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.

Short communication: placental collagen and premature rupture of fetal membranes.

Collagen content of 43 placentae from clinically normal females who went into labour spontaneously was determined by assaying hydroxyproline. In 23 cases the membranes ruptured before or at the beginning of labour, and in 20 cases the rupture was intrumentally provoked during the expulsive period. In the group with prematurely ruptured membranes, hydroxyproline concentration was 11.52 +/- 1.83 micrograms/mg lyophilized tissue, whereas in the other group concentration was 20.29 +/- 4.32 micrograms/mg tissue. These data disclose a much lower collagen placental content in the group with premature rupturing of the membranes.

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.

[Arterial hypertension in childhood and adolescence]. / Hipertension arterial en la niñez y en la adolescencia.

One thousand six hundred and ninety-eight children and adolescents four to eighteen years-old were studied, eight hundred and forty of them were males and eight hundred and fifty-eight females. No individual following, was performed. Two determinations of both systolic and diastolic pressure were registered after a fifteen minutes rest, and the average figures of both, of them was registered. The group analyzed belonged to upper middle class and the hypertension figures were: females 28 (3.26%) and males 30 (3.57%). The influence of bodily area was observed en hypertensive patients. Those located between the average +/- two standard deviations were considered as normal. (95% of the cases).

Plasma fibrinogen response in the rat after thyroid stimulating hormone therapy.

Thyroid Stimulating Hormone (TSH) increased the levels of plasma fibrinogen in the presence or absence of the thyroid gland. This finding suggests that this hormone produces an elevation of fibrinogen in rats by an extra-thyroideal mechanism.

CO2 laser in decubitus ulcers: a comparative study.

This is a comparative study of conventional surgery (knife/electric knife) and CO2 laser surgery and their effect on the outcome of stage III (including muscle) and stage IV (including bone) decubitus ulcers with an average area of 400 cm2. It is a prospective clinical study done with two groups of patients of similar age, economic and social background, as well with similar types of decubitus ulcers. Thirty patients were studied in each group. The study demonstrated a statistically significant difference in favor of the patients treated with CO2 laser with regard to operative blood loss, 0.5 cc/cm2 or 20% (P less than .01), infection rate (chi 2 test, P less than .01), and difference (60%) in recovery time (P less than .01). This translated into an average saving of 23 hospitalization days per patient. It also showed a difference, though not statistically significant, favoring the group treated with laser with respect to survival and full recovery. This probably is attributable to the lowered blood loss and infection rate as well as improved operative time and analgesia.

Effects of insulin on plasma fibrinogen levels in rats submitted to tissue injury or ACTH administration.

Insulin is necessary to produce an increase of plasma fibrinogen in rats submitted to tissue injury or ACTH administration. This increase is more significant when endogenous or exogenous excess of insulin is present, while in uninjured rats the absence or excess insulin does not modify plasma fibrinogen.

Effects of indomethacin on plasma fibrinogen levels in rats with tissue injury.

The present investigation was designed to study the effect of indomethacin (5 mg kg-1 day-1) on plasma fibrinogen levels in laparotomized rats. Whereas tissue injury significantly increased plasma fibrinogen when compared to normal uninjured rats, indomethacin completely blocked that effect. Conversely, indomethacin did not prevent fibrinogen increase in laparotomized rats injected with epinephrine, with spinal cord transection + epinephrine or with adrenal medullectomy + epinephrine. Indomethacin or epinephrine administration to normal rats did not modify plasma fibrinogen. Taking into account that epinephrine is a key hormone in plasma fibrinogen response in laparotomized rats, and according to our results, prostaglandins might act by two possible pathways: 1) by decreasing of the pain threshold of the sensory nerve endings and stimulating sympathetic adreno-medullar system; 2) by entering into the blood stream and enhancing epinephrine action on plasma fibrinogen. It would appear that indomethacin inhibits both pathways.

Interactions of prostaglandin E1, bradykinin and histamine and the increase of plasma fibrinogen in rats.

Considering that tissue injury caused by laparotomy significantly increases the liver synthesis of plasma fibrinogen, and that PGE1, bradykinin and histamine are released into the injured tissues, the effect of above mentioned inflammatory agents and of the adrenal medulla on plasma fibrinogen levels in rats was studied. The subcutaneous administration of PGE1, bradykinin or histamine does not modify plasma fibrinogen levels acting independently comparing with non-injected animals or injected with the drug vehicle. Bradykinin + histamine did not modify plasma fibrinogen levels either. However the administration of prostaglandin E1 + bradykinin + histamine reproduced the increase of fibrinogen characteristics of laparotomy. This increase was partially but significantly inhibited in rats that had undergone bilateral removal of the adrenal medulla or administration of PGE1 + bradykinin + histamine + bupivacaine (a local anesthetic), but it was not modified when the adrenal medullectomy was unilateral. It is concluded that plasma fibrinogen increase is obtained only when PGE1 acts in presence of bradykinin or histamine and the adrenal medulla should be partially responsible for said increase.

Rôle of histamine on plasma fibrinogen levels in rats with surgical injury (laparotomy).

The probable rôle of endogenous histamine in the increase of plasma fibrinogen in rats submitted to tissue injury (laparotomy) was studied. In laparotomized rats with 10 mg kg-1 day-1 of diphenhydramine (a H1-histamine receptor blocker) plasma fibrinogen decreased significantly as compared to the group of rats laparotomized only (P less than 0.02), reaching values similar to those observed in rats laparotomized with removal of the adrenal medulla or laparotomized with severing of splanchnic nerves. There is a significant difference between these latter groups and the normal noninjured group (P less than 0.01). Plasma fibrinogen did not modify (as compared with the uninjured group) in rats injected only with histamine (1 mg kg-1 day-1) or with diphenhydramine. Taking into account the results obtained and the mechanism of action of diphenhydramine, it would seen that endogenous histamine takes part in the increase of plasma fibrinogen in laparotomized rats, perhaps indirectly through stimulation of the adrenal medulla secretion.

Effects of the administration of progesterone and adrenal medullectomy on the plasma fibrinogen levels in rats with surgical injury (laparotomy).

The probable rôle played by the adrenal medulla in the decrease of plasma fibrinogen due to the administration of progesterone (0.5 mg kg-1 day-1 during 72 h) in rats submitted to surgical injury (laparotomy) was studied. The results obtained lead to assume that the decrease of plasma fibrinogen observed in laparotomized rats injected with progesterone is indirectly produced through inhibition of the adrenal medulla. The action of progesterone on the plasma fibrinogen would be a pharmacological effect of the drug, since in doses of 0.10 mg kg-1 day-1 the decrease of the fibrinogen is not observed in laparotomized rats. The administration of progesterone in non injured rats does not modify the plasma fibrinogen as compared to the group of non injected rats.

Effects of diethylstilbestrol, 17 beta estradiol, and progesterone on plasma fibrinogen levels in rats submitted to tissue injury (laparotomy).

Participation of estrogens (17 beta estradiol, diethylstilbestrol) and progesterone in the increase of plasma fibrinogen levels in female rats submitted to tissue injury (laparotomy) was studied. Ovariectomy avoided the increase of fibrinogen observed in laparotomized rats, while the administration of 17 beta estradiol or diethylstilbestrol to laparotomized-ovariectomized rats increased fibrinogen to levels similar to those observed in the group of laparotomized rats without other treatment. On the other hand, progesterone inhibited the increase of fibrinogen which is typical of laparotomy in both groups: one of laparotomized rats and the other of laparotomized rats injected with estrogens. Neither estrogens nor progesterone modify plasma fibrinogen levels in uninjured rats. It is concluded that estrogens might participate in the fibrinogen increase observed after tissue injury in female rats, and on the contrary, the administration of progesterone would render that increase null.

Effects of epinephrine on plasma fibrinogen levels in rats submitted to tissue injury.

Tissue injury (laparotomy) produces an increase in plasma fibrinogen. This increase is inhibited by the removal of the adrenal medulla, but injection of epinephrine in laparotomized-medullectomized rats returns fibrinogen levels to values similar to those observed in only laparotomized rats. Epinephrine administration to laparotomized rats increases the fibrinogen compared with the group of laparotomized rats without treatment, but epinephrine by itself does not modify plasma fibrinogen levels in uninjured rats. Epinephrine is apparently responsible for the increase of plasma fibrinogen in rats subjected to tissue injury, probably through beta adrenergic stimulation.