Prospective randomised trial of endobronchial ultrasound-guide sheath versus computed tomography-guided percutaneous core biopsies for peripheral lung lesions.

AIM: To determine diagnostic rate, complications and patient tolerability of endobronchial ultrasound-guide sheath (EBUS-GS) and computed tomography (CT)-guided percutaneous core biopsy for peripheral lung lesions. METHODS: Lesions >1 cm diameter on CT were randomised to either EBUS-GS or CT-guided biopsy. Excluded were patients with severe chronic obstructive airway disease, lesions touching visceral pleura or hilum, and patients with symptoms needing bronchoscopic evaluation. Patients completed preprocedure and postprocedure questionnaires on tolerability. RESULTS: Of 64 participants (mean lesion size 29 ± 16 mm), 57 completed the study. Diagnostic sensitivity was 67% for EBUS-GS and 78% for CT-guided biopsy (P = not significant). In those with negative results, in the EBUS group, nine had a CT-guided biopsy as a cross-over, seven of which were positive. In the CT group, four had cross-over EBUS-GS of which three were diagnostic. Sensitivity for malignancy was 17/23 for EBUS-GS (74%) and 23/26 (88%, P = not significant). For lesions <2 cm, CT-guided biopsy had a significantly better diagnostic yield (80% vs 50%, P = 0.05). In EBUS-GS cases, for lesions with an air bronchogram, sensitivity was 89%. Pneumothorax and intercostal catheter insertion occurred in three and two cases, respectively, for EBUS, and 10 and 3 cases for CT-guided biopsy (P = 0.02 for pneumothorax). Nine unexpected admissions occurred after CT-guided biopsy compared with three after EBUS-GS. Overall, tolerability was high for both groups; however three patients had moderate-to-severe pain after CT-guided biopsy. CONCLUSIONS: In lesions <2 cm, CT-guided biopsy had higher yields; however, EBUS-GS had better tolerability and fewer complications.

Comparison of actionable events detected in cancer genomes by whole-genome sequencing, in silico whole-exome and mutation panels.

BACKGROUND: Next-generation sequencing is used in cancer research to identify somatic and germline mutations, which can predict sensitivity or resistance to therapies, and may be a useful tool to reveal drug repurposing opportunities between tumour types. Multigene panels are used in clinical practice for detecting targetable mutations. However, the value of clinical whole-exome sequencing (WES) and whole-genome sequencing (WGS) for cancer care is less defined, specifically as the majority of variants found using these technologies are of uncertain significance. PATIENTS AND METHODS: We used the Cancer Genome Interpreter and WGS in 726 tumours spanning 10 cancer types to identify drug repurposing opportunities. We compare the ability of WGS to detect actionable variants, tumour mutation burden (TMB) and microsatellite instability (MSI) by using in silico down-sampled data to mimic WES, a comprehensive sequencing panel and a hotspot mutation panel. RESULTS: We reveal drug repurposing opportunities as numerous biomarkers are shared across many solid tumour types. Comprehensive panels identify the majority of approved actionable mutations, with WGS detecting more candidate actionable mutations for biomarkers currently in clinical trials. Moreover, estimated values for TMB and MSI vary when calculated from WGS, WES and panel data, and are dependent on whether all mutations or only non-synonymous mutations were used. Our results suggest that TMB and MSI thresholds should not only be tumour-dependent, but also be sequencing platform-dependent. CONCLUSIONS: There is a large opportunity to repurpose cancer drugs, and these data suggest that comprehensive sequencing is an invaluable source of information to guide clinical decisions by facilitating precision medicine and may provide a wealth of information for future studies. Furthermore, the sequencing and analysis approach used to estimate TMB may have clinical implications if a hard threshold is used to indicate which patients may respond to immunotherapy.

Endobronchial ultrasound convex-probe transbronchial needle aspiration as the first diagnostic test in patients with pulmonary masses and associated hilar or mediastinal nodes.

BACKGROUND: In the diagnosis of patients with a lung mass and hilar or mediastinal lymph nodes (N1or N2) it may be that patients are unnecessarily having biopsies of the primary lung cancer when sampling of the nodes would give both a tissue diagnosis and staging. By comparing node station and size in patients having just one procedure (endobronchial ultrasound transbronchial needle aspiration [EBUS TBNA]) with those having extra procedures on the primary mass before EBUS TBNA, similarity of nodes in the two groups might suggest that the extra procedures were unnecessary. METHODS: A prospective case series of patients with coexistent lung mass and N1or N2 nodes compared results for EBUS TBNA in patients with no prior bronchoscopy (group A) with patients who had a bronchoscopy or transthoracic needle aspiration elsewhere directed at the primary mass (group B). RESULTS: Sixty-eight EBUS TBNA procedures were carried out in 67 patients with 23 patients in group A, and 45 in group B. Nodes sampled included stations 2, 3, 4, 7, 10, 11 and 12. Node size was approximately the same in both groups, 16.5 +/- 6 mm in group A and 16.9 +/- 6 mm in group B. For malignancy sensitivity by EBUS TBNA was 94% in group A and 95% in group B, with surgical sampling showing three TBNA false negatives. CONCLUSION: There was no difference between the two groups in node size or location. Diagnostic yield overall was high. With expanding use of EBUS TBNA, a new guideline for its initial application in such patients could reduce the overall number of procedures.

Biopsy site selection for endobronchial ultrasound guide-sheath transbronchial biopsy of peripheral lung lesions.

BACKGROUND: Choice of biopsy method for peripheral lung lesions is usually between CT-guided fine-needle aspiration biopsy (CT FNA) and bronchoscopy. Endobronchial ultrasound guide-sheath biopsy (EBUS GS) is a new method to improve the yield of bronchoscopy. Guidance on which lesions would be appropriate for either method is needed. The aim of the study was to compare the diagnostic yields and pneumothorax rate of EBUS GS and CT FNA in terms of the location of the lesion needing biopsy, in particular, whether the lesion is touching the pleura. METHODS: Prospective series of EBUS GS were compared to retrospective review of CT FNA carried out simultaneously in a large teaching hospital. RESULTS: For EBUS GS 140 cases were carried out with mean lesion size 29 mm. Overall diagnostic sensitivity was 66%. For lesions not touching visceral pleura it was 74% compared with 35% where it was on the pleura (P < 0.01). For CT FNA 121 cases were carried out with mean lesion size 37 mm. The overall diagnostic sensitivity was 64%. Rate of pneumothorax and ICC placement in EBUS GS was 1 and 0% and in CTFNA was 28 and 6%, with P < 0.001 for both. CONCLUSION: Lesion location, in particular, connection to the visceral pleura, can improve decision-making in referral for either CT FNA or EBUS GS to maximize diagnostic yield and minimize pneumothorax rate.

A phase I study of moderate-dose radiation therapy and weekly gemcitabine in patients with locally advanced non-small cell lung cancer not suitable for radical chemoradiation therapy.

AIMS: To describe the toxicity and response seen in patients receiving moderate-dose radiation therapy with concurrent weekly low-dose gemcitabine in the management of locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Eighteen patients with confirmed NSCLC were enrolled over a 17-month period from August 2000 until January 2002. All had localised disease but were considered unsuitable for curative therapy. Radiation therapy was given to a dose of 30 Gy in 15 fractions over 3 weeks. Gemcitabine was given weekly before and within 3 h of fractions 1, 6 and 11. The study was designed as a dose-escalation study, commencing at 100 mg/m2 and increasing at levels of 50 mg/m2, until the maximum tolerated dose (MTD) was reached. RESULTS: The MTD was regarded as being 150 mg/m2. The major acute toxicity observed was oesophagitis. Skin reactions were also reported. The overall response rate in all patients was 88%, with 44% achieving a complete response. CONCLUSION: The combination of gemcitabine and moderate-dose radiation therapy is feasible, and offers low toxicity and excellent response rates in patients with localised NSCLC not suitable for high-dose therapy.

Stimulation of Na,K-ATPase by hypothyroidism in the thyroid gland.

Although studies have documented the regulatory effects of thyroid hormones on the Na,K-ATPase in peripheral tissues, there is little information on the regulation of this transporter in the thyroid gland itself. Accordingly, we investigated the effects of thyroid status on Na,K-ATPase specific activity and the abundance of its constituent subunits in rat thyroid. Exogenous tri-iodothyronine (T3) was administered daily to produce hyperthyroidism. 6n-propyl-2-thiouracil (PTU), an inhibitor of thyroid hormone synthesis, was used to induce hypothyroidism. There was a four-fold increase in Na,K-ATPase specific activity in the follicular membranes from PTU-treated animals after 7 days. Enzymatic activities were not changed in the T3-treated glands. Immunoblotting of membranes from T3-treated rats revealed a 75% reduction in alpha1 subunit abundance and a slight, but nonsignificant reduction in beta1 abundance. On the other hand, the membranes from PTU-treated rats displayed 136 and 567% increases in the abundance of the alpha1 and beta1 subunits respectively. These data demonstrate that thyroid hormone status regulates Na,K-ATPase in the gland, but the effects are in direct contrast to those seen in the periphery.

Fine-needle interstitial photodynamic therapy of the lung parenchyma: photosensitizer distribution and morphologic effects of treatment.

STUDY OBJECTIVE: To look at the effect of interstitial photodynamic therapy (PDT) in normal lung parenchyma to assess its potential for treating localized, peripheral lung tumors. DESIGN: Studies were performed on normal Wistar rats using the photosensitizer meso-tetrahydroxyphenyl chlorine. Drug distribution was measured by fluorescence microscopy on tissue sections. Light was delivered to the lungs via a single fiber inserted percutaneously under x-ray control and the PDT effect studied in animals killed at times up to 6 months later. RESULTS: Fluorescence studies showed that the drug was initially distributed throughout the lung, but was later predominantly in the vasculature, bronchi, and macrophages. PDT produced sharply defined zones of hemorrhagic necrosis up to 12 mm in diameter that healed with regeneration of bronchial epithelium and local fibrosis. Different histologic effects were seen between drug light intervals of 1 and 3 days. Treatment was well tolerated, there was a low incidence of pneumothorax, and as long as the fiber tip was within the lung parenchyma, there was no damage to adjacent tissues. CONCLUSION: Interstitial PDT produces zones of necrosis in normal lung that heal safely by a percutaneous technique without affecting adjacent areas of untreated lung. If the lesion size can be increased by using multiple fibers, this could be a promising new technique for treating localized, peripheral lung cancers in patients who are unfit for surgery.

Bridging the professions: an integrated and interdisciplinary approach to teaching health care ethics.

In 1993, the authors introduced an interdisciplinary course in health care ethics at the University of British Columbia. They were motivated by two convictions: (1) an interdisciplinary approach to health care decision making is best; and (2) every significant health care decision has an ethical component. They wanted to encourage students from the various health care disciplines to participate in interdisciplinary decision making in their future practices by giving them an opportunity to study health care ethics together during their training. The authors give detailed descriptions of the objectives, format, curriculum, and evaluation of this innovative course in the hope that other educators who may want to develop similar courses can learn from their experience.

Children with end-stage renal failure: psychological effects on patients, siblings and parents.

Thirty-two children diagnosed as suffering from renal failure, their parents and siblings were the subjects of this study. Anxiety, depression and psychosomatic complaints were examined in the parents and behaviour problems in the child and siblings using standardised tests. The personality characteristics (EPQ) of the child and the child's view of the family (modified family relations test) were also ascertained. Parents showed greater levels of anxiety and depression than a normal sample and more psychosomatic problems than a control group consisting of parents of children with other chronic physical conditions. Siblings and the sick child did not have more behaviour problems at school than a normal control group. Positive correlations were found between age on diagnosis of renal failure and fathers' depression and anxiety scores. Mothers' anxiety and depression scores were also positively correlated with those of father. Negative correlations were found between age on diagnosis of renal failure and lie scores on the EPQ.

An interview with a child to assess psychiatric disturbance: a note on its reliability and validity.

Forty-six children with enuresis were given a psychiatirc interview. The two writers made independent ratings of 10 behavioral variables. Seven of these showed satisfactory interrater reliability. No relationship was established between child psychiatric disturbance assessed in this way and estimates of disorder obtained from information given by mothers and teachers.

The relevance of lowered personal control for patients who have stoma surgery to treat cancer.

OBJECTIVES: The objective of this study was to explore the experience of patients who had stoma surgery to treat cancer in order to explicate why problems associated with stoma surgery are not decreasing despite technical improvements in stoma care. DESIGN: A longitudinal design was used in order to capture the process of preparing for surgery and dealing with its aftermath. Participants were interviewed using a semi-structured protocol on three occasions; 1-2 weeks before surgery (eight participants), 1-2 weeks after surgery (seven participants), and 3 months after surgery (four participants). METHOD: Transcripts were analysed guided by the procedures of grounded theory. This involved developing categories from the data and linking them together to form a conceptual understanding of our participants' experience. RESULTS: Lowered personal control was the most important concept to emerge from the analysis. We identified perceived causes of lowered control, its mitigating factors, the strategies used to manage this experience and the consequences of these processes. CONCLUSIONS: We make three recommendations based on the conclusion that improvements could be implemented in the psychological aspects of stoma care and, in particular, the enabling of patient perceived self-efficacy. First, improvements could be made in doctor-patient communication with doctors becoming more aware of their psychological impact on patients. Second, specialist stoma care nurses could be trained to recognize patients with dysfunctional self-efficacy beliefs and/or delayed psychological adaptation. Finally, we identify a need for more prolonged practical and emotional support for at least some stoma out-patients.

Adherence to medical regime and related factors in youngsters on dialysis.

A pilot study is reported in which 18 children in end-stage renal failure, undergoing either haemodialysis or continuous ambulatory peritoneal dialysis were assessed with regard to adherence to their treatment regime. Measures were used to assess level of depression, locus of control and social desirability. Adherent behaviour was significantly related to high social desirability, and a shorter length of time on dialysis. There was no relationship between adherence and depression or locus of control.

The treatment of scriptophobia by in vivo exposure and cognitive restructuring.

A 23-year-old woman with a debilitating fear of signing her name in public was treated in 8 weeks and six treatment sessions using graded exposure in vivo and cognitive restructuring. Progress was maintained in all settings, at home and at work and when the patient was unaccompanied. Treatment gains were maintained at 6-month and 2-year follow-ups.

Eucalyptus: a sustainable self-delivery molluscicide?

Attention is drawn to the limitations of conventional methods of controlling important trematode infections such as schistosomosis and fasciolosis. Plant molluscicides could have a role in the future control of these infections. There are, however, major problems with most plant molluscicides in that their use is labour-intensive, in many cases relatively skilled workers are required, they must be applied regularly and arable land may be required for their cultivation. Thus, little progress is to be expected until plant species with sustainable self-delivery systems are identified. Eucalyptus is proposed as a likely candidate. The leaves of many species in this genus have molluscicidal properties and their intermittent fall could effect self-delivery if the trees were planted in appropriate places. Relatively little work has been carried out on this possibility and much more is necessary, especially field trials. Before field trials are started, more laboratory testing is also necessary to determine the LC50 values for different snail species and to study toxicity to non-target organisms.

Prospects for plant anthelmintics in tropical veterinary medicine.

The current use of anthelmintic plants in tropical veterinary medicine is reviewed and attention is drawn to the lack of scientific evidence for the effectiveness of many now in use. The case for anthelmintic plants as a means of overcoming some of the serious limitations of manufactured anthelmintics is outlined. Reasons why anthelmintic plants are not generally used in veterinary medicine, in contrast to their greater acceptance in human medicine, are considered. Strategies for their development and use are discussed, in particular the need for in vivo trials to identify those plants which are effective and suitable for general use: attention is drawn to possible candidates, including pyrethrum and papaya latex. Those helminths of most economic importance should be targeted first. Anthelmintic plants offer a traditional alternative to manufactured anthelmintics that is both sustainable and environmentally acceptable. Such plants could have a more important role in the future control of helminth infections in the tropics.

Infection control. A long time coming.

This article presents the case of a doctor who developed multidrug-resistant tuberculosis in his right lung. Development of the disease was attributed to treatment errors and resulted in surgical intervention to effect a cure. The isolation and management of this patient spanned a total of 12 months. Infection control interventions to minimise the effects of sensory deprivation, given the length of stay of the patient, appear to have been satisfactory, with no treatment for any clinical depression required. The availability of negative pressure ventilation and the then controversial use of masks prevented any nosocomial transmission of MDR TB. Use of masks resulted in a two-tier system of infection control. It was difficult to make such a decision in the absence of any published UK guidelines. Guidelines have subsequently been published.

Is closure of entire wards necessary to control norovirus outbreaks in hospital? Comparing the effectiveness of two infection control strategies.

The standard approach for norovirus control in hospitals in the UK, as outlined by the Health Protection Agency guidance and implemented previously by Lancashire Teaching Hospitals, involves the early closure of affected wards. However, this has a major impact on bed-days lost and cancelled admissions. In 2008, a new strategy was introduced in the study hospital, key elements of which included closure of affected ward bays (rather than wards), installation of bay doors, enhanced cleaning, a rapid in-house molecular test and an enlarged infection control team. The impact of these changes was assessed by comparing two norovirus seasons (2007-08 and 2009-10) before and after implementation of the new strategy, expressing the contrast between seasons as a ratio (r) of expected counts in the two seasons. There was a significant decrease in the ratio of confirmed hospital outbreaks to community outbreaks (r = 0.317, P = 0.025), the number of days of restricted admissions on hospital wards per outbreak (r = 0.742, P = 0.041), and the number of hospital bed-days lost per outbreak (r = 0.344, P <0.001). However, there was no significant change in the number of patients affected per hospital outbreak (r = 1.080, P = 0.517), or the number of hospital staff affected per outbreak (r = 0.651, P = 0.105). Closure of entire wards during norovirus outbreaks is not always necessary. The changes implemented at the study hospital resulted in a significant reduction in the number of bed-days lost per outbreak, and this, together with a reduction in outbreak frequency, resulted in considerable cost savings.

Apparent prevention of neural tube defects by periconceptional vitamin supplementation. 1981.

An earlier preliminary paper is expanded. Women who had given birth to one or more infants with a neural tube defect were recruited into a trial of periconceptional vitamin supplementation. Two hundred mothers attending five centres were fully supplemented (FS), 50 were partially supplemented (PS), and 300 were unsupplemented (US). Neural tube defect recurrences in the study pregnancies were 1(0.5%), in FS, none in PS, and 13 (4%) in US mothers. The difference in outcome between FS and US mothers is significant. The most likely explanation is that supplementation has prevented some neural tube defects, but further studies are needed.