations. Seven lines were assayed for tumorigenicity by intraocular implantation into syngeneic hosts. Repeated light exposure and/or high oxygen increased the frequency of minute chromosomes, which result from chromatid breaks, and also increased the rate of shift from diploid to heteroploid state. Four cell lines showed no cytologic changes indicative of neoplastic change during the test period. Two of these were assayed in vivo and failed to grow as tumors. In the remaining 6 lines, cytologically neoplastic colonies appeared earlier or more abundantly in the light-exposed cultures and/or those gassed with high oxygen. In 3 of these lines, tumors developed only from the light-exposed cultures; in the other 2, tumor latency periods were significantly shorter in the cultures exposed to light or gassed with atmospheric oxygen.
Assuntos
Transformação Celular Neoplásica , Aberrações Cromossômicas , Luz/efeitos adversos , Oxigênio , Animais , Divisão Celular/efeitos da radiação , Linhagem Celular , Sobrevivência Celular/efeitos da radiação , Embrião de Mamíferos , Camundongos , Camundongos Endogâmicos C3H , Transplante de Neoplasias , Neoplasias Experimentais/etiologia , Transplante HomólogoRESUMO
An assay for ataxia-telangiectasia (A-T) heterozygotes, i.e., healthy carriers of the A-T gene(s), requiring only a small sample (3.5 mL) of peripheral blood, is described. Frequencies of chromatid aberrations in phytohemagglutinin-stimulated blood lymphocytes collected by demecolcine from 0.5 hour to 1.5 hours after x irradiation with 58 roentgens were twofold to threefold higher in A-T heterozygotes than in clinically normal controls and twofold to three-fold higher in A-T patients (homozygotes) than in A-T gene carriers. The persistence of chromatid breaks and gaps in lymphocytes following radiation-induced DNA damage during G2 suggests a deficiency or deficiencies in DNA repair that may be the defect at the molecular level that results in the enhanced radiosensitivity and cancer proneness characterizing A-T gene carriers and patients.
Assuntos
Ataxia Telangiectasia/genética , Cromátides/efeitos da radiação , Dano ao DNA , Interfase/efeitos da radiação , Adolescente , Adulto , Idoso , Criança , Feminino , Heterozigoto , Humanos , Linfócitos/efeitos da radiação , Masculino , Pessoa de Meia-Idade , Tolerância a RadiaçãoRESUMO
BACKGROUND: In many patients with early breast cancer, the sentinel lymph node (SLN) is the sole site of regional nodal metastasis. This subgroup of patients may not benefit from completion axillary lymph node dissection (CALND). AIMS: This pilot study evaluates the status of 2nd echelon (station) lymph nodes in the axilla as a predictor of additional positive nodes in the axilla in the presence of sentinel node metastasis. SETTINGS AND DESIGN: Cross-sectional study of 40 breast cancer patients. MATERIALS AND METHODS: Forty patients with invasive breast cancer underwent SLN biopsy followed by 2nd echelon lymph node biopsy in the same sitting. SLN mapping was performed using a combined technique of isosulfan blue and 99 mTc-sulfur colloid. SLNs (Station I) were defined as blue and/or hot nodes. These nodes were then injected with 0.1 ml of blue dye using a fine needle and their efferent lymphatic was traced to identify the Station II nodes. Then a complete ALND was performed. All the specimens were sent separately for histopathological evaluation. RESULTS: SLNs (Station I nodes) were successfully identified in 98% (39/40) patients. Of the 17 patients with a positive SLN, 8 (47%) patients had no further positive nodes in the axilla, 9 (53%) patients had additional metastasis in nonsentinel lymph nodes upon CALND. Station II nodes were identified in 76% (13/17) patients with a positive SLN. Station II nodes accurately predicted the status of the remaining axilla in 92% patients (12/13). STATISTICAL ANALYSIS: We calculated the Sensitivity, Negative predictive value, Positive predictive value, False negative rate and Identification rate. CONCLUSION: Station II nodes may predict metastatic involvement of additional nodes in the axilla.
Assuntos
Axila , Neoplasias da Mama/patologia , Metástase Linfática/diagnóstico , Biópsia de Linfonodo Sentinela/métodos , Adulto , Idoso , Corantes , Estudos Transversais , Reações Falso-Negativas , Feminino , Humanos , Excisão de Linfonodo , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , PrognósticoRESUMO
Thirteen cell lines derived from human tumors of diverse tissue origin and histopathology were compared with 12 lines of normal skin fibroblasts with respect to chromatid damage induced by 25, 50, or 100 R of X-irradiation during the G2 period of the cell cycle. Only cells in metaphase were examined, and these had been irradiated 1.5 hr before fixation. When irradiated under identical conditions, the tumor cells showed significantly more chromatid breaks and gaps than did the normal cells at all doses tested. The data suggest that the increased G2 chromosomal radiosensitivity of the tumor cells is associated with deficient DNA repair during the G2-prophase period of the cell cycle.
Assuntos
Cromossomos Humanos/efeitos da radiação , Interfase/efeitos da radiação , Neoplasias/genética , Linhagem Celular , Cromátides/efeitos da radiação , Aberrações Cromossômicas , Transtornos Cromossômicos , Fibroblastos/efeitos da radiação , Humanos , Metáfase/efeitos da radiação , Neoplasias/patologia , Pele/citologia , Pele/efeitos da radiaçãoRESUMO
A deficiency in DNA repair, manifest as enhanced chromatid radiosensitivity during the G2 phase of the cell cycle, together with a proliferative stimulus such as that provided by active oncogenes may be necessary and sufficient for the malignant neoplastic transformation of human keratinocytes in culture. Normal epidermal keratinocytes established as continuous cell lines by transfection with pSV3-neo or infection with adeno 12-SV40 hybrid virus developed enhanced G2 chromatid radiosensitivity after 18 passages in culture. In contrast to cells from primary or secondary culture, these cells could be transformed to malignant neoplastic cells by infection with Kirsten murine sarcoma virus containing the Ki-ras oncogene or in one line by the chemical carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine; both of these agents produced a marked proliferative response. Cytological heterogeneity and karyotypic instability characterized the cells during their progression to neoplasia. These results are interpreted in terms of a mechanism for neoplastic transformation.
Assuntos
Transformação Celular Neoplásica , Cromátides/efeitos da radiação , Interfase , Tolerância a Radiação , Neoplasias Cutâneas/patologia , Animais , Carcinógenos , Transformação Celular Neoplásica/patologia , Células Cultivadas , Aberrações Cromossômicas , Reparo do DNA , Humanos , Queratinas , Camundongos , Oncogenes , Neoplasias Cutâneas/etiologia , TransfecçãoRESUMO
The increased susceptibility of mouse cells to fluorescent light-induced chromatid damage following their spontaneous malignant transformation in culture could result from loss or inactivation of catalase that decomposes the photoproduct H2O2 or from impaired capacities to repair DNA damage. No consistent change in catalase activity with respect to neoplastic state could be established. To interpret the cytogenetic damage in terms of DNA strand breaks, we determined the incidence of chromatid breaks induced by light exposure during the G1 and late S-G2 phases of the cell cycle in normal and malignant derivatives of a C3H mouse cell line. Chromatid breaks at metaphase following light exposure during G1 would result from DNA strand breaks, cross-links, or base damage, whereas breaks following exposure during late S-G2 would result from single-or double-strand breaks. Both G1 and late S-G2 were susceptible in malignant cells but only G1 in normal. Since caffeine inhibits DNA repair, we compared its effects on light-induced chromatid damage in the normal and malignant cells to assess their DNA repair capacities. Treatment of normal cells with caffeine (50 microgram/ml) directly following five hr of light exposure in G1 increased the chromatid damage to that in malignant cells exposed with or without caffeine. Similarly, treatment of normal cells with caffeine during late S-G2 exposure increased chromatid damage to a level not significantly different from that in malignant cells exposed without caffeine. Caffeine had little influence on chromatid damage in malignant cells. The increased susceptibility of malignant mouse cells to fluorescent light-induced chromatid breaks thus appears to result from impaired capacities to repair DNA damage.
Assuntos
Transformação Celular Neoplásica/metabolismo , Cromátides/efeitos da radiação , Reparo do DNA , Luz , Animais , Cafeína/farmacologia , Catalase/metabolismo , Ciclo Celular , Linhagem Celular , Aberrações Cromossômicas , Interfase , CamundongosRESUMO
Exposure of mouse cells in culture to fluorescent light has been shown to produce chromatid breaks and exchanges. Hydrogen peroxide formed in the cell during illumination has been implicated as the causative agent. The present results indicate that susceptibility to light-induced chromosome damage increases with time in culture and seems to be associated with or requisite for the spontaneous malignant transformation of mouse cells. All three cell lines followed during long-term culture that either became tumorigenic or showed cytological evidence of neoplastic transformation developed a concomitant increase in susceptibility. In three additional cell lines, susceptibility to light-induced chromatid damage was significantly increased in the spontaneously transformed malignant cells as compared with their nonneoplastic precursors. The increased susceptibility is not simply the result of long-term culture, since three other nonneoplastic cell lines after prolonged culture were significantly less susceptible than their malignant counterparts. Increased susceptibility to light-induced chromatid damage could result from impaired DNA repair or from the loss of defense mechanisms for destroying H2O2 or scavenging free radicals.
Assuntos
Transformação Celular Neoplásica , Aberrações Cromossômicas , Luz/efeitos adversos , Animais , Linhagem Celular , Troca Genética/efeitos da radiação , DNA/metabolismo , Peróxido de Hidrogênio/metabolismo , Camundongos , Fatores de TempoRESUMO
The relationship between tumorigenicity and enhanced chromosomal radiosensitivity during the G2 cell cycle phase was examined through the use of nontumorigenic human cell hybrids and their nontumorigenic and tumorigenic segregants. The hybrid cells were produced by fusion of a normal and tumor cell. The parental lines, including HeLa and three fibroblast lines, one of skin and two of fetal lung origin, were also examined. The tumorigenic lines, which had cytological features associated with clinical cancer, showed a significantly higher incidence of chromatid breaks and gaps following X-irradiation during G2 than the normal skin line or the nontumorigenic hybrids. The hybrids and their nontumorigenic subclones had cytological features which are predominantly found with a benign clinical course and had the G2 chromosomal radiosensitivity more characteristic of the normal parental cells. Like tumorigenic cells, fetal cells exhibited enhanced G2 chromosomal radiosensitivity which could be suppressed in fetal X tumor cell hybrids. This observation suggests that the molecular basis for radiosensitivity in fetal cells differs from that of tumor cells. The enhanced G2 chromosomal radiosensitivity of a tumor cell, which appears to result from deficient DNA repair, is suppressed by fusion with a normal cell. Thus, the radiosensitivity, like tumorigenicity, behaves as a recessive trait. Although a Mendelian analysis is not possible with this material, the segregation of enhanced G2 chromosomal radiosensitivity with the neoplastic phenotype suggests that the two may be genetically linked.
Assuntos
Cromossomos Humanos/efeitos da radiação , Células Híbridas/ultraestrutura , Interfase , Neoplasias/genética , Linhagem Celular , Cromátides/efeitos da radiação , Células HeLa , Humanos , Células Híbridas/patologia , Neoplasias/patologiaRESUMO
BACKGROUND: Histamine receptor antagonists have been shown to induce tumor-infiltrating lymphocytes (TILs) in colonic cancers and improve survival. The role of histamine receptor anatagonists in breast cancer is unclarified. AIM: To evaluate the role of histamine receptor antagonists in inducing (TILs) in breast cancer. METHOD: Forty-five patients with operable breast cancers (25 cases who received preoperative famotidine and 20 controls) were studied for the effect of famotidine in inducing TILs and survival in breast cancer. RESULTS: Significant TILs were seen in 75% (18/24) of cases as opposed to 35% (7/20) controls. In logistic regression analysis the only variable found to be predictive of TILs was famotidine, odds ratio 7.324 (1.693-31.686) P=0.008. In Cox's regression presence of TILs was favorably associated with improved disease free survival at a median follow up of 35.56 months. The hazard ratio for disease relapse was 3.327 (1.174-9.426) P=0.024 in TIL negative as compared to TIL positive patients. Famotidine use alone was not significant in the original model, however, on incorporation of quadrant of involvement in addition to other established prognostic factors in the above multivariate model, it assumed borderline significance with a hazard ratio for disease free survival 3.404 (1.005-11.531, P=0.049). CONCLUSIONS: Preoperative short course famotidine induces TILs in breast cancer. Patients with TILs demonstrable in tumor specimens had an improved disease free survival. Famotidine may improve disease free survival in breast cancer and these findings need validation in larger population subsets.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Famotidina/uso terapêutico , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Adulto , Biópsia por Agulha , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Imuno-Histoquímica , Mastectomia/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Pré-Operatórios/métodos , Probabilidade , Prognóstico , Modelos de Riscos Proporcionais , Valores de Referência , Medição de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
Each chromatid contains a single continuous molecule of double-stranded DNA, so chromatid breaks represent unrepaired DNA double-strand breaks. Frequencies of chromatid breaks after G2 phase x-irradiation were determined in phytohemagglutinin-stimulated blood lymphocytes from normal subjects and from four categories of patients with dysplastic nevi with or without cutaneous melanoma or with melanoma alone. Some cells were treated with an inhibitor of DNA repair replication to determine enzymatic incision activity at damaged sites after exposure to x-rays, UVC, or fluorescent light. Whereas one of 16 normal controls had deficient DNA repair, all 17 patients from families with hereditary dysplastic nevi with or without melanoma (category I) had a deficiency in repair of radiation-induced DNA damage, manifested as an abnormally high frequency of chromatid breaks after x-irradiation or a reduced capacity to incise the damaged sites after UV exposure. Four of 11 patients with sporadic dysplastic nevi alone (category II) and eight of 12 with sporadic dysplastic nevi and melanoma (category III) showed deficient DNA repair after x-irradiation. One of two patients with sporadic melanoma and no dysplastic nevi (category IV) was also deficient in repair of x-ray-induced damage. Deficient DNA repair thus appears to be associated with hereditary dysplastic nevi with or without melanoma. It also characterizes some patients with sporadic dysplastic nevi or melanoma.
Assuntos
Cromátides/efeitos da radiação , Dano ao DNA , Reparo do DNA , Síndrome do Nevo Displásico/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Células Sanguíneas/fisiologia , Síndrome do Nevo Displásico/sangue , Feminino , Humanos , Linfócitos/fisiologia , Masculino , Melanoma/sangue , Pessoa de Meia-Idade , Neoplasias Cutâneas/sangueRESUMO
Deficient repair of DNA double-strand breaks, resulting in an abnormally high frequency of chromatid breaks after G(2) exposure of cells to radiation, appears to be associated with cancer predisposition. Unrepaired DNA strand breaks contribute to genomic instability. Unrepaired chromatid breaks representing DNA strand breaks can result in chromosome deletions, translocations and gene amplifications seen in human cancers. This cytogenetic response of cells to radiation may be useful as a marker of cancer susceptibility and in identifying individuals at risk of developing cancer in cancer families.