Phase 3 trial of three thalidomide-containing regimens in patients with newly diagnosed multiple myeloma not transplant-eligible.

The introduction of agents such as thalidomide, lenalidomide, and bortezomib has changed the management of patients with multiple myeloma who are not eligible for autologous transplantation, many of whom are elderly. We sought to compare three thalidomide-based oral regimens among such patients in Latin America. We randomized patients with newly diagnosed multiple myeloma with measurable disease to one of the following regimens: melphalan, prednisone, and thalidomide (MPT); cyclophosphamide, thalidomide, and dexamethasone (CTD); and thalidomide and dexamethasone (TD). The TD arm was closed prematurely and was analyzed only descriptively. The primary endpoint was the overall response rate (ORR), whereas progression-free survival (PFS) and overall survival (OS) were secondary endpoints. The accrual rate was slower than expected, and the study was terminated after 82 patients had been randomized. The ORRs were 67.9 % with MPT, 89.7 % with CTD, and 68.7 % with TD (p = 0.056 for the comparison between MPT and CTD). The median PFS was 24.1 months for MPT, 25.9 months for CTD, and 21.5 months for TD. There were no statistically significant differences in PFS or OS between MPT and CTD. In an unplanned logistic regression analysis, ORR was significantly associated with treatment with CTD (p = 0.046) and with performance status of 0 or 1 (p = 0.035). Based on the current results, no definitive recommendations can be made regarding the comparative merit of the regimens tested. Nevertheless and until the results of further studies become available, we recommend either CTD or MPT as suitable frontline regimens for patients with multiple myeloma who are not candidates to transplantation in settings where lenalidomide and bortezomib are not available.

Keratocystic odontogenic tumour arising as a periapical lesion.

AIM: To document a case of a keratocystic odontogenic tumour (KOT) involving the apical region in the maxilla mimicking a periapical lesion of endodontic origin. SUMMARY: Benign and malignant tumours, including odontogenic lesions, can be erroneously diagnosed as periapical radiolucencies. KOTs mimicking periapical lesions of endodontic origin are uncommon, especially when the lesions involve the maxilla. This article describes a 55-year-old man with a well-delimited, oval-shaped, radiolucent lesion, occupying the middle and apical third of teeth 22 and 23. After 30 days, the clinical and radiographic findings remained unchanged and the patient was referred for surgical removal of the lesion. Clinical, radiographic and histopathological features are also discussed and compared with current literature.

Actinic cheilitis among agricultural workers in Campinas, Brazil.

OBJECTIVE: To assess the prevalence of Actinic Cheilitis (AC) among agricultural workers and analyze its risk factors. DESIGN: A cross sectional epidemiological study. A lip lesion was defined as an abnormal change on the lip mucosa surface, such as erythematous pigmented, ulcerative or swelling (Cataldo and Doku, 1981). Data were gathered according to age group, gender, ethnicity-time and frequency of occupational sunlight exposure, smoking habits, drinking habits and socio-economic status. SETTING: Sugar-cane plantation farms in Brazil. PARTICIPANTS: Full-time workers of both genders employed at sugar-cane plantation farms for at least six months. OUTCOME MEASURES: Correlations between AC prevalence, demographic and socioeconomic risk factors. RESULTS: 202 people were examined and the prevalence of AC was 39.6%. Results revealed that being black (0.15-0.88- 95% CI; OR = 0.36; p = 0.025) or mulatto (0.21-0.82- 95% CI; OR = 0.42; p =0.011) decreased the risk for AC, while age and gender sex had no effect. In relation to socioeconomic variables, formal education and more than four years of education (0.07-0.68- 95% CI; OR = 0.22; p = 0.009) decreased the risk for AC. Moreover, drinking alcohol was a risk for AC (1.05-3.37- 95% CI; OR = 1.88; p = 0.034), while tobacco smoking was not (0.60-2.02- 95% CI; OR = 1.10; p = 0.763). CONCLUSIONS: The prevalence of AC is high in agricultural workers who were fairskinned, had low education and high alcohol intake. Prevention and early diagnosis are required for workers exposed to sunlight.

Glutaraldehyde-treated homologous vein graft as a vein substitute: experimental study in rabbits.

AIM: Vein reconstruction using grafts may prevent sequelae of venous interruption or lesion. Autologous vein is sometimes unsuitable or absent for a vascular restoration. The aim of this study was to study glutaraldehyde-treated homologous vein graft as vein substitute and compare it with autologous vein as a substitute for a vena cava segment in rabbits. METHODS: Sixty rabbits were allocated into two groups: autologous vein graft (AG), and glutaraldehyde-treated homologous vein graft (HG). Each group was subdivided into three subgroups (N.=10) to be studied at: 24 hours, 14 days, and 28 days. The veins were treated in 0.19% glutaraldehyde, pH=7.4, for 1 hour and kept at 4 degrees C in saline with added gentamicin and amphotericin B. The animals received benzanthine penicillin on the day of graft implantation and heparin only during surgery. The grafts were implanted into the vena cava. Anastomosis was performed with interrupted sutures. Cavography was performed, after surgery, and at the time the animals were killed. Evaluation of the veins was made macroscopically and by light and scanning electron microscopy. RESULTS: Fibrosis was seen around the grafts at 14 and 28 days, with no difference in intensity between the groups. Cavography performed before euthanasia of the animals showed 4 partial thrombi in AG (2 at 24 hours and 2 at 14 days), 3 in HG (2 at 24 hours and 1 on day 14), and 4 occlusive thombi in HG (3 at 14 days and 1 at 28 days). Macroscopic examination did not show any thrombus in AG. In HG, two partial thrombi were confirmed at 24 hours and three occlusive thrombi at 14 days. There was no statistical difference in relation to patency between the two groups. At 14 and 28 days, the histological sections showed intimal hyperplasia of similar intensity and variable distribution in both groups. Evaluation by electron microscopy showed at 24 hours lesion areas characterized by absence of the endothelium on the graft surface, presence of inflammatory cells, and, at some sites, presence of mural thrombi in AG and HG. Both groups at 14 and 28 days showed endothelial cells covering the lesion area on the graft surface, this covering being larger in AG than in HG. CONCLUSIONS: In the studied model, both grafts behaved similarly in relation to patency and morphological characteristics. This suggests that the glutaraldehyde-treated graft can be a promising alternative for vein reconstruction, justifying further animal studies with the aim of using it in human surgery.

Annexin A1 subcellular expression in laryngeal squamous cell carcinoma.

AIMS: Annexin A1 (ANXA1) is a soluble cytoplasmic protein, moving to membranes when calcium levels are elevated. ANXA1 has also been shown to move to the nucleus or outside the cells, depending on tyrosine-kinase signalling, thus interfering in cytoskeletal organization and cell differentiation, mostly in inflammatory and neoplastic processes. The aim was to investigate subcellular patterns of immunohistochemical expression of ANXA1 in neoplastic and non-neoplastic samples from patients with laryngeal squamous cell carcinomas (LSCC), to elucidate the role of ANXA1 in laryngeal carcinogenesis. METHODS AND RESULTS: Serial analysis of gene expression experiments detected reduced expression of ANXA1 gene in LSCC compared with the corresponding non-neoplastic margins. Quantitative polymerase chain reaction confirmed ANXA1 low expression in 15 LSCC and eight matched normal samples. Thus, we investigated subcellular patterns of immunohistochemical expression of ANXA1 in 241 paraffin-embedded samples from 95 patients with LSCC. The results showed ANXA1 down-regulation in dysplastic, tumourous and metastatic lesions and provided evidence for the progressive migration of ANXA1 from the nucleus towards the membrane during laryngeal tumorigenesis. CONCLUSIONS: ANXA1 dysregulation was observed early in laryngeal carcinogenesis, in intra-epithelial neoplasms; it was not found related to prognostic parameters, such as nodal metastases.

Substance P regulates the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinase in cultured human gingival fibroblasts.

BACKGROUND AND OBJECTIVE: Substance P may play a role in the pathogenesis of periodontal disease; however, its mechanisms of modulation are not clear. This study evaluated the effect of two concentrations of Substance P on the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in cultured human gingival fibroblasts. MATERIAL AND METHODS: Fibroblasts were stimulated for 48 h with 10(-4) or 10(-9) m Substance P; untreated fibroblasts served as controls. The expression of MMP-1, -2, -3, -7 and -11 and of TIMP-1 and -2 was evaluated using real-time polymerase chain reaction and western blotting. RESULTS: There was a significant, concentration-dependent stimulatory effect of Substance P on MMP-1, -2, -3 and -7 and TIMP-2 gene expression (p < 0.05), and a probable effect on MMP-11 (p = 0.06). At the higher concentration (10(-4) m Substance P), MMP-1, -2, -3, -7 and -11 and TIMP-2 showed the greatest up-regulation; at the lower concentration (10(-9) m Substance P), MMP-1, -3 and -7 and TIMP-2 exhibited diminished up-regulation, with MMP-2 and -11 showing down-regulation (p < 0.05). Expression of TIMP-1 was not affected by Substance P (p > 0.05). Western blotting confirmed that Substance P up-regulated MMP-1, -2, -3 and -11 and TIMP-2. MMP-1, -3 and -11 and TIMP-2 showed greater up-regulation at the higher Substance P concentration and diminished up-regulation at the lower concentration. MMP-2 was up-regulated to a similar degree at both Substance P concentrations. CONCLUSION: In gingival fibroblast cells, Substance P at the higher concentration (10(-4) m) induced greater up-regulation of MMP-1, -3 and -11 and TIMP-2 expression, but at the lower concentration (10(-9) m) induced diminished up-regulation, which may represent a mechanism for modulating periodontal breakdown.

Skin allograft survival and analysis of renal parameters after FTY720 + tacrolimus treatment in mice.

Calcineurin inhibitors such as cyclosporine (CsA) and tacrolimus (FK506) show similar efficacy to prevent rejection within the first year after organ transplantation. However, their use is limited by side effects, such as kidney damage, hypertension, new-onset diabetes, and hyperlipidemia. The consensus opinion suggests that compared with CsA, FK506 has fewer negative effects on blood pressure, serum lipids, and renal function. Nevertheless, FK506 use is associated with a higher incidence of posttransplantation diabetes mellitus. FTY720 is a new compound that has shown beneficial effects in animal models of rejection in transplantation, ischemia/reperfusion injury, autoimmune diseases, and tumor development. Our aim was to investigate whether FTY720 + tacrolimus association could provide additional immunosuppression without causing renal toxicity. FTY720 as a monotherapy or in association with FK506 was administered to C57BL/6 mice for 21 days to prevent skin graft rejection and to evaluate renal function and structure. Increased skin allograft survival in the FTY720 + FK506 group was associated with decreased cell numbers in the spleen, blood, and axillary lymph nodes. Changes in major histocompatibility complex (MHC) class II and intercellular adhesion molecule-1 (ICAM-1) expressions in splenocytes were also found in this group. The major effects already described for FK506 (diabetes) or FTY720 (lymphopenia) were observed after 21 days administration even when the drugs were associated. FTY720 associated with FK506 caused fewer changes in kidney structure, and blood glucose levels were lower than in FK506 monotherapy.

Apoptosis in different gastric lesions and gastric cancer: relationship with Helicobacter pylori, overexpression of p53 and aneuploidy.

Apoptosis has an essential function in maintaining the integrity of the gastrointestinal mucosa. Its deregulation is associated with the occurrence of lesions such as in atrophic gastritis, peptic ulcers, intestinal metaplasia, and stomach tumorigenesis. Thus, the aim of the present study was to investigate the frequency of apoptotic cells (apoptotic index, AI) by using two different immunohistochemical techniques, TUNEL and anti-activated caspase-3 antibody (CPP32), in gastric dyspepsia [chronic gastritis (CG, N = 34), chronic atrophic gastritis (CAG, N = 11), gastric ulcer (GU, N = 17), and intestinal metaplasia (IM, N = 15)], normal gastric mucosae (NM, N = 8), and gastric adenocarcinoma (GC, N = 12). The relationship was investigated between the AI and Helicobacter pylori infection, diagnosed by PCR, overexpression of p53 protein determined by immunohistochemistry, and aneuploidy by fluorescence in situ hybridization, as performed by our laboratory in previous studies. No significant differences were observed in AI between the different groups, whether by the TUNEL technique (F = 1.60; p = 0.1670) or by CPP32 antibody (F = 1.70; p = 0.1420). Nonetheless, CAG and CG groups had AI statistically higher than those of normal mucosae. These two groups (CAG and CG) also showed a higher frequency of apoptosis-positive cases (TUNEL+ or CPP32+). Generally, there was no correlation between the AI detected by the TUNEL and CPP32 techniques in the groups studied, except in the GC group (r = 0.70). Moreover, there was no significant association between apoptosis and H. pylori infection, overexpression of p53 protein and aneuploidy, but the H. pylori-positive cases only of GU (p = 0.0233) and IM (p = 0.0253) groups displayed a statistically higher AI compared to H. pylori-negative NM, when the CPP32 antibody technique was used. Thus, CG and CAG have increased apoptosis, which may occur independent of an association with H. pylori infection, aneuploidy and overexpression of p53 protein.

FTY720 prevents renal T-cell infiltration after ischemia/reperfusion injury.

Ischemia/reperfusion (I/R) injury, a common early feature in renal transplantation, results from both free radical species generation and local inflammatory responses that attract different types of cells. The interaction with infiltrating leukocytes could promote damage and death of resident renal cells contributing to worsening of renal function. It has been shown that depletion of host T cells protects against kidney damage after I/R injury, although the mechanism is not fully understood. FTY720, a synthetic analog of a natural product extracted from Isaria sincclairii has shown modulatory properties in experimental models of autoimmune disease, transplantation, and I/R injury. FTY720 alters lymphocyte responses to chemokine homing signals, thereby decreasing the number of lymphocytes in inflammatory sites. We evaluated renal function in mice at 3, 5, and 7 days after I/R injury in the presence or absence of FTY720 treatment. FTY720 treatment promoted earlier recovery of renal function associated with a lower number of renal-infiltrating lymphocytes. These findings confirm previous results showing a protective effect of FTY720 in I/R injury models.

Rhabdomyolysis, acute renal failure, and death after monensin ingestion.

We report a case of human monensin intoxication; to our knowledge, this is the first reported case in the medical literature. The patient took a dose of monensin three times higher than a dose considered lethal for cattle and developed a clinical picture similar to that reported in veterinary medicine. There was an early and extremely severe rhabdomyolysis followed by acute renal failure, heart failure, and death. The main changes observed at autopsy were extensive skeletal muscle necrosis, complement deposition at the myocardial level, pulmonary edema, and acute tubular damage.

Silver nitrate is superior to talc slurry in producing pleurodesis in rabbits.

STUDY OBJECTIVE: The ideal agent for producing pleurodesis has not been identified. Although talc is the agent most commonly used at the present time, there are concerns about its safety. Silver nitrate is a possible alternative agent. The purpose of the present study was to compare the effectiveness of intrapleural silver nitrate and talc slurry in producing pleurodesis in rabbits. Additionally, the total amount of pleural collagen and the distribution of thick and thin collagen fibers were studied. DESIGN: Two groups of 10 rabbits received either 0.50% silver nitrate or 400 mg/kg talc in a total volume of 2 mL intrapleurally. The animals were killed 28 days after injection, and the pleural spaces were assessed grossly for evidence of pleurodesis and microscopically for evidence of inflammation and fibrosis. Collagen was assessed with the van Gieson's and picrosirius stains. RESULTS: The macroscopic pleurodesis (scale, 0 to 4; mean +/- SEM) resulting from the intrapleural injection of silver nitrate (3.4+/-0.2) was significantly better (p<0.001) than that resulting from talc (1.6+/- 0.1). The mean degree of microscopic pleural fibrosis induced by silver nitrate (3.3+/-0.3) was significantly higher (p = 0.003) than that induced by talc (1.8+/-0.1). The mean amount of microscopic pleural collagen (van Gieson's) was significantly greater (p<0.001) in the rabbits that received silver nitrate (3.0+/-0.2) than in those that received talc (1.6+/-0.2). The distribution of thick and thin collagen fibers did not differ between the groups. CONCLUSIONS: We conclude that, in our rabbit model, intrapleural silver nitrate was more effective than talc in producing a pleurodesis.

Autopsy findings in early and late postoperative death after partial left ventriculectomy.

BACKGROUND: Partial left ventriculectomy (PLV) is an alternative to heart transplantation for patients with severe heart failure. However, this procedure is accompanied by high morbidity and mortality. Therefore, we studied the hearts of 12 patients who underwent this procedure to increase our understanding of the causes of bad outcome. METHODS: We analyzed the autopsy hearts of 11 of 16 patients who died after PLV, and one heart from a patient who underwent heart transplantation. RESULTS: Six patients died less than 30 days postoperatively, 4 of cardiogenic shock, 1 of arrhythmia, and 1 of coagulopathy. Five patients died from 36 to 120 days after the procedure, 4 of cardiogenic shock and 1 of arrhythmia. The patient who underwent heart transplantation had a cardiogenic shock 230 days after PLV. Ten hearts weighed more than 500 g and nine had myocardial infarction that extended to the papillary muscles. Four patients had infarction of both papillary muscles and 3 of them had episodes of arrhythmia, suggesting some relation between these events. CONCLUSIONS: We found several important morphologic clues for bad outcome: infarction of both papillary muscles, which may be associated with the development of arrhythmia, and myocardial infarction and pericardial hemorrhage, which may contribute to the outcome of heart failure.

Aortic atresia with aortopulmonary window and interrupted aortic arch, simulating common arterial trunk: a case report.

The authors describe the cross-sectional echocardiographic and angiographic features besides the postmortem findings of a newborn with aortic atresia associated with the aortopulmonary window and an interrupted aortic arch, as the third known similar case reported in the literature. Anatomical and clinical similarities with common arterial trunk are emphasized and a more correct management is established to avoid risks, in which Norwood-type techniques would be preferable.

Techniques in electromanometry of the upper esophageal sphincter.

The various pull-through techniques used to measure pressure and length of the upper esophageal sphincter have not been studied in depth. Because of the importance of obtaining further information about these techniques, a group of 25 dogs was submitted to upper esophageal sphincter pressure and length measurements by three different pull-through techniques (two of the continuous type and one of the station type), each with three replications per animal, to determine possible differences among techniques. A single introduction provided reliable results, with no sequential effect of the measurements or of any one technique on resting pressure. However, each technique yielded different sphincter lengths, higher values being obtained when the continuous techniques were used.

Long-term results of guided tissue regeneration therapy in the treatment of class II furcation defects: a randomized clinical trial.

BACKGROUND: The purpose of this study was to evaluate the results after guided tissue regeneration (GTR) using a bioabsorbable membrane in Class II furcation defects in mandibular molars over a 24-month period. METHODS: Nine patients with 2 comparable Class II furcation defects were included. The defects in each patient were randomly assigned to either test (GTR) or control (open flap debridement) group. Clinical measurements and standardized radiographs were taken at baseline, and at 6, 12, 18, and 24 months. The radiographs were analyzed by subtraction radiography. RESULTS: There were significant probing depth reductions for both test and control groups (P < 0.007, P < 0.0005, respectively); however the differences between groups were not significant at any examination. The intra-group and inter-group differences in the vertical clinical attachment level gain were not significant (P > 0.05). Over 24 months, a significant horizontal clinical attachment level gain was observed in the test group compared to control (P<0.03). In the test group, 2 sites showed complete closure, one was converted to Class I, and one tooth was lost due to root resorption. In the control group, 2 defects progressed to Class III over 24 months. At 6 months, the test group showed 0.14 mm of bone loss while the control group showed 0.86 mm of bone gain (P = 0.035). The inter-group differences were not significant at 12, 18, and 24 months. A significant bone height gain was observed in the test group at 24 months when compared to the values obtained after 6 months (P = 0.015). CONCLUSION: GTR may provide a greater horizontal clinical attachment level gain with the possibility of complete closure of some defects and stability over time.

Urban levels of air pollution modifies the progression of urethane-induced lung tumours in mice.

This paper investigates the effects of air pollution in urethane-induced lung tumours in mice by means of histological, morphometrical, and DNA ploidy. The experimental exposure was done in locations with different air pollution profiles: a polluted area (downtown São Paulo) and a "clean" environment. Swiss mice were employed and urethane (3 g/kg) was used as a carcinogenic substance. All the animals, whether exposed or not to air pollution, were sacrificed after 6 months, and the lung lesions were analysed. The results showed a significant effect of air pollution on tumour progression, observed by changes in the phenotype of the tumour cells as demonstrated by morphometry and DNA ploidy. We observed more atypical adenomas in the air pollution-exposed group (p = 0.02). Coherently, morphometric differences were also detected between the two groups. Neoplasms of exposed mice exhibited an increase in the nuclear fraction (p = 0.002) and in the nucleus/cytoplasm ratio (p = 0.011), as a decrease in the stromal fraction (p < 0.001). There was a higher risk of aneuploidy in the 6-months-of-air-pollution-exposure group (relative risk: 1.58; 95% of confidence interval: 1.007 to 2.403). These results indicate that urban air pollution accelerates the process of progression towards malignancy.

Platelet activation in experimental arterial thrombosis.

Platelet aggregates were studied in dogs with induced arterial thrombosis, by the method of Wu and Hoak. Blood was withdrawn from a jugular vein and from the femoral vein on the operated side 24 h after thrombus induction and immediately and 2 h after blood flow was restored by thrombectomy. Platelet activation was significant in dogs with obstructive arterial thrombosis and which tended to subside after thrombectomy. Activation or formation of platelet aggregates seemed to occur in the ischemic limb. It is suggested that this experimental model could be useful to test the action of anti-platelet drugs in vivo.

Functional hypotheses for aberrant glycosylation in tumor cells.

Aberrant glycosylation is a common feature of neoplastic cells. Although described for many years, the role of aberrant patterns of glycosylation is not fully understood. Our group has been focusing on the role of glycosylation in cell:matrix interactions, such as adhesion, spreading and migration on defined substrata (e.g., laminin and fibronectin). Animal lectins, such as galaptins, also seem to be involved in these processes.

Morphometric evaluation of the time course of right ventricular hypertrophy after left coronary artery ligation in rats.

1. In order to describe the time course of compensatory right ventricular hypertrophy after infarction, rats submitted to left coronary obstruction and sham-operated controls were compared in terms of heart weight, chamber weight and right ventricular fiber diameter 1, 8 and 21 days after surgery. 2. One day after infarction, only the left ventricle weight increased (0.583 +/- 0.045 g vs 0.698 +/- 0.062 g, P less than 0.05), while right ventricular weight and fiber diameter suffered no change. 3. Eight days after infarction, heart weight (0.781 +/- 0.127 g vs 0.856 +/- 0.100 g, P greater than 0.05) as well as right ventricular fiber diameter (16.5 +/- 1.0 microns vs 17.5 +/- 2.1 microns, P greater than 0.05) and left ventricular weight did not differ between sham-operated animals and animals with left coronary obstruction. However, a significant increase in right ventricular weight was observed in infarcted animals (0.168 +/- 0.026 g vs 0.242 +/- 0.017 g, P less than 0.05). 4. Twenty-one days after infarction, right ventricular weight (0.198 +/- 0.034 g vs 0.316 +/- 0.118 g, P less than 0.05), heart weight (0.864 +/- 0.095 g vs 0.985 +/- 0.105 g, P less than 0.05) and right ventricular fiber diameter (15.0 +/- 1.8 microns vs 21.3 +/- 2.3 microns, P less than 0.05) were significantly increased in infarcted animals, whereas left ventricular weight (0.665 +/- 0.065 g vs 0.669 +/- 0.039 g, P greater than 0.05) was unchanged. 5. We conclude that hypertrophy occurs in the right ventricle of randomized infarcted rats 21 days after infarction, and that this phenomenon precedes the increase in fiber diameter.(ABSTRACT TRUNCATED AT 250 WORDS)

Perioperative myocardial infarction in a patient with tuberculous constrictive pericarditis in the absence of coronary artery disease.

A 34-year-old man developed severe heart failure due to constrictive pericarditis. Pericardiectomy was carried on and the patient died 12 hours after surgery. Necropsy revealed an extensive hemorrhagic myocardial infarction involving the lateral free wall of the left ventricle in the absence of coronary artery disease. In addition, necropsy revealed tuberculosis as the etiology of constrictive pericarditis. Thus, myocardial infarction may occur in constrictive pericarditis in the setting of pericardiectomy and absence of coronary artery disease.