Long-term risks of bisphosphonate therapy / Riscos do tratamento a longo prazo com bisfosfonatos

The objective this study was to summarize long-term risks associated with bisphosphonate therapy. Search of relevant medical publications for data from clinical trials, trial extensions, observational studies and post-marketing reports. Trial extensions and modifications did not reveal significant long-term safety issues. Observational data suggest at least as many benefits as risks. Post-marketing reports of musculoskeletal pain, osteonecrosis of the jaw and atypical femur fractures have been widely circulated in the lay press. Most focus on long-terms risks has been on osteonecrosis of the jaw and atypical femur fractures which occur in patients who have not received bisphosphonate therapy but may be more frequent (though still uncommon) in patients who have been on treatment for 5 years or longer. Lower-risk patients may be able to stop treatment after 3-5 years for a “drug holiday,” which mitigates these long-term risks; for higher risk patients, therapy through 6-10 years appears to be advisable and offers more benefits than risks.

O objetivo deste estudo foi resumir os riscos associados ao tratamento a longo prazo com bisfosfonatos. Foram pesquisadas as publicações médicas relevantes incluindo ensaios clínicos, extensões de ensaios clínicos, estudos observacionais e relatórios pós-comercialização (vigilância farmacológica). As extensões e modificações de ensaios clínicos não indicaram nenhuma situação de alarme quanto à segurança dos bisfosfonatos a longo prazo. Dados observacionais sugerem pelo menos tantos benefícios quanto riscos. Entretanto, relatos pós-comercialização de dor musculoesquelética, osteonecrose da mandíbula e fraturas de fêmur atípicas foram amplamente divulgados na imprensa leiga. O foco nos riscos a longo prazo do tratamento com bisfosfonatos tem sido pincipalmente a osteonecrose da mandíbula e as fraturas atípicas de fêmur. Essas últimas, embora mais frequentes (ainda que pouco comuns) em pacientes que receberam tratamento com bisfosfonatos por 5 anos ou mais, podem ocorrer em indivíduos não tratados com esses medicamentos. Pacientes com baixo risco de fratura podem potencialmente parar o tratamento depois de 3 a 5 anos (“drug holiday”). Esse procedimento reduz os riscos desses medicamentos a longo prazo. Não obstante, nos pacientes de maior risco a terapia por 6 a 10 anos parece ser aconselhável e oferece mais benefícios do que riscos.

Evaluation of the heme oxygenase-1 expression in esophagitis and esophageal cancer induced by different reflux experimental models and diethylnitrosamine / Avaliação da expressão da Heme Oxigenase-1 em esofagite e câncer de esôfago induzidos por diferentes modelos experimentais de refluxo e diethilnitrosamina

PURPOSE: To study the expression of heme-oxygenase-1 (HO-1), an enzyme induced by oxidative stress, in specimens obtained from an experimental model in rats that evaluated the role of gastric and duodenal reflux in esophageal carcinogenesis. METHODS: Esophageal specimens embedded in paraffin obtained from different experimental groups of rats were used for immunohistochemistry analysis of HO-1 expression. The rats had been divided into the following groups and were killed after 22 weeks: (1) cardioplasty to induce acid reflux; (2) esophagoduodenal anastomosis to induce duodenal reflux; (3) no treatment; (4) cardioplasty + diethylnitrosamine (DEN); (5) esophagoduodenal anastomosis + DEN; and (6) DEN. The study sample comprised 3 specimens from each group with the most severe histopathological lesions found on each study branch. RESULTS: The expression of HO-1 was seen only in rat specimens submitted to esophagoduodenal anastomosis (Groups 2 and 5), and the analysis of mean fluorescence intensity revealed a significant increase of HO-1 expression (4.8 and 4.6 fold, respectively) when compared with the control group (Group 3) (p<0.05). The main target for HO-1 induction was the inflammatory cells inside the tumor or in subepithelial areas. Rats exposed to gastric reflux had no HO-1 expression. CONCLUSION: Reflux esophagitis induced by reflux of duodenal contents, which provoked considerable oxidative stress, may play an important role in esophageal carcinogenesis. Acid reflux did not induce oxidative stress in this experimental model.

OBJETIVO: Estudar a expressão da HO-1 (enzima induzida pelo estresse) em diferentes peças esofágicas obtidas de um estudo experimental em ratos que avaliou o papel do refluxo gastroesofágico e duodeno esofágico na carcinogênese experimental. MÉTODOS: Blocos de parafina contendo peças de esôfago provenientes de um estudo experimental com ratos foram utilizados para verificar a expressão imunohistoquímica da HO-1. Os ratos haviam sido divididos nos seguintes grupos: (1) Cardioplastia com o objetivo de promover refluxo ácido, (2) Anastomose esofagoduodenal para indução de refluxo misto (ácido e biliar), (3) sem tratamento (controles), (4) cardioplastia + dietil-nitrosamina (DEN), (5) Anastomose esofagoduodenal + DEN, (6) DEN. Amostras contendo três peças de cada grupo com as lesões histopatológicas mais graves encontradas em cada braço do estudo foram escolhidas para avaliação da expressão imunoistoquímica da HO-1. RESULTADOS: A expressão da HO-1 foi observada somente nas peças de esôfago de ratos submetidos à anastomose esofagoduodenal (Grupos 2 e 5) e analise da intensidade média da fluorescência demonstrou uma diferença significativa na expressão da HO-1 nesses grupos quando comparada com o grupo controle (4,8 e 4,6 vezes respectivamente) (p<0,05). As células inflamatórias localizadas dentro dos tumores e nas regiões adjacentes ao epitélio foram as que mais intensamente expressaram a HO-1. Ratos expostos ao refluxo ácido (gástrico) apresentaram pouca ou nenhuma atividade da HO-1. CONCLUSÃO: Esofagite de refluxo induzida pelo refluxo com conteúdo duodenal provocou considerável estresse oxidativo, que parece exercer um papel importante na carcinogênese esofágica. O refluxo puramente ácido não foi capaz de induzir estresse oxidativo nesse modelo experimental

Modelo experimental de carcinoma mamário em ratas induzidas com 7, 12-dimetilbenz(a)antraceno / Induction of experimental mammary carcinogenesis in rats with 7, 12-dimethylbenz(a)anthracene

Objetivo: Testar um modelo experimental de indução de carcinogênese em raras Sprague-Dawley. Métodos: Foram estudadas 30 ratas fêmeas virgens Sprague-Dawley, induzidas ao carcinogênese mamário. Com 50 dias de vida, foi injectado 7,12-dimerilbenz(a)antrace no ventre por gavage. Com 12 semanas, as glândulas mamárias foram examinadas, assim como os tecidos cerebrais, pulmonares, ossos do fêmur e fígado. Resultados: Doze semanas após a injeção de DMBA, 85% das ratas apresentaram pelo menos um tumor mamário visível. Conclusão: O modelo experimental de carcinoma mamário induzido por DMBA mostrou-se efetivo e de fácil reprodução.

Objective: To test an experimental model of chemical mammary carcinogenesis induction in Sprague-Dawley rats. Methods: Thirty virgin Sprague-Dawley female rats, aged 50 days, received 20 mg of 7,12-dimethyLbenz(a)anthracene (DMBA) intragastrically by gavage. At 12 week their mammary glands were examined. Brain, Liver, bone and Lung tissue were also analyzed. Results: Twelve weeks after DMBA injection, 85% rats presented at Least one breast tumor. Conclusion: This experimental animal model of chemical mammary induced carcinogenesis is feasible and can be used in further experiments on the role of tumorigenic biomodulator substances.

Fish oil ingestion reduces the number of aberrant crypt foci and adenoma in 1, 2-dimethylhydrazine-induced colon cancer in rats

We determined the effect of fish oil (FO) ingestion on colonic carcinogenesis in rats. Male Wistar rats received 4 subcutaneous injections (40 mg/kg body weight each) of 1,2-dimethylhydrazine (DMH) at 3-day intervals and were fed a diet containing 18 percent by weight FO (N = 10) or soybean oil (SO, N = 10) for 36 weeks. At sacrifice, the colon was removed, aberrant crypt foci were counted and the fatty acid profile was determined. Intestinal tumors were removed and classified as adenoma or carcinoma. Liver and feces were collected and analyzed for fatty acid profile. FO reduced the mean (± SEM) number of aberrant crypt foci compared to SO (113.55 ± 6.97 vs 214.60 ± 18.61; P < 0.05) and the incidence of adenoma (FO: 20 percent vs SO: 100 percent), but carcinoma occurred equally in FO and SO rats (2 animals per group). The polyunsaturated fatty acid (PUFA) profile of the colon was affected by diet (P < 0.05): total ù-3 (FO: 8.18 ± 0.97 vs SO: 1.71 ± 0.54 percent) and total ù-6 (FO: 3.83 ± 0.59 vs SO: 10.43 ± 1.28 percent). The same occurred in the liver (P < 0.05): total ù-3 (FO: 34.41 ± 2.6 vs SO: 6.46 ± 0.59 percent) and total ù-6 (FO: 8.73 ± 1.37 vs SO: 42.12 ± 2.33 percent). The PUFA profile of the feces and liver polyamine levels did not differ between groups (P > 0.05). In conclusion, our findings indicate that chronic FO ingestion protected against the DMH-induced preneoplastic colon lesions and adenoma development, but not against carcinoma in rats.

Terapia hormonal na menopausa: quando não usar: [revisão] / Hormone therapy in menopause: when not to use: [review]

A menopausa corresponde à cessação permanente da menstruação, conseqüente à perda da função folicular ovariana ou à remoção cirúrgica dos ovários. A idade média para ocorrência da menopausa natural gira em torno de 50 anos. A deficiência estrogênica decorrente da menopausa está associada com sintomas vasomotores, atrofia urogenital, declínio cognitivo, assim como a um aumento no risco de doenças crônico-degenerativas, aterosclerose e doença cardiovascular, osteoporose e doença de Alzheimer. A estrogenioterapia permanece sendo o tratamento mais efetivo para o manejo dos sintomas vasomotores e atrofia urogenital. Em mulheres com útero presente, a progesterona natural ou os progestogênios devem ser associados ao tratamento com estradiol para antagonizar os efeitos proliferativos deste hormônio sobre o endométrio e anular o risco de hiperplasia/carcinoma endometrial. Por outro lado, em determinadas condições clínicas, a terapia hormonal não é recomendada ou é mesmo contra-indicada. Neste artigo, focalizamos criticamente essas situações clínicas em que não se deve indicar a terapia hormonal na menopausa.

Menopause is defined as the permanent cessation of menses, as a result of the loss of ovarian follicular function or of surgical removal of ovaries. The mean age for occurrence of natural menopause is around 50 years. Estrogen deficiency has been associated with vasomotor symptoms, urogenital atrophy, and cognitive impairment, as well as increased risk of chronic degenerative diseases such as osteoporosis and Alzheimer’s disease. Estrogen therapy remains the most effective treatment for the management of vasomotor symptoms and urogenital atrophy. Progesterone or progestins should be added to estrogen treatment in women with uterus, in order to antagonize the estrogen-induced endometrial proliferation. In turn, in specific clinical conditions hormone therapy is not recommended. In the present article, the authors critically focus these clinical conditions in which hormone therapy should not be used.

Carcinomatosis múltiple de localización bucal en un paciente de zona de hidroarsenicismo crónico regional endémico (HACRE) / Oral multiple carcinomatosis in a patient from an area with endemic regional chronica hydroarsenicism (ERCH)

Antecedentes: La acción nociva del arsénico (As) y sus compuestos sobre el organismo humano es múltiple, afectando procesos biológicos de gran importancia. En extensas zonas de la República Argentina se consume agua de pozo contaminada con As, lo que produce una enfermedad denominada"Hidroarsenicismo Crónico Regional Endémico (HACRE), en cuyo cuadro clínico se han observado pacientes con múltiples lesiones carcinomatosas de la piel. coexistentes o sucesivas en largos periodos de tiempo. Objetivo: presentar el caso clínico de una paciente residente en la zona arsenical de la Provincia de Córdoba con lesiones carcinomatosas orales. Materiales y Métodos: Se realizó Historia Clínica, iconografía, eliminación quirúrgica de lesiones de labio, estudios anatomopatológicos de los especimenes obtenidos y control evolutivo. Resultados: Por los datos obtenidos de la Historia Clínica, y por el seguimiento realizado, se pudo comprobar la existencia de múltiples y sucesivas lesiones carcinomatosas en la mucosa bucal. Conclusión: Del estudio de este caso se concluye que el AS presente en el agua de bebida en cantidades superiores a las aceptadas por la Organización Mundial de la Salud (0,05 ppm), puede producir, al igual que en la piel, múltiples lesiones carcinomatosas en la mucosa oral.

Background: Arsenic (As) and its compounds may cause multiple harmful effects on the human rganism, interfering with biological processes of vital importance. It is known that the inhabitants of vast areas of the Argentine Republic drink well water contaminated with AS, which results in a disease known as Endemic Regional Chronic Hydroarsenicism (ERCH). It has been observed that these patients present a clinical picture characterized by multiple carcinomatous skin lesions which occur concurrently or successively along long periods of time. Purpose: To present the clinical case of a female patient from the arsenical area of Cordoba Province, who had multiple carcinomatous oral lesions. Materials and method: The patient's history was written and iconographies, surgical excision of the lip lesions, pathological studies of the samples, and evolution observations were done. Results: Based on both the patient’s history and follow-upstudies, it was possible to preve the presence of multiple successive carcinomatous lesions in the oral mucose. Conclusion: it is conclude that drinking water containing more AS than the quantity accepted by the WHO (0,05 ppm) can cause multiples carcinomatous lesions on the oral mucosa as on the skin.

Induction of experimental mammary carcinogenesis in rats with 7, 12-dimethylbenz(a)anthracene

OBJETIVO: Testar um modelo experimental de indução química de carcinogênese mamária em ratas. MATERIAL E MÉTODOS: Com 47 dias de vida, 20 ratas Sprague-Dawley, jovens e virgens, receberam por gavagem intragástrica 20 mg de 7,12-dimetilbenz(a)antraceno (DMBA). Oito e 13 semanas depois da injeção de droga as mamas das ratas foram examinadas. Ao final os animais foram sacrificados e fragmentos dos tumores foram estudados ao microscópio. RESULTADO: Oito semanas depois da injeção de DMBA 16 ratas apresentavam tumor nas mamas (80%). Com 13 semanas todas desenvolveram carcinomas de mama (100%), que foram confirmados por análise histopatológica. CONCLUSÃO: Este modelo experimental de indução química de carcinogênese mamária é factível e pode ser empregado em futuras pesquisas para avaliar o papel de substâncias biomoduladoras da tumorigênese.

Proliferación y apoptosis en epitelio lingual de ratones con tumores salivales inducidos por dimetilbenzantraceno (DMBA) y modulados por lípidos dietarios / Proliferation and apoptosis in tongue epithelium of mice bearing salivary tumors induced by dimetilbenzantraceno (DMBA) and modulated by dietary lipids

INTRODUCTION: According to the concept of field defects during the carcinogenesis process, excessive epithelial proliferation/apoptosis may exist in areas near tumors. Proliferation or apoptosis could be modified by dietary lipids. PURPOSE: The present study was designed to analyze proliferation and apoptosis in tongue epithelium of mice fed diets based on different lipids followed by induction of salivary tumors with DMBA. MATERIALS AND METHODS: Forty-five days after weaning, ten BALB/c mice were assigned to two diets: corn oil (CO) and fish oil (cod liver, FO). Two weeks later, DMBA was injected in the submandibular area. Animals were sacrificed at the 13th post-injection week. Samples of tongue were fixed in formalin-ethanol and immunohistochemically stained for proliferation (Ki-67) and apoptosis (Bax). By light microscopy, the number of nuclei positive for these markers were counted out of three-hundred total interphase cells both in dorsal and in ventral tongue surfaces. Results were analyzed through Analysis of Variance and t Test. RESULTS: Cell proliferation was greater in dorsal than in ventral tongue surfaces (p < 0.0001) with no diet difference. Apoptosis was significantly greater in mice fed FO than CO, particularly in tongue dorsal epithelia (p < 0.018). CONCLUSIONS: This study shows that FO diet induces higher levels of apoptosis in tongue epithelia suggesting a tissue defensive mechanism when exposed to a carcinogenic-tumoral agent.

Introducción: Según el concepto de cancerización de campo, existría alteración en la proliferación epitelial en áreas cercanas a tumores. Dicha proliferación podría ser modificada por lípidos dietarios. Objetivos: este estudio fue diseñado para analizar proliferación y apoptosis en epitelio lingual de ratones portadores de tumores salivalesinducidos por DMBA y alimentados con dietas a base de diferentes lípidos. Materiales y Métodos: Cuarenta y cinco días posteriores al destete, diez ratones BALB/c fueron asignados a dos dietas: maíz(M) y bacalao (B). Dos semanas después se inyectó DMBA en la zona submandibular. Los animales fueron sacrificados a ala 13º semana post-inyección. Muestras de lengua fueron fijadas en formal-etanl y procesadas inmunohistoquímicamente con marcadores de proliferación (Ki-67) y apoptosis. Mediante microscopia óptica, se efectuó un conteo de núcleos positivos a ambos marcadosres en un total de trecientas células en interfase, tanto en cara dorsal como ventral de lengua. Los resultados fueron analizados mediante Anális de Varianza y Test t. Resultados: La proliferación celular fue mayor en cara dorsal que en ventral (p> 0.001), sin diferencias por dieta. La apoptosis fue significativamentes mayor en ratones alimentados con B que M, en particular en cara dorsal (p<0.018). Conclusiones: Este estudio demuestra que la dieta B induce mayor apoptosis en ela epitelio lingua, sgiriendo un mecanismo defensivo de los tejidos ante el agente cancerígeno-tumoral.

Histopathology of skin lesions in chronic arsenic toxicity--grading of changes and study of proliferative markers.

Chronic arsenic toxicity (CAT) manifests predominantly as cutaneous lesions in the form of melanosis, keratosis and neoplastic changes. We have studied skin biopsies from 42 patients of CAT. Histological study of H/E stained sections showed--hyperkeratosis in 13, parakeratosis in 13, acanthosis in 12, papillomatosis in 24, elongation of reteridges in 21, increased basal pigmentation in 27 and dysplastic changes in 8 cases. Squamous cell carcinoma was present in 2, basisquamous in 1 and basal cell carcinoma in 1 case. Changes of skin lesions after drug DMSA and DMPS therapy compared to placebo were studied. The result was inconclusive. Proliferative activity of skin lesions in CAT were studied by AgNOR stain to assess the biological behaviour of the lesions. AgNOR score showed--normal control 1.08, benign changes (e.g. Hyperkeratosis, parakeratosis, acanthosis, papillomatosis etc.) without dysplasia--1.35, mild to moderate dysplasia--1.735, severe dysplasia--3.0 and carcinoma--3.56. Thus, AgNOR score gives some idea on the biological behaviour of CAT lesions. It is suggested that AgNOR staining should be done regularly along with H&E staining for proper assessment of the cases.

Lipídios nutricionais e câncer mamário / Dietary lipids and mammary carcinogenesis

Os lípidios e ácidos graxos dietários interferem na estrutura e funçäo das membranas biológicas, nos níveis hormonais, no sistema imunológico e no reparo do ácido desoxirribonucléico (DNA). Estes efeitos podem estar relacionados com o desenvolvimento da carcinogênese mamária por mecanismos ainda pouco conhecidos. O aumento do consumo diário de lipídios está fortemente associado com o aumento da incidência e da mortalidade por câncer da mama como demonstrado em várias populaçöes humanas