Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial.

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment in early-stage HER2-positive breast cancer based on the phase III ExteNET study. In that trial, in which no antidiarrheal prophylaxis was mandated, grade 3 diarrhea was observed in 40% of patients and 17% discontinued due to diarrhea. The international, open-label, sequential-cohort, phase II CONTROL study is investigating several strategies to improve tolerability. PATIENTS AND METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year plus loperamide prophylaxis (days 1-28 or 1-56). Sequential cohorts evaluated additional budesonide or colestipol prophylaxis (days 1-28) and neratinib dose escalation (DE; ongoing). The primary end point was the incidence of grade ≥3 diarrhea. RESULTS: Final data for loperamide (L; n = 137), budesonide + loperamide (BL; n = 64), colestipol + loperamide (CL; n = 136), and colestipol + as-needed loperamide (CL-PRN; n = 104) cohorts, and interim data for DE (n = 60; completed ≥six cycles or discontinued; median duration 11 months) are available. No grade 4 diarrhea was observed. Grade 3 diarrhea rates were lower than ExteNET in all cohorts and lowest in DE (L 31%, BL 28%, CL 21%, CL-PRN 32%, DE 15%). Median number of grade 3 diarrhea episodes was one; median duration per grade 3 episode was 1.0-2.0 days across cohorts. Most grade 3 diarrhea and diarrhea-related discontinuations occurred in month 1. Diarrhea-related discontinuations were lowest in DE (L 20%, BL 8%, CL 4%, CL-PRN 8%, DE 3%). Decreases in health-related quality of life did not cross the clinically important threshold. CONCLUSIONS: Neratinib tolerability was improved with preemptive prophylaxis or DE, which reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Lower diarrhea-related treatment discontinuations in multiple cohorts indicate that proactive management can allow patients to stay on neratinib for the recommended time period. CLINICALTRIALS.GOV: NCT02400476.

Volumetric laser endomicroscopy and its application to Barrett's esophagus: results from a 1,000 patient registry.

Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett's esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291.

Brown-sequard syndrome after endovascular embolization of vertebral hemangioma.

STUDY DESIGN: Several causes of Brown-Sequard syndrome have been described. Endovascular embolization can be used to treat symptomatic vertebral hemangiomas. We describe a previously undocumented case of Brown-Sequard syndrome followed by endovascular embolization with microcoils of a vertebral hemangioma. We also provide a clinical-radiological correlation of this finding and review the relevant literature. CASE REPORT: A 39-year-old male was referred to our hospital for endovascular treatment of a right T9 hemivertebral hemangioma with compromise of the spinal canal. Fifteen minutes after the procedure, the patient developed right lower limb weakness and numbness on the left leg. The emergency magnetic resonance imaging (MRI) of the spine showed no abnormalities. Five days later, a new spinal MRI revealed an infarction in the right half of the spinal cord at T6 and T7 level. This stroke was probably caused by a microcoil ended up in the right sulcocommisural artery. One week after surgery, the patient was able to raise the right leg against gravity, but sensory deficit showed no improvement. CONCLUSIONS: To the best of our knowledge this is the first case of a Brown-Sequard syndrome related to vertebral hemangioma embolization, a relatively safe technique with no important complications made known until this report. Clinicians should always weight the benefits with the potential devastating complications of this therapeutic option.

[Brain death: is it an appropriate term?]. / Muerte cerebral: ¿es un término adecuado?

INTRODUCTION: Brain death is generally accepted as a concept to indicate death. It was introduced about 40 years ago, and it was considered the ideal situation for donation of organs. METHODS: During this time, however, there have been problems in the understanding of this concept both in the medical profession and in the general population. University students from medical and non-medical schools were tested for their understanding of this concept. RESULTS: Our results show that less than one third of the non-medical students identified brain death as death. The data from the medical students changed as they progressed through their studies, but only 2/3 of the graduating medical class believed that brain death is death. CONCLUSION: Similar results have been seen in other universities around the world, and a renewed effort on the re-education of the concept of brain death may be worthwhile. Although we cannot extrapolate these results to the general population, the confusion is probably similar; hence an effort should be made to solve this problem.

A probable cluster headache case from a textbook of 1726: Francisco Suarez de Rivera's description.

BACKGROUND: Few descriptions of cluster and cluster-like headache made before the 19th century have been reported. CASE DESCRIPTION: We present a previously unreported early description of a probable cluster headache case made by Francisco Suárez de Rivera (1686-c.1751), one of the main physicians of the Spanish Age of Enlightenment, writer of almost 40 textbooks about medicine, surgery, pharmacology, and therapeutics. DISCUSSION: The depiction here reported of a woman with probable cluster headache is possibly one of the earliest known and, to our knowledge, the first in Hispanic literature. We also review other descriptions of cluster and cluster-like headache from the same time period.

An open-label study of chronic polyethylene glycol laxative use in chronic constipation.

BACKGROUND: Polyethylene glycol 3350 (MiraLAX, Braintree Laboratories Inc., Braintree, MA, USA) is approved for the short-term treatment of occasional constipation. AIM: To extend the safety data of polyethylene glycol used for chronic treatment of chronic constipation. METHODS: Study subjects who met defined criteria for chronic constipation were enrolled in this open-labelled, single-treatment multi-centre study to receive polyethylene glycol laxative as a single daily dose of 17 g for 12 months. Subjects returned to their study centres after 2, 4, 6, 9 and 12 months of treatment where blood and urine samples were collected and adverse events were reviewed. At each visit, subjects were queried for ROME constipation criteria and they rated their overall improvement using a global efficacy scale. RESULTS: 311 patients including 117, age 65 and older, were enrolled and received treatment at one of 50 centres. One hundred and eighty-four completed all 12 months of treatment. With respect to the 'Global Efficacy Assessment', depending on the month of observation, 80-88% of enrolled patients, and 84-94% of the elderly, were treated successfully. Similar results were obtained from secondary efficacy measures that assessed individual ROME constipation criteria at each visit. The response to treatment was durable over time. Over the 1-year course of study representing 218 patient-years at the labelled dose, medication-associated adverse effects were gastrointestinal complaints of diarrhoea, loose stool, flatulence and nausea. These effects were generally mild or moderate in severity. There were no clinically significant changes in haematology or blood chemistry, particularly electrolytes, for the study population as a whole or the elderly group. CONCLUSIONS: Polyethylene glycol laxative is safe and effective for treating constipation in adult and elderly patients for periods up to 12 months, with no evidence of tachyphylaxis.

Electrocardiographic characterization in Trypanosoma cruzi reinfected mice.

Chagas' disease, caused by Trypanosoma cruzi, affects approximately 20 million people. There are 3 stages in the disease: acute, intermediate and chronic, the diversity and severity of the symptoms range from a mild electrocardiographic alteration to sudden death. We have previously demonstrated that when reinfections were carried out in the acute phase they produce greater cardiac damage. The aim of the present work was to investigate whether T. cruzi reinfected mice present electrocardiographic abnormalities that could be characteristic and only achieved after reinfections. Of the mice reinfected during the acute phase 100% showed abnormalities from days 90 post-infection, with a predominance of auricle ventricle blocks (67-71%). All the mice reinfected during the chronic infection showed electrocardiographic alteration after 30 days post-first reinfection. Of the mice infected, without reinfection, 60% exhibited electrocardiographic dysfunction at 90 days post-infection. Our results demonstrated that when the host was reinfected in the acute phase, more serious electrocardiographic alterations were developed than when the reinfections were carried out in the chronic stage. Sudden death described in some chagasic patients, might be related to some of the findings described here.

He-Ne laser on microcrystalline arthropathies.

OBJECTIVE: The objective of this work is to assess the anti-inflammatory capacity of He-Ne laser therapy as determined by the plasmatic levels of inflammatory markers, fibrinogen, and TNFalpha and by histopathological study in rats with arthropathy induced by calcium pyrophosphate crystals. BACKGROUND DATA: Microcrystalline arthropathies are a group of diseases characterized by the deposit of different crystals in joints. MATERIALS AND METHODS: Two milligrams of dicalcium pyrophosphate crystals (DCPP) were injected in both joints of the lower limbs of rats during 2 days. A group was treated with laser of He-Ne (6 mW) on the injected joints during 3 consecutive days. After 96 h of the first injection, animals were sacrificed to determine TNFalpha using the ELISA method and fibrinogen was assessed using spectrophotometry. Sections from the lower limbs were used for histopathology. RESULTS: A statistically significant increase (p < 0.001) in plasma fibrinogen levels and TNFalpha was noted between the control group and the laser-treated group. The histological transversal section of a posterior limb joint of a rat injected with DCPP showed fibroadipose tissue with diffuse chronic infiltrate. The histopathology of the group of rats injected with DCPP and subsequently treated with He-Ne laser showed no inflammatory response. CONCLUSION: He-Ne laser treatment in the microcrystalline arthropathy induced in rats by DCPP injection might have an antiinflammatory effect, evaluated by fibrinogen plasma levels and TNF-alpha (inflammatory markers) and by the histopathology regressive process.

Hemostatic technique: extracapsular prostatic adenomectomy.

PURPOSE: We describe extracapsular prostatectomy performed by applying lateral capsular transfixing sutures after adenoma enucleation and minimum operative hemorrhage. MATERIALS AND METHODS: A total of 117 patients with prostatic hypertrophy underwent surgery. After adenomectomy transfixing sutures were placed at the 3 and 9 o'clock positions clockwise around the prostatic capsule (hila). Five variables were used to quantify intraoperative and postoperative hemorrhage. RESULTS: Average intraoperative blood loss was 175 cc and average minimal decrease in hematocrit was 3.9%. Most patients had postoperative bleeding through the urethral and suprapubic catheters. CONCLUSIONS: Extracapsular prostatectomy with the application of lateral capsular transfixing sutures causes minimum operative hemorrhage.

Thioridazine treatment modifies the evolution of Trypanosoma cruzi infection in mice.

Thioridazine, a tricyclic drug, is known to have a direct effect on Trypanosoma cruzi, disrupting the parasites' mitochondria and kinetoplasts. In the present study, the drug was used orally, at 80 mg/kg.day for 3 days, to treat mice inoculated with low numbers of T. cruzi. The drug caused no apparent toxicity in the host. It cleared trypomastigotes from the bloodstream, prevented the histological and functional alterations of the heart normally observed in the chronic phase of the experimental disease, and greatly reduced the mortality rate compared with that in untreated, infected controls. When checked 135 days post-infection, the density of cardiac beta receptors and the cardiac histology of the treated mice were indistinguishable from those of uninfected, untreated controls. The drug is already used to treat humans, as a neuroleptic drug. It appears to be able to prevent acute infection with T. cruzi evolving into chronic disease, at least in mice, and may be a useful base from which to design new agents for the treatment of Chagas disease.

Effects of diclofenac sodium and He:Ne laser irradiation on plasmatic fibrinogen levels in inflammatory processes.

OBJECTIVE: The aim of the present work was to determine the possible synergic effect on the concentration of plasma fibrinogen (PF) by injecting diclofenac sodium associated with laser therapy postsurgery. SUMMARY BACKGROUND DATA: Nonsteroidal anti-inflammatory drugs (NSAIDs) and He:Ne laser irradiation as a therapy were used to inhibit the effects generated by inflammation. Tissue injury produces significant increases in PF levels, which are reduced to normal values by administration of NSAIDs or laser irradiation of the injured zone. MATERIALS AND METHODS: Rate were divided into groups in which different presurgical and postsurgical treatment were used; the inflammation was induced by laparotomy. RESULTS: Parenteral diclofenac or He:Ne laser irradiation used separately in normal rats did not produce changes in the PF levels. Diclofenac and laser irradiation combined postsurgery produced a significant reduction of PF levels compared with normal values, or with groups that were injected or irradiated postsurgically. CONCLUSION: The inflammatory response could be reduced by the effect of the diclofenac sodium upon the COX-2/COX-1 inhibitory relation associated with the photobiological effect of the He:Ne laser.

Tecnica hemostatica en adenomectomia prostatica extracapsular / Prostatic technique in extracapsular prostatic adenomectomy

Los autores describen una experiencia con una técnica hemostática de adenomectomía vesicocapsular de abordaje extracapsular. Fueron intervenidos 117 pacientes; el sangrado intraoperatorio fue de 100 a 250 ml (promedio de 150 ml) y los pacientes no necesitaron transfusión sanguínea. De acuerdo con estos resultados las operaciones se acompañaron de menor sangrado intra y postoperatorio. Se evitaron las transfusion es sanguíneas y por lo tanto sus posibles complicaciones(AU)

Tecnica hemostatica en adenomectomia prostatica extracapsular / Prostatic technique in extracapsular prostatic adenomectomy

Los autores describen una experiencia con una técnica hemostática de adenomectomía vesicocapsular de abordaje extracapsular. Fueron intervenidos 117 pacientes; el sangrado intraoperatorio fue de 100 a 250 ml (promedio de 150 ml) y los pacientes no necesitaron transfusión sanguínea. De acuerdo con estos resultados las operaciones se acompañaron de menor sangrado intra y postoperatorio. Se evitaron las transfusion es sanguíneas y por lo tanto sus posibles complicaciones

In vitro synthesis of prostaglandin E2 by synovial tissue after helium-neon laser radiation in rheumatoid arthritis.

This paper reports the effect of helium-neon laser radiation (power of 5 mW and 632.8 nm wave length) on the synthesis of PGE2 in vitro in synovial tissue of biopsy samples of knee joints in patients with chronic rheumatoid arthritis stages II or III. Twelve patients were studied. Each patient received 15 applications of He-Ne laser. Eleven points for He-Ne laser applications were selected in one of the affected knees. The energy density used was 8 J/cm2 per application point. The He-Ne laser therapy reduced the synthesis of PGE2. The analysis of the data revealed a statistically significant difference between the levels of the synthesis of PGE2 before treatment (17.69 +/- 2.65 ng mg-1 of dry tissue h-1) and after treatment (13.85 +/- 2.73 ng mg-1 of dry tissue h-1), with p < 0.01 comparing mean values. This was also accompanied by relief of pain (91.6%), and a favorable subjective report from the patient. We conclude that PGE2 is a quantifiable parameter that could explain what causes pain relief in patients with rheumatoid arthritis that are treated with He-Ne laser.

Cardiac beta receptors' density or affinity modified by different Trypanosoma cruzi amount.

Chagas' disease presents complex physiopathogenic mechanism, many of them poorly understood, that in our country generally produce cardiac lesions. The acute phase related with the presence of the parasite is usually asymptomatic. This report studies if the amount of T. cruzi that induced acute infection could modify the myocardiopathy evolution. Previous works have shown that Albino Swiss mice inoculated with 45 tripomastigotes (AcL) presented alterations in the cardiac pharmacological response to adrenergic agonist and antagonist studied at 30 days post-infection (p.i). Mice inoculated with 7 x 10(4) parasites/animal showed similar behaviour at 7 days p.i. We studied the involvement of the affinity and density of cardiac beta receptors in both acute groups by binding with 3H/DHA. The AcH group presented less cardiac beta receptors number (p < 0.001), but their affinity was conserved. The AcL model presented significantly less affinity (p < 0.01) but density was not different from non infected animals. beta receptors' affinity of both infected groups were similar, but AcH density was significantly diminished when compared with AcL. These studies demonstrates that the amount of T. cruzi received by the host determines and acelerates the evolution of the chagasic myocardiopathy.

Cardiac beta-receptors in experimental Chagas' disease.

Experimental Chagas' disease (45 to 90 days post-infection) showed serious cardiac alterations in the contractility and in the pharmacological response to beta adrenergic receptors in normal and T. cruzi infected mice (post-acute phase). Chagasic infection did not change the beta receptors density (78.591 +/- 3.125 fmol/mg protein and 73.647 +/- 2.194 fmol/mg protein for controls) but their affinity was significantly diminished (Kd = 7.299 +/- 0.426 significantly diminished (Kd = 7.299 +/- 0.426 nM and Kd = 3.759 +/- 0.212 nM for the control) p < 0.001. This results demonstrate that the alterations in pharmacological response previously reported in chagasic myocardium are related to a significantly less beta cardiac receptor affinity. During this experimental period serious cardiac cell alterations take place and functional consequences will be detected in the chronic phase.

Isometric developed tension and histopathology of myocardium of chagasic mice. II.

In a preceding paper we reported the evolution of chagasic cardiopathy in mice inoculated with low number of T. cruzi from 2 days to 75 days post-infection (p.i.). The present work analyzed the contractility, pharmacological response and histopathology of myocardium isolated from chronic chagasic mice from 90 days until 180 days. p.i. Myocardium contractile force reached values similar to controls until 165 days p.i. From this to the end contractility was significantly lower. At 90 days p.i. NE provoked negative inotropic effect or had no effect in 13% of the cases tested. The others had a reactivity to NE similar to normal ventricles. From 105 days until 180 days p.i. NE induced to a positive inotropic effect significantly lower than in normal. ACh effect was significantly smaller from 165 days to the end. Previously ACh ventricles responses were as control. The effects of dibenamine, propranolol and atropine (10-6M) on chagasic ventricles were similar to those observed in normal tissues. At 90 days p.i. the histopathology showed focalized inflammatory infiltrates. At 180 days p.i. fibers fragmentations and loss of typical striated characteristic of cardiac tissue. The abnormal pharmacological response described could be attributed to alterations in cardiac beta and muscarinic receptors probably due to a lower oxygen support. The present paper shows that during chronic Chagas' disease myocardial function and pharmacological reactivity are seriously and definitively compromised.

Isometric developed tension and histopathology of myocardium of chagasic mice. II.

In a preceding paper we reported the evolution of chagasic cardiopathy in mice inoculated with low number of T. cruzi from 2 days to 75 days post-infection (p.i.). The present work analyzed the contractility, pharmacological response and histopathology of myocardium isolated from chronic chagasic mice from 90 days until 180 days. p.i. Myocardium contractile force reached values similar to controls until 165 days p.i. From this to the end contractility was significantly lower. At 90 days p.i. NE provoked negative inotropic effect or had no effect in 13

of the cases tested. The others had a reactivity to NE similar to normal ventricles. From 105 days until 180 days p.i. NE induced to a positive inotropic effect significantly lower than in normal. ACh effect was significantly smaller from 165 days to the end. Previously ACh ventricles responses were as control. The effects of dibenamine, propranolol and atropine (10-6M) on chagasic ventricles were similar to those observed in normal tissues. At 90 days p.i. the histopathology showed focalized inflammatory infiltrates. At 180 days p.i. fibers fragmentations and loss of typical striated characteristic of cardiac tissue. The abnormal pharmacological response described could be attributed to alterations in cardiac beta and muscarinic receptors probably due to a lower oxygen support. The present paper shows that during chronic Chagas disease myocardial function and pharmacological reactivity are seriously and definitively compromised.

Isometric developed tension and histopathology of myocardium of chagasic mice. II.

In a preceding paper we reported the evolution of chagasic cardiopathy in mice inoculated with low number of T. cruzi from 2 days to 75 days post-infection (p.i.). The present work analyzed the contractility, pharmacological response and histopathology of myocardium isolated from chronic chagasic mice from 90 days until 180 days. p.i. Myocardium contractile force reached values similar to controls until 165 days p.i. From this to the end contractility was significantly lower. At 90 days p.i. NE provoked negative inotropic effect or had no effect in 13

of the cases tested. The others had a reactivity to NE similar to normal ventricles. From 105 days until 180 days p.i. NE induced to a positive inotropic effect significantly lower than in normal. ACh effect was significantly smaller from 165 days to the end. Previously ACh ventricles responses were as control. The effects of dibenamine, propranolol and atropine (10-6M) on chagasic ventricles were similar to those observed in normal tissues. At 90 days p.i. the histopathology showed focalized inflammatory infiltrates. At 180 days p.i. fibers fragmentations and loss of typical striated characteristic of cardiac tissue. The abnormal pharmacological response described could be attributed to alterations in cardiac beta and muscarinic receptors probably due to a lower oxygen support. The present paper shows that during chronic Chagas disease myocardial function and pharmacological reactivity are seriously and definitively compromised.