A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer.

BACKGROUND: This phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC). METHODS: Patients with refractory stage IV CRC were treated with bevacizumab 5 mg kg(-1) i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed every two cycles. Pharmacokinetics of imatinib and cyclophosphamide and circulating tumour, endothelial, and immune cell subsets were measured. RESULTS: Thirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50 mg q.d., imatinib 400 mg q.d., and bevacizumab 5 mg kg(-1) i.v. every 2 weeks. Dose-limiting toxicities (DLTs) included nausea/vomiting, neutropaenia, hyponatraemia, fistula, and haematuria. The DLT window required expansion to 42 days (1.5 cycles) to capture delayed toxicities. Imatinib exposure increased insignificantly after adding cyclophosphamide. Seven patients (20%) experienced stable disease for >6 months. Circulating tumour, endothelial, or immune cells were not associated with progression-free survival. CONCLUSION: The combination of metronomic cyclophosphamide, imatinib, and bevacizumab is safe and tolerable without significant drug interactions. A subset of patients experienced prolonged stable disease independent of dose level.

Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility.

Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed "ATAC-array", an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.

Visually and posturally mediated tilt illusion in Parkinson's disease and in labyrinthine defective subjects.

We tested 24 normal subjects, 24 patients with idiopathic Parkinson's disease (PD), and eight patients with bilateral absence of vestibular function (labyrinthine defective [LD] subjects) in their ability to set a straight line to the perceived gravitational vertical (visual vertical). Measurements were taken in static conditions, sitting upright, and lying down on the right side, and during visual background motion at constant angular velocities around the line of sight (roll-motion) in both sitting upright and sideways position. Aims of the study were to determine if the reported increased "visual dependence" in PD was present in a psychophysical task that is independent of motor performance, and to examine the interaction between visual motion and proprioceptive cues in the perception of verticality, in the absence of vestibular function. LD patients showed abnormally large deviations of the visual vertical induced both by lateral body tilt and by visual roll-motion. This suggests that vestibular cues play a significant part in counterbalancing visually and proprioceptive mediated biases on the perception of verticality. In contrast, PD patients were normal in all these tasks indicating that visual dependence in PD is not present at an afferent/perceptual level.

Antimicrobial associations of an outbreak of diarrhoea due to Clostridium difficile.

An increased incidence of diarrhoea due to Clostridium difficile (CDD) at the Northern General Hospital, Sheffield, prompted an investigation into antibiotic use on the renal, medical and geriatric wards, those mostly affected. For the first half of 1997 affected patients on these wards were identified and data collected as to which antimicrobials they had taken between admission and diagnosis. Rates were then calculated of the number of affected patients on a drug over the quantity prescribed (N/1000 x defined daily doses). These were expressed as rate ratios (RR) over the rate of ampicillin/amoxycillin. A corrective procedure was also applied to the RR in an attempt to compensate for bias from the effect of drug combinations. Additionally, quarterly data were collected of numbers of patients with CDD and the amount of cefotaxime, ceftriaxone and cefuroxime issued between January 1996 and September 1997. Those drugs with the greatest association with CDD were cefotaxime (RR = 27.5, P < 0.000001), ceftriaxone (15.1, 0.00004), cefuroxime (8.6, < 0.000001) and ceftazidime (6.4, 0.00008). Several other drugs had increased uncorrected RR (P < 0.05). However, after correction for drug combinations, only the above four drugs remained with significantly increased RRs of 16.9, 8.6, 5.3 and 4.8, respectively. The time course of the outbreak showed a correlation with the use of cefotaxime and ceftriaxone. The incidence peaked in the first months of 1997, following greatest use of cefotaxime in the last quarter of 1996 and of ceftriaxone in the first quarter of 1997. This study confirms the association of cephalosporin and particularly cefotaxime usage with CDD incidence and shows the need to review the use of these drugs, especially in the treatment of respiratory infection. The method is useful for looking at local effects of prescribing with a view to controlling outbreaks of antibiotic resistant bacteria.

How convincing is the evidence for cognitive slowing in Parkinson's disease?

The issue of whether or not Parkinson's disease (PD) patients process information more slowly than normal is unresolved. Across a range of paradigms the evidence for slowing is scant, and many show no slowing. Even the results of a single experimental paradigm can be conflicting; some studies have obtained evidence for slowed memory scanning in subgroups of PD patients whereas others have not. The present study sought the cause of these discrepant results. Old-old (n = 11) and young-old (n = 7) PD subjects and controls (n = 16, n = 9) completed both fixed and varied set versions of the memory scanning task. No evidence for slowing in PD was found. These results indicated that PD did not interact with age or task version in its effects on information processing rates in the memory scanning task. It was concluded that PD patients do not have any cognitive slowing that is detectable with the memory scanning task.

P300 assessment of chronic fatigue syndrome.

The P3(00) event-related brain potential (ERP) was elicited with an auditory tone-discrimination paradigm in 25 patients diagnosed with chronic fatigue syndrome (CFS) and 25 matched normal control subjects. Target stimulus probability was varied systematically (0.20, 0.50, 0.80) in different task conditions. No differences between the CFS and control subjects were found for either P3 amplitude or latency. No group effects were observed for the N1, P2, and N2 components. Despite the attentional and immediate memory deficits reported in CFS, the P3 ERP from auditory stimuli does not reliably discriminate CFS from matched control subjects.

Postural fluctuation of hemifacial spasm. Case report.

A patient is described who demonstrated an impressive fluctuation in the severity of hemifacial spasm with change in head position. Postmortem examination revealed a large fusiform aneurysm impinging on the facial nerve.

How effective is the acute low back pain screening questionnaire for predicting 1-year follow-up in patients with low back pain?

OBJECTIVES: The aim of this study was to investigate potential associations between the Acute Low Back Pain Screening Questionnaire (ALBPSQ), a biopsychosocial screening instrument for identifying patients at risk of chronicity, and relevant variables at 1-year follow-up in a cohort of patients with low back pain. STUDY DESIGN: A 1-year prospective study was conducted in which patients who had previously received treatment in the Northern Ireland National Health Service (n = 118) were requested to complete a follow-up questionnaire package of pain and functional disability measures and a patient-centered questionnaire of seven variables considered relevant from the patient's perspective. PATIENTS: Ninety patients (76% response rate) returned the completed questionnaire package. RESULTS: The ALBPSQ total score and cutoff score of 112 were significantly positively associated with the pain and functional disability questionnaire scores at follow-up but did not significantly discriminate for difference scores on these measures. Although six of the seven patient-centered variables were significantly associated with the screening questionnaire total score, the cutoff score was strongly predictive of only one variable (work loss) and failed to demonstrate high levels of sensitivity for other variables (i.e., medication use, additional treatment, poor exercise participation). CONCLUSIONS: The findings of this study demonstrate that scores on the ALBPSQ were positively correlated with patients' levels of pain and functional disability at 1-year follow-up and correctly classified all patients reporting some degree of work loss but had minimal predictive strength for the other patient-centered variables evaluated.

Biopsychosocial screening questionnaire for patients with low back pain: preliminary report of utility in physiotherapy practice in Northern Ireland.

OBJECTIVE: The aim of this study was to investigate the potential utility of a new biopsychosocial screening questionnaire (Acute Low Back Pain Screening Questionnaire) by exploring the relation between it and several physical risk factors and posttreatment outcomes so as to establish a cutoff point for the local population. The relation between the screening questionnaire and valid and reliable outcome measures of pain and functional disability was also explored. DESIGN: Cross-sectional and longitudinal studies were conducted on patients referred for physiotherapy for low back pain to a large Healthcare Trust in Northern Ireland. Before initial assessment, patients completed the screening questionnaire and outcome measures, were questioned about known physical risk factors, and then received physiotherapy. At final discharge, the outcome variables--the "number of treatments" and patient's current work status ("return to work [yes/no]")--were recorded, and patients recompleted the outcome measures. PATIENTS: One hundred eighteen patients gave written informed consent to participate in this study. RESULTS: Significant associations were detected between questionnaire scores and pretreatment "leisure time exercise," "analgesic medication use," and "subjective anesthesia"; posttreatment "return to work"; and "number of physiotherapy treatments" as well as pain and functional disability measures. A cutoff "at-risk" score of 112 was calculated, which correctly classified 74% of patients who received more than six treatments and 80% of patients who failed to return to work at the end of treatment. CONCLUSIONS: The findings of this study provide preliminary evidence of the utility of this biopsychosocial screening questionnaire for future use in clinical intervention studies in the Northern Ireland National Health Service. Further comparative investigations in other health care settings are warranted.

Botulinum toxin type A in the treatment of lower limb spasticity in cerebral palsy.

OBJECTIVES: To determine whether botulinum toxin (BtA) is an effective and safe treatment for lower limb spasticity in children with cerebral palsy. Functional outcomes are of particular interest. SEARCH STRATEGY: Studies for inclusion in the review were identified using the Movement Disorders Review Group trials register, the Cochrane Controlled Trials Register, MEDLINE, pharmaceutical company databases, communication with other researchers in the field and reference lists of papers found using above search strategies. SELECTION CRITERIA: Studies were considered eligible for inclusion in the review if they evaluated the efficacy of BtA for the treatment of leg spasticity in children with cerebral palsy. They must have been randomised and include a concurrent control group receiving another intervention. DATA COLLECTION AND ANALYSIS: A paper pro forma was used to collect data from the included studies using double extraction by two independent reviewers. Each trial was assessed for internal validity by each of the two reviewers. Meta-analysis was not possible because results were presented in an incompatable form. A Peto odds ratio was calculated where this was appropriate, otherwise a descriptive summary of the results of the individual studies was compiled. MAIN RESULTS: Three eligible studies were found each with small numbers of subjects. They were short term, used single injection sessions with follow-up of between 4 and 26 weeks. One study (Koman), of twelve ambulant children, compared BtA with injection of a placebo and found non-significant improvements in gait in the BtA group compared to the placebo group. Two studies (Corry, Flett) compared BtA with the use of casts. Each included 20 ambulant children and found improvements in gait, range of ankle movement and muscle tone in both the BtA and cast groups. However there were no significant differences between the groups in either trial. One of these trials (Flett) also assessed motor function using the gross motor function measure (GMFM) (Russell, 1989) and found significant improvements in each group compared to baseline but no significant differences between the groups. The other trial (Corry) performed 3D gait analysis on those children able to co-operate. Maximal plantar flexion and maximal dorsiflexion during walking were both found to be significantly greater in the BtA group compared to the cast group. In all other dimensions there were no significant differences between the groups. REVIEWER'S CONCLUSIONS: This systematic review has not revealed strong controlled evidence to support or refute the use of BtA for the treatment of leg spasticity in cerebral palsy. Ongoing randomised controlled trials are likely to provide useful data on the short term effects of BtA for leg spasticity. Future research should also assess the longer term use of BtA. Ideally studies should be pragmatic in their approach to dose and distribution of toxin to reflect practise. Outcome measures assessing function and disability would give the most useful information.

The contribution of apraxic speech to working memory deficits in Parkinson's disease.

This article links two formerly separate areas of research associated with Parkinson's disease (PD): speech and memory. It is proposed that speech deficits occur in PD not merely at the level of muscular control, as is commonly termed dysarthria, but also at the level of speech planning and programming, more aptly described as a form of apraxia. It is further argued that PD patient groups exhibit small deficits in verbal span, and the link between apraxic speech and verbal span is elucidated via Baddeley's (1986) model of working memory. An experiment is described in which aspects of speech of 36 PD and 43 healthy control subjects were rated and classified, and measures of span and articulation rate for words of different syllable lengths were taken. Twenty-three PD subjects had dysarthric speech, while 14 of them had apraxic speech, which was associated with lower memory span scores for longer words. It is concluded that apraxic speech can be a source of reduced memory span in PD. In addition to implications for rehabilitation and therapeutic work with PD sufferers, these findings advance our theoretical understanding of the Parkinsonian syndrome.

The development of a new form of instrument fixation for the OSI CA 6000 spine motion analyzer.

The CA 6000 Spine Motion Analyzer (OSI Inc., Union City, CA, USA) is an instrument with a computer interface which utilises electrogoniometry to provide an index of ranges of motion and patterns of movement for the cervical, thoracic or lumbar spines. A new method of securing the instrument on a subject by means of a skin fixation system is described. The design criteria for the new system are detailed along with the development stages required to attain these criteria. It is argued that availability of the CA 6000 with the new skin fixation system described, now provides a practical and ethically acceptable means of providing an accurate index of spinal motion and pattern of movement in both asymptomatic and symptomatic subjects.

Intra-operator and inter-operator reliability of the OSI CA 6000 Spine Motion Analyzer with a new skin fixation system.

Following the independent development in the University of Brighton of a new skin fixation system for use with the OSI CA 6000 Spine Motion Analyzer, a series of studies were initiated to test the reliability of the instrument with the new skin fixation system, and the repeatability of the results thus obtained. This paper reports on the outcome of an initial pilot study to compare the existing manufacturer-supplied strap fixation system with the new system. This was followed by a second pilot study to establish single intra-operator reliability utilising 23 asymptomatic subjects. Following successful conclusion of the pilot studies, full inter/intra-operator reliability studies were initiated, utilising 11 asymptomatic subjects. The mean ranges of motion obtained from these results are reported and analyses of variance were used to calculate Intra-class Correlation Coefficients (ICCs) as an indication of reliability. These are summarised as follows: flexion/extension ranges 0.807; lateral flexion ranges 0.923; rotation ranges 0.822. A detailed methodology is explained, along with in-depth discussion of the reasoning behind its adoption, and detailed discussion of the results obtained. This study forms a foundation for the establishment of normative data for ranges of motion and patterns of movement in the lumbar spine, as part of a long-term programme of work investigating the effects of low back pain in specific occupational groups on lumbar spine ranges of motion. It is concluded that the results reported justify progression to the collection of normative data for the lumbar spine, utilising the CA 6000 Spine Motion Analyzer with the new skin fixation system, and the widespread application of that data in the clinical setting.

Measuring longitudinal nerve motion using ultrasonography.

While it is known that peripheral nerves slide longitudinally in response to limb movements, the clinical relevance of this phenomenon remains largely speculative. This technical note introduces a new application for noninvasive measurement of longitudinal movement of peripheral nerves. The rationale for developing the technique is given including a brief overview of nerve motion theories and how these are related to clinical practice. Current ultrasound applications for nerves and tissue motion are outlined and details of the Doppler measurement procedure are described. Limitations of the technique and potential future applications are discussed. Spectral Doppler ultrasound may provide an effective method for noninvasive quantification of longitudinal nerve motion.

M-mode ultrasound: a reliable measure of transversus abdominis thickness?

OBJECTIVE: The purpose of this study was to establish a reliable method for measuring transversus abdominis thickness in asymptomatic human subjects in supine lying, standing and walking. DESIGN AND METHODS: This was a single operator reliability study using ultrasound imaging to measure 22 subjects on three separate occasions. A purpose built high-density foam reinforced belt was used to house and position the transducer over the mid-point of the transversus abdominis. Each subject was imaged in supine, standing, and treadmill walking at 3 kph. Intraclass correlation coefficients and standard error of measurement analysis were used to measure the data. RESULTS: The correlation coefficient data analysis resulted in intraclass correlation coefficients of 0.94 (standard error of measurement 0.35) in supine lying, 0.88 (0.66) in standing and 0.88 (0.56) in walking. CONCLUSION: The method described is a reliable tool for measuring changes in thickness of transversus abdominis in supine lying, standing and walking. RELEVANCE: This procedure has the potential to detect dysfunctional changes in abdominal muscle activity for patients with low back pain in a functional setting.

Peripheral nerve motion measurement with spectral Doppler sonography: a reliability study.

This study evaluates single operator test-retest reliability of spectral Doppler ultrasound measurement of median nerve excursion during wrist extension. Longitudinal motion of the median nerve was measured at the elbow on three occasions in both upper limbs of 16 healthy subjects using a standard colour Doppler ultrasound system. The mean of the three maximum velocity time integrals was calculated from the spectral Doppler sonogram of each test. Analysis of data with intraclass correlation coefficient indicated a high degree of repeatability (0.92). Spectral Doppler ultrasound may provide a valuable method for measurement of peripheral nerve motion and may have a role in the clinical assessment of entrapment syndromes.

Medical treatment of recurrent temporomandibular joint dislocation using botulinum toxin A.

This paper describes a new technique for prophylactic treatment of recurrent mandibular dislocation using injection of botulinum toxin A (BtA) into the lateral pterygoid muscles. BtA temporarily weakens muscles by blocking acetylcholine release, and thus operates through a principle different from established treatments such as joint sclerosant therapy, eminectomy or Dautry's procedure. The patient suffered recurrent mandibular dislocations caused by tardive dystonia. We injected 75 mu BtA percutaneously into each lateral pterygoid muscle under electromyographic guidance. No further dislocations occurred over the subsequent 10 months, and follow-up continues. There were no immediate or delayed side effects. More experience is required before this becomes an established treatment. BtA is usually given in outpatients, and is less invasive or destructive than previous options. It may not be suitable if dislocation is due to lax ligaments or weak muscles. Operators must be aware that other BtA preparations require a different dose.

The medical management of masseteric hypertrophy with botulinum toxin type A.

We describe the successful outpatient medical treatment of a patient with bilateral masseteric hypertrophy using botulinum toxin type A in a double-blind placebo controlled study. No significant side-effects occurred, and benefit has so far lasted for 6 months.

A modified Delphi consensus study to identify UK osteopathic profession research priorities.

There is an increasing emphasis to take an evidence-based approach to healthcare. To obtain evidence relevant to the osteopathic profession a clear research direction is required based on the views of stakeholders in the osteopathic profession. A modified Delphi consensus approach was conducted to explore the views of osteopaths and patients regarding research priorities for osteopathy. Osteopaths and patients were invited to complete an online questionnaire survey (n = 145). Round 1 requested up to 10 research priority areas and the rationale for their selection. All of the themes from Round 1 were fed back verbatim, and in Round 2 participants were asked to rank the importance of the research priorities on a 5-point Likert scale. Finally, in Round 3 participants were asked to rank the importance of a refined list of research topics which had reached consensus. Descriptive analysis and use of Kendall's coefficient of concordance enabled interpretation of consensus. The response rate for Round 1 was 87.9% and identified 610 research priority areas. Round 2 identified 69 research themes as important, and Round 3 identified 20 research priority topic areas covering four themes: effectiveness of osteopathic treatment (7 areas prioritised), role of osteopathy: the management of four conditions were prioritised, risks with osteopathic treatment (two areas prioritised) and outcomes of osteopathic treatment (two areas prioritised). The findings will be taken forward to develop the research strategy for osteopathy.