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.

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.

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.

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.

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.

The effect of dermatology consultations in secondary care on treatment outcome and quality of life in new adult patients with atopic dermatitis.

BACKGROUND: The prevalence of atopic dermatitis (AD) is increasing worldwide, and many patients present to secondary care in adult life. This is a significant contribution to the workload of all dermatology departments. There are no studies investigating the impact of a dermatology consultation within secondary care. OBJECTIVES: To examine the effect of dermatology consultations in secondary care on treatment outcome and quality of life in new adult patients with AD. METHODS: This prospective observational study recruited new adult patients with AD referred from primary care. Eczema severity was assessed using the SCORAD (Severity Scoring of AD) index and subjective good or poor clinical outcome. The Dermatology Life Quality Index (DLQI) was used to quantify the impact of AD on adult patients. Patients were assessed at initial consultation (T1), 6 weeks (T2) and 3 months (T3). Statistical analysis was performed using independent t-tests, repeated-measures analysis of variance, correlation coefficients and Bonferroni post hoc comparisons. RESULTS: Sixty-three patients were recruited (37 women, 26 men) with a mean age of 34 years. Mean SCORAD at T1 was 48.2 and the majority (51%) had severe eczema (objective SCORAD>40). Mean SCORAD reduced by 52% from T1 to T2 (P<0.001) but there was no significant change in SCORAD from T2 to T3. A subjective good clinical outcome was validated by a decrease in SCORAD of >20 (P<0.001). Patients in the good clinical outcome group were significantly older than those in the poor clinical outcome group (38 vs. 27 years, P<0.05). The mean age at presentation of women was significantly younger than men (29 vs. 43 years, P<0.01). Women's mean SCORAD improved over all three visits, while men's mean SCORAD improved from T1 to T2 but worsened from T2 to T3 (P<0.001). The mean DLQI reduced over all three visits, from 9.5 at T1 to 8.8 at T2 and 7.0 at T3, and was significantly correlated with SCORAD at T1 and T2 (P<0.01). Patients accurately self-scored their eczema on a body map as shown by a significant correlation between these scores and SCORAD at T1 and T2 (P<0.001). CONCLUSIONS: We have shown that within the first 3 months of referral to secondary care, new adult patients with AD have the greatest improvement in AD, measured by SCORAD, after their initial appointment. Quality of life, as measured by DLQI, continued to improve over all three visits.

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.

A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma.

Our previous phase II study of cisplatin and gemcitabine in malignant mesothelioma showed a 47.6% (95% CI 26.2-69.0%) response rate with symptom improvement in responding patients. Here we confirm these findings in a multicentre setting, and assess the effect of this treatment on quality of life and pulmonary function. Fifty-three patients with pleural malignant mesothelioma received cisplatin 100 mg m(-2) i.v. day 1 and gemcitabine 1000 mg m(-2) i.v. days 1, 8, and 15 of a 28 day cycle for a maximum of six cycles. Quality of life and pulmonary function were assessed at each cycle. The best response achieved in 52 assessable patients was: partial response, 17 (33%, 95% CI 20-46%); stable disease, 31 (60%); and progressive disease, four (8%). The median time to disease progression was 6.4 months, median survival from start of treatment 11.2 months, and median survival from diagnosis 17.3 months. Vital capacity and global quality of life remained stable in all patients and improved significantly in responding patients. Major toxicities were haematological, limiting the mean relative dose intensity of gemcitabine to 75%. This schedule of cisplatin and gemcitabine is active in malignant mesothelioma in a multicentre setting. Investigation of alternative scheduling is needed to decrease haematological toxicity and increase the relative dose intensity of gemcitabine whilst maintaining response rate and quality of life.

Interstitial laser photocoagulation and interstitial photodynamic therapy of normal lung parenchyma in the pig.

Interstitial laser photocoagulation (ILP) and interstitial photodynamic therapy (PDT) involve delivery of light to lesions in solid organs using thin fibres passed through needles inserted percutaneously under image guidance. In ILP, the laser energy heats the tissue, whereas in PDT it activates a previously administered photosensitising agent. This study looks at their potential for treating localised, small, peripheral lung cancers in patients unsuitable for surgery. Experiments were undertaken on nine normal pigs, up to four fibres being inserted into the lung parenchyma percutaneously under X-ray guidance (ILP: 2-3 W, 1000 q/fibre, from 805 nm diode laser, PDT, 100-200 J/fibre from 652 nm diode laser at 50-100 W, 3 days after 0.15 mg/kg mTHPC). Animals were killed from 3 days to 3 months later and the treated areas examined macroscopically and microscopically. Both techniques were well tolerated, producing well-defined, localised lesions, typically 3.5 x 2 x 2 cm using four fibres. Histology showed thermal coagulative necrosis after ILP and haemorrhagic necrosis after PDT. Early small haematomas and late cavitation were sometimes seen after ILP, but not after PDT. PDT lesions healed with preservation of larger arteries and bronchi in the treated area. A few small pneumothoraces were seen which resolved spontaneously, probably related to the chest wall puncture. It was concluded that ILP and PDT lesions of a size large enough to cover a small tumour can be made safely in the lung parenchyma, although healing was better after PDT. Pilot clinical studies with both techniques are now justified on carefully selected patients.

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.

Factors related to psychosocial adjustment in children with end-stage renal failure.

Psychological functioning and adjustment to dialysis were assessed in the families of 60 children and adolescents undergoing chronic dialysis. Sociodemographic factors, treatment variables, health status and satisfaction with health care provision were also measured. Correlation analyses identified a number of important factors associated with poor adjustment to dialysis and/or anxiety and depression in children and parents. Particularly at risk are parents in lower socioeconomic status households, parents with large families, parents with limited support and parents of young children. Children were more at risk where there was greater functional impairment caused by illness.

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.

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.

Interstitial laser photocoagulation of normal lung parenchyma in rats.

BACKGROUND: Management of peripheral lung tumours may be risky in patients with poor lung function or in the elderly. A new possibility is interstitial laser photocoagulation (ILP) in which tumours are gently coagulated using thin laser fibres placed percutaneously under radiological guidance. This could have a useful palliative role in selected patients, but to be safe the effects on normal lung parenchyma must first be understood. This paper describes the creation and healing of ILP lesions in the normal rat lung. METHODS: ILP was performed using single laser fibres placed percutaneously in the left lung of normal rats under general anaesthetic with radiological guidance (laser power 1-3 W at 805 nm, treatment time 250-1000 s). The lesion size and healing were studied in rats killed at times from three days to six months after treatment, the bursting pressure was measured, and any complications noted. RESULTS: Zones of necrosis up to 12 mm in diameter were produced, the size depending on the laser power and treatment time. Histological examination showed typical thermal effects with complete healing with fibrosis by two months. The effect was very localised with remarkably little effect on the structure and function of the rest of the lung. Adverse effects in the lung parenchyma only occurred if the ILP lesion involved the hilar vessels or the oesophagus, causing pulmonary congestion and perforation, respectively. Pneumothorax was seen in 6% of cases. CONCLUSIONS: ILP with a single fibre can produce a localised zone of necrosis in normal lung parenchyma which heals safely and which has little effect on the rest of the lung. Further study of this technique using multiple fibres in a larger animal model is warranted to see if it is feasible and safe to produce a large enough volume of necrosis to be of value in the treatment of small peripheral lung tumours in patients who are unsuitable for surgery or palliative radiotherapy.

An activity week for children with cancer: who wants to go and why?

Many children now live with cancer rather than die from it, and such children need both to continue their social, emotional and cognitive development and to make long-term psychological adjustments. This paper presents the findings of a research project set up to explore issues pertinent to the current provision of an activity week experience for a group of British paediatric cancer patients. The aims of the study included finding out which factors discriminate between families who apply for a place to attend the week for their child and families who do not, and to develop a knowledge of what factors are considered by parents and children. The findings suggest that the week appeals to children who are confident, active and able to separate from parents and whose parents are keen to encourage independence and new experiences. Children diagnosed and treated at a younger age and further away from treatment were more likely to express concerns about being homesick and safety and to not apply for the week. Issues of protection, independence and disability are discussed with reference to the importance of parental attitude on children's psychological accommodation to disease and treatment and to the experiences of adult survivors of childhood cancer.

Motivation, attitudes and experience of donation: a follow-up of women donating eggs in assisted conception treatment.

This paper reports a follow-up of 39 women who had donated eggs to an assisted conception unit. Their experience of donation and their motivation and attitudes were assessed. Comparisons were made with a group of semen donors who were attending a second unit. Female and male donors donated for altruistic reasons and neither group wished to have contact with recipients or donor offspring or have their identity revealed. Female donors were more involved in the donation process and more interested in the outcome of donation. They also appeared to be more motivated by 'helping' than male donors. The sample of female donors contained a small group of women who were donating to sisters and friends. In comparison with anonymous donors, these women reported more effects upon the family and issues of secrecy and openness were more apparent. The results are discussed in the light of previous studies and the legal framework for donation in the UK. Attention is drawn to the lack of social psychological analyses in this controversial medical area.