Uncertain diagnosis and prognosis in advanced melanoma: a qualitative study of the experiences of bereaved carers in a time of immune and targeted therapies.

BACKGROUND: Recent advances in advanced melanoma therapies are associated with improved survival for some patients. However, how patients with diagnoses of advanced disease and their carers experience this expanding treatment paradigm is not well understood. OBJECTIVES: To explore bereaved carers' accounts of the trajectory of advanced melanoma involving treatment by immune or targeted therapies, to build an understanding of their experiences of care relating to diagnosis and prognosis. METHODS: A qualitative exploratory design, using methods drawn from grounded theory, was adopted. Analyses drew on in-depth interviews with 20 bereaved carers from three metropolitan melanoma treatment centres in Australia. A flexible interview guide and structured approach to concurrent data collection and analysis were applied. RESULTS: Carers described qualities of the experience, including the shock of diagnosis after a sometimes-innocuous presentation with vague symptoms. They reported an unclear prognosis with complexity arising from interplay between an uncertain disease trajectory and often ambiguous expectations of outcomes of emerging immune and targeted therapies. Uncertainty dominated carers' experiences, increasing the complexity of care planning. CONCLUSIONS: Effective communication of an advanced melanoma diagnosis and prognosis is critical. Recognition of the uncertainty inherent in the benefit of immune and targeted therapies in a constructive manner may facilitate more timely and effective care-planning conversations between patients, carers and medical specialists.

Metabolism and disposition of the anticancer quinolone derivative vosaroxin, a novel inhibitor of topoisomerase II.

Background Vosaroxin is a first-in-class anticancer quinolone derivative that is being investigated for patients with relapsed or refractory acute myeloid leukemia (AML). The primary objective of this study was to quantitatively determine the pharmacokinetics of vosaroxin and its metabolites in patients with advanced solid tumors. Methods This mass balance study investigated the pharmacokinetics (distribution, metabolism, and excretion) of vosaroxin in cancer patients after a single dose of 60 mg/m2 14C-vosaroxin, administered as short intravenous injection. Blood, urine and feces were collected over 168 h after injection or until recovered radioactivity over 24 h was less than 1% of the administered dose (whichever was earlier). Total radioactivity (TRA), vosaroxin and metabolites were studied in all matrices. Results Unchanged vosaroxin was the major species identified in plasma, urine, and feces. N-desmethylvosaroxin was the only circulating metabolite detected in plasma, accounting for <3% of the administered dose. However, in plasma, the combined vosaroxin + N-desmethylvosaroxin AUC0-∞ was 21% lower than the TRA AUC0-∞ , suggesting the possible formation of protein bound metabolites after 48 h when the concentration-time profiles diverged. The mean recovery of TRA in excreta was 81.3% of the total administered dose; 53.1% was excreted through feces and 28.2% through urine. Conclusions Unchanged vosaroxin was the major compound found in the excreta, although 10 minor metabolites were detected. The biotransformation reactions were demethylation, hydrogenation, decarboxylation and phase II conjugation including glucuronidation.

Quantification of vosaroxin and its metabolites N-desmethylvosaroxin and O-desmethylvosaroxin in human plasma and urine using high-performance liquid chromatography-tandem mass spectrometry.

Vosaroxin is a first-in-class anticancer quinolone derivative topoisomerase II inhibitor that is currently in development in combination with cytarabine for the treatment of acute myeloid leukemia (AML). To investigate vosaroxin pharmacokinetics (PK) in patients, liquid chromatography tandem mass spectrometry (LC-MS/MS) assays to quantify vosaroxin and the two metabolites N-desmethylvosaroxin and O-desmethylvosaroxin in human plasma and urine were developed and validated. Immediately after collection the samples were stored at -80°C. Prior to analysis, the plasma samples were subjected to protein precipitation and the urine samples were diluted. For both assays the reconstituted extracts were injected on a Symmetry Shield RP8 column and gradient elution was applied using 0.1% formic acid in water and acetonitrile-methanol (50:50, v/v). Analyses were performed with a triple quadruple mass spectrometer in positive-ion mode. A deuterated isotope of vosaroxin was used as internal standard for the quantification. The validated assays quantify vosaroxin and N-desmethylvosaroxin in the concentration range of 2-500ng/mL in plasma and urine. For O-desmethylvosaroxin the concentration range of 4-500ng/mL in plasma and urine was validated. Dilution integrity experiments show that samples can be diluted 25 fold in control matrix prior to analysis. The expanded concentration range for plasma and urine for vosaroxin and N-desmethylvosaroxin is therefore from 2 to 15,000ng/mL and in plasma for O-desmethylvosaroxin from 4 to 15,000ng/mL.

Prospective Assessment of Radiation in Pediatric Urology: The Pediatric Urology Radiation Safety Evaluation Study.

PURPOSE: Pediatric tissues are exquisitely sensitive to ionizing radiation from diagnostic studies and therapies involving fluoroscopy. We prospectively monitored radiation exposure in our pediatric urology patients during fluoroscopy guided operative procedures with single point dosimeters to quantify radiation dose. MATERIALS AND METHODS: Children undergoing fluoroscopy guided urological procedures were prospectively enrolled in the study from 2013 to 2015. Single point dosimeters were affixed to skin overlying the procedural site for the durations of the procedures to record dosimetry data. Patient demographics, procedural variables and fluoroscopic settings were recorded. RESULTS: A total of 78 patients underwent 96 procedures, including retrograde pyelography, ureteral stent insertion, ureteroscopy and percutaneous nephrolithotomy. Median patient age was 12 years (range 0.3 to 17) and median body mass index percentile for age was 70.7 (1.0 to 99.1). Median skin entrance radiation dose for all procedures performed was 0.56 mGy. Median dosages associated with the 29 diagnostic procedures and 49 definitive interventions were 0.6 mGy (mean 0.8, range 0.1 to 2.2) and 0.7 mGy (1.1, 0.0 to 5.5), respectively. The dose associated with the 18 procedures of temporization was significantly higher by comparison (median 1.0 mGy, mean 2.6, range 0.1 to 10.7, p = 0.02). CONCLUSIONS: Pediatric radiation exposure is not insignificant during urological procedures. Further multi-institutional work would provide context for our findings. Protocols to optimize fluoroscopic settings and minimize patient exposure, and guidelines for radiation based imaging should have a key role in all pediatric radiation safety initiatives.

Tracking of radiation exposure in pediatric stone patients: The time is now.

BACKGROUND: Despite the increasing incidence of pediatric nephrolithiasis, there is little data quantifying the radiation exposure associated with treatment of this disease. In this study, pediatric patients with nephrolithiasis who were managed at a single institution were identified, and the average fluoroscopy time and estimated radiation exposure associated with their procedures were reported. METHODS: Stone procedures performed on pediatric patients between 2005 and 2012 were retrospectively identified. Procedures were classified as primary ureteroscopy (URS), stent placement prior to ureteroscopy (SURS), percutaneous nephrolithotomy (PCNL), and bilateral ureteroscopy (BLURS). Patient demographic information, stone size, stone location, number of radiographic images, and fluoroscopy times were analyzed. RESULTS: A total of 152 stone procedures were included in the final analysis (92 URS, 38 SURS, eight BLURS and 14 PCNL). Mean patient age at time of stone treatment was 15.94 ± 4.1 years. Median fluoroscopy times were 1.6 (IQR 0.8-2.4), 2.1 (IQR 1.6-3.0), 2.5 (IQR 2.0-2.9), and 11.7 (IQR 5.0-18.5) minutes for URS, SURS, BLURS and PCNL, respectively. There was a moderate correlation between stone size and fluoroscopy time (r = 0.33). When compared with ureteroscopic procedures, PCNL was associated with a significantly higher fluoroscopy time (11.7 vs 2.1 min, P < 0.001). The estimated median effective dose was 3 mSv for ureteroscopic procedures and 16.8 mSv for PCNL. In addition to radiation exposure during treatment, patients in this cohort were exposed to an average of one (IQR1-3) CT scan and three (IQR 1-8) abdominal X-rays. No new malignancies were identified during the limited follow-up period. CONCLUSIONS: Radiation exposure during treatment of pediatric stone disease is not trivial, and is significantly greater when PCNL is performed. Given the recommended maximum effective dose of 50 mSv in any one year, urologists should closely monitor the amount of fluoroscopy used, and consider the potential for radiation exposure when choosing the operative approach. Prospective studies are currently underway to elucidate precise dose measurements and localize sites of radiation exposure in children during stone treatment.

Emergent transesophageal echocardiography in hemodynamically unstable obstetric patients.

BACKGROUND: The obstetric population has an increasing incidence of comorbid conditions. These, coupled with the possibility of acute embolic events involving air, amniotic fluid, and thrombus, increase the likelihood of hemodynamic instability. Although the utility of transesophageal echocardiography to guide management in cardiac and high-risk, non-cardiac surgical populations has been well established, the emergent use in critically-ill parturients has not been comprehensively evaluated. METHODS: Using our departmental transesophageal echocardiography database of 28 293 examinations, parturients were identified who underwent emergent transesophageal echocardiography for evaluation of hemodynamic instability, including cardiac arrest, between January 1999 and March 2014. Transesophageal echocardiography findings and their impact on patient management were analyzed. RESULTS: Ten peripartum patients were evaluated. Six patients became unstable during dilation and evacuation procedures; one after a forceps delivery; one during and one after cesarean delivery; and one during a postpartum laparotomy. Six patients proceeded to cardiac arrest; however, all women survived their initial operation and resuscitation. Transesophageal echocardiography was instrumental in determining the etiology and guiding resuscitation in all 10 patients including emergent cardiac surgical intervention with cardiopulmonary bypass (n=2). Seven patients survived to hospital discharge, but three died after experiencing neurologic complications. CONCLUSIONS: Severe hemodynamic instability and cardiac arrest can occur in previously healthy parturients in pregnancy. Our data suggest that emergent transesophageal echocardiography is a valuable tool in determining the etiology and directing therapy of refractory hypotension or cardiac arrest in obstetric patients.

Balloon tamponade for variceal haemorrhage: a practical approach.

Balloon tamponade with compression tubes is used to stabilise life-threatening variceal bleeds when first-line endotherapy has failed and acts as a bridge to early definitive therapy. We present an overview of the use of compression tubes for variceal haemorrhage with a focus on insertion technique and aftercare.

A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia.

This study of vosaroxin evaluated dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics (PK), clinical activity and pharmacodynamics in relapsed/refractory leukemia. Dosing was weekly (days 1, 8 and 15) or twice weekly (days 1, 4, 8 and 11). Seventy-three treated patients had a median age of 65 years, 85% had acute myeloid leukemia and 78% had refractory disease. Weekly schedule: 42 patients received 18-90 mg/m(2); MTD was 72 mg/m(2). Twice-weekly schedule: 31 patients received 9-50 mg/m(2); MTD was 40 mg/m(2). DLT was stomatitis; primary non-hematologic toxicity was reversible gastrointestinal symptoms and febrile neutropenia. Thirty-day all-cause mortality was 11%. Five patients had complete or incomplete remissions; median duration was 3.1 months. A morphologic leukemia-free state (bone marrow blast reduction to <5%) occurred in 11 additional patients. Antileukemic activity was associated with total dose or weekly time above 1 µmol/l plasma vosaroxin concentration (P<0.05). Vosaroxin exposure was dose proportional over 9-90 mg/m(2). The average terminal half-life was ~25 h and clearance was non-renal. No induction or inhibition of vosaroxin metabolism was evident. Vosaroxin-induced DNA damage was detected as increased intracellular γH2AX. Vosaroxin had an acceptable safety profile, linear PK and encouraging clinical activity in relapsed/refractory leukemia.

Budd-Chiari syndrome--a review of the diagnosis and management.

Budd-Chiari syndrome (BCS) is the liver disease resulting from hepatic venous outflow obstruction comprising a triad of abdominal discomfort, hepatomegaly and ascites. Advances in the management of this disorder over the last three decades have dramatically improved survival. We present a review of the management of BCS followed by a case which illustrates some key points in the diagnosis and treatment of this condition.

Development of late, symptomatic abdominopelvic lymphoceles more than 10 years following pediatric reconstructive urologic procedures.

PURPOSE: Rare reports of symptomatic abdominopelvic lymphoceles following pediatric genitourinary reconstruction do exist; however there are no data regarding the development or management of late symptomatic lymphoceles. We report on the clinical presentation of these lymphoceles 10 or more years following initial urologic surgery. MATERIALS AND METHODS: We reviewed 480 patients following major intra-abdominal urologic reconstructive procedures from 1986 to 2009 for development of late, symptomatic abdominopelvic lymphoceles. A minimum of 10 years post-surgical follow up was required for inclusion. RESULTS: Late symptomatic lymphoceles developed in 4/480 (0.8%) patients. Median length of follow up post reconstruction was 13.5 years (range 10-17). Median time to lymphocele development was 12 years (range 8-16). Symptoms at presentation included abdominal distension (4/4, 100%), nausea and vomiting (3/4, 75%), flank pain/progressive hydroureteronephrosis (3/4, 75%), and obstructive pyelonephritis (1/4, 25%). Additional surgical procedures that may have contributed to lymphocele development were present in 100%. 75% (3/4) of the patients underwent open surgical drainage, with one electing observation for intermittent symptoms. Exploration revealed loculated fluid collections between bowel loops and dense adhesions; symptoms resolved although small asymptomatic recurrences developed in all patients. CONCLUSIONS: Late, symptomatic abdominopelvic lymphoceles following major pediatric urinary tract reconstruction or diversion develop in <1% patients. Many undergo subsequent abdominopelvic surgery, which may contribute to development of these late, pathologic lymphoceles. Open surgical drainage is usually required with excellent outcome.

Augmentation cystoplasty and risk of neoplasia: fact, fiction and controversy.

PURPOSE: We determined if ileal/colonic bladder augmentation performed in patients with congenital bladder abnormalities is an independent risk factor for bladder malignancy. MATERIALS AND METHODS: We reviewed a registry of patients with bladder dysfunction due to neurological abnormalities, exstrophy and posterior urethral valves. Individuals treated with augmentation cystoplasty were matched (1:1) to a control group treated with intermittent catheterization based on etiology of bladder dysfunction, gender and age (±2 years). RESULTS: We evaluated 153 patients with an ileal/colonic cystoplasty and a matched control population. There was no difference (p=0.54) in the incidence of bladder cancer in patients with augmentation cystoplasty (7 patients [4.6%]) vs controls (4 [2.6%]). In addition, there was no difference between the 2 groups regarding age at diagnosis (51 vs 49.5 years, p>0.7), stage (3.4 vs 3.8, p>0.5), mortality rate (5 of 7 [71%] vs 4 of 4 [100%], p>0.4) or median survival (18 vs 17 months, p>0.8). Irrespective of augmentation status patients with a history of renal transplant on chronic immunosuppression had a significantly higher incidence of bladder cancer (3 of 20 [15%]), compared to patients who were not immunosuppressed (8 of 286 [2.8%], p=0.03). CONCLUSIONS: In patients with congenital bladder dysfunction ileal/colonic bladder augmentation does not appear to increase the risk of bladder malignancy over the inherent cancer risk associated with the underlying congenital abnormality. In addition, immunosuppression irrespective of bladder treatment is an independent risk factor for malignancy in this patient population.

Acute Intermittent Porphyria: Some Diagnoses are Only Made If Thought of.

A 20-year-old Asian, female, student nurse of thin body habitus (Body Mass Index 16.5) but otherwise previously well had numerous admissions to our centre under a variety of surgical sub-specialities over a 5-month period. Each month, coinciding with menses, she complained of non-specific abdominal discomfort in the absence of any other symptoms. With the exception of the presence of a sinus tachycardia coupled with incidental hyponatraemia full physical examinations and routine baseline investigations were unremarkable.

Cardiovascular aspects of glossopharyngeal insufflation and exsufflation.

Breath-hold divers use glossopharyngeal breathing to inhale above total lung capacity (glossopharyngeal insufflation, GI) or exhale below residual volume (glossopharyngeal exsufflation, GE). In these maneuvers, air is moved using glossopharyngeal rather than respiratory muscle activity. Four competitive divers performed several GI and GE maneuvers in sitting or standing position, while cardiovascular parameters were measured with a photoplethysmographic method; echocardiography was also performed during GE. During GI, the divers showed a 48% drop in mean arterial pressure (MAP) to 50 mmHg, with a 88% decrease in pulse pressure (PP), while heart rate (HR) increased by 36% to 103 beats/min and cardiac output (CO) dropped by 79% to 1.3 l/min. The increase in intrathoracic pressure during GI, measured in separate experiments, is probably responsible for these hemodynamic changes, by impeding venous return into the chest. Associated with the drop in MAP during GI were various neurological signs and symptoms, including dizziness, tunnel vision, involuntary twitching of facial muscles and one brief episode of loss of consciousness. During GE, initially MAP and PP increased by 36% and 61%, to 149 and 95 mmHg respectively; later HR decreased by 37% to 45 beats/min and CO dropped by 37% to 4.3 l/min. The early cardiovascular changes of GE may be related to a decrease in intrathoracic pressure, enhancing venous return, as shown by a 6 to 15% increase in end-diastolic diameter; later changes are similar to the responses to apnea at low lung volumes. Because of their hemodynamic effects, these breathing maneuvers should be performed with caution, particularly in the case of GI.

Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety.

Apo2L/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a member of the tumor necrosis factor gene family known to induce apoptosis in a number of cancer cell lines and may have broad-spectrum activity against human malignancies. These studies have evaluated the potency of recombinant soluble human Apo2L/TRAIL in a mouse xenograft model and the disposition and safety of Apo2L/TRAIL in rodents and nonhuman primates. Mice with established COLO205 tumors were given daily i.v. injections of Apo2L/TRAIL (30-120 mg/kg/day). Control tumors doubled in size every 2 to 3 days, while time to tumor doubling in the treatment groups was significantly longer and related to dose (14-21 days). For pharmacokinetic studies, Apo2L/TRAIL was given as an i.v. bolus to mice (10 mg/kg), rats (10 mg/kg), cynomolgus monkeys (1, 5, and 50 mg/kg), and chimpanzees (1 and 5 mg/kg). Apo2L/TRAIL was rapidly eliminated from the serum of all species studied. Half-lives were approximately 3 to 5 min in rodents and approximately 23 to 31 min in nonhuman primates. Allometric scaling provided estimates of Apo2L/TRAIL kinetics in humans, suggesting that on a milligram per kilogram basis, doses significantly lower than those used in xenograft studies could be effective in humans. Apo2L/TRAIL clearance was highly correlated with glomerular filtration rate across species, indicating that the kidneys play a critical role in the elimination of this molecule. Safety evaluations in cynomolgus monkeys and chimpanzees revealed no abnormalities associated with Apo2L/TRAIL exposure. In conclusion, these studies have characterized the disposition of Apo2L/TRAIL in rodents and primates and provide information that will be used to predict the pharmacokinetics of Apo2L/TRAIL in humans.

Composite stentless valve with graft extension for combined replacement of the aortic valve, root and ascending aorta.

OBJECTIVE: The composite mechanical valve conduit has been most commonly used for patients who require combined aortic valve, root, and ascending aorta replacement, but is limited, especially in the elderly, because of the need for long-term anticoagulation. We report the first consecutive series of patients in whom a composite stentless valve with graft extension, which does not require long-term anticoagulation, was performed. METHODS: Between April 1998 and July 2000, eight patients with severe aortic root and ascending aortic pathology underwent a combined aortic valve, root, and ascending aorta replacement with a Freestyle stentless porcine valve with a Hemashield graft extension. Mean age was 74 (range 56--82), three were males. Concomitant procedures included coronary artery bypass graft (CABG) alone (n=2), mitral valve replacement with atrial septal defect repair (n=1) and CABG with septal myomectomy (n=1). RESULTS: Operative mortality was zero. Median aortic cross-clamp and cardiopulmonary bypass times were 150 and 203 min, respectively. Two patients returned to the operating room for bleeding. Median blood transfusions and hospital length of stay were 4 units and 11 days, respectively. CONCLUSIONS: The composite stentless valve with graft extension is a reasonable alternative to a mechanical valve conduit for patients who require a combined aortic valve, root, and ascending aorta replacement, in whom anticoagulation is not desirable or contraindicated.

The safety of intraoperative transesophageal echocardiography: a case series of 7200 cardiac surgical patients.

UNLABELLED: Transesophageal echocardiography (TEE) is an invaluable intraoperative diagnostic monitor that is considered to be relatively safe and noninvasive. Insertion and manipulation of the TEE probe, however, may cause oropharyngeal, esophageal, or gastric trauma. We report the incidence of intraoperative TEE-associated complications in a single-center series of 7200 adult cardiac surgical patients. Information related to intraoperative TEE-associated complications was obtained retrospectively from the intraoperative TEE data form, routine postoperative visits, and cardiac surgical morbidity and mortality data. The overall incidences of TEE-associated morbidity and mortality in the study population were 0.2% and 0%, respectively. The most common TEE-associated complication was severe odynophagia, which occurred in 0.1% of the study population. Other complications included dental injury (0.03%), endotracheal tube malpositioning (0.03%), upper gastrointestinal hemorrhage (0.03%), and esophageal perforation (0.01%). TEE probe insertion was unsuccessful or contraindicated in 0.18% and 0.5% of the study population, respectively. These data suggest that intraoperative TEE is a relatively safe diagnostic monitor for the management of cardiac surgical patients. IMPLICATIONS: The overall morbidity (0.2%) and mortality (0%) rates of intraoperative transesophageal echocardiography (TEE) were determined in a retrospective case series of 7200 adult, anesthetized cardiac surgical patients. The most common source of TEE-associated morbidity was odynophagia (0.1%), which resolved with conservative management. These results suggest that TEE is a safe diagnostic tool for the management of cardiac surgical patients.

High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R.

Immunoglobulin G (IgG) Fc receptors play a critical role in linking IgG antibody-mediated immune responses with cellular effector functions. A high resolution map of the binding site on human IgG1 for human Fc gamma RI, Fc gamma RIIA, Fc gamma RIIB, Fc gamma RIIIA, and FcRn receptors has been determined. A common set of IgG1 residues is involved in binding to all Fc gamma R; Fc gamma RII and Fc gamma RIII also utilize residues outside this common set. In addition to residues which, when altered, abrogated binding to one or more of the receptors, several residues were found that improved binding only to specific receptors or simultaneously improved binding to one type of receptor and reduced binding to another type. Select IgG1 variants with improved binding to Fc gamma RIIIA exhibited up to 100% enhancement in antibody-dependent cell cytotoxicity using human effector cells; these variants included changes at residues not found at the binding interface in the IgG/Fc gamma RIIIA co-crystal structure (Sondermann, P., Huber, R., Oosthuizen, V., and Jacob, U. (2000) Nature 406, 267-273). These engineered antibodies may have important implications for improving antibody therapeutic efficacy.

Natural selection for grazer resistance to toxic cyanobacteria: evolution of phenotypic plasticity?

We studied the selection response of the freshwater grazing zooplankter, Daphnia galeata, to increased abundance of cyanobacteria in its environment. Cyanobacteria are a poor-quality and often toxic food. Distinct genotypes of D. galeata were hatched from diapausing eggs extracted from three time horizons in the sediments of Lake Constance, Europe, covering the period 1962 to 1997, a time of change in both the prevalence of planktonic cyanobacteria and levels of phosphorus pollution. We assessed whether the grazers evolved to become more resistant to dietary cyanobacteria by exposing genetically distinct clones to two diets, one composed only of the nutritious green alga, Scenedesmus obliquus (good food), and the other a mixture of S. obliquus and the toxic cyanobacterium Microcvstis aeruginosa (poor food). Genotype performance was measured as the specific rate of weight gain from neonate to maturity (gj). We evaluated evolutionary change in the Daphnia population using an analysis of reaction norms based on relative (log-transformed) changes in gj. Log(gj) is a measure of the proportional effect of dietary cyanobacteria on other fitness components of the Daphnia phenotype. For comparison, we also analyze absolute (i.e., nontransformed) changes in gj and discuss the interpretations of the two approaches. Statistical results using a general linear model demonstrate a significant effect of genotype (showing differences in gj among genotypes), a significant genotype x food-type interaction (showing differences in phenotypic plasticity among genotypes), and, in the case of log-transformed data, a significant sediment-genotype-age x food-type interaction. The latter shows that phenotypic plasticity evolved over the period studied. Two constraints act on response to selection in the D. galeata-Lake Constance system. First, gj on a diet containing poor food is highly correlated with gj on a diet of good food, thus evolving resistance also meant evolving an increase in gj on both diets. Second, because genotypes with a high gj also grow to a large adult body size, which in turn increases Daphnia vulnerability to fish predation, we suggest that selection only acted to favor genotypes possessing a high potential gj after cyanobacteria became prevalent. The presence of cyanobacteria depressed realized gj and led to animals of small adult body size even if their genotypes had the potential for high gj and large size. With realized gj reduced, genotypes with an inherently high value could be selected even in the presence of predatory fish. The joint action of selection by dietary cyanobacteria and vulnerability to fish predation provides an explanation for the observed evolution of resistance to poor food through reduced phenotypic plasticity.

Immunotherapy approach to allergic disease.

The causal role of immunoglobulin E (IgE) in triggering the cascade of biochemical events leading to allergic disease is well established. Treatments that selectively inhibit IgE activity are a logical approach in managing the allergic response. One such strategy utilizes rhuMAb-E25, a recombinant humanized IgG(1) monoclonal anti-IgE antibody, which binds to IgE. This anti-IgE antibody binds at the same epitope site of IgE that binds to FcvarepsilonRI and is thus non-anaphylactogenic. By binding to IgE and removing it via immune complex formation, the pool of IgE available to interact with mast cells and basophils is thereby reduced and the allergic response is attenuated. The clinical safety and efficacy of rhuMAb-E25 demonstrated in phase II studies of allergic asthma will be outlined.