A multicenter, open-label, randomized, phase II study of cediranib with or without lenalidomide in iodine 131-refractory differentiated thyroid cancer.

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131-refractory DTC. PATIENTS AND METHODS: In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (≥18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible. RESULTS: Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months [95% confidence interval (CI) 8.5-23.8 months] in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm. CONCLUSIONS: Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.

Response-adapted volume de-escalation (RAVD) in locally advanced head and neck cancer.

BACKGROUND: Efforts to reduce the late toxicity associated with chemoradiation (CRT) for locally advanced head and neck squamous cell cancer (LA-HNSCC) have focused on radiotherapy (RT) dose de-escalation. In this phase I/II protocol investigating the addition of everolimus to induction chemotherapy (IC), we incorporated a novel response-adapted volume de-escalation (RAVD) approach using IC response to guide the extent of RT volume reduction. PATIENTS AND METHODS: Patients with measurable LA-HNSCC received two cycles of IC (cisplatin, paclitaxel, cetuximab ± everolimus). Patients with ≥50% reduction in the sum of tumor diameters [good response (GR)] received TFHX (paclitaxel, fluorouracil, hydroxyurea, and 1.5 Gy twice daily RT every other week) to a dose of 75 Gy with the single planning target volume (PTV1) encompassing exclusively gross disease. Patients with <50% response [non-response (NR)] were treated with TFHX encompassing PTV1 and the next nodal station at risk (PTV2) to a dose of 45 Gy followed by a sequential boost to PTV1 to a dose of 75 Gy. RESULTS: Ninety-four patients were enrolled. Randomization to everolimus was discontinued on interim analysis after 50 patients due to futility. IC response was evaluable in 89 patients. Thirty-seven patients (41.6%) had GR and 52 (58.4%) had NR. There was a trend for improved progression-free (P = 0.086) but not overall survival (P = 0.94) for GR versus NR. The 2-year PFS and OS were 86.0% and 83.5% for GR and 68.7% and 85.4% for NR, respectively. NR were significantly more likely to undergo G-tube placement during treatment (50.0% GR versus 73.5% NR, P = 0.040) and be G-tube dependent at 6-month follow-up (5.7% GR versus 32.6% NR, P = 0.005). CONCLUSIONS: The addition of everolimus to IC was not beneficial. The elimination of elective nodal coverage in patients with GR to IC did not appear to compromise outcomes and resulted in significantly decreased late toxicity. Further investigation of RAVD is warranted. CLINICALTRIALSGOV: NCT01133678.

Randomized, double-blind, sham-controlled trial to evaluate the efficacy and tolerability of electroconvulsive therapy in patients with clozapine-resistant schizophrenia.

There is no established treatment for patients with clozapine-resistant schizophrenia (CRS). Clozapine augmentation strategies with antipsychotics or others substances are effective in comparison with placebo while and Electroconvulsive therapy (ECT) showed to be effective in comparison with treatment as usual (TAU) but not with placebo (sham-ECT). In the present double- blind randomized controlled trial, we compared 40 outpatients who received 20 sessions of ECT (n = 21) or sham-ECT (n = 19) (age = 37.40 ± 9.62, males = 77.5 %, illness duration = 14.95 ± 8.32 years, mean total Positive and Negative Syndrome Scale (PANSS) = 101.10 ± 24.91) who fulfilled well-defined CRS criteria including baseline clozapine plasma levels ≥350 ng/mL. The primary outcome was the ≥50 % PANSS Total Score reduction; secondary outcomes were the scores of the PANSS subscales, PANSS five-factor dimensions, PANSS-6 and the Calgary Depression Rating Scale (CDRS). Treatment response was analyzed by percentage reduction, Linear Mixed Models and effect sizes. At baseline both groups showed no differences except for years of school education (included as a covariate). At endpoint, only 1/19 of the completers (5.26 %) in the ECT group and 0/17 in the sham-ECT group showed a ≥50 % total PANSS score reduction. Both groups showed no significant differences of the total PANSS score (F = 0.12; p = 0.73), Positive (F = 0.27, p = 0.61), Negative (F = 0.25, p = 0.62), and General Psychopathology scores (F = 0.01, p = 0.94) as well for all PANSS five factors, the PANSS-6 and CDRS. Thus, the present study found no evidence that ECT is better than Sham-ECT in patients with CRS. Future sham-ECT controlled studies with larger sample sizes are warranted to test the efficacy of ECT for patients with CRS.

The effect of fermented milk on the deciduous enamel in the presence and absence of fluoride: in vitro study.

AIM: This study assessed the effect of fermented milk on the enamel of primary teeth in the presence and absence of fluoride. METHODS: Sixty enamel blocks (4X4 mm) underwent surface microhardness analysis (Knoop). The blocks were randomly distributed into 5 groups of 12 samples in each group according to the following treatments: Group 1) pH cycling and fermented milk (control); Group 2) pH cycling and dentifrice; Group 3) pH cycling and fermented milk and dentifrices; Group 4) varnish and pH cycling and fermented milk; Group 5) varnish and pH cycling and fermented milk and dentifrice. After the treatments, new microhardness determination was carried out and the surface microhardness change ratio was calculated (%SMH). The data were submitted to the Shapiro-Wilk normality test, ANOVA test, Tukey's test and paired t-test (P<0.05). RESULTS: It was observed that after treatment, all groups showed statistically significant reduction (P<0.05) for initial surface microhardness. Group 1 showed the lowest microhardness (73.01±9.68 KNH) compared to groups 2, 3 and 4. Group 5 (172.5±45.89KNH) showed a greater surface microhardness than Group 4 (122.0±22.33 KNH). CONCLUSION: It was concluded that the fermented milk adversely altered the microhardness of the samples and that fluorine contributes to a smaller reduction in the microhardness change ratio (SMH%). The combined solution of toothpaste with fluoride varnish provided a lower surface microhardness reduction of the samples.

Effect of periodontal treatment on the incidence of preterm delivery: a systematic review.

Preterm birth is a major problem in public health in developed and developing countries and the search for risk factors of this event is important. The aim of this study was to review the effect of periodontal treatment on the incidence of preterm delivery. A wide research was executed considering an evaluation period between November of 1998 and October of 2009 at MEDLINE/PUBMED databases. The selection strategy consisted of the search for the following key-words: "periodontal therapy" or "periodontal disease" and "pregnancy outcome" or "preterm birth". The search was limited for articles written in English. The randomized clinical trials that evaluated the effect of the non-surgical periodontal treatment on the incidence of Preterm Low Birth Weight (PLBW) were selected. In a total of 7 papers selected, the incidence of PLBW was lower in groups of women who were submitted to periodontal treatment. Reductions of Preterm Birth (PTB) ranged from 0.8% to 28.01%, while reduction of Low Birth Weight (LBW) ranged from 0.44% to 33%. In studies that analyzed these two variables together, there was variation between 4.57% to 71.5% in rates reduction. Due to heterogeneity of the data, the meta-analysis was not applied. The majority of the studies concluded that non-surgical periodontal treatment in pregnant women reduces incidence of preterm babies with low weight.

Pharyngocutaneous fistulae following total laryngectomy comparison between manual and mechanical sutures.

The extension of the surgery and closure type of the pharynx can be the determinants in the pharyngocutaneous fistula development. The objective of the study is to evaluate the incidence of pharingocutaneous salivary fistulae after total laryngectomies comparing manual and mechanical sutures. The study is designed as non-randomized, prospective clinical study. Sixty patients with squamous cell carcinoma were submitted to total laryngectomies. In 30 cases, the linear stapler (75 mm) closure (surgical technique described in details) and in other 30 cases manual suture was used. The cases of mechanical suture were prospective and consecutive and the cases of manual suture were a review series of patients who underwent a manual suture of pharynx, in the same period of time. The statistical analysis between the two groups concluded that both were comparable. Fistulae incidence was 6.7% (2/30) in the group with the mechanical suture and 36.7% (11/30) in the group with manual suture closure, presenting a significant difference (p = 0.0047). The total laryngectomy with mechanical closure is an easy and fast learning technique, allowing watertight closure of the pharynx with a low risk of contamination of the surgical field. It is an assured method, even in previously irradiated patients, since we respect the limits of its indication regarding the extension of primary tumor that must be confirmed by previous suspension laryngectomy performed in the operating room.

Treatment with ascorbic acid and α-tocopherol modulates oxidative-stress markers in the spinal cord of rats with neuropathic pain.

Vitamin E (vit. E) and vitamin C (vit. C) are antioxidants that inhibit nociception. The effect of these vitamins on oxidative-stress markers in the spinal cord of rats with chronic constriction injury (CCI) of the sciatic nerve is unknown. This study investigated the effect of intraperitoneal administration of vit. E (15 mg·kg-1·day-1) and vit. C (30 mg·kg-1·day-1), given alone or in combination, on spinal cord oxidative-stress markers in CCI rats. Adult male Wistar rats weighing 200-250 g were divided equally into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve), which received injections of vitamins or vehicle (saline containing 1% Tween 80) for 3 or 10 days (n=6/each group). The vitamins prevented the reduction in total thiol content and the increase in superoxide-anion generation that were found in vehicle-treated CCI rats. While nitric-oxide metabolites increased in vehicle-treated CCI rats 3 days after surgery, these metabolites did not show significant changes in vitamin-treated CCI rats. In all rats, total antioxidant capacity and hydrogen-peroxide levels did not change significantly. Lipid hydroperoxides increased 25% only in vehicle-treated CCI rats. These changes may contribute to vit. C- and vit. E-induced antinociception, because scavenging reactive oxygen species seems to help normalize the spinal cord oxidative status altered by pain.

N-acetylcysteine downregulates phosphorylated p-38 expression but does not reverse the increased superoxide anion levels in the spinal cord of rats with neuropathic pain.

We determined the effect of N-acetylcysteine (NAC) on the expression of the phosphorylated p38 (p-p38) protein and superoxide anion generation (SAG), two important players in the processing of neuropathic pain, in the lumbosacral spinal cord of rats with chronic constriction injury (CCI)-induced neuropathic pain. The sciatic functional index (SFI) was also measured to assess the functional recovery post-nerve lesion. Thirty-six male Wistar rats were divided equally into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve), which received 2, 4, or 8 intraperitoneal injections of NAC (150 mg·kg-1·day-1) or saline beginning 4 h after CCI. Rats were sacrificed 1, 3, and 7 days after CCI. The SFI was measured on these days and the lumbosacral spinal cord was used for analysis of p-p38 expression and SAG. CCI induced a decrease in SFI as well as an increase in p-p38 expression and SAG in the spinal cord. The SFI showed a partial recovery at day 7 in saline-treated CCI rats, but recovery was improved in NAC-treated CCI rats. NAC induced a downregulation in p-p38 expression at all time-points evaluated, but did not reverse the increased SAG induced by CCI. Since p-p38 is a mediator in neuropathic pain and/or nerve regeneration, modulation of this protein may play a role in NAC-induced effects in CCI rats.

Effects of N-acetylcysteine on spinal cord oxidative stress biomarkers in rats with neuropathic pain.

N-acetylcysteine (NAC) inhibits nociceptive transmission. This effect has been associated partly with its antioxidant properties. However, the effect of NAC on the levels of lipid hydroperoxides (a pro-oxidant marker), content of ascorbic acid (a key antioxidant molecule of nervous tissue) and total antioxidant capacity (TAC) is unknown. Thus, our study assessed these parameters in the lumbosacral spinal cord of rats with chronic constriction injury (CCI) of the sciatic nerve, one of the most commonly employed animal models of neuropathic pain. Thirty-six male Wistar rats weighing 200-300 g were equally divided into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve). All rats received intraperitoneal injections of NAC (150 mg·kg-1·day-1) or saline for 1, 3, or 7 days. Rats were killed 1, 3, and 7 days after surgery. NAC treatment prevented the CCI-induced increase in lipid hydroperoxide levels only at day 1, although the amount was higher than that found in naive rats. NAC treatment also prevented the CCI-induced increase in ascorbic acid content, which occurred at days 1, 3, and 7. No significant change was found in TAC with NAC treatment. The changes observed here may be related to the antinociceptive effect of NAC because modulation of oxidative-stress parameters seemed to help normalize the spinal cord oxidative status altered by pain.

Percutaneous balloon mitral valvuloplasty in comparison with open mitral valve commissurotomy for mitral stenosis during pregnancy.

OBJECTIVES: We sought to compare the maternal and fetal outcomes of patients with severe mitral stenosis submitted to percutaneous balloon dilation versus open mitral valve commissurotomy (MVC) during pregnancy. BACKGROUND: Heart failure in patients with mitral stenosis complicating pregnancy is a common problem in developing countries. Since 1984, percutaneous dilation of the mitral valve using a balloon catheter has become a therapeutic alternative to open heart surgery. Although the efficacy of percutaneous mitral valve balloon dilation is well established, its results have never before been compared with the results of commissurotomy during pregnancy. METHODS: We compared the clinical and obstetric complications in 45 women who were treated with percutaneous mitral valve balloon dilation (group I, n = 21; from 1990 to 1995) or open MVC (group II, n = 24; from 1985 to 1990) for severe heart failure due to mitral stenosis during pregnancy. RESULTS: In our study, percutaneous balloon dilation of the mitral valve had a success rate of 95% (Gorlin formula) and 90.5% (echocardiographic "pressure half-time" method), as demonstrated by the final mitral valve area achieved. This improvement was followed by a marked decrease in the mitral valve gradient, left atrial pressure and mean pulmonary artery pressure. Patients in both groups had similar improvements in symptoms. Patients who underwent percutaneous balloon dilation had significantly fewer fetal complications, with a reduction in fetal and neonatal mortality (1 death in group I vs. 8 in group II, p = 0.025). CONCLUSIONS: Percutaneous balloon mitral valvuloplasty is safe and effective and appears to be preferable for the fetus, compared with open MVC during pregnancy.

A three-year follow-up study of infection with Trypanosoma cruzi and electrocardiographic abnormalities in a rural community in northeast Brazil.

The relationship between parasitemia, seroreactivity to Trypanosoma cruzi, and electrocardiographic abnormalities was studied in 115 individuals from a rural community in northeast Brazil where Chagas' disease is endemic. Vector control measures were introduced, and after 3 years 106 of the original participants were located and re-examined. Serum antibodies to T. cruzi were measured by complement fixation and indirect fluorescent antibody tests and parasitemia by xenodiagnosis and blood cultures. On both examinations more seropositive children than seropositive adults showed parasitemia, and parasitemia was more likely to persist over the 3-year period in younger individuals. Electrocardiographic (ECG) abnormalities were seen more frequently in seropositive individuals without parasitemia. However, ECG abnormalities, as expected, were more prevalent in older individuals and therefore no specific inverse relationship between ECG findings and parasitemia could be shown. The decreased prevalence of infection noted in younger individuals following the introduction of vector control measures indicates that this approach limited transmission.

Epidemiological aspects of three Trypanosoma cruzi zymodemes in Bahia State, Brazil.

Culture forms of 104 stocks of Trypanosoma cruzi isolated in different regions of the State of Bahia were compared by electrophoresis of six enzymes. The three distinct combinations of isoenzyme patterns seen were designated ZI, Z2 and Z3. In an area of endemic Chagas's disease in eastern Bahia, T. cruzi Z1 was associated with sylvatic mammals and sylvatic triatomines, whereas T. cruzi Z2 was associated with a separate domestic cycleof transmission. T. cruzi Z1 was also found in sylvatic triatomines from other parts of the State. In contrast, in an area of the São Francisco Valley region of western Bahia, both T. cruzi Z1 and Z2 were isolated from man, domestic animals, and peridomestic rats. T. cruzi Z3 was isolated from an armadillo and from Panstrongylus geniculatus, a triatomine commonly found in armadillo burrows. Both T. cruzi Z1 and Z2 appeared to be pathogenic in man: T. cruzi Z1 was isolated from patients with acute Chagas's disease and from a single patient with chronic cardiac manifestations. T. cruzi Z2 was isolated from some asymptomatic individuals but was also associated with acute disease and chronic cardiac and digestive syndromes.

Comparative effects of fish oil given by gavage and fish oil-enriched diet on leukocytes.

The comparative effects of fish oil given by gavage and fish oil enriched diet on metabolism and function of lymphocytes and macrophages were investigated. For this purpose, the following parameters were examined: 1) phagocytosis capacity, production of superoxide (O2*-) and hydrogen peroxide (H2O2) by macrophages, 2) lymphocytes proliferation capacity, 3) antioxidant enzyme activities in the mesenteric lymph nodes (MEN) and liver, 4) Thiobarbituric Acid Reactive Substances (TBARS) content in MLN, liver, and plasma, 5) total antioxidant capacity of the plasma, and 6) fatty acid composition of macrophages, MLN, liver and plasma. Both FO treatments did not affect phagocytosis capacity but increased hydrogen peroxide production by macrophages in the presence of PMA. FO given by gavage markedly increased lymphocytes proliferation both in the absence (5.8-fold) and in the presence (16.7-fold) of Con A, whereas FO-rich diet showed an increase in the presence of Con A only (53.3%). FO given by gavage raised the proliferation index by 2.9-fold and FO-rich diet increased by 29% only as compared to controls. Concomitantly, FO given by gavage was more effective to increase TBARS content in plasma. The proportion of some fatty acids in the tissues and cells was also differently changed depending on the way FO was administered to rats: in particular: myristic, arachidonic, and eicosapentaenoic acids. This fact may partially explain the differences between both FO treatments.

Criss-cross heart with intact ventricular septum.

We report a case of a criss-cross heart in a 6-month-old male child with echocardiographic and angiocardiographic findings of concordant atrioventricular and discordant ventriculoarterial connexions and an intact ventricular septum. This entity has been described with a ventricular septal defect as part of its own anatomic spectrum. The concept of the criss-cross heart, however, is best restricted to a form of spatial atrioventricular arrangement in which the atrioventricular connexions are criss-crossed.

It is valid to dilate native aortic coarctation with a balloon catheter.

We report our experience in 37 patients with aortic coarctation who underwent balloon aortoplasty. Of the 37, the lesion was native in 34 cases. Clinical re-evaluation was possible in 22 patients, with a mean follow-up period of 13 months and, of these, 21 patients were asymptomatic. Haemodynamic and angiographic studies were performed in 13 patients, with a mean period of follow-up of 12 months, showing excellent results in 11 patients. Aneurysmal formation had occurred in one and recoarctation in the other patient. Our experience has proved that balloon aortoplasty is an effective method for treating patients with aortic coarctation. Adequate selection in terms of the morphology of the coarctation and the size of the balloon catheter are crucial factors in the success of the procedure.

[Chronic post-traumatic headache after mild head injuries]. / Cefaléia pós-traumática crônica em traumatismos crânio-encefálicos leves.

Current evidence indicates that chronic post-traumatic headache (cPTH) has organic causes. Nevertheless, these patients are considered as neurotics or malingering by health professionals, mainly if the headache originates from mild head injuries (MHI). Our aim was to identify the features of cPTH after MHI. We studied 27 consecutive patients fulfilling the criteria established for cPTH and MHI. Headache began on the same day of the trauma in 51.8% of patients. The clinical features allowed the following diagnosis: migraine (70.3%); tension type headache (51.8%); cervicogenic headache (11.1%). Concomitance of migraine and tension type headache was found in 29.6%. Thirty three percent of employees, 40% of housewives and 50% of students in our series referred prejudice in their productive activities. However, only three patients (11.1%) were claiming for compensation. The lack of potential gain and the uniformity of the clinical presentation are suggestive that the cPTH has an organic cause.

[Primary chronic daily headache: clinical factors]. / Cefaléia crônica diária primária. Características clínicas.

Under the denomination primary chronic daily headache (CDH) there are different types of headache which present daily or near-daily, during long spells. This concept refers to temporality and not to a specific kind of headache. It is important to know the CDH and its natural history, as well as some factors that possibly turn it into chronic. They are critically reviewed here.

[Primary chronic daily headache: a report on 52 cases]. / Cefaléia crônica diária primária. A propósito de 52 casos.

Fifty-two patients (48 women, 4 men, ages varying between 13 and 71 years) that fulfilled the criteria by Silberstein et al. (1994) for chronic daily headache (CDH) were studied. The main clinical characteristics allowed three diagnostic types of CDH: transformed migraine (n = 39; 75%); chronic tension-type headache (n = 11; 21.1%); and new daily persistent headache (n = 2; 3.9%). Thirty-four patient used to take symptomatic medication in excess and were considered as having drug-induced headache. The treatment included increasing doses of amitriptyline alone or associated with propranolol besides the interruption of the symptomatic medication. This scheme was effective to lower the frequency of headache in most CDH patients and its beneficial effects had lasted even six months after the beginning of the follow-up. In the few patients in which the treatment was unsuccessful, the persistence of abusive use of symptomatic drugs was statistically significant.

[Stenting for iatrogenic coronary dissection treatment]. / Utilização de stent para tratamento de dissecção coronária iatrogênica.

Catheter-induced coronary dissection is rare but has a significant mortality and morbidity. The ideal management of acute coronary occlusion, whatever the cause, is the prompt restoration of the vessel patency to limit the extent and duration of ischemia. In the setting of dissection during angiography the usual approach to myocardial salvage has been emergency aortocoronary bypass surgery preceded by insertion of an intra-aortic balloon. The main disadvantages of this approach is the delay in performing emergency surgery, mainly in centers without surgical back-up on site. The authors present a case of an elderly woman with left circumflex artery dissection caused by the catheter during coronary angiography. This problem was successfully managed using an intracoronary stent. This technique has potential advantages in terms of the speed of reperfusion and availability in centers performing diagnostic angiography without surgical back-up on site.

[Utilization of self-expandable prosthesis (stent) introduced through the femoral artery for treatment of dissection of the descending aorta]. / Utilização de endoprótese auto-expansível (stent) introduzida através da artéria femoral para tratamento de dissecção da aorta descendente.

PURPOSE: We present four cases of dissection of the thoracic descending aorta that underwent treatment with an auto expandable dácron-covered stent. METHODS: The stent was deployed through the femoral artery in the hemodynamic laboratory after sedation, local anesthesia in both inguinal areas and systemic heparinization. The catheter with the stent was introduced through a cutdown in the left femoral artery until the area in the thoracic aorta with the previously diagnosed tear. RESULTS: The stent was expanded with immediate occlusion of the false lumen. The whole procedure took 90 minutes and the patients were discharged without complications. CONCLUSION: Stent utilization is an important step to improve treatment results in type B aortic dissection.