A retrospective analysis of clinical outcome of patients with chemo-refractory metastatic breast cancer treated in a single institution phase I unit.

BACKGROUND AND METHODS: Novel approaches to treat chemo-refractory metastatic breast cancer (MBC) are currently under investigation. This retrospective series reviews the outcome of 70 MBC patients who have participated in 30 phase I trials at the Royal Marsden Hospital from 2002 to 2009. RESULTS: The median treatment lines before phase I trial entry for MBC was 5 (range: 1-12 lines). The overall response rate was 11.4% (95% CI: 4.0-18.9%) and the clinical benefit rate at 4 months was 20% (95% CI: 10.6-29.3). The median time to progression was 7.0 weeks (95% CI: 6.4-7.5) and median overall survival was 8.7 months (95% CI: 7.6-9.8) from start of first phase I treatment. No patients discontinued trial because of treatment-related toxicities. Abnormal lactate dehydrogenase, serum albumin <35 mg per 100 ml, >or=5 previous treatment lines, liver metastases and Eastern Cooperative Group performance status >or=2 at study entry were significantly associated with poor overall survival in multivariate analysis. CONCLUSION: This retrospective analysis provides evidence that patients with MBC tolerate phase I clinical trials and a significant proportion of patients with chemo-refractory disease, particularly those with triple-negative or Her2-positive breast cancer, may benefit from treatment.

The effects of sample size on the outcome of ovarian tissue cryopreservation.

Cryopreservation of ovarian tissue is known to affect follicular survival. Several variables may be responsible for this. Little attention has focused on the effect of the size of the fragment to be cryopreserved. This study was conducted to assess the effect of the size of the tissue on follicular histology after freezing with 1,2-propanediol. Histological evaluations were performed of control and cryopreserved tissue. Fragments were cut 10 x 3 x 2 mm(3) (2 mm group) or 10 x 3 x 4 mm(3) (4 mm group). Percentages of normal follicles in control fragments cut into 2 and 4 mm slices were 56% and 34%, respectively. The relative risks to obtain normal follicles in the 2 mm and the 4 mm fragments after cryopreservation were 0.63 and 0.47, respectively. Freezing reduced follicle survival to a significantly greater extent in the larger tissue fragments. There is an increased risk of damage to primary and primordial follicles, when the tissue slices are cut with all dimensions larger than 2 mm.

Phase II study of teniposide in patients with AIDS-related Kaposi's sarcoma.

Antitumour activity of cytotoxic agents, evaluated in patients with AIDS-related Kaposi's sarcoma (KS), is about 30-80%. However, responses are mostly partial and short. Experience with etoposide is similar. Teniposide has a longer elimination half-life and superior antitumour activity compared with etoposide in some experimental models. Thus a phase II trial was done in 25 patients with AIDS-related KS. Teniposide was given by 60-min infusion at 360 mg/m2 every 3 weeks. 10 (40%) showed a partial response, median duration of 9 (6-20) weeks. The main side-effects were leukopenia, thrombocytopenia, nausea and vomiting, alopecia and mucositis.

Pharmacokinetics of oxicam nonsteroidal anti-inflammatory agents.

Oxicam nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of structurally closely related substances with anti-inflammatory, analgesic and antipyretic activities. They have a weakly acidic character and are extensively bound to plasma proteins. Piroxicam, the most widely used oxicam, is well absorbed after oral administration. Peak plasma concentrations (Cmax) of the drug are reached within 2 to 4 hours. Piroxicam has a small volume of distribution and a low plasma clearance. It undergoes hepatic metabolism and only 5 to 10% is excreted unchanged in urine. The elimination half-life varies between 30 and 70 hours. Age of the patient and renal or hepatic dysfunction do not seem to have any major effect on the pharmacokinetics of piroxicam. The drug reduces the renal excretion of lithium to a clinically significant extent, but the clinical significance of piroxicam-aspirin (acetylsalicylic-acid) and piroxicam-acenocoumarol interaction has not been established. Ampiroxicam, droxicam and pivoxicam are prodrugs of piroxicam that have been synthesised to reduce piroxicam-related gastrointestinal irritation. All prodrugs are well absorbed, but Cmax values are reached later than those following administration of piroxicam. Tenoxicam is used in the management of rheumatic and inflammatory diseases. Mean Cmax values are achieved 2 hours postdose. Food reduces the rate but not the extent of absorption. The oral bioavailability of tenoxicam is 100% and rectal bioavailability is 80%. Like piroxicam, tenoxicam has a low volume of distribution and low plasma clearance. It is eliminated through hepatic metabolism. The mean elimination half-life is 60 to 75 hours. The pharmacokinetics of tenoxicam are independent of patient age, or concurrent liver or renal diseases. High doses of aspirin have been shown to increase the elimination of tenoxicam, but this has little clinical significance. Isoxicam was in widespread clinical use until its worldwide marketing was suspended because of fatal skin reactions. Isoxicam is completely absorbed, but Cmax values are not reached until 10 hours postdose. It has a low plasma clearance, approximately 5 ml/min (0.3 L/h), and low volume of distribution. The mean elimination half-life is 30 hours and does not appear to be affected by the age of the patient. Isoxicam potentiated the anticoagulant effect of warfarin, necessitating a 20% dosage reduction. Lornoxicam differs from other oxicam NSAIDs because it has a short elimination half-life of 3 to 4 hours. On the basis of limited data, some individuals seem to eliminate lornoxicam very slowly, suggesting the presence of polymorphic metabolism. The pharmacokinetics of cinnoxicam and sudoxicam have not been studied thoroughly.(ABSTRACT TRUNCATED AT 400 WORDS)

Radiographic imaging modalities for the patient in the emergency department with abdominal complaints.

The emergency physician should be aware of the sensitivity and specificity of any radiologic study being considered. Radiographic examinations should be used to answer specific questions raised by the history and physical examination. The need to obtain a given radiologic evaluation should be based on the potential information it may reveal and the likelihood that this information will alter patient care. This cost-effective approach minimizes unnecessary radiation exposure and has been advocated by many authorities. The emergency physician should resist the "knee jerk" tendency to order radiographs to reassure himself or herself of the safety of the patient at discharge. Documentational and legal concerns are equally invalid reasons, as is the feeling that "it's what we always order for patients with this abdominal complaint." A given study may be indicated if the yield is acceptable and treatment of the patient may be altered by the results.

Effects of arm bracing posture on respiratory muscle strength and pulmonary function in patients with chronic obstructive pulmonary disease.

OBJECTIVE: To analyze the effect of arm bracing posture on respiratory muscle strength and pulmonary function in patients with Chronic Obstructive Pulmonary Disease (COPD). METHODS: 20 patients with COPD (11 male; 67 ± 8 years; BMI 24 ± 3 Kg · m⁻²) were submitted to assessments of Maximal Inspiratory and Expiratory Pressures (MIP and MEP, respectively) and spirometry with and without arm bracing in a random order. The assessment with arm bracing was done on standing position and the height of the support was adjusted at the level of the ulnar styloid process with elbow flexion and trunk anterior inclination of 30 degrees promoting weight discharge in the upper limbs. Assessment without arm bracing was also performed on standing position, however with the arms relaxed alongside the body. The time interval between assessments was one week. RESULTS: MIP, MEP and maximal voluntary ventilation (MVV) were higher with arm bracing than without arm bracing (MIP 64 ± 22 cmH2O versus 54 ± 24 cmH2O, p = 0,00001; MEP 104 ± 37 cmH2O versus 92 ± 37 cmH2O, p = 0,00001 and MVV 42 ± 20 L/min versus 38 ± 20 L/min, p = 0,003). Other variables did not show statistical significant difference. CONCLUSION: The arm bracing posture resulted in higher capacity to generate force and endurance of the respiratory muscles in patients with COPD.

Recent therapeutic advances for treating medulloblastoma: focus on new molecular targets.

Medulloblastoma is the most common malignant brain tumor in children. This malignant tumor of the cerebellum commonly affects children and is believed to arise from the precursor cells of the external granule layer or neuroepithelial cells from the cerebellar ventricular zone of the developing cerebellum. The standard treatment, consisting of surgery, craniospinal radiotherapy and chemotherapy, still provides a poor overall survival for infants and young children. Furthermore, the dose of radiation that can be safely given without causing extensive neurocognitive and endocrinologic sequelae is limited. Therefore, understanding the oncogenic pathways that lead to medulloblastoma, as well as the identification of specific molecular targets with significant therapeutic implications in order to develop new strategies for therapy, is crucial to improve patient survival without substantially increasing toxicity. In this review, we discuss recent therapeutics for treating medulloblastoma, focusing on new molecular targets, as well as advances in translational studies for the treatment of this malignancy.

Sodium butyrate enhances the cytotoxic effect of antineoplastic drugs in human lymphoblastic T-cells.

Sodium butyrate (NaB), a potent histone deacetylase inhibitor, induces cell cycle arrest and apoptosis in malignant cells. We investigated the effects on cellular proliferation in vitro when combining NaB with antineoplastic drugs commonly used to treat leukemias. Our results demonstrate that NaB increases the cytotoxic effects of cytarabine and etoposide, but not of bleomycin, doxorubicin, vincristine or methotrexate. These data suggest that NaB is a promising adjuvant therapeutic agent for the treatment of lymphoblastic leukemias, and provides a basis for further studies in this field.

Effects of gender and aerobic fitness on cardiac autonomic responses to head-up tilt in healthy adolescents.

Cardiovascular autonomic responses to orthostatic challenges are affected by gender and cardiorespiratory fitness in adults. However, little is know about the effects of these factors in healthy adolescents. We studied 41 adolescents (20 boys and 21 girls) aged 12-17 years, divided into aerobic fitness tertiles based on the results of a maximal treadmill exercise test. Cardiac autonomic modulation was assessed by heart rate variability (HRV) analysis of 5-minute RR interval recordings before and after 70 degrees head-up tilt maneuver. HRV was analyzed by time (TD) and frequency domain (FD) methods. TD was analyzed by standard deviation of the RR intervals and the root mean square of successive differences of RR intervals. The power spectral components were studied at low (LF) and high (HF) frequencies and as the LF/HF ratio. We did not find any differences in TD and FD measures before and after tilt in either gender or fitness groups, except for a higher heart rate response for boys. These results suggests that cardiac autonomic responses to head-up tilt in healthy adolescents are not affected by gender or aerobic fitness.

Vanilmandelic acid and homovanillic acid levels in patients with neural crest tumor: 24-hour urine collection versus random sample.

Neuroblastoma is the most common solid tumor in childhood and is the most frequent neural crest tumor (NCT). More than 90% of the patients excrete high levels of vanilmandelic acid (VMA) and homovanillic acid (HVA) in the urine. Original biochemical methods for measuring these two metabolites of catecholamines employed a collection of urine for 24 hours to avoid errors related to circadian cycle variations. More recently, attempts have been made to replace the 24-hour collections by random samples (RSs). This has practical advantages particularly for young children. The objective of this study is to assess whether urinary VMA related to urinary creatinine levels can be determined reliably by the method of Pisano et al. from RSs in patients with NCT. The determination of the consumption of VMA in urine stored for prolonged periods of time was also studied. We found a good correlation between the values of metabolites of catecholamines in RSs compared with 24-hour urine collections. There was consumption of VMA in urine samples after storage. We conclude that determination of VMA in RSs of urine by Pisano's method may identify NCT production of catecholamines and that the consumption of these catecholamines is an important factor to consider in the interpretation of values obtained with stored urine specimens.

Limited brain access for leptin in obesity.

Obesity is a major health problem that contributes to the development of type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease. The current pharmacological therapies for obesity are limited and may have significant side effects. Leptin therapy was shown to effectively cause weight loss in obese rats, however its effectiveness in humans is still under investigation. Obese humans have significantly elevated plasma leptin concentrations compared with lean individuals. Plasma leptin concentrations strongly correlated with percentage of body fat. Leptin concentration in the cerebrospinal fluid (CSF) is correlated, in a nonlinear manner, with plasma leptin levels and body mass index (BMI). The ratio of CSF leptin levels to serum leptin levels was 4 times greater in lean individuals than in obese individuals. One interpretation of this finding is that human obesity could be secondary to a central resistance to leptin action, causing a relative leptin deficiency in the CNS. Six years after the discovery of leptin we still do not have a clear understanding of how leptin accesses its targets in the brain, or whether there is defect in this process in the brain of obese individuals. In this manuscript we will review the different leptin gateways to the brain and the potential sites where a defect in leptin action may be present, as well as some potential clinical implications of leptin. A better understanding of how leptin reaches the brain and how it modulates the release of hypothalamic neuropeptides will be important in understanding the role that leptin plays in the pathophysiology of obesity.

[Bone marrow transplantation and cord blood transplantation in children] / Transplante de medula óssea e transplante de sangue de cordão umbilical em pediatria.

OBJECTIVE: To review the indications, main steps and complications of bone marrow transplantation in children. SOURCES: Medline-based literature review. SUMMARY OF THE FINDINGS: We comment about the indications of autologous, allogeneic and syngeneic bone marrow transplantation, donor selections, harvest and infusion of the hematopoietic progenitor cells that will reconstitute the hematopoietic and immune systems. We describe the different conditioning regimens and the new sources of cells, such as cord blood. We also describe the most common events after the procedure, including infections, graft versus host disease, and cardiovascular, pulmonary, hepatic, genitourinary, and gastrointestinal complications. The late effects and their impact on quality of life are also discussed. CONCLUSIONS: Bone marrow transplantation does not confer an absolutely normal life span to all the patients; however, it represents the only chance of cure for children with certain neoplastic or immunological diseases. By knowing the steps of the procedure, pediatricians can be a source of information on bone marrow transplantation to the patients and their families.

Effects of isolated cycle ergometer training on patients with moderate-to-severe chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary rehabilitation (PR) programs are beneficial to patients with chronic obstructive pulmonary disease (COPD), and lower-extremity training is considered a fundamental component of PR. Nevertheless, the isolated effects of each PR component are not well established. OBJECTIVE: We aimed to evaluate the effects of a cycle ergometry exercise protocol as the only intervention in a group of COPD patients, and to compare these results with a control group. METHODS: 25 moderate-to-severe COPD patients were evaluated regarding pulmonary function, respiratory muscle strength, exercise capacity, quality of life and body composition. Patients were allocated to one of two groups: (a) the trained group (TG; n = 13; 6 men) was submitted to a protocol of 24 exercise sessions on a cycle ergometer, with training intensity initially set at a heart rate (HR) close to 80% of maximal HR achieved in a maximal test, and load increase based on dyspnea scores, and (b) the control group (CG; n = 12; 6 men) with no intervention during the protocol period. RESULTS: TG showed within-group significant improvements in endurance cycling time, 6-min walking distance test, maximal inspiratory pressure and in the domain 'dyspnea' related to quality of life. Despite the within-group changes, no between-group significant differences were observed. CONCLUSION: In COPD patients, the results of isolated low-to-moderate intensity cycle ergometer training are not comparable to effects of multimodality and high-intensity training programs.

[A paradigmatic case of partial agenesis of the pericardium]. / Un caso paradigmatico di agenesia parziale del pericardio.

Complete or partial absence of the pericardium is an uncommon congenital abnormality. Since its first description, several cases have been reported. Although the clinical and instrumental features of this defect are well described, at present it is often overlooked. We report a case of a 19-year old boy referred to our Echocardiography laboratory because of a suspected interatrial septal defect. For this reason it has been recommended to undergo cardiac catheterization. The patient, completely asymptomatic, had a negative physical examination. The echocardiogram excluded the presence of an interatrial septal defect, but some abnormalities, regarding overall right-sided heart, were found (paradoxical interventricular septal movement, apparent right-sided heart enlargement, with unusual bulging of the apex of the right ventricle, an excessive basculant heart movement). In the absence of any other heart disease, we thought that these abnormalities reflected a congenital absence of the pericardium. Indeed, the chest X-ray showed some features, considered patognomonic for congenital absence of the pericardium (levoposition of the heart, lung interposition between the diaphragm and the base of the heart and between the aorta and pulmonary artery). Nuclear magnetic resonance study showed the absence of the pericardium in the posterior and posterolateral wall, confirming our suspicion. Furthermore, the posterior wall of the heart leaned to herniate through the pericardial defect. Since the partial absence of the pericardium can lead to severe complications, surgery was recommended. The correct diagnosis of this disease is very important because of its prognostic implications; this case represents a further contribution to the understanding of this defect.

Clostridium difficile in an oncology unit.

In one year 21 new cases of Clostridium difficile infection occurred on a paediatric oncology unit. Eleven cases were in a two month period. This infection should be regarded as a communicable disease. Investigations to detect C difficile should be carried out in children with malignant disease who have diarrhoea.

The effect of pharmacological modification of gastric emptying and mouth-to-caecum transit time on the absorption of sugar probe marker molecules of intestinal permeability in normal man.

The present study examined the hypothesis that altered motility of the gastrointestinal tract affects absorption of probe markers of intestinal permeability. Seven healthy subjects, aged 32-44 years, received saline, 600 micrograms atropine or 10 mg metoclopramide in randomized order at weekly intervals. After 10 min they ingested a test solution containing 5 g lactulose, 5 g mannitol and 2 g 3-O-methyl glucose in 100 ml tap water. The molarity of the solution was 542 mmol l-1 and the dose administered was 80 ml m-2 body surface area. Gastric emptying was measured by ultrasound, mouth-to-caecum transit time by breath hydrogen analysis and sugar concentrations by gas-liquid chromatography. Gastric emptying half-times (min) were [mean (95% confidence intervals)] 14.9 (11:4-18.5) after saline, 22 (18.7-25.2) after atropine and 10.3 (7.0-12.6) after metoclopramide (P less than 0.002). Transit times (min) were 68.9 (52-85.2) after saline, 143 (126-159) after atropine and 38 (21.2-54.5) after metoclopramide; P less than 0.0001. Analysis of plasma levels of mannitol and 3-O-methyl glucose showed a significant within-subject effect of drug with time (P less than 0.03). Urinary excretion of mannitol in the first 5 h after ingestion of the test solution was 1256 (974-1620) mg after saline, 1560 (1210-2013) mg after atropine and 955 (740-1232) mg after metoclopramide (P less than 0.03). There were no significant differences in lactulose and 3-O-methyl glucose urinary excretion between drug treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Active and passive sugar absorption in pancreatic insufficiency.

Urinary excretion of lactulose, mannitol, and 3-0-methylglucose, following oral administration (5 g, 5 g, and 2 g, respectively, in 100 ml H2O; 80 ml/m2), has been measured in subjects with cystic fibrosis (CF) (22), Shwachman syndrome (3), chronic pancreatitis (3), and normal controls (46). Mean lactulose excretion was increased 10-fold in CF (p less than 0.001), and two-fold in other disorders associated with pancreatic insufficiency (PI) (p less than 0.05). Mean mannitol excretion was 1.6 times greater in CF (p less than 0.001), compared with controls, but was reduced in other forms of PI (p less than 0.03). The mean lactulose/mannitol excretion ratio was increased in all types of PI (p less than 0.001). There were no significant differences in 3-0-methylglucose excretion. This study confirms the large increase in lactulose absorption recently reported in CF and also demonstrates increased absorption of mannitol; these changes are different than those in other forms of PI. This study provides further evidence for a specific abnormality of the mucosal barrier to the absorption of passively absorbed, water soluble molecules in CF.