Manoel Odorico de Moraes Filho

Preoperative Pulmonary Rehabilitation Versus Chest Physical Therapy in Patients Undergoing Lung Cancer Resection: A Pilot Randomized Controlled Trial

OBJECTIVE To evaluate the effect of 4 weeks of pulmonary rehabilitation (PR) versus chest physical therapy (CPT) on the preoperative functional capacity and postoperative respiratory morbidity of patients undergoing lung cancer resection. DESIGN Randomized single-blinded study. SETTING A teaching hospital. PARTICIPANTS Patients undergoing lung cancer resection (N=24). INTERVENTIONS Patients were randomly assigned to receive PR (strength and endurance training) versus CPT (breathing exercises for lung expansion). Both groups received educational classes. MAIN OUTCOME MEASURES Functional parameters assessed before and after 4 weeks of PR or CPT (phase 1), and pulmonary complications assessed after lung cancer resection (phase 2). RESULTS Twelve patients were randomly assigned to the PR arm and 12 to the CPT arm. Three patients in the CPT arm were not submitted to lung resection because of inoperable cancer. During phase 1 evaluation, most functional parameters in the PR group improved from baseline to 1 month: forced vital capacity (FVC) (1.47L [1.27-2.33L] vs 1.71L [1.65-2.80L], respectively; P=.02); percentage of predicted FVC (FVC%; 62.5% [49%-71%] vs 76% [65%-79.7%], respectively; P<.05); 6-minute walk test (425.5±85.3m vs 475±86.5m, respectively; P<.05); maximal inspiratory pressure (90±45.9cmH(2)O vs 117.5±36.5cmH(2)O, respectively; P<.05); and maximal expiratory pressure (79.7±17.1cmH(2)O vs 92.9±21.4cmH(2)O, respectively; P<.05). During phase 2 evaluation, the PR group had a lower incidence of postoperative respiratory morbidity (P=.01), a shorter length of postoperative stay (12.2±3.6d vs 7.8±4.8d, respectively; P=.04), and required a chest tube for fewer days (7.4±2.6d vs 4.5±2.9d, respectively; P=.03) compared with the CPT arm. CONCLUSIONS These findings suggest that 4 weeks of PR before lung cancer resection improves preoperative functional capacity and decreases the postoperative respiratory morbidity.

Synthesis and in vitro anticancer activity of novel thiazacridine derivatives

Acridine derivatives represent a well-known class of anticancer agents that generally interfere with DNA synthesis and inhibit topoisomerase II. A series of eight new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione and 3-acridin-9-ylmethyl-5-arylidene-thiazolidine-2,4-dione derivatives were synthesized. All the compounds were evaluated for their cell antiproliferation activity with the 3-(4,5-dimethyl-2-thiozolyl)-2,5-diphenyl-2H-tetrazolium bromide, MTT assay. The antiproliferative effects of the synthesized compounds were tested against several tumoral cell lines, namely SF-295 (central nervous system), HCT-8 (colon carcinoma), and MDA-MB-435 (melanoma) cells using doxorubicin as a positive control. Among the synthesized compounds, 3-acridin-9-ylmethyl-5-acridin-9-ylmethylene-thiazolidine-2,4-dione, 3-acridin-9-ylmethyl-5-(4-methoxy-benzylidene)-thiazolidine-2,4-dione, and 3-acridin-9-ylmethyl-5-(4-bromo-benzylidene)-thiazolidine-2,4-dione exhibited the most potent anticancer activity against the HCT-8 and MDA-MB-435 cell lines. After a detailed analysis of the structure of the thiazacridine molecules, we revealed the main possible interactions using the compound 3-acridin-9-ylmethyl-5-acridin-9-ylmethylene-thiazolidine-2,4-dione as an example. The benefits of these compounds, regardless of the pharmacological target are the presence of two aromatic rings (pi systems), significant planarity (intercalating ability) and the presence of three hydrogen-bond acceptors, two of which are stronger (oxygen atoms) than the other (sulfur atom).

Immunoexpression of tumor suppressor genes p53, p21WAF1/CIP1 and p27KIP1 in humam astrocystic tumors

The aim of the present study was to evaluate the tumor suppressor genes p53, p21 WAF1/CIP1 and p27 KIP1 expression in astrocytic tumors, correlating the findings with the histopathological grade (WHO). An immunohistochemical study of the p53, p21 and p27 proteins using the streptavidin-biotin-peroxidase method was performed in fifty-five astrocytomas (13 grade I, 14 grade II, 7 grade III and 21 grade IV) and five samples of non-tumor brain tissue (negative control). p53 positive indices (PI) and labeling indices (LI) showed tendency to increase according to malignant progression. The nuclear expression of p27 presented similar inclination, except for the PI reduction verified in grade IV tumors. Otherwise, the cytoplasmic p27 staining was more evident between high-grade tumors (III and IV). p53 and nuclear p27 expression was correlated with the histological classification (p<0.01; test H). On the other hand, p21 indices revealed a propensity to reduction in agreement with malignant evolution of the astrocytic tumors, except for high scores observed in grade IV tumors. The non-tumor samples did not show any expression of these proteins. These results indicated the p53 mutation as an initial, relevant and potentially predictor of tumor progression event in astrocytomas, with the detection of p21 protein as an important resource for the deduction of functional situation of this gene. Moreover, the activation of p27 KIP1 was preserved in the astrocytic tumors and its cytoplasmic manifestation seems to be resultant of its nuclear expression, not demonstrating a direct impact in astrocytomas tumorigenesis.

TP53 mutations in astrocytic gliomas: an association with histological grade, TP53 codon 72 polymorphism and p53 expression

TP53 mutations and polymorphisms have been widely related to many cancers as long as these alterations may impair its capacity to induce cell cycle arrest, DNA repair mechanisms, and apoptosis. Although TP53 alterations have been studied in astrocytic tumors, there is a lack of analysis considering specific TP53 mutations and their associations with p53 immunostainning, polymorphisms and their significance among the histological grades. Thus, we analyzed TP53 alterations in exons 2–11, including the codon 72 polymorphism, using DNA sequencing in 96 astrocytic gliomas (18 grade I, 20 grade II, 14 grade III, and 44 grade IV). Also, immunohistochemistry was assessed to evaluate the p53 protein expression. In this study, we found that the higher histological grades were statistically associated with TP53 mutations. Some of these mutations, such as TP53 P98T and TP53 G244S, seemed to be a specific marker for the higher grades, and the TP53 E286K mutation appears to be a World Health Organization grade III–IV progression marker. Also, the TP53 P98T mutation, in exon 4, is very likely to be important on the stabilization of the p53 protein, leading to its immunopositivity and it is potentially associated with the TP53 72Pro/Pro genotype.

Evaluation of the Cytotoxicity of Structurally Correlated p-Menthane Derivatives

Compounds isolated from essential oils play an important role in the prevention and treatment of cancer. Monoterpenes are natural products, and the principal constituents of many essential oils. The aim of this study was to investigate the cytotoxic potential of p-menthane derivatives. Additionally, analogues of perillyl alcohol, a monoterpene with known anticancer activity, were evaluated to identify the molecular characteristics which contribute to their cytotoxicity, which was tested against OVCAR-8, HCT-116, and SF-295 human tumor cell lines, using the MTT assay. The results of this study showed that (−)-perillaldehyde 8,9-epoxide exhibited the highest percentage inhibition of cell proliferation (GI = 96.32%–99.89%). Perillyl alcohol exhibited high cytotoxic activity (90.92%–95.82%), while (+)-limonene 1,2-epoxide (GI = 58.48%–93.10%), (−)-perillaldehyde (GI = 59.28%–83.03%), and (−)-8-hydroxycarvotanacetone (GI = 61.59%–94.01%) showed intermediate activity. All of the compounds tested were less cytotoxic than perillyl alcohol, except (−)-perillaldehyde 8,9-epoxide (IC50 = 1.75–1.03 µL/mg). In general, replacement of C-C double bonds by epoxide groups in addition to the aldehyde group increases cytotoxicity. Furthermore, stereochemistry seems to play an important role in cytotoxicity. We have demonstrated the cytotoxic influence of chemical substituents on the p-menthane structure, and analogues of perillyl alcohol.

Radiographic and histological evaluation of bisphosphonate alendronate and metotrexate effects on rat mandibles inoculated with Walker 256 carcinosarcoma

PURPOSE To investigate the effects of bisphosphosnate alendronate (ALD) and metotrexate (MTX) on an experimental model of Walker 256 carcinosarcoma developed in the oral cavity of rats. METHODS Walker 256 carcinosarcoma cell suspension (0,1 mL) containing 10(6) cell/mL was implanted in the alveoli of the first and second molars. The animals were divided and treated with saline, MTX, ALD, and MTX plus ALD. Later, the animals were sacrificed, the tumors were measured and the mandibles were removed for radiographic and histological analysis. RESULTS In the control group, the radiographic images demonstrated radioluscency with poorly defined borders, and the microscopic examination revealed tumor infiltration into the peripheral and central regions of the bone. Areas of necrosis were commonly seen. In the treated groups with ALD, associated or not with MTX, the radiographic analysis revealed circumscribed tumor-induced osteolysis and various degrees of radiotransparence; while, histologically, preserved bone trabeculae with osteoid formation was observed among malignant cells. CONCLUSION The bisphosphonate alendronate exherted an osteoprotective effect and induced bone neoformation on the Walker 256 carcinosarcoma inoculated in rat mandibles. The combination of metotrexate with bisphosphonate alendronate is more successful than treatment with the agents alone in controlling the growth of neoplastic cells and in stimulating reactive new bone. Therefore, this may be an alternative treatment to malignant lesions of maxillaries with osteolysis.

Viscoelásticos oftálmicos: comparação entre os comerciais e formulações de galactomanana de Dimorphandra gardneriana

Ophthalmic viscosurgical devices (OVD) are materials injected in intraocular space during cataract removal to reduce trauma in the patients eye. Three Brazilian commercially available OVDs (Medilon®, Metilcelulose® and Ofthyal®) were evaluated as well as formulations based on Dimorphandra gardneriana galactomannan. Viscosity and viscoelastic parameters, such as viscosity at zero shear, pseudoplasticity index, elastic and viscous moduli, relaxation time, were determined and compared. Characteristics of an effective OVD were proposed. None of the Brazilian devices studied fulfill the rheological requirements. Only the galactomannan at 3% concentration showed potential to be used as effective OVD.

Um novo modelo de isolamento do tumor de Walker utilizando o gradiente de Ficoll-Hypaque

PURPOSE The purpose was to evaluate a novel technique for isolation of Walkers tumoral cells using a Ficoll-Hypaque gradient and its further influence on tumor development. METHODS Twenty male Wistar rats have been divided in 2 groups: G1= without ficoll, G2= with ficoll. Tumor was excised, homogenized and suspended in lactate ringer. A sample of the cell suspension was adjusted at a concentration of 1x10(6) cells/ml (G1). A second sample was centrifuged on a Ficoll-Hypaque gradient and the cell concentration was then adjusted (G2). Tumor was implanted by subcutaneous injection of 1.0 ml in the right armpit of rats. Tumor volume (TV) and tumor weight (TW) were compared in two groups. RESULTS There were no differences between the two groups in TV (G1=17.9+/-3.8 cm3 vs. G2=17.2+/-4.4 cm3; p=0.190) and TW (G1=7.0+/-1.8 g vs. G2=7.3+/-2.8 g; p=0.569). The histological analysis showed similar patterns of infiltration by small-undifferentiated cells and necrosis in both groups. However, a mild to moderate granulocytic exudate was more frequent in the animals whose tumors derived from Ficoll-isolated cells. Hemorrhage from slight to moderate was only observed in this group. CONCLUSION A Ficoll-Hypaque gradient can provide more adequate isolation of Walkers tumor and the cell suspension obtained by this technique has lower contamination by other cell types.

Experimental model of ultrasound thermotherapy in rats inoculated with Walker-236 tumor

PURPOSE To develop a model to evaluate the effects of focal pulsed ultrasound (US) waves as a source of heat for treatment of murine subcutaneous implanted Walker tumor. METHODS An experimental, controlled, comparative study was conducted. Twenty male Wistar rats (160-300 g) randomized in 2 equal groups (G-1: Control and G-2: Hyperthermia) were inoculated with Walker-256 carcinosarcoma tumor. After 5 days G-2 rats were submitted to 45ºC hyperthermia. Heat was delivered directly to the tumor by an ultrasound (US) equipment (3 MHz frequency, 1,5W/cm³). Tumor temperature reached 45º C in 3 minutes and was maintained at this level for 5 minutes. Tumor volume was measured on days 5, 8, 11, 14 e 17 post inoculation in both groups. Unpaired t-test was used for comparison. P<0.05 was considered significant. RESULTS Tumor volume was significantly greater in day 5 and decreased in days 11, 14 and 17 in treated rats. Rats treated with hyperthermia survived longer than control animals. On the 29th day following tumor inoculation, 40% of control rats and 77.78% of hyperthermia-treated rats remained alive. CONCLUSION The proposed model is quite simple and may be used in less sophisticated laboratory settings for studying the effects of focal hyperthermia in the treatment of malignant implanted tumours or in survival studies.

Expressão das proteínas BCL-2 e BAX em tumores astrocíticos humanos

INTRODUCAO: Os astrocitomas constituem os mais frequentes tumores primarios do sistema nervoso central (SNC). Admite-se que parte do crescimento tumoral seja resultante da inibicao da morte celular programada: a apoptose. Tal fenomeno e basicamente regulado pelo equilibrio entre moleculas antiapoptoticas (ex.: B-cell lymphoma protein 2 [BCL-2]) e pro-apoptoticas (ex.: BCL-2 associated protein X [BAX]). OBJETIVO: O presente estudo objetivou avaliar a expressao de BCL-2 e BAX em tumores astrociticos humanos. MATERIAL E METODOS: Procedeu-se ao estudo imuno-histoquimico dessas proteinas utilizando-se o metodo da avidina-biotina-peroxidase em 55 astrocitomas (13 do grau I, 14 do II, sete do III e 21 do grau IV) e cinco amostras de tecido cerebral nao-tumoral (grupo controle). RESULTADOS: Os indices de positividade para BCL-2 e BAX demonstraram propensao ao acrescimo, de acordo com a gradacao tumoral, com positividade geral de 43,26% e 24,67%, respectivamente. Essas proteinas nao foram detectadas entre os especimes nao-tumorais. Os escores de marcacao para BCL-2 apresentaram tendencia ao aumento conforme a progressao histologica, enquanto os para BAX mostraram-se semelhantes nas diversas graduacoes. A analise conjunta dessas proteinas demonstrou significativa correlacao com a gradacao tumoral (p < 0,05; teste H), sendo mais evidente nos glioblastomas (grau IV) em comparacao com os astrocitomas de baixo grau (I e II) (p < 0,05; teste U). A relacao BCL-2/BAX indicou o aumento da orientacao a sobrevida celular dos tumores astrociticos de acordo com a progressao maligna. CONCLUSOES: Tais resultados indicam as alteracoes na expressao das proteinas BCL-2 e BAX como resultantes do processo tumorigenico nos astrocitomas, com o crescente predominio do perfil antiapoptotico de acordo com a transformacao maligna. Nesse sentido, sugere-se que a superexpressao de BCL-2 nos tumores astrociticos possa ser indicativa de fenotipos mais agressivos, configurando ainda um potencial alvo terapeutico.