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1.
Support Care Cancer ; 26(11): 3873-3882, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29754212

RESUMO

PURPOSE: Radiotherapy-induced gut toxicity (RIGT) is associated with significant diarrhoea, pain and rectal bleeding. Matrix metalloproteinases (MMPs) have been reported to be involved in chemotherapy-induced gut toxicity and RIGT following single-dose irradiation in vivo. We therefore proposed MMPs would be involved in the pathobiology of RIGT following fractionated irradiation. METHODS: Dark Agouti rats were treated with fractionated radiation (3 × 2.5 Gy/week for 6 weeks). Rats were killed at 3, 6 and 15 weeks to represent acute and chronic toxicities. Sections of jejunum and colon were immunostained for MMP-1, MMP-2, MMP-9 and MMP-14. Relative mRNA expression in jejunum and colon was quantified by RT-PCR for MMP-1, MMP-2, MMP-9 and MMP-14. Western blotting was also conducted on jejunum and colon tissue collected at week 6 to determine protein levels of pro- and active MMP-2. RESULTS: MMP-2 total protein levels, determined by western blotting, significantly increased in both the jejunum (p = 0.0359) and the colon (p = 0.0134) 6 weeks into the fractionated radiation schedule. MMP-1, MMP-2, and MMP-14 mRNA expression significantly increased in the jejunum. MMP-2 mRNA expression was also significantly increased in the colon. Immunostaining of MMP-2 was observed to be increased in both crypt enterocytes and the lamina propria. CONCLUSIONS: MMP-2 plays a role in the pathobiology of gastrointestinal toxicities following fractionated irradiation. Whilst MMP-1 and MMP-14 mRNA expression was increased, this occurred only in the jejunum, suggesting MMPs are differentially involved in RIGT depending on the intestinal region. Further studies are needed to elucidate the role these mediators play in the development and potentiation of RIGT.


Assuntos
Intestino Grosso/metabolismo , Intestino Grosso/efeitos da radiação , Intestino Delgado/metabolismo , Intestino Delgado/efeitos da radiação , Metaloproteinases da Matriz/genética , Lesões por Radiação/genética , Animais , Fracionamento da Dose de Radiação , Relação Dose-Resposta à Radiação , Feminino , Gastroenteropatias/etiologia , Gastroenteropatias/genética , Regulação Enzimológica da Expressão Gênica/efeitos da radiação , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/efeitos da radiação , Intestino Grosso/patologia , Intestino Delgado/patologia , Metaloproteinases da Matriz/metabolismo , Doses de Radiação , Lesões por Radiação/patologia , Ratos , Ratos Transgênicos
2.
Support Care Cancer ; 25(6): 1973-1983, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28175996

RESUMO

PURPOSE: Radiotherapy-induced gut toxicity (RIGT) is associated with diarrhoea, pain and rectal bleeding and can occur as an acute or chronic toxicity. The microvasculature has been shown to be altered in the development of RIGT; however, the features are not yet characterized. We hypothesized that apoptosis of microvascular cells would occur early in the gastrointestinal tract following fractionated irradiation, followed by late microvascular changes, including sclerosis and telangiectasis. METHODS: Female Dark Agouti rats were treated with a 6-week fractionated radiation schedule of 3 × 2.5 Gy doses per week localized to the abdomen. At 3, 6 and 15 weeks, the intestines were assessed for markers of acute and chronic injury including morphological changes, collagen deposition, apoptosis and proliferation. RESULTS: Apoptosis of microvascular cells significantly increased at 6 and 15 weeks in the jejunum (p = 0.0026 and p = 0.0062, respectively) and at 6 and 15 weeks in the colon (p < 0.0001 and p = 0.0005, respectively) in rats receiving fractionated radiation to the abdomen. Histopathological changes of the colon microvasculature were also seen from week 3, including thickening of the lamina propria and dilated, thickened, telangiectatic vessels. CONCLUSIONS: Findings of this study provide evidence of regional and timing-specific changes in the intestinal microvasculature in response to fractionated radiotherapy which may play a role in development of both acute and chronic RIGT.


Assuntos
Abdome/efeitos da radiação , Gastroenteropatias/etiologia , Trato Gastrointestinal/efeitos da radiação , Intestinos/patologia , Microvasos/efeitos da radiação , Lesões por Radiação/etiologia , Animais , Modelos Animais de Doenças , Feminino , Gastroenteropatias/patologia , Trato Gastrointestinal/irrigação sanguínea , Trato Gastrointestinal/patologia , Humanos , Lesões por Radiação/patologia , Ratos
3.
Acta Oncol ; 55(5): 604-10, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27046049

RESUMO

Background Chronic gastrointestinal (GI) morbidity occurs in ≥50% of patients after external beam radiotherapy (EBRT) for carcinoma of prostate (CaP). This prospective, longitudinal study examines which baseline measurements of: 1) homocysteine and micronutrients in plasma; 2) chromosome damage/misrepair biomarkers; and 3) anal and rectal dose volume metrics predict GI morbidity after EBRT. Patients and methods In total, 106 patients with CaP had evaluations of GI symptoms (modified LENT-SOMA questionnaires) before EBRT and at one month, one, two and three years after its completion. Other variables measured before EBRT were: 1) plasma concentrations of homocysteine and micronutrients including caroteinoids and selenium; 2) chromosome damage/DNA misrepair (micronuclei/nucleoplasmic bridge) indices; and 3) mean anal and rectal wall doses and volumes of anal and rectal walls receiving ≥40 Gy and ≥60 Gy. Univariate and multivariate analyzes examined the relationships among: 1) plasma levels of homocysteine and micronutrients; 2) indices of chromosome damage/DNA misrepair; and 3) mean anal and rectal wall doses and volumes of anal and rectal walls receiving ≥40 Gy and ≥60 Gy and total GI symptom scores from one month to three years after EBRT. Results Increased frequency and urgency of defecation, rectal mucous discharge and bleeding after EBRT resulted in sustained rises in total GI symptom scores above baseline at three years. On univariate analysis, total GI symptom scores were significantly associated with: 1) plasma selenium and α tocopherol; 2) micronuclei indices of DNA damage; 3) mean anal and rectal wall doses; and 4) volumes of anal and rectal wall receiving ≥40 Gy and ≥60 Gy (p = 0.08-<0.001). On multivariate analysis, only volume of anal wall receiving ≥40 Gy was significant for increased GI symptoms after EBRT (p < 0.001). Conclusion The volume of anal wall receiving ≥40 Gy predicts chronic GI morbidity after EBRT for CaP.


Assuntos
Gastroenteropatias/epidemiologia , Neoplasias da Próstata/radioterapia , Lesões por Radiação/epidemiologia , Radioterapia Conformacional/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Canal Anal/efeitos da radiação , Doença Crônica , Defecação/efeitos da radiação , Fracionamento da Dose de Radiação , Relação Dose-Resposta à Radiação , Gastroenteropatias/dietoterapia , Gastroenteropatias/etiologia , Homocisteína/sangue , Humanos , Estudos Longitudinais , Masculino , Micronutrientes/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Próstata , Doses de Radiação , Lesões por Radiação/dietoterapia , Lesões por Radiação/etiologia , Reto/efeitos da radiação , Austrália do Sul/epidemiologia
4.
Acta Oncol ; 54(6): 882-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25734401

RESUMO

BACKGROUND: The precise etiology of fecal incontinence (FI), which occurs frequently following external beam radiotherapy (EBRT) for prostate carcinoma is unknown. It is possibly related to pelvic nerve injury. The aim of this study was to assess the incidence of pudendal nerve dysfunction in men with FI after EBRT for prostate cancer compared to men with FI but no history of EBRT. MATERIAL AND METHODS: Data were evaluated from 74 men with intact anal sphincters on endo-anal ultrasound (17 post-EBRT) who had been investigated for FI at a tertiary center. Wexner incontinence scores, pudendal nerve function, anorectal manometry, and rectal sensitivity were compared between the two patient groups. RESULTS: Post-radiotherapy patients were older (77±6 vs. 62±17 years, p<0.005) and had worse incontinence than those with no history of radiotherapy (Wexner score; 13±3 vs. 8±4; p<0.005). Bilateral pudendal nerve terminal motor latency (PNTML) was abnormal in 87% of radiotherapy versus 22% of non-radiotherapy patients (p<0.001) and the significant difference persisted even after correction for age differences. Anal sphincter pressures and rectal sensitivity for both groups were similar. CONCLUSION: There is a markedly higher incidence of pudendal nerve dysfunction in men with FI after EBRT for prostate cancer compared with men with FI from other etiologies. The increased severity of incontinence in radiotherapy patients is not matched by alterations in either anal sphincter pressures or rectal sensitivity compared to FI in non-ERBT patients.


Assuntos
Carcinoma/radioterapia , Incontinência Fecal/etiologia , Neoplasias da Próstata/radioterapia , Nervo Pudendo/efeitos da radiação , Lesões por Radiação/etiologia , Idoso , Idoso de 80 Anos ou mais , Canal Anal/fisiopatologia , Incontinência Fecal/fisiopatologia , Humanos , Masculino , Manometria , Pessoa de Meia-Idade , Nervo Pudendo/lesões , Nervo Pudendo/fisiopatologia , Lesões por Radiação/fisiopatologia , Radioterapia/efeitos adversos , Dosagem Radioterapêutica , Tempo de Reação , Reto/fisiopatologia , Sensação
5.
Int J Colorectal Dis ; 29(3): 273-83, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24150230

RESUMO

PURPOSE: Pelvic radiotherapy may lead to changes of anorectal function resulting in incontinence-related complaints. The aim of this study was to systematically review objective findings of late anorectal physiology and mucosal appearance after irradiation for prostate cancer. METHODS: MEDLINE, EMBASE, and the Cochrane library were searched. Original articles in which anal function, rectal function, or rectal mucosa were examined ≥3 months after EBRT for prostate cancer were included. RESULTS: Twenty-one studies were included with low to moderate quality. Anal resting pressures significantly decreased in 6 of the 9 studies including 277 patients. Changes of squeeze pressure and rectoanal inhibitory reflex were less uniform. Rectal distensibility was significantly impaired after EBRT in 7 of 9 studies (277 patients). In 4 of 9 studies on anal and in 5 of 9 on rectal function, disturbances were associated with urgency, frequent bowel movements or fecal incontinence. Mucosal changes as assessed by the Vienna Rectoscopy Score revealed telangiectasias in 73 %, congestion in 33 %, and ulceration in 4 % of patients in 8 studies including 346 patients, but no strictures or necrosis. Three studies reported mucosal improvement during follow-up. Telangiectasias, particularly multiple, were associated with rectal bleeding. Not all bowel complaints (30 %) were related to radiotherapy. CONCLUSIONS: Low to moderate quality evidence indicates that EBRT reduces anal resting pressure, decreases rectal distensibility, and frequently induces telangiectasias of rectal mucosa. Objective changes may be associated with fecal incontinence, urgency, frequent bowel movements, and rectal bleeding, but these symptoms are not always related to radiation damage.


Assuntos
Canal Anal/fisiopatologia , Canal Anal/efeitos da radiação , Neoplasias da Próstata/radioterapia , Reto/fisiopatologia , Reto/efeitos da radiação , Defecação/efeitos da radiação , Incontinência Fecal/etiologia , Humanos , Mucosa Intestinal/patologia , Mucosa Intestinal/efeitos da radiação , Masculino , Pressão , Radioterapia/efeitos adversos , Telangiectasia/etiologia , Úlcera/etiologia
6.
Support Care Cancer ; 21(1): 357-64, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23052919

RESUMO

PURPOSE: The aim of this study was to review the available literature from 1966 until December 31, 2010 and define clinical practice guidelines for the use of amifostine for the prevention and treatment of oral mucositis in cancer patients. METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. The body of evidence for the use of amifostine, in each cancer treatment setting was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, or no guideline possible. RESULTS: Thirty papers were reviewed for evidence on amifostine as an intervention for oral mucositis. No guideline was possible for amifostine in any cancer treatment setting due to inadequate and conflicting evidence. CONCLUSION: Review of the amifostine studies for the prevention and treatment of oral mucositis has found insufficient evidence to support its use in any cancer treatment setting for this purpose. Additional well-designed research is needed to clarify the role of amifostine as an intervention for oral mucositis.


Assuntos
Amifostina/uso terapêutico , Neoplasias/complicações , Protetores contra Radiação/uso terapêutico , Estomatite/terapia , Administração Tópica , Amifostina/administração & dosagem , Amifostina/efeitos adversos , Medicina Baseada em Evidências , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Guias de Prática Clínica como Assunto , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/efeitos adversos , Estomatite/etiologia , Estomatite/prevenção & controle
7.
Support Care Cancer ; 21(11): 3179-89, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23702538

RESUMO

PURPOSE: The aim of this project was to review the available literature and define clinical practice guidelines for the use of anti-inflammatory agents for the prevention and treatment of oral mucositis in cancer patients. MATERIALS AND METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. The body of evidence for use of each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible. RESULTS: Forty-one papers were reviewed. There was sufficient evidence to recommend the use of benzydamine mouthwash for the prevention of oral mucositis in head and neck cancer patients receiving moderate-dose radiation therapy (up to 50 Gy), without concomitant chemotherapy. A new suggestion was developed against the use of misoprostol mouthwash for the prevention of oral mucositis in head and neck cancer patients receiving radiation therapy. Positive results were reported for some other anti-inflammatory agents. However, no guidelines were able to be developed for any other agents due to insufficient and/or conflicting evidence. CONCLUSIONS: The use of anti-inflammatory agents continues to be a promising strategy for the prevention and treatment of oral mucositis. Additional well-designed studies are needed to examine the use of this class of agents for oral mucositis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Neoplasias de Cabeça e Pescoço/complicações , Estomatite/tratamento farmacológico , Quimiorradioterapia/efeitos adversos , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Antissépticos Bucais/uso terapêutico , Guias de Prática Clínica como Assunto , Estomatite/prevenção & controle
8.
Med Phys ; 37(9): 5126-37, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20964232

RESUMO

PURPOSE: Normal tissue complication probability (NTCP) of the rectum, bladder, urethra, and femoral heads following several techniques for radiation treatment of prostate cancer were evaluated applying the relative seriality and Lyman models. METHODS: Model parameters from literature were used in this evaluation. The treatment techniques included external (standard fractionated, hypofractionated, and dose-escalated) three-dimensional conformal radiotherapy (3D-CRT), low-dose-rate (LDR) brachytherapy (I-125 seeds), and high-dose-rate (HDR) brachytherapy (Ir-192 source). Dose-volume histograms (DVHs) of the rectum, bladder, and urethra retrieved from corresponding treatment planning systems were converted to biological effective dose-based and equivalent dose-based DVHs, respectively, in order to account for differences in radiation treatment modality and fractionation schedule. RESULTS: Results indicated that with hypofractionated 3D-CRT (20 fractions of 2.75 Gy/fraction delivered five times/week to total dose of 55 Gy), NTCP of the rectum, bladder, and urethra were less than those for standard fractionated 3D-CRT using a four-field technique (32 fractions of 2 Gy/fraction delivered five times/week to total dose of 64 Gy) and dose-escalated 3D-CRT. Rectal and bladder NTCPs (5.2% and 6.6%, respectively) following the dose-escalated four-field 3D-CRT (2 Gy/fraction to total dose of 74 Gy) were the highest among analyzed treatment techniques. The average NTCP for the rectum and urethra were 0.6% and 24.7% for LDR-BT and 0.5% and 11.2% for HDR-BT. CONCLUSIONS: Although brachytherapy techniques resulted in delivering larger equivalent doses to normal tissues, the corresponding NTCPs were lower than those of external beam techniques other than the urethra because of much smaller volumes irradiated to higher doses. Among analyzed normal tissues, the femoral heads were found to have the lowest probability of complications as most of their volume was irradiated to lower equivalent doses compared to other tissues.


Assuntos
Modelos Biológicos , Neoplasias da Próstata/radioterapia , Lesões por Radiação/etiologia , Lesões por Radiação/patologia , Braquiterapia , Humanos , Masculino , Probabilidade , Lesões por Radiação/diagnóstico
9.
Int J Radiat Oncol Biol Phys ; 72(2): 522-8, 2008 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-18374505

RESUMO

PURPOSE: To describe the development of a proctitis-specific quality-of-life module to supplement the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). METHODS AND MATERIALS: The module was developed according to EORTC guidelines, which consisted of an extensive literature review to identify previously described issues and interviews conducted with seven health professionals and 10 patients to rationalize the item list for construction into a provisional module. The module developed was then pretested with 28 patients and five health professionals. RESULTS: The final module contains 21-items that are suitable to obtain information about the patients' quality of life after high-dose pelvic irradiation. The questionnaire has now been translated into four languages and commenced field testing in late 2007. CONCLUSIONS: The EORTC QLQ-C30, supplemented by EORTC QLQ-PRT21, will enable health professionals to more accurately monitor the side effects that patients experience after pelvic irradiation.


Assuntos
Neoplasias Pélvicas/radioterapia , Proctite , Qualidade de Vida , Lesões por Radiação/complicações , Inquéritos e Questionários , Idoso , Idoso de 80 Anos ou mais , Incontinência Fecal/etiologia , Feminino , Flatulência , Hemorragia Gastrointestinal/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pelve , Radioterapia (Especialidade)/normas
10.
Mol Cancer Ther ; 6(8): 2319-27, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17699727

RESUMO

Radiation-induced mucositis is a common and serious side effect of radiotherapy. Molecular mechanisms of mucosal injury, however, are still poorly understood and extremely difficult to study in humans. A novel Dark Agouti rat model using fractionated radiotherapy to induce mucositis has been developed to investigate the occurrence of alimentary mucosal injury. Twenty-four Dark Agouti rats were randomly assigned to receive either fractionated radiotherapy or no radiotherapy. The irradiated rats received a fractionated course of abdominal radiotherapy at 45 Gy/18 fractions/6 weeks treating thrice weekly (i.e., at a radiation dose of 2.5 Gy per fraction). After each week of radiation, a group of irradiated rats was killed. Histomorphology and mucin distribution in the alimentary tract was investigated. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used to examine apoptosis in the colon and jejunum, and intestinal morphometry was used to assess villus length, crypt length, and mitotic crypt count. Immunohistochemistry of p53, nuclear factor-kappaB, cyclooxygenase (COX)-1, and COX-2 was also done. The fractionated radiotherapy course induced alimentary mucositis from week 1, with more severe injury seen in the small intestine. The hallmark appearance of apoptosis was present in the crypts of the small and large intestine. In the jejunum and colon, goblet cell disorganization and degeneration was obvious and crypt mitotic counts were severely depleted throughout the treatment. Expression of p53, nuclear factor-kappaB, COX-1, and COX-2 was increased in the irradiated intestinal sections. Fractionated radiation-induced alimentary mucositis has been effectively documented in the Dark Agouti rat for the first time. Further studies investigating the molecular mechanisms underlying radiation-induced mucositis are planned to ultimately achieve anti-mucotoxic-targeted therapies.


Assuntos
Apoptose , Sistema Digestório/patologia , Mucosite/etiologia , NF-kappa B/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Radioterapia/efeitos adversos , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos da radiação , Colo/patologia , Colo/efeitos da radiação , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Sistema Digestório/enzimologia , Sistema Digestório/efeitos da radiação , Modelos Animais de Doenças , Fracionamento da Dose de Radiação , Feminino , Imuno-Histoquímica , Intestino Delgado/patologia , Intestino Delgado/efeitos da radiação , Microvilosidades/patologia , Microvilosidades/efeitos da radiação , Mitose/efeitos da radiação , Mucosite/enzimologia , Ratos
11.
Integr Med (Encinitas) ; 17(2): 24-32, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30962783

RESUMO

BACKGROUND: The demand for the use of human universal energy (HUE) as a form of complementary alternative medicine (CAM) for cancer treatment is increasing, but scientific evidence of its efficacy is lacking. AIMS: The aims of this first randomized study of external beam radiotherapy (EBRT) + HUE versus EBRT + sham HUE in subjects with early breast cancer were to (1) document the changes in health related quality of life (HRQoL) during EBRT and immediately 1 mo after completion of radiation treatment within each subject group and to (2) compare the differences in HRQoL between the 2 groups of subjects. METHOD: Eligible subjects were randomized to either HUE (n = 16) or sham-HUE (n = 16). HRQoL measurements were taken in each patient group before starting treatment, during week 3 of EBRT, immediately after completing treatment, as well as 1 mo after EBRT. These results were evaluated using the validated functional assessment of cancer therapy-breast cancer (FACT-B) HRQoL instrument consisting of the FACT-G and breast cancer specific subscales and trial outcome index (TOI) summary scores. Changes in the scores relevant to both groups were compared using a Mann-Whitney U test. The effect of the HUE treatment was quantified by analysis of covariance (ANCOVA) models. All statistical analysis was done at a 95% confidence interval and the differences were considered significant if P ≤ .05. RESULTS: The tests associated with FACT-G, social wellbeing, and emotional well-being scores returned insignificant P value > .05. The test associated with physical well-being and FWB returned significant P value ≤ .05, but the (adjusted) quantified influence of the HUE treatment on these scores was less than the clinically significant threshold of 5 points, and the FWB clinically significant threshold of greater than 2.9 points. The test associated with FACT-B, breast cancer specific (BCS), and TOI scores returned significant or close to significant P value, α ≤ .05, and the (adjusted) quantified influence of HUE treatment on these scores is more than the accepted thresholds (5 points for BCS and 10 points for FACT-B and TOI) for clinical difference. CONCLUSION: Although some results, such as P values for Mann-Whitney U tests and coefficients of HUE treatment in initial ANCOVA models showed promising and positive effects of HUE treatment on the subject, further research with a larger sample size is necessary to confidently conclude whether HUE treatment has significant positive influence on subject HRQoL.

12.
Environ Mol Mutagen ; 59(9): 813-821, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30264500

RESUMO

Prostate cancer (PC) is commonly diagnosed cancer in men but only a few risk factors, such as family history, ethnicity, and age have been established. Chromosomal instability is another possible risk factor but this has not been adequately explained previously. In this study, we tested the hypotheses that peripheral blood lymphocytes (PBL) of PC patients have (1) an abnormally high level of chromosomal instability; (2) that they are hypersensitive to ionizing radiation-induced DNA damage; and (3) that these phenotypes are affected by hOGG1 (C1245G) polymorphism. These experiments were performed using the cytokinesis-block micronucleus Cytome (CBMN cyt) assay in PC cases and controls. We found that spontaneous or radiation-induced (3G) micronucleus (MN) frequency is not significantly different between both groups. However, spontaneous frequency of nucleoplasmic bridges (NPBs) and radiation-induced nuclear buds (NBuds) were significantly higher in patients vs. controls (P < 0.0001; P = 0.0005, respectively). In addition, apoptosis and nuclear division index (NDI) was significantly higher in patients compared to controls after radiation treatment (P = 0.006; P = 0.0002, respectively). Furthermore carriage of at least one G allele of hOGG1 (C1245G) polymorphism was associated with a significantly increased odds ratio (OR) to have a base-line MN, NPB, or NBud frequency greater than medium level compared to homozygotes for C allele (OR:1.94, 1.77, 2.36, respectively, P = 0.02; 0.04, and 0.004, respectively). Our results support the hypotheses that those who develop PC have significantly higher level of genomic instability which is further increased in those who carry G allele of the hOGG1 (C1245G) polymorphism. Environ. Mol. Mutagen. 59:813-821, 2018. © 2018 Wiley Periodicals, Inc.


Assuntos
DNA Glicosilases/genética , Reparo do DNA , Micronúcleos com Defeito Cromossômico , Testes para Micronúcleos , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Tolerância a Radiação/genética , Idoso , Substituição de Aminoácidos , Estudos de Casos e Controles , Marcadores Genéticos , Humanos , Masculino , Micronúcleos com Defeito Cromossômico/efeitos da radiação , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Neoplasias da Próstata/radioterapia
13.
Int J Radiat Biol ; 94(7): 645-655, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29855218

RESUMO

PURPOSE: Radiotherapy-induced gut toxicity (RIGT) is a debilitating effect of radiotherapy for cancer, often resulting in significant diarrhea and pain. Previous studies have highlighted roles of the intestinal microvasculature and matrix metalloproteinases (MMPs) in the development of RIGT. We hypothesized vascular mediators would be significantly altered in a dark agouti (DA) rat model of RIGT. Additionally, we aimed to assess the effect of MMP-2 and -9 inhibition on the response of tumor-associated microvascular endothelial cells (TAMECs) to radiation. METHODS: DA rats were administered 2.5 Gy abdominal irradiation (3 times/week over 6 weeks). Vascular endothelial growth factor (VEGF), transforming growth factor beta (TGFß), von Willebrand factor (VWF), angiostatin, and endostatin expression was assessed at 3, 6, and 15 weeks. Additionally, DA rat mammary adenocarcinoma tumor-associated microvascular endothelial cells (TAMECs) were used to assess the effects of radiation (12 Gy) and the MMP inhibitor SB-3CT on MMP, VEGF, and TGFß expression, and cell viability. RESULTS: VEGF mRNA expression was significantly increased in the colon at week 15 (p = .0012), and TGFß mRNA expression was significantly increased in both the jejunum and colon at week 3 (p = .0280 and p = .0310, respectively). Endostatin immunostaining was significantly increased at week 3 (p = .0046), and angiostatin at 3 and 6 weeks (p = .0022 and p = .0135, respectively). MMP-2 and -9 mRNA and total protein levels were significantly increased following irradiation of TAMECs. Although this increase was significantly attenuated by SB-3CT, it did not significantly alter endothelial cell viability or VEGF and TGFß mRNA expression. CONCLUSIONS: Findings of this study support the involvement of VEGF, TGFß, angiostatin, endostatin, and MMP-2 in the pathobiology of RIGT. However, the relationship between these mediators is complex and needs further investigation to improve understanding of their therapeutic potential in RIGT.


Assuntos
Trato Gastrointestinal/efeitos da radiação , Radioterapia/efeitos adversos , Angiostatinas/análise , Angiostatinas/fisiologia , Animais , Fracionamento da Dose de Radiação , Endostatinas/análise , Endostatinas/fisiologia , Feminino , Trato Gastrointestinal/química , Compostos Heterocíclicos com 1 Anel/farmacologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Ratos , Sulfonas/farmacologia , Fator de Crescimento Transformador beta/análise , Fator de Crescimento Transformador beta/fisiologia , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/fisiologia
14.
Phys Med ; 42: 253-258, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28302493

RESUMO

BACKGROUND: Out-of-field organs can be affected by secondary radiations originating from high energy linear accelerators, leading to an increased risk of carcinogenesis. The aim of this work was to determine the risk of second primary cancers (SPC) in the organs distal to the prostate during 3D conformal radiotherapy. MATERIALS AND METHODS: Based on previously measured peripheral photon and neutron doses in a Rando phantom using an 18MV photon beam, SPC risks in the out-of-field organs were estimated using the linear-no-threshold and the competitive risk models. Whole body as well as organ specific risk coefficients were used to calculate the SPC risks in order to estimate upper and lower risk limits, given the uncertainties associated with the coefficients. RESULTS: The corresponding estimated average SPC risks ranged from 1.5±0.3% for thyroid to 4.5±4.2% for colon using whole body risk coefficients and 0.12±0.03% and 1.45±1.34%, respectively, using organ specific risk coefficients. The linear-no-threshold and the competitive risk models resulted in the same risk estimates (within the estimated errors) in the dose range received by out-of-field organs (≤1Gy). Distally located organs such as lungs, oesophagus, and thyroid received higher neutron versus photon dose. CONCLUSIONS: The findings have important radiation protection implications when using high energy linear accelerators, as radiation protective measures could be employed to minimize the secondary out-of-field radiation for patients undergoing high energy external beam irradiation of the prostate.


Assuntos
Neoplasias Induzidas por Radiação/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Nêutrons/efeitos adversos , Fótons/efeitos adversos , Neoplasias da Próstata/radioterapia , Radioterapia Conformacional/efeitos adversos , Humanos , Masculino , Segunda Neoplasia Primária/etiologia , Nêutrons/uso terapêutico , Órgãos em Risco , Fótons/uso terapêutico , Neoplasias da Próstata/epidemiologia , Medição de Risco
15.
Cancer Treat Rev ; 32(8): 645-51, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17046165

RESUMO

Radiation therapy is one of the three major treatment modalities used in eradicating malignant tumours. When ionising radiation is used to treat abdominal tumours, severe side effects largely due to mucosal damage in the alimentary tract are common, particularly when it is combined with chemotherapy. Radiation-induced mucositis may not only limit the therapeutic doses of combined treatment but also adversely affect the quality of life of the patient. Treatment strategies to treat and prevent radiation-induced mucositis have been reviewed and published in the Clinical Practice Guidelines, 2004. However evidence supporting an effective treatment approach is tenuous, probably because the mechanistic evolution of radiation-induced mucositis is poorly understood. Several animal models have been used to examine the various effects of radiation but no single animal model has been able to effectively capture the effects of radiation on the alimentary tract at the molecular level before symptoms begin. This review will outline the events which occur following radiation exposure; from chromosomal aberrations in the mucosal cells leading to apoptotic and mitotic death, to the evolution of mucositis involving changes in gene activations and signaling. A better understanding of the mechanisms of radiation therapy-induced mucositis is necessary as it will allow for future pharmaceutical interventions to alleviate if not eliminate the debilitating side effects.


Assuntos
Trato Gastrointestinal/efeitos da radiação , Mucosite/prevenção & controle , Neoplasias/radioterapia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Fracionamento da Dose de Radiação , Trato Gastrointestinal/metabolismo , Humanos , Mucosite/etiologia , NF-kappa B/metabolismo , Guias de Prática Clínica como Assunto , Radioterapia/efeitos adversos
16.
J Med Imaging Radiat Oncol ; 59(1): 77-81, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25186469

RESUMO

INTRODUCTION: According to international best practice guidelines, staging abdominal and pelvic computed tomography (CTAP) and whole body bone scan (WBBS) are not recommended for asymptomatic low and intermediate-risk prostate cancer. Despite this, many patients undergo these investigations. Our aim was to determine the rate and cost of scans being performed for this group of patients. METHOD: We utilised a database of prostate cancer patients treated by a radiation oncologist specialising in prostate cancer at the Royal Adelaide Hospital between January 2008 and December 2012. Risk criteria were defined according to the D'Amico system. We identified the staging investigations ordered. RESULTS: Of 236 consecutive eligible patients, 69 (70%) and 85 (86%) of 99 low risk, and 112 (82%) and 126 (92%) of 137 intermediate-risk patients, were found to have had staging CTAP and WBBS, respectively. In fact, only 9.7% of the patients followed the international best practice guidelines and had no staging investigations. None of these scans showed evidence of metastatic disease. The total costs of these investigations for the low and intermediate-risk groups were approximately AUD 75 000 and AUD 116 000, respectively. CONCLUSION: We found that there is clearly a significant overuse of staging investigations for both these groups while the incidence of metastases identified was very low. This is likely to have a significant impact on the waiting time for scans and lead to substantial waste of resources. It places unnecessary financial burden on the patients and the healthcare system. There are also issues of increased radiation and contrast exposure, and potentially unnecessary further investigations.


Assuntos
Diagnóstico por Imagem/economia , Diagnóstico por Imagem/estatística & dados numéricos , Mau Uso de Serviços de Saúde/economia , Mau Uso de Serviços de Saúde/estatística & dados numéricos , Neoplasias da Próstata/economia , Neoplasias da Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Detecção Precoce de Câncer/economia , Detecção Precoce de Câncer/estatística & dados numéricos , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nova Zelândia/epidemiologia , Neoplasias da Próstata/epidemiologia , Medição de Risco
17.
Int J Radiat Oncol Biol Phys ; 55(4): 943-55, 2003 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-12605972

RESUMO

PURPOSE: We performed a randomized trial to compare the GI and urogenital toxicity of radiotherapy (RT) for localized (confined to the organ), early-stage (T1-T2N0M0, TNM classification) carcinoma of the prostate, using a conventional (64 Gy in 32 fractions within 6.5 weeks) vs. a hypofractionated (55 Gy in 20 fractions within 4 weeks) schedule and to determine the efficacy of the respective treatment schedules. METHODS AND MATERIALS: This report is based on an interim analysis of the first 120 consecutive patients in this Phase III trial after a median follow-up of 43.5 months (range 23-62). RT planning was based on two-dimensional CT data, and the treatment was delivered using a three- or four-field 6-23-MV photon technique. GI and urogenital toxicity (symptom questionnaires incorporating the subjective elements of the late effects of normal tissues-subjective, objective, management, analytic classification of late effects and the European Organization for Research and Treatment of Cancer sexual function questionnaire) were evaluated before RT and 1 month, 1 year, and 2 years after RT completion. The efficacy of RT was assessed clinically (digital rectal examination and radiologic imaging) and biochemically (prostate-specific antigen assay) at baseline, and every 3 months for 2 years after RT and every 6 months subsequently. RESULTS: RT, whether conventional or hypofractionated, resulted in an increase in all six symptom categories used to characterize GI toxicity and in four of five symptom categories used to document urinary morbidity 1 month after therapy completion. Sexual dysfunction (based on limited data), which existed in more than one-third of patients before RT, also increased to just more than one-half of patients 1 month after RT. The increase in urinary toxicity after RT was not sustained (diurnal urinary frequency had decreased significantly at 2 years). In contrast, all six symptom categories of GI toxicity remained increased 1 year after RT. Four of the six GI symptom categories (rectal pain, mucous discharge, urgency of defecation, and rectal bleeding) were still increased at 2 years compared with baseline. Except for a slightly greater percentage of patients experiencing mild rectal bleeding at 2 years among those who received hypofractionated RT, no differences were noted in toxicity between the conventional and hypofractionated RT schedule. The mean prostate-specific antigen level was 14.0 +/- 1.0 ng/mL at baseline and declined to a nadir of 1.3 +/- 0.2 ng/mL at a median of 16.8 months (range 0.8-28.3) after RT completion. However, it then rose in 17 patients (8 in the hypofractionated and 9 in the conventional treatment group). Only 8 of these 17 patients were found to have signs of clinical relapse (5 local, 1 regional lymph node, and 2 systemic [bony metastases]) after histopathologic and radiologic reassessment). The remaining 9 patients had biochemical relapse only (defined as three consecutive rises in prostate-specific antigen after nadir). The 4-year biochemical relapse-free survival rate was 85.8% for all patients and did not differ significantly between the two radiation dose schedules (86.2% for the hypofractionated and 85.5% for the conventional fractionation group). CONCLUSION: RT for prostate carcinoma, using a three- or four-field 6-23-MV photon technique without posterior shielding of the lateral fields, is an underestimated cause of persistent GI morbidity. The incidence of clinically significant GI and urogenital toxicity after conventional and hypofractionated RT appears to be similar. Hypofractionated RT for carcinoma of the prostate seems just as effective as conventional RT after a median follow-up approaching 4 years.


Assuntos
Carcinoma/radioterapia , Neoplasias da Próstata/radioterapia , Lesões por Radiação/complicações , Doenças Retais/etiologia , Transtornos Urinários/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/sangue , Carcinoma/patologia , Defecação/efeitos da radiação , Fracionamento da Dose de Radiação , Hemorragia Gastrointestinal/etiologia , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Muco/metabolismo , Estadiamento de Neoplasias , Dor/etiologia , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Reto/metabolismo , Reto/efeitos da radiação
18.
Int J Radiat Oncol Biol Phys ; 87(5): 954-9, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24113059

RESUMO

PURPOSE: To evaluate and compare the effect of argon plasma coagulation (APC) and topical formalin for intractable rectal bleeding and anorectal dysfunction associated with chronic radiation proctitis. METHODS AND MATERIALS: Thirty men (median age, 72 years; range, 49-87 years) with intractable rectal bleeding (defined as ≥1× per week and/or requiring blood transfusions) after radiation therapy for prostate carcinoma were randomized to treatment with APC (n=17) or topical formalin (n=13). Each patient underwent evaluations of (1) anorectal symptoms (validated questionnaires, including modified Late Effects in Normal Tissues-Subjective, Objective, Management, and Analytic and visual analogue scales for rectal bleeding); (2) anorectal motor and sensory function (manometry and graded rectal balloon distension); and (3) anal sphincteric morphology (endoanal ultrasound) before and after the treatment endpoint (defined as reduction in rectal bleeding to 1× per month or better, reduction in visual analogue scales to ≤25 mm, and no longer needing blood transfusions). RESULTS: The treatment endpoint was achieved in 94% of the APC group and 100% of the topical formalin group after a median (range) of 2 (1-5) sessions of either treatment. After a follow-up duration of 111 (29-170) months, only 1 patient in each group needed further treatment. Reductions in rectal compliance and volumes of sensory perception occurred after APC, but no effect on anorectal symptoms other than rectal bleeding was observed. There were no differences between APC and topical formalin for anorectal symptoms and function, nor for anal sphincteric morphology. CONCLUSIONS: Argon plasma coagulation and topical formalin had comparable efficacy in the durable control of rectal bleeding associated with chronic radiation proctitis but had no beneficial effect on anorectal dysfunction.


Assuntos
Canal Anal/efeitos da radiação , Coagulação com Plasma de Argônio/métodos , Coagulantes/administração & dosagem , Formaldeído/administração & dosagem , Hemorragia Gastrointestinal/terapia , Proctite/complicações , Neoplasias da Próstata/radioterapia , Lesões por Radiação/terapia , Reto/efeitos da radiação , Administração Tópica , Idoso , Idoso de 80 Anos ou mais , Canal Anal/fisiopatologia , Hemorragia Gastrointestinal/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Lesões por Radiação/complicações , Lesões por Radiação/fisiopatologia , Reto/fisiopatologia , Sensação/fisiologia , Sensação/efeitos da radiação
19.
Int J Radiat Oncol Biol Phys ; 84(5): e593-9, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22836050

RESUMO

PURPOSE: To characterize the prevalence, pathophysiology, and natural history of chronic radiation proctitis 5 years following radiation therapy (RT) for localized carcinoma of the prostate. METHODS AND MATERIALS: Studies were performed in 34 patients (median age 68 years; range 54-79) previously randomly assigned to either 64 Gy in 32 fractions over 6.4 weeks or 55 Gy in 20 fractions over 4 weeks RT schedule using 2- and later 3-dimensional treatment technique for localized prostate carcinoma. Each patient underwent evaluations of (1) gastrointestinal (GI) symptoms (Modified Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scales including effect on activities of daily living [ADLs]); (2) anorectal motor and sensory function (manometry and graded balloon distension); and (3) anal sphincteric morphology (endoanal ultrasound) before RT, at 1 month, and annually for 5 years after its completion. RESULTS: Total GI symptom scores increased after RT and remained above baseline levels at 5 years and were associated with reductions in (1) basal anal pressures, (2) responses to squeeze and increased intra-abdominal pressure, (3) rectal compliance and (4) rectal volumes of sensory perception. Anal sphincter morphology was unchanged. At 5 years, 44% and 21% of patients reported urgency of defecation and rectal bleeding, respectively, and 48% impairment of ADLs. GI symptom scores and parameters of anorectal function and anal sphincter morphology did not differ between the 2 RT schedules or treatment techniques. CONCLUSIONS: Five years after RT for prostate carcinoma, anorectal symptoms continue to have a significant impact on ADLs of almost 50% of patients. These symptoms are associated with anorectal dysfunction independent of the RT schedules or treatment techniques reported here.


Assuntos
Canal Anal/efeitos da radiação , Carcinoma/radioterapia , Proctite/fisiopatologia , Neoplasias da Próstata/radioterapia , Lesões por Radiação/fisiopatologia , Reto/efeitos da radiação , Atividades Cotidianas , Idoso , Canal Anal/diagnóstico por imagem , Canal Anal/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Pressão , Proctite/etiologia , Estudos Prospectivos , Neoplasias da Próstata/fisiopatologia , Lesões por Radiação/complicações , Dosagem Radioterapêutica , Reto/diagnóstico por imagem , Reto/fisiopatologia , Reflexo/fisiologia , Reflexo/efeitos da radiação , Sensação/fisiologia , Sensação/efeitos da radiação , Fatores de Tempo , Ultrassonografia
20.
Urol Oncol ; 29(6): 641-6, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-19914098

RESUMO

OBJECTIVE: Single nucleotide polymorphisms (SNPs) in DNA repair genes may impact on DNA damage, and cancer risk. To elucidate the role of SNPs in DNA repair genes in prostate cancer (PC) we conducted a case-control study comprising of 118 Caucasian men affected with late onset PC and 132 age-matched healthy controls from South Australia. METHODS AND MATERIALS: We examined the association between PC risk with nonsynonymous SNPs (nsSNPs) in 5 genes involved in 3 DNA-repair pathways: (1) base excision repair (BER): hOGG1 C1245G (Ser326Cys) and XRCC1 G28152A (Arg399Gln); (2) nucleotide excision repair (NER): XPD G23591A (Asp312Asn); (3) homologous recombination repair: RAD51 G135C (in 5' untranslated region) and XRCC3 C18067T (Thr241Met). RESULTS: Prostate cancer risk was significantly increased only for carriers of the G allele of the C1245G polymorphism in the hOGG1 gene (OR = 2.28; 95% CI = 1.36-3.83; P = 0.002). CONCLUSION: Our results suggest that this common nsSNP in a gene involved in repair of oxidative damage to DNA may contribute to PC susceptibility in South Australian men.


Assuntos
DNA Glicosilases/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Idoso , Austrália , Estudos de Casos e Controles , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Genótipo , Humanos , Masculino , Projetos Piloto , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Rad51 Recombinase/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X , Proteína Grupo D do Xeroderma Pigmentoso/genética
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