Continuous Clinical Assessment Research Articles

Hereditary or acquired? Comprehensive genetic testing assists in stratifying angioedema patients

Hereditary angioedema (HAE) poses diagnostic challenges due to its episodic, non-specific symptoms and overlapping conditions. This study focuses on the genetic basis of HAE, particularly focusing on unresolved cases and those with normal C1-inhibitor levels (nC1-INH HAE). This study reveals that conventional testing identified pathogenic variants in only 10 patients (n = 32), emphasizing the necessity for an integrative approach using genome, exome, and transcriptome sequencing. Despite extensive genetic analyses, the diagnostic yield for nC1-INH HAE remains low in our study, the pathogenic variant for nC1-INH HAE was identified in only 1 patient (n = 21). Investigation into candidate genes yielded no pathogenic variants, prompting a re-evaluation of patients’ diagnoses. This study advocates for a nuanced approach to genetic testing, recognizing its limitations and emphasizing the need for continuous clinical assessment. The complex genetic landscape of nC1-INH HAE necessitates further research for a more comprehensive understanding. In conclusion, this study contributes valuable insights into the genetic intricacies of HAE, highlighting the challenges in diagnosis and the evolving nature of the disease. The findings underscore the importance of advanced sequencing techniques and an integrated diagnostic strategy in unravelling the complexities of HAE, particularly in nС1-INH HAE cases.

Monitoring an unconscious patient in the Intensive Care Unit

Monitoring an unconscious patient is complex and involves continuous clinical, haemodynamic and neurological assessment aided by various tools. This article discusses the various methods of monitoring a patient with and without a primary neurological insult. Regardless of the tools employed, monitoring, in itself, does not change the outcome. Processing the information obtained along with sound clinical judgment can, however, have a significant impact.

Pulse Oximeter Performance during Rapid Desaturation.

The reliability of pulse oximetry is crucial, especially in cases of rapid changes in body oxygenation. In order to evaluate the performance of pulse oximeters during rapidly developing short periods of concurrent hypoxemia and hypercapnia, 13 healthy volunteers underwent 3 breathing phases during outdoor experiments (39 phases in total), monitored simultaneously by five different pulse oximeters. A significant incongruity in values displayed by the tested pulse oximeters was observed, even when the accuracy declared by the manufacturers were considered. In 28.2% of breathing phases, the five used devices did not show any congruent values. The longest uninterrupted congruent period formed 74.4% of total recorded time. Moreover, the congruent periods were rarely observed during the critical desaturation phase of the experiment. The time difference between the moments when the first and the last pulse oximeter showed the typical study endpoint values of SpO2 85% and 75% was 32.1 ± 23.6 s and 24.7 ± 19.3 s, respectively. These results suggest that SpO2 might not be a reliable parameter as a study endpoint, or more importantly as a safety limit in outdoor experiments. In the design of future studies, more parameters and continuous clinical assessment should be included.

Avaliação clínica contínua por enfermeiros essencial à promoção da saúde na hemodiálise

The aim was to discuss how the continuous clinical assessment by nurses is an essential action in promoting the health of people with chronic kidney disease. Qualitative, exploratory and descriptive study, based on a recorded interview, with eight nurses on hemodialysis at a University Hospital, Southeast region of Brazil, in 2017. The analysis was processed with the help of the NVivo® 11 software. To place the patient at the center of care, clinical assessment must be continuous; must be monitored gradually; it needs to encompass complaints, needs and clinical oscillations; must consider everyday conditions experienced by him. Everything helps in understanding the behavioral and clinical profile in the face of the changes necessary for adherence to treatment. Continuously valuing the psychological, physical, social, emotional state and the ability to understand the patient in each clinical evaluation has a positive impact when performed frequently and when interdisciplinary interventions are available, in favor of promoting their health.

Metabolic Syndrome in Male Survivors of Pediatric Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Total Body Irradiation, Low-Grade Inflammation, and Hypogonadism

Metabolic syndrome (MetS) is a growing concern in survivors of pediatric hematopoietic stem cell transplantation (HSCT), but little is known about the underlying mechanisms. This study aimed to determine the prevalence and clinical presentation of MetS in male long-term survivors of pediatric HSCT and to investigate predisposing factors, including low-grade inflammation, altered fat distribution, and low testosterone levels. We included 98 survivors age 19 to 47 years at a median follow-up of 18 years (range, 8 to 35 years) after pediatric HSCT. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The prevalence and clinical manifestations of MetS were compared between our cohort and a control group of males from the background population (n=4767). Fat distribution was assessed by android/gynoid ratio from a whole-body dual-energy X-ray absorptiometry scan. Systemic inflammation was evaluated by IL-6 and high-sensitivity C-reactive protein (hsCRP). Serum testosterone levels were measured in morning samples. The prevalence of MetS was 30%, corresponding to the prevalence in the 50- to 80-year-old males from the background population. In individuals with MetS, hyperglycemia was more frequent in the HSCT survivors compared with age-matched controls with MetS (76% versus 20%; P < .001), whereas hypertension was more dominant in the control group with MetS (69% versus 93%; P=.01). In addition, normal or low body mass index was more commonly observed among HSCT survivors with MetS compared with age-matched controls with MetS (41% versus 11%; P=.002). MetS was more often associated with total body irradiation (TBI) compared with chemotherapy regimens (odds ratio [OR], 4.3; 95% confidence interval [CI], 1.2 to 24.4; P=.02), lower testosterone levels (OR, 5.4; 95% CI, 1.3 to 23.6; P=.02), higher IL-6 levels (OR, 1.8; 95% CI, 1.2 to 2.8; P=.004), and higher hsCRP levels (OR, 1.8; 95% CI, 1.3 to 2.6; P < .001) (estimates per 2-fold increase). In addition, an increased android/gynoid (AG) fat ratio was strongly associated with MetS (OR, 2.1; 95% CI, 1.5 to 2.9; P < .001), even though only 7% of patients met the criteria for increased abdominal circumference. Our results indicate an increased risk of MetS in early adulthood after pediatric HSCT. The clinical manifestations differed from those seen in age-matched controls with MetS, indicating different pathophysiology driven by hyperglycemia, altered fat distribution (despite no clinical abdominal obesity), and low-grade inflammation. Risk factors included TBI-based conditioning and low testosterone levels. These results underline the importance of continuous clinical assessment of the cardiometabolic risk profile and stress the presence of important dissimilarities in the pathophysiology of MetS in HSCT survivors compared with the background population.

Thermal liquid biopsy for monitoring melanoma patients under surveillance during treatment: A pilot study

BackgroundDifferential Scanning Calorimetry (DSC) is a technique traditionally used to study thermally induced macromolecular transitions, and it has recently been proposed as a novel approach for diagnosis and monitoring of several diseases. We report a pilot study applying Thermal Liquid Biopsy (TLB, DSC thermograms of plasma samples) as a new clinical approach for diagnostic assessment of melanoma patients. MethodsMultiparametric analysis of DSC thermograms of patient plasma samples collected during treatment and surveillance (63 samples from 10 patients) were compared with clinical and diagnostic imaging assessment to determine the utility of thermograms for diagnostic assessment in melanoma. Nine of the ten patients were stage 2 or 3 melanoma subjects receiving adjuvant therapy after surgical resection of their melanomas. The other patient had unresectable stage 4 melanoma and was treated with immunotherapy. Two reference groups were used: (A) 36 healthy subjects and (B) 13 samples from 8 melanoma patients who had completed successful surgical management of their disease and were determined by continued clinical assessment to have no evidence of disease. ResultsPlasma thermogram analysis applied to melanoma patients generally agrees with clinical evaluation determined by physical assessment or diagnostic imaging (~80% agreement). No false negatives were obtained from DSC thermograms. Importantly, this methodology was able to detect changes in disease status before it was identified clinically. ConclusionsThermal Liquid Biopsy could be used in combination with current clinical assessment for the earlier detection of melanoma recurrence and metastasis. General significanceTLB offers advantages over current diagnostic techniques (PET/CT imaging), limited in frequency by radiation burden and expense, in providing a minimally-invasive, low-risk, low-cost clinical test for more frequent personalized patient monitoring to assess recurrence and facilitate clinical decision-making.

Multidisciplinary therapy for the treatment of malocclusion in a patient with chronic periodontitis with a five-year follow-up: A case report.

Multidisciplinary therapy is essential in dental practice to achieve optimized outcomes. The present case report describes the application of periodontal surgery with a five-year follow-up in a patient with malocclusion and chronic periodontitis. In the presence of periodontal inflammation, orthodontic therapy may result in further periodontal breakdown due to plaque accumulation. In order to prevent this progression, scaling and root planning with a periodontal endoscope was applied, and continuous clinical monitoring and risk assessment was performed every 3 months using a Florida Probe. This combined treatment supports the long-term maintenance of periodontal conditions, functional occlusion and harmony of the facial profile.

Continuous Clinical Assessment (CCA) in Baccalaureate Nursing Education: The Application of Action Research

Continuous Clinical Assessment (CCA) in Baccalaureate Nursing Education: The Application of Action Research

A Phase I Open-Label Study to Evaluate the Safety and Tolerability of Medi4736, an Anti-Programmed Cell Death-Ligand 1(Pd-L1) Antibody, in Combination with Tremelimumab in Patients with Advanced Non-Small Cell Lung Cancer (Nsclc)

ABSTRACT Aim: Programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are inhibitory regulators of T cell activation. MEDI4736 (M) is a human IgG1 mAb, engineered to prevent ADCC activity, that blocks PD-L1 binding to PD-1 and CD-80. Tremelimumab (T) is a human IgG2 monoclonal antibody directed against CTLA-4. M + T in NSCLC may have greater antitumor activity compared with each agent alone. Methods: A Phase 1 study (NCT02000947) is evaluating the safety/tolerability, pharmacokinetics, immunogenicity and antitumor activity of M + T in patients (pts) with NSCLC. The study has dose-escalation phase and dose-expansion phase (immunotherapy-naive and -pretreated cohorts). The study will assess pharmacokinetic, pharmacodynamic parameters, including serum/tissue PDL1, immune cell phenotypes and cytokine profiling. Pharmacogenomic analysis of blood/tumor samples may be performed to examine gene expression patterns at baseline versus changes in response to treatment. Results: As of April 23, 2014, 12 pts were treated: 3 pts each in Cohort 1a (3 mg/kg M + 1 mg/kg T), Cohort 2a (10 mg/kg M + 1 mg/kg T); Cohort 3a (15 mg/kg M + 1 mg/kg T), Cohort 3b (10 mg/kg M + 3 mg/kg T). Pts had 2–5 lines of prior therapy (Median = 3). ECOG PS ranged from 0–1. The most frequent drug-related AEs (reported in ≥ 2 pts) included increased amylase, abdominal pain, arthralgia, colitis, diarrhea, epigastric discomfort, fatigue and nausea. ≥Grade (Gr) 3 drug-related AEs: 2 pts with Gr 3 (Cohort 2a: increased AST/ALT, 3b: diarrhea/colitis), 1 pt with Gr 4 (Cohort 3a: increased amylase), and 1 pt with Gr 5 (Cohort 2a: myasthenia gravis resulting in respiratory failure). Drug-related AEs leading to treatment discontinuation: 2 pts (Cohort 2a: increased ALT, myasthenia gravis, 3b: colitis). On first assessment at 8 weeks for 12 subjects: 2 unconfirmed PRs, 3 additional pts with tumor shrinkage not meeting PR, and 5 pts (Cohort 1a: 3; Cohort 3b: 2) with PD. 10 pts remain on study. Conclusions: The current safety profile and early anti-tumor activity of M + T supports continued clinical assessment. Disclosure: S.J. Antonia: Honoraria from BMS and MedImmune/Astra Zeneca for work related to designing, implementing, and analyzing various clinical trials. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; S. Goldberg: I have received research funding from MedImmune and AstraZeneca. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Balmanoukian: Research/clinical trials funded by MedImmune. I have also agreed to be a speaker for Boehringer Ingelheim Pharmaceuticals. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; R. Narwal: Employee of Medimmune and owns stock/stock options in AstraZeneca; P.B. Robbins: Employee of Medimmune and owns stock/stock options in AstraZeneca; G. D'angelo: Employed by MedImmune. I currently hold stock ownership of AstraZeneca; A. Blake-Haskins: Employee of Medimmune and owns stock/stock options in AstraZeneca; J.J. Karakunnel: Employee of Medimmune and owns stock/stock options in AstraZeneca; N. Rizvi: I receive consulting income from Medimmune, Roche, Merck and BMS. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.

NEUROMONITORINGO METODŲ VERTĖ ATLIEKANT ENDARTEREKTOMIJŲ OPERACIJAS

Žurnalas „Sveikatos mokslai / Health sciences“ yra recenzuojamas tarptautinis mokslinis žurnalas, skirtas skleisti naujas žinias ir informaciją apie visuomenės sveikatą, sveikatos ugdymą, ligas, klinikinius tyrimus ir klinikinius atvejus, naujas technologijas, slaugą, reabilitaciją, sveikatos ekonomiką ir vadybą. Žurnalas spausdina mokslinius straipsnius lietuvių, anglų ir rusų kalbomis, kasmet išeina 1 tomas (6 numeriai) spausdintiniu ir elektroniniu variantais. Daugiau nei 140 mokslinių straipsnių publikuojami per metus. Žurnalas priklauso Lietuvos mokslo periodikos asociacijai.

In Tribute: Dennis L. Hart, PT, PhD, A Functional Outcome Measurement Visionary

Previous article Next article Full AccessEditorialIn Tribute: Dennis L. Hart, PT, PhD, A Functional Outcome Measurement VisionaryMark W. Werneke, PT, MSc, , PT, MScDaniel Deutscher, PT, PhD, , PT, PhDSteven Z. George, PT, PhD, PT, PhDAuthorsMark W. Werneke, PT, MScSearch for more papers by this author, Daniel Deutscher, PT, PhDSearch for more papers by this author, Steven Z. George, PT, PhDSearch for more papers by this authorJournal of Orthopaedic & Sports Physical TherapyPublished OnlineJune 1, 2012Volume42Issue6Pages489-490https://www.jospt.org/doi/10.2519/jospt.2012.0109SectionsPDFPDF PLUS ToolsAdd to FavoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinkedInRedditEmail AboutAbstractIn remembrance of Dennis L. Hart, PT, PhD.J Orthop Sports Phys Ther 2012;42(6):489–490. doi:10.2519/jospt.2012.0109On April 11, 2012, our physical therapy profession lost yet another esteemed colleague after an extended battle with cancer. Although Dennis is not with us physically, we are confident that his uncompromising love and contributions to our physical therapy profession will live on. Dennis was a clinician, national and international speaker, and renowned researcher, educator, and author. He started his education at Northeastern University as a math major before changing his major and graduating in 1971 to begin his career in physical therapy. He continued his formal education by completing his Master of Public Administration at New Haven University in 1976 and his PhD in Industrial Engineering at West Virginia University in 1985.Dennis's scholarly contributions were extensive. He published over 85 articles in scientifically refereed journals and authored chapters in several books on industrial rehabilitation. He also served on the editorial board for the Journal of Rehabilitation Outcomes Measurement; reviewed manuscripts and NIH grants; mentored students who became prominent authors in the physical therapy literature; and received multiple awards, including the 2010 John Medeiros, Distinguished Authorship Award for best clinical research paper published in the Journal of Manual & Manipulative Therapy, the 2004 APTA Chattanooga Research Award for best clinical research paper published in Physical Therapy, and the 2000 Rose Excellence in Research Award. Dennis will be best remembered for his leadership and expertise in the development and clinical application of rehabilitation functional outcome measures using modern psychometrics based on item response theory mathematics.4 Over the past 2 years, Dennis challenged a group of physical therapy researchers to publish a series of papers related to efficient measurement of key clinical predictors and outcomes. His last article, in print in this issue of the Journal of Orthopaedic & Sports Physical Therapy, compared the relative validity and important change between 2 disease-specific functional outcome measures for patients with lumbar impairments: the modified Oswestry Low Back Pain Disability Questionnaire and the functional status lumbar computerized adaptive test.5Download FigureDownload PowerPointDennis believed in continuous clinical data collection and performance assessment. Over the past 14 years, he was a founding member and Director of Consulting and Research at Focus On Therapeutic Outcomes, Inc. Dennis's professional vision for future research was the use of large clinical databases to promote clinical comparative effectiveness research with the ultimate goal to identify the right treatment for the right patient.1 Comparative effectiveness research is now consistently recognized by many prominent researchers and clinicians as an important research method complementing data and results from other research designs, such as the randomized control trial.2,6 Dennis was the first physical therapist to develop, implement, and publish a value-based purchasing method for quantifying the quality of orthopaedic outpatient rehabilitation, demonstrating treatment effectiveness and efficiency when managing patients.3 His favorite saying was, “In God we trust—everyone else better bring data.”With this, Dennis's high professional productivity left us a rich heritage of knowledge to be studied and implemented in routine care for the benefit of our patients. His work influenced numerous researchers and brought thousands of physical therapists both in the United States and Israel to better understand and integrate data collected during everyday clinical practice to help guide patient management and improve patient outcomes. Dennis will be greatly missed, but his contributions to the physical therapy profession will be long lasting.

The snapshot pre-registration assessment tool. Part 2: Data, discussion and future directions

This paper is the second of a two-part article presenting a new assessment tool (the snapshot) for pre-registration nurses in clinical practice that is being used at Kingston University/St George's University of London during year 3 of the Diploma and BSc programme. Part 1 of this article presented background to the snapshot tool and the research approach used in the evaluative research study. Part 2 will present the data collection, findings and discussion which show that the snapshot is perceived positively by students in terms of the criteria, documentation and process. However, mentor understanding of these factors varied with some mentors having an inadequate understanding and additional questions of assessment validity also arose and need to be addressed. Both parts of this article make a contribution to the practice assessment agenda and to the continuous clinical assessment methods currently in use that tests students' competence against agreed criteria. The snapshot reflects the reality of practice and assesses skills in a realistic environment.

The snapshot pre-registration assessment tool. Part 1: Background, literature and research

This is the first of a two-part article that presents a new assessment tool - the snapshot - for pre-registration nurses in clinical practice, that is being used at Kingston University/St George's University of London during year 3 of the Diploma and BSc programmes. A pilot study of the use of the snapshot in a simulation environment had previously been undertaken and as a result of this, the snapshot was piloted as part of continuous clinical assessment in practice on two cohorts of third-year pre-registration student nurses. An evaluative study was undertaken. This article describes the background to the project, the literature and the research methods used to undertake the evaluative research study. Part 2 will focus on the findings and a discussion of these findings mapped against the literature.

Outcome scales - an observational study of the use of continuous clinical outcome assessment and therapy management in neurosurgery

Outcome scales - an observational study of the use of continuous clinical outcome assessment and therapy management in neurosurgery

Treatment of spasticity related to multiple sclerosis with intrathecal baclofen: A long-term follow-up

Spasticity is a frequent disabling symptom in patients with multiple sclerosis, which contributes to functional deterioration. To evaluate the long-term effect of intrathecal baclofen therapy in multiple sclerosis-related spasticity and to evaluate the side-effects of long-term therapy, and the doses of baclofen required. Fourteen patients with multiple sclerosis were followed up clinically for a mean of 62 months (range 19-137 months). Clinical evaluation was made using individual goals, modified Ashworth scale, and Kurtzke Expanded Disability Status Scale. Spasticity, measured with the modified Ashworth score, decreased in all patients by a mean of 1 point. The score on the Expanded Disability Status Scale improved in 2 cases. Prior to implantation, 10 patients (72%) reported severe pain. After implantation 3 improved and 7 became pain-free. The daily doses needed for treatment were highly individual. The effect of intrathecal baclofen on spasticity lasted observation time. One patient experienced progressive cognitive impairment as a side-effect of baclofen. Intrathecal baclofen is well-tolerated and the effect lasts for up to 12 years. A thorough continuous clinical assessment is required because the differentiation between symptoms of multiple sclerosis progression and side-effects of baclofen may be difficult. Intrathecal baclofen should be considered as an option for long-term treatment of patients with advanced spasticity. Pain control can also be achieved by optimized intrathecal baclofen treatment.

Ventricular arrhythmic disturbances and autonomic modulation after beating-heart revascularization in patients with pulmonary normotension

De-novo ventricular arrhythmias are potentially life-threatening complications after beating-heart revascularization (off-pump CABG). Whether pulmonary hypertension can influence initiation of ventricular arrhythmias through increased sympathetic activity is controversial. In order to determine the influence of pulmonary hypertension on its relative contribution to ventricular arrhythmia, we first had to define the role of cardiac autonomic modulation in patients with pulmonary normotension. We aimed to observe how parameters of linear and nonlinear heart rate variability are changed pre- and postoperatively in patients with pulmonary normotension undergoing off-pump CABG. Fifteen-minute ECG recordings were collected before and after off-pump CABG in 54 patients with multivessel coronary artery disease and pulmonary normotension to determine linear (TP, HF, LF, LF:HF ratio) and nonlinear detrended fluctuation analysis (alpha1, alpha2) and fractal dimension (average, high and low) parameters of heart rate variability. Arrhythmia was monitored preoperatively in 24-hour Holter recordings and postoperatively by continuous monitoring and clinical assessment. Deterioration from simple (Lown I-II) to complex (Lown III-V) ventricular arrhythmia was observed in 19 patients, and improvement from complex to simple arrhythmia in five patients (P = 0.022). Patients with postoperative deterioration of ventricular arrhythmia had preoperatively significantly lower values of TP, HF and LF (P = 0.024-0.043) and postoperatively significantly higher values on the low fractal dimension index (P = 0.031) than patients with postoperative improvement of arrhythmia. Patients experiencing postoperative deterioration of ventricular arrhythmia already have impaired autonomic regulation before surgery. Higher postoperative values on the low fractal dimension index indicate that sympathetic predominance with or without concomitant vagal withdrawal is the underlying neurogenic mechanism contributing to ventricular arrhythmia.

Optimizing follow-up after breast cancer treatment

This review focuses on studies that help elucidate the optimum approach to posttreatment follow-up of breast cancer patients. The re-conceptualization of follow-up under the rubric of survivorship care and the benefit of survivorship care plans, studies on the elements of follow-up care including surveillance mammograms, alternative models of follow-up care including primary care based follow-up, and patterns of care studies that involve population-based samples are discussed. Posttreatment follow-up of breast cancer patients continues to be controversial despite almost two decades of research. The research does show that surveillance mammograms are beneficial and guidelines recommend routine surveillance mammograms annually. Other routine surveillance tests are not beneficial and are not recommended. The precise frequency and duration of clinical visits is not known and recommendations vary; but most do support continued clinical assessment. Alternative models, such as nurse-led follow-up or less frequent follow-up, show good patient satisfaction and quality-of-life outcomes. Primary care based followup results in similar clinical and quality-of-life outcomes as specialist-based follow-up. Instead of trying to find a one-size-fits-all approach, the focus should be on an individualized tailored approach in which the patient makes an informed decision on the basis of evidence of actual benefits and risks.

Assessment of myocardial scarring by contrast enhanced magnetic resonance imaging in a patient 11 years after percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy

We report on a 60 year-old male who was one of the first patients who underwent percutaneous transluminal septal myocardial ablation (PTSMA) in our institution in 1996. Contrast enhanced cardiac magnetic resonance imaging (MRI) 11 years after the PTSMA demonstrated extensive scarring, in septal and inferior segments of the left ventricle, and an excellent functional result. It has been previously demonstrated that contrast-enhanced MRI allows detailed evaluation of size and location of septal myocardial infarction induced by PTSMA, and that infarction size detected by MRI correlates well with clinical indexes of infarct size. Our case report underlines the importance of ongoing specialized care and reassessment of patients after PTSMA including continuous clinical risk assessment.

Carotid endarterectomy: Intraoperative monitoring of cerebral perfusion

Carotid endarterectomy (CEA) is a commonly performed surgical procedure aiming to relieve the neurological symptoms of carotid artery atherosclerosis and to prevent embolic stroke. There is unequivocal evidence to support CEA in both symptomatic and asymptomatic patients with certain degrees of carotid artery stenosis and the operation is increasingly performed early following neurological symptoms. One of the goals for the anaesthetist during CEA is to protect the brain from ischaemic injury. The brain is particularly susceptible to ischaemic insult during carotid cross-clamping and therefore the anaesthetist and surgeon must be able to detect significant falls in cerebral perfusion and intervene appropriately. The commonest intervention in this situation is the insertion of a surgical shunt, which is not without associated risk. Several methods exist for monitoring cerebral perfusion during CEA although the ideal method has yet to be determined as none is perfect. Techniques available include continuous clinical assessment in the awake patient, electroencephalography (EEG), somatosensory evoked potentials (SSEPs), transcranial Doppler (TCD), near infrared spectroscopy (NIRS), xenon blood flow and internal carotid artery stump pressure monitoring.

The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases

AbstractThe receptor tyrosine kinase FLT3 is a promising molecular therapeutic target in acute myeloid leukemia (AML). Activating mutations of FLT3 are present in approximately one-third of patients, while many nonmutants show evidence of FLT3 activation, which appears to play a significant role in leukemogenesis. We studied the effects of lestaurtinib (CEP701) and PKC412, 2 small molecule inhibitors of FLT3, on 65 diagnostic AML blast samples. Both agents induced concentration-dependent cytotoxicity in most cases, although responses to PKC412 required higher drug concentrations. Cytotoxic responses were highly heterogeneous and were only weakly associated with FLT3 mutation status and FLT3 expression. Importantly, lestaurtinib induced cytotoxicity in a synergistic fashion with cytarabine, particularly in FLT3 mutant samples. Both lestaurtinib and PKC412 caused inhibition of FLT3 phosphorylation in all samples. Translation of FLT3 inhibition into cytotoxicity was influenced by the degree of residual FLT3 phosphorylation remaining and correlated with deactivation of STAT5 and MAP kinase. FLT3 mutant and wild-type cases both varied considerably in their dependence on FLT3 signaling for survival. These findings support the continued clinical assessment of FLT3 inhibitors in combination with cytotoxic chemotherapy: Entry to future clinical trials should include FLT3 wild-type patients and should remain unrestricted by FLT3 expression level.