Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin's lymphoma: results of a phase I study.

PURPOSE Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. This was a phase I study to determine the maximum-tolerated dose (MTD), safety, and preliminary efficacy of inotuzumab ozogamicin in an expanded MTD cohort of patients with relapsed or refractory CD22(+) B-cell non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Inotuzumab ozogamicin was administered intravenously as a single agent once every 3 or 4 weeks at doses ranging from 0.4 to 2.4 mg/m(2). Outcomes included MTD, safety, pharmacokinetics, response, progression-free survival (PFS), and overall survival. Results Seventy-nine patients were enrolled. The MTD was determined to be 1.8 mg/m(2). Common adverse events at the MTD were thrombocytopenia (90%), asthenia (67%), and nausea and neutropenia (51% each). The objective response rate at the end of treatment was 39% for the 79 enrolled patients, 68% for all patients with follicular NHL treated at the MTD, and 15% for all patients with diffuse large B-cell lymphoma treated at the MTD. Median PFS was 317 days (approximately 10.4 months) and 49 days for patients with follicular NHL and diffuse large B-cell lymphoma, respectively. CONCLUSION Inotuzumab ozogamicin has demonstrated efficacy against CD22(+) B-cell NHL, with reversible thrombocytopenia as the main toxicity.

Portuguese validation of the Symptom Inventory of the M.D. Anderson Cancer Center

Objective To analyze the reliability and validity of the psychometric properties of the Brazilian version of the instrument for symptom assessment, titled MD Anderson Symptom Inventory - core. Method A cross-sectional study with 268 cancer patients in outpatient treatment, in the municipality of Ijuí, state of Rio Grande do Sul, Brazil. Results The Cronbach’s alpha for the MDASI general, symptoms and interferences was respectively (0.857), (0.784) and (0.794). The factor analysis showed adequacy of the data (0.792). In total, were identified four factors of the principal components related to the symptoms. Factor I: sleep problems, distress (upset), difficulties in remembering things and sadness. Factor II: dizziness, nausea, lack of appetite and vomiting. Factor III: drowsiness, dry mouth, numbness and tingling. Factor IV: pain, fatigue and shortness of breath. A single factor was revealed in the component of interferences with life (0.780), with prevalence of activity in general (59.7%), work (54.9%) and walking (49.3%). Conclusion The Brazilian version of the MD Anderson Symptom Inventory - core showed adequate psychometric properties in the studied population.

Foodborne norovirus outbreak: the role of an asymptomatic food handler

Background: In July 2005 an outbreak of acute gastroenteritis occurred on a residential summer camp in the province of Barcelona (northeast of Spain). Forty-four people were affected among residents and employees. All of them had in common a meal at lunch time on 13 July (paella, round of beef and fruit). The aim of this study was to investigate a foodborne norovirus outbreak that occurred in the residential summer camp and in which the implication of a food handler was demonstrated by laboratory tests. Methods: A retrospective cohort study was designed. Personal or telephone interview was carried out to collect demographic, clinical and microbiological data of the exposed people, as well as food consumption in the suspected lunch. Food handlers of the mentioned summer camp were interviewed. Ten stool samples were requested from symptomatic exposed residents and the three food handlers that prepared the suspected food. Stools were tested for bacteries and noroviruses. Norovirus was detected using RT-PCR and sequence analysis. Attack rate, relative risks (RR) and its 95% confidence intervals (CI) were calculated to assess the association between food consumption and disease. Results: The global attack rate of the outbreak was 55%. The main symptoms were abdominal pain (90%), nausea (85%), vomiting (70%) and diarrhoea (42.5%). The disease remitted in 24-48 hours. Norovirus was detected in seven faecal samples, one of them was from an asymptomatic food handler who had not eaten the suspected food (round of beef), but cooked and served the lunch. Analysis of the two suspected foods isolated no pathogenic bacteria and detected no viruses. Molecular analysis showed that the viral strain was the same in ill patients and in the asymptomatic food handler (genotype GII.2 Melksham-like). Conclusions: In outbreaks of foodborne disease, the search for viruses in affected patients and all food handlers, even in those that are asymptomatic, is essential. Health education of food handlers with respect to hand washing should be promoted.

Development of a pediatric eosinophilic esophagitis activity index (ped-EEsAI): International experts propose dysphagia, whitish exudates on endoscopy , and intraepithelial eosinophili count as major items related to EoE activity

Background and Aims: The international EEsAI study group aims to develop, validate and evaluate the first pediatric EoE activity index (ped-EEsAI). We report on results of phase 1, which aims to generate candidate items. Methods: This study involves 3 phases: (1) item generation, (2) index derivation and testing on a first patient cohort, and (3) validation in a second cohort. In phase 1, item generation, weighting and reduction are achieved through a Delphi process with an international EoE expert group. The experts proposed and ranked candidate items on a 7-point Likert scale (0 = no, 6 = perfect relationship with EoE activity). Results: 23 international EoE experts proposed and ranked 39 items (20 clinical, 6 endoscopic, 8 histologic, 5 laboratory items). Rank order for clinical items: dysphagia related to food consistencies (median 5, range 2-6), severity of dysphagia (5, 3-6), frequency of dysphagia episodes (5, 3-6), regurgitation and vomiting (4, 2-5), response to dietary restrictions (4, 1-6); endoscopic items: whitish exudates (5, 3-6), furrowing (4, 3-6), corrugated rings (4, 2-6), linear shearing (4, 2-6), strictures (3, 2-6); histologic items: intraepithelial eosinophil count (5, 4-6), lamina propria fibrosis (3, 2-6), basal layer enlargement (3, 1-5); laboratory items: % blood eosinophils (3, 0-5). Conclusions: These items will now be reduced in further Delphi rounds, tested on a cohort of 100 pediatric EoE patients and validated in a second independent cohort, resulting in a robust, broadly accepted disease activity index for use in clinical trials and daily care.

Temozolomide combined with bevacizumab in metastatic melanoma. A multicenter phase II trial (SAKK 50/07)

Background: Single agent DTIC is the standard therapy for metastatic melanoma (MM) with response rates of 5−20%. Temozolomide (Tem) as an oral drug has shown equal efficacy in phase III trials. Preclinical models have shown an inhibitory effect for bevacizumab (Bev) on the proliferation of melanoma cells as well as on sprouting endothelial cells. Therefore, a therapeutic approach that combines angiogenesis inhibitors with cytotoxic agents may provide clinical benefit in MM. Methods: Design: Multicenter phase II trial. Primary endpoint: Clinical benefit (CR, PR and SD) at 12 weeks; secondary endpoints: best overall response by RECIST, response duration, progression free survival, adverse events, survival after 6 months and overall survival. Sample size was calculated according to Simon's two stage optimal design (5% significance level and 80% power) with an overall sample size of 62 patients (pts) to test H0: 20% versus H1: 35% rate of clinical benefit. Response assessment was done every 6 weeks (3 cycles). Eligibility: Stage IV MM, ECOG PS 0−2, no prior treatment for metastatic disease. Treatment regimen: One cycle consisted of Tem at 150 mg/m2 days 1−7 po and Bev at 10 mg/kg day 1 over 30 min iv and was repeated every 2 weeks until progression or unacceptable toxicity. Results: Between January 2008 and April 2009, 62 pts (40 male/22 female) at a median age of 61 years (range 30−86) with stage IV (M1a:4, M1b:12, M1c:46) melanoma were enrolled in 9 centers. The first 50 pts, who received 415 cycles are included in this interim report. The overall response rate was 26% (CR: 1 pt, PR: 12 pts; PR not confirmed yet in 3 pts), and 44% (22 pts) had stable disease over 1.5−7.5 months (median: 3). Only 30% (15 pts) had disease progression at the first evaluation at week 6. The hematological grade 3/4 toxicities according to NCI CTAE 3.0 were thrombocytopenia 10% (5 pts), neutropenia 8% (4 pts), lymphopenia and leucocytopenia each 2% (1 pt). Cumulative non-hematological toxicities grade 3/4 were nausea and fatigue each 6% (3 pts), hypertension, vomiting and hemorrhage, each 4% (2 pts), thrombosis/embolism, infection, constipation, anorexia, elevation of alkaline phosphatase, bilirubin, GGT, ALT and AST each 2% (1 pt). Conclusion: In metastatic melanoma the combination of Tem/Bev is a safe regimen with a promising efficacy and few grade 3/4 toxicities. Updated results of all 62 pts will be presented.

Epidemiological, clinical and immunohistochemical aspects of canine lymphoma in the region of Porto Alegre, Brazil

This paper describes the epidemiological, clinical and immunohistochemical characteristics of canine lymphomas diagnosed in the region of Porto Alegre, Brazil. Thirty dogs were enrolled in the study; most of them were male (60%), mixed-breed (23%) and middle-aged or older. The majority (87%) of affected dogs showed the multicentric form. The B-cell phenotype was most frequently detected (62%); 37% of the animals were in clinical stage IV, and 83% were classified as sub-stage "b". Lymphadenopathy was observed in 67% of the cases, and dyspnea, prostration, decreased appetite and vomiting were the most common clinical signs encountered. Anemia was a frequently encountered laboratory alteration (57%), as were leukocytosis (40%), thrombocytopenia (33%), lymphopenia (30%), hyperglobulinemia (20%) and hypercalcemia (13%). The results of this study indicate that the clinical features of dogs with lymphoma in the region of Porto Alegre are similar to those observed worldwide.

Negative inotropic and chronotropic effects on the guinea pig atrium of extracts obtained from Averrhoa carambola L. leaves

It has been reported that star fruit can lead to a fatal outcome in uremic patients. The intoxication syndrome consists of hiccups, mental confusion, dizziness, and vomiting. On the other hand, folk medicine uses teas and infusions of carambola leaves to treat headache, vomiting, cough, insomnia, and diabetes. This motivated us to determine if Averrhoa carambola can act on the contractility and automaticity of the guinea pig heart. We measured the atrial isometric force in stimulated left atria and determined the chronotropic changes in spontaneously beating right atria. The carambola leaf extracts (1.5 mg/ml) abolished the contractile force in a concentration-dependent manner. Among the crude, methanolic, ethanolic, aqueous, and acetic extracts, the aqueous one was the most potent (EC50 = 520 ± 94 µg/ml; flavonoids and tannins are the main constituents; Na+ and K+ contents in 1.0 mg/ml of aqueous extract were 0.12 ± 0.016 and 1.19 ± 0.15 mM, respectively). The aqueous extract abolished the positive Bowditch staircase phenomenon and reduced the inotropic response to CaCl2 (0.17-8.22 mM), events that are dependent on the cellular Ca2+ inward current. The adrenergic, muscarinic or opioid membrane receptors do not seem to participate in the mechanism of action of the cardioactive substance(s). In spontaneously beating atria, the aqueous extract promoted a negative chronotropic effect that was antagonized by 0.1 µM isoproterenol bitartrate. With this agonist, the EC50 of the aqueous extract increased from 133 ± 58 to 650 ± 100 µg/ml. These data regarding the effect of A. carambola on guinea pig atrial contractility and automaticity indicate an L-type Ca2+ channel blockade.

High incidence of adverse reactions to initial antiretroviral therapy in Brazil

A concurrent prospective study was conducted from 2001 to 2003 to assess factors associated with adverse reactions among individuals initiating antiretroviral therapy at two public referral HIV/AIDS centers in Belo Horizonte, MG, Brazil. Adverse reactions were obtained from medical charts reviewed up to 12 months after the first antiretroviral prescription. Cox proportional hazard model was used to perform univariate and multivariate analyses. Relative hazards (RH) were estimated with 95% confidence intervals (CI). Among 397 charts reviewed, 377 (95.0%) had precise information on adverse reactions and initial antiretroviral treatment. Most patients received triple combination regimens including nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. At least one adverse reaction was recorded on 34.5% (N = 130) of the medical charts (0.17 adverse reactions/100 person-day), while nausea (14.5%) and vomiting (13.1%) were the most common ones. Variables independently associated with adverse reactions were: regimens with nevirapine (RH = 1.78; 95% CI = 1.07-2.96), indinavir or indinavir/ritonavir combinations (RH = 2.05; 95% CI = 1.15-3.64), female patients (RH = 1.93; 95% CI = 1.31-2.83), 5 or more outpatient visits (RH = 1.94; 95% CI = 1.25-3.01), non-adherence to antiretroviral therapy (RH = 2.38; 95% CI = 1.62-3.51), and a CD4+ count of 200 to 500 cells/mm³ (RH = 2.66; 95% CI = 1.19-5.90). An independent and negative association was also found for alcohol use (RH = 0.55; 95% CI = 0.33-0.90). Adverse reactions were substantial among participants initiating antiretroviral therapy. Specially elaborated protocols in HIV/AIDS referral centers may improve the diagnosis, management and prevention of adverse reactions, thus contributing to improving adherence to antiretroviral therapy among HIV-infected patients.

Sodium taste threshold in children and its relationship to blood pressure

Popular science has emphasized the risks of high sodium intake and many studies have confirmed that salt intake is closely related to hypertension. The present mini-review summarizes experiments about salt taste sensitivity and its relationship with blood pressure (BP) and other variables of clinical and familial relevance. Children and adolescents from control parents (N = 72) or with at least one essential hypertensive (EHT) parent (N = 51) were investigated. Maternal questionnaires on eating habits and vomiting episodes were collected. Offspring, anthropometric, BP, and salt taste sensitivity values were recorded and blood samples analyzed. Most mothers declared that they added "little salt" when cooking. Salt taste sensitivity was inversely correlated with systolic BP (SBP) in control youngsters (r = -0.33; P = 0.015). In the EHT group, SBP values were similar to control and a lower salt taste sensitivity threshold. Obese offspring of EHT parents showed higher SBP and C-reactive protein values but no differences in renin-angiotensin-aldosterone system activity. Salt taste sensitivity was correlated with SBP only in the non-obese EHT group (N = 41; r = 0.37; P = 0.02). Salt taste sensitivity was correlated with SBP in healthy, normotensive children and adolescents whose mothers reported significant vomiting during the first trimester (N = 18; r = -0.66; P < 0.005), but not in "non-vomiter offspring" (N = 54; r = -0.18; nonsignificant). There is evidence for a linkage between high blood pressure, salt intake and sensitivity, perinatal environment and obesity, with potential physiopathological implications in humans. This relationship has not been studied comprehensively using homogeneous methods and therefore more research is needed in this field.

In vitro and in vivo studies of pirarubicin-loaded SWNT for the treatment of bladder cancer

Intravesical chemotherapy is an important part of the treatment for superficial bladder cancer. However, the response to it is limited and its side effects are extensive. Functional single-walled carbon nanotubes (SWNT) have shown promise for tumor-targeted accumulation and low toxicity. In the present study, we performed in vivo and in vitro investigations to determine whether SWNT-based drug delivery could induce high tumor depression in rat bladder cancer and could decrease the side effects of pirarubicin (tetrahydropyranyl-adriamycin, THP). We modified SWNT with phospholipid-branched polyethylene glycol and constructed an SWNT-THP conjugate via a cleavable ester bond. The cytotoxicity of SWNT-THP against the human bladder cancer cell line BIU-87 was evaluated in vitro. Rat bladder cancer in situ models constructed by N-methyl-N-nitrosourea intravesical installation (1 g/L, 2 mg/rat once every 2 weeks for 8 weeks) were used for in vivo evaluation of the cytotoxicity of SWNT and SWNT-THP. Specific side effects in the THP group including urinary frequency (N = 12), macroscopic hematuria (N = 1), and vomiting (N = 7) were identified; however, no side effects were observed with SWNT-THP treatment. Flow cytometry was used to assess the cytotoxicity in vitro and in vivo. Results showed that SWNT alone did not yield significant tumor depression compared to saline (1.74 ± 0.56 and 1.23 ± 0.42%) in vitro. SWNT-THP exhibited higher tumor depression than THP-saline in vitro (74.35 ± 2.56 and 51.24 ± 1.45%) and in vivo (52.46 ± 2.41 and 96.85 ± 0.85%). The present findings indicate that SWNT delivery of THP for the treatment of bladder cancer leads to minimal side effects without loss of therapeutic efficacy. Therefore, this nanotechnology may play a crucial role in the improvement of intravesical treatment of bladder cancer.

A Study on the Efficiency of Synbiotics for Prevention and Control of Diarrhoea in 21 Dogs Submitted to Radiotherapy

A synbiotic is a formulation containing both probiotics and prebiotics. This study aims to evaluate the effect of supplementation with a synbiotic containing Enterococcus faecium strain E1707 (NCIMB 10415) in preventing or controlling diarrhoea and other gastrointestinal signs in boarded canine radiotherapy patients. A double-blind, randomized, placebocontrolled clinical trial was carried out in 21 adult dogs undergoing radiotherapy and boarded for a duration period of 2 to 3 weeks to treat their cancers. Dogs were randomly divided between two groups: A and B, the synbiotic and placebo group, respectively. The content of the sachets was added to the food once daily. Faecal score was assessed daily, and dogs were also monitored for the development of diarrhoea and other gastrointestinal signs such as weight loss, reduced appetite and vomiting. The results from descriptive statistics seem to favour group B, however these findings were not validated with inferential statistics due to insufficient statistical sample power. Because of this, it is not possible to make conclusions about the benefits of synbiotic as supportive treatment for dogs undergoing radiotherapy. All results should be considered to be preliminary, until they are elucidated by further animal inclusion.

Physiological and bifidogenic effects of prebiotic supplements in infant formulae

This randomized controlled trial involving 110 healthy neonates studied physiological and bifidogenic effects of galactooligosaccharides (GOS), oligofructose and long-chain inulin (FOS) in formula. Subjects were randomized to Orafti Synergy1 (50 oligofructose: 50 FOS) 0.4g/dl or 0.8g/dl, GOS:FOS (90:10) 0.8g/dl or a standard formula according to Good Clinical Practise (GCP) guidelines. A breast-fed group was included for comparison. Outcome parameters were weight, length, intake, stool characteristics, crying, regurgitation, vomiting, adverse events and fecal bacterial population counts. Statistical analyses used non-parametric tests. During the first month of life weight, length, intake and crying increased significantly in all groups. Regurgitation and vomiting scores were low and similar. Stool frequency decreased significantly and similarly in all formula groups but was lower than in the breast-fed. All prebiotic groups maintained soft stools, only slightly harder than those of breast-fed infants. The standard group had significantly harder stools at wks 2 and 4 compared to 1 (P<0.001 & P=0.0279). The total number of fecal bacteria increased in all prebiotic groups (9.82, 9.73 and 9.91 to 10.34, 10.38 and 10.37, respectively, log10 cells/g feces, P=0.2298) and resembled more the breast-fed pattern. Numbers of lactic acid bacteria, bacteroides and clostridia were comparable. In the SYN1 0.8 g/dl and GOS:FOS groups Bifidobacterium counts were significantly higher at D14 & 28 compared to D3 and comparable to the breast-fed group. Tolerance and growth were normal. In conclusion, stool consistency and bacterial composition of infants taking SYN1 0.8 g/dl or GOS:FOS supplemented formula was closer to the breast-fed pattern. There was no risk for dehydration.

Africanized honeybee stings: how to treat them

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The cetacean offal connection: Feces and vomits of spinner dolphins as a food source for reef fishes

At Fernando de Noronha Archipelago, southwest Atlantic, reef fishes associated with spinner dolphins (Stenella longirostris) were recorded when the cetaceans congregated in a shallow inlet. In the reef waters the dolphins engaged in several behaviors such as resting, aerial displays and other social interactions, as well as eliminative behaviors such as defecating and vomiting. Twelve fish species in seven families were recorded feeding on dolphin offal. The black durgon (Melichthys niger) was the most ubiquitous waste-eater, and its group size was positively and significantly correlated with dolphin group size. The durgons recognized the postures a dolphin adopts prior to defecating or vomiting, and began to converge to an individual shortly before it actually voided. Offal was quickly fed upon, and the fishes concentrated in the area occupied by the dolphins until the latter left the shallows. Since all the recorded offal-feeding species feed on plankton or drifting algae, feeding on cetacean droppings may be regarded as a switch from foraging on drifting organisms to foraging on drifting offal, a predictable food source in the inlet. Further instances of this cetacean-fish association are predicted to occur at sites where these mammals congregate over reefs with clear water and plankton-eating fishes.

The comparative efficacy of yohimbine and atipamezole to treat amitraz intoxication in dogs

This study compared the efficacy of yohimbine with atipamezole, a new α2-adrenergic antagonist, to treat canine amitraz intoxication. Thirty dogs were divided equally into 3 groups (A, AY, and AA). Group A received 2.5% amitraz iv at 1 mg/kg; Group AY received the same dose of amitraz followed 30 min later by 0.1 mg/kg (2 mg/mL) yohimbine iv; and Group AA received the same dose of amitraz followed 30 min later by 0.2 mg/kg (5 mg/mL) atipamezole iv. Temperature, heart rate, respiratory frequency, mean arterial pressure, degree of sedation, mean time of tranquilization and diameter of pupils were monitored for 360 min. Sedation, logs of reflexes, hypothermia bradycardia, hypotension, bradypnea and mydriasis were observed in Group A, with 3rd eyelid prolapse, increased diuresis and vomiting in some animals. Yohimbine reversed all alterations induced by amitraz, but induced significant cardiorespiratory effects such as tachycardia and tachypnea. Atipamezole was a useful antagonist for amitraz, with less cardiorespiratory effects, suggesting its potential role as an alternative treatment of amitraz intoxication in dogs.