Genomic Landscape of Non-Small Cell Lung Cancer (NSCLC) in East Asia Using Circulating Tumor DNA (ctDNA) in Clinical Practice.

Plasma-based next-generation sequencing (NGS) has demonstrated the potential to guide the personalized treatment of non-small cell lung cancer (NSCLC). Inherent differences in mutational genomic profiles of NSCLC exist between Asian and Western populations. However, the published mutational genomic data of NSCLC has largely focused on Western populations. We retrospectively analyzed results from comprehensive NGS of plasma (Guardant360®) from patients with advanced non-squamous NSCLC, as seen in clinical practice. Tests were ordered between January 2016 and December 2020 in Hong Kong, Korea, Taiwan, Japan and Southeast Asia. The assay identified single-nucleotide variants (SNV), insertions and deletions, and fusions and amplifications in 74 genes. In total, 1608 plasma samples from patients with advanced non-squamous NSCLC were tested. The median turnaround time for test results was 7 days. Of the samples with detectable ctDNA (85.6%), 68.3% had alterations in at least one NCCN-recommended NSCLC biomarker. EGFR driver mutations were most frequent (48.6%), followed by alterations of KRAS (7.9%), ERBB2 (4.1%) and ALK (2.5%). Co-mutations of EGFR and KRAS occurred in 4.7% of samples. KRAS G12C was identified in 18.6% of all samples with KRAS mutations. Common mutations, such as exon 19 deletions and L858R, accounted for 88.4% of EGFR driver mutations. Among the samples with any EGFR driver mutation, T790M was present in 36.9%, including 7.7% with additional alterations associated with osimertinib resistance (MET amplification, C797X). Comprehensive plasma-based NGS provided the timely and clinically informative mutational genomic profiling of advanced non-squamous NSCLC in East Asian patients.

Getting the most out of MRI in perianal fistula: update on surgical techniques and radiological features that define surgical options.

Perianal fistulas affect approximately 2 in 10,000 people, causing symptoms such as pain and discharge, which can have a debilitating effect on a patient's quality of life. Surgical treatment, which can offer a potential cure or palliation of symptoms, must be considered carefully in cases with extensive sphincter involvement. In complex cases, the use of preoperative magnetic resonance imaging (MRI) can help to determine the best course of operative action. This review describes common and contemporary surgical procedures for perianal fistula, highlighting technical features, as well as important surgical considerations associated with each method and how these can be assessed radiologically. We focus on the anatomical features and MRI findings that take procedural elements into account and help determine the most appropriate method of treatment. The aim of this article is to provide a basis for informed and focused discussion between surgeons and radiologists to ensure the most appropriate procedure is selected for each case, with the ultimate aim of obtaining the most favourable outcomes for patients.

Meeting the new joint British Society of Gastrointestinal and Abdominal Radiology and Royal College of Radiologists CT colonography standards: a 6-year experience.

AIM: To audit the performance of computed tomography colonography (CTC) at St Mark's Hospital against the joint British Society of Gastrointestinal and Abdominal Radiology (BSGAR) and Royal College of Radiologists (RCR) standards. MATERIALS AND METHODS: A retrospective audit of all CTC studies between January 2012 to December 2017 was performed against the BSGAR/RCR standards along with additional data outwith the guidelines. Evidence was obtained from a central database, radiology information systems (RISs), picture archiving and communication systems (PACSs), and electronic patient records (EPRs). RESULTS: Over the 6 years, 13,143 CTCs were performed and 12,996 (99%) were adequate or better. Of the cases 1,867 had a >6 mm polyp or cancer reported (polyp identification rate [PIR] 14%) and the positive predictive value (PPV) was 93% (1,148/1,240). Median radiation dose was 458 mGy·cm, mean additional acquisition rate was 19% (2,505/13,143), subsequent endoscopy rate was 9% (1,222/13,143) and mean interpretation time for a negative study was 34.6 minutes. Nine perforations occurred (perforation rate of 0.068%) and one was symptomatic (symptomatic perforation rate of 0.008%). For suspected cancers, the same-day endoscopy rate was 27% (96/360) and same-day staging rate was 76% (272/360). Post-imaging colorectal cancer rates (PICRC) was 3.06 per 100 cancers detected and 0.23 per 1,000 CTCs. The service was always rated "good" or higher by patients. CONCLUSION: This audit shows the CTC service at St Mark's Hospital to be safe and of sufficiently high quality to meet the BSGAR/RCR standards with most outcomes equal to or above the aspirational target. Areas for service and individual reader improvement were also identified.

Perianal fistula and the ileoanal pouch - different aetiologies require distinct evaluation.

AIM: Restorative proctocolectomy has been widely adopted as the procedure of choice for restoring gastrointestinal continuity following proctocolectomy. It is often associated with improved quality of life and high patient satisfaction; however, the development of a pouch anal fistula can cause significant morbidity. Pouch fistulas are notoriously difficult to treat and there is great heterogeneity in the management reported of these fistulas. A lack of classification, and the assumption that fistulas originating from completely different aetiologies will behave and respond similarly to a particular treatment strategy, precludes meaningful comparison of management outcomes. We aim to introduce consistency in the reporting of pouch fistulas using a novel classification system. METHODS: A consensus process involving clinicians experienced in the management of pouch fistulas from two high volume tertiary centres was performed. RESULTS: We propose that pouch anal fistulas should be classified into four distinct groups according to their aetiology: group 1, anastomotic related; group 2, inflammatory bowel disease related, with sub-classifications Crohn's (type A) and non-Crohn's (type B) in origin; group 3, cryptoglandular related; and group 4, malignancy related. CONCLUSION: Classification of pouch fistulas according to their aetiology will provide consistency in the literature and improve the quality of prospective evidence for the management of pouch fistulas.

Acceptability, effectiveness and safety of a Renew® anal insert in patients who have undergone restorative proctocolectomy with ileal pouch-anal anastomosis.

INTRODUCTION: Restorative proctocolectomy has gained acceptance in the surgical management of medically refractive ulcerative colitis and cancer prevention in familial adenomatous polyposis. Incontinence following restorative proctocolectomy occurs in up to 25% of patients overnight. The Renew® insert is an inert single-use device which acts as an anal plug. The aim of this study was to assess the acceptability, effectiveness and safety of the Renew® insert in patients who have undergone restorative proctocolectomy. The device has yet to be assessed in patients who have undergone restorative proctocolectomy. METHOD: This was a prospective study exploring the acceptability, effectiveness and safety of the Renew® insert in improving incontinence in patients who had undergone restorative proctocolectomy. A total of 15 patients with incontinence were asked to use the Renew® insert for 14 days following their standard care. The Incontinence Questionnaire-Bowels was used pre- and posttreatment to assess response and patients were asked to report the perceived acceptability, effectiveness and safety of the device at the end of the trial. RESULTS: The device was acceptable to 8/15 (53%) of patients and was effective in 6/15 (40%). Only 2/15 (13%) of patients raised any safety concerns, and these were minor. The device was associated with a significant reduction in night seepage (P = 0.034). CONCLUSION: In a small study, the Renew® insert can be both acceptable and effective and is also associated with few safety concerns. It is also associated with significant reductions in night-time seepage.

Review article: pathogenesis of Crohn's perianal fistula-understanding factors impacting on success and failure of treatment strategies.

BACKGROUND: Evidence from groups who have studied fistula aetiology and extrapolation from interventional studies supports a multifactorial hypothesis of Crohn's perianal fistula, with several pathophysiological elements that may contribute to fistula formation, persistence and resistance to treatment. AIM: An evidence synthesis of current understanding of pathophysiological factors underlying Crohn's perianal fistula is presented, exploring the fundamental reasons why some treatments succeed and others fail, as a means of focussing clinical knowledge on improving treatment of Crohn's perianal fistula. METHODS: Evidence to support this review was gathered via the Pubmed database. Studies discussing pathophysiological factors underpinning perianal fistula, particularly in Crohn's disease, were reviewed and cross-referenced for additional reports. RESULTS: Pathophysiological factors that impact on success or failure of interventions for Crohn's perianal fistulae include the high-pressure zone, obliterating the dead space, disconnecting the track from the anus, removing epithelialisation, eradicating sepsis and by-products of bacterial colonisation, correcting abnormalities in wound repair and removing the pro-inflammatory environment which allows fistula persistence. Most current interventions for Crohn's perianal fistulae tend to focus on a single, or at best two, aspects of the pathophysiology of Crohn's anal fistulae; as a result, failure to heal fully is common. CONCLUSIONS: For an intervention or combination of interventions to succeed, multiple factors must be addressed. We hypothesise that correct, timely and complete attention to all of these factors in a multimodal approach represents a new direction that may enable the creation of an effective treatment algorithm for Crohn's anal fistula.

The body composition profile is associated with response to anti-TNF therapy in Crohn's disease and may offer an alternative dosing paradigm.

BACKGROUND: Anti-tumour necrosis factor (TNF)s form a major part of therapy in Crohn's disease and have a primary nonresponse rate of 10%-30% and a secondary loss of response rate of 5% per year. Myopenia is prevalent in Crohn's disease and is measured using body composition analysis tools. AIM: To test the hypothesis that body composition can predict outcomes of anti-TNF primary nonresponse and secondary loss of response. METHODS: Between January 2007 and June 2012, 106 anti-TNF naïve patients underwent anti-TNF therapy for Crohn's disease with body composition parameters analysed using CT scans to estimate body fat-free mass. The outcome measures were primary nonresponse and secondary loss of response. COX-regression analysis was used with 3 year follow-up data. RESULTS: A total of 106 patients were included for analysis with 26 (24.5%) primary nonresponders and 29 (27.4%) with secondary loss of response to anti-TNF therapy. Sex-specific cut-offs for muscle and fat were ascertained by stratification analysis. On univariate analysis, primary nonresponse was associated with low albumin (OR 0.94; 0.88-0.99, P = .04) and presence of myopenia (OR 4.69; 1.83-12.01, P = .001) when taking into account patient's medical therapy, severity of disease and body composition. On multivariate analysis, presence of myopenia was associated with primary nonresponse (OR 2.93; 1.28-6.71, P = .01). Immunomodulator therapy was associated with decreased secondary loss of response (OR 0.48; 0.23-0.98, P = .04). BMI was poorly correlated with lean body mass (r2 = 0.15, P = .54). CONCLUSIONS: In this cohort study, body composition profiles did not correlate well with BMI. Myopenia was associated with primary nonresponse with potential implications for dosing and serves as an explanation for pharmacokinetic failure.

An analysis of the accuracy of computed tomography colonography when defining anatomy for novel full-thickness colonic excision techniques in early colonic neoplasia.

AIM: Full-thickness laparo-endoscopic excision (FLEX) is a new technique developed for the full-thickness excision of colonic adenomas and, potentially, early cancer, avoiding the need for colectomy. FLEX requires accurate preoperative characterization of three key morphological features of the tumour, including its relation to the mesenteric border, its diameter and the circumferential extent of involvement of the bowel wall. This study evaluated the accuracy of CT colonography (CTC) for the assessment of these features in early colonic tumours. METHOD: Consecutive patients undergoing CTC prior to colonic resection for complex benign polyps or UICC Stage 1 cancer were retrospectively analysed by two specialist gastrointestinal radiologists blinded to the subsequent histopathological findings. The location of the tumour in relation to the mesenteric border, its maximum diameter and the circumferential extent of involvement of the colonic wall were correlated with the histopathological examination of the surgical resection specimen. Pearson's correlation coefficient (r) and Kappa agreement (κ) were used to compare the maximum diameter and the circumferential extent of involvement of the colonic wall. RESULTS: Twenty-eight patients with early colonic neoplasia were included. All had had a surgical segmental resection. Four had a benign adenoma and 24 had a TNM Stage 1 cancer. Histopathological assessment of the resected surgical specimen showed that 21 of the 28 lesions were located on the mesenteric border. The median diameter was 35 (interquartile range 28-42) mm; 13 lesions involved less than one-third of the circumference, 11 between one and two-thirds and four more than two-thirds. CTC correctly identified the location of the lesion in relation to the mesenteric border in all 28 cases. Correlation between CTC and histopathology was good for the assessment of the maximum diameter of the lesion (r = 0.81) and the circumferential extent of involvement of the colonic wall (κ = 0.76). CONCLUSION: CTC can accurately assess the key morphological features for the selection of patients with early colonic neoplasia for full-thickness laparo-endoscopic excision.

Implementation of a new CT colonography service: 5 year experience.

AIM: To describe our experience using a 5 year audit of computed tomography colonography (CTC) practice and identify factors that influence diagnostic performance to guide implementation in other centres. MATERIAL AND METHODS: Consecutive patients referred for CTC at a single institution over a 5 year period were identified, and reporting rates and positive predictive value (PPV) calculated for small polyps, large polyps, and colorectal cancer. Diagnostic performance was compared using the Chi-squared test, and trends over time were examined with logistic regression. The effect of faecal tagging and an intravenous spasmolytic were investigated using Fisher's exact test. RESULTS: In total, 4355 CTC examinations were performed. Overall reporting rates and PPV were 17% and 92%, respectively. Negative predictive value (NPV) for cancer was 99.9%. A significant decrease in reporting rate (p < 0.001) was accompanied by an increase in PPV for small polyps (p = 0.02) following the introduction of faecal tagging. Adequacy rates for CTC improved over time (96% to 99%), with improved adequacy rates when using a spasmolytic, 98% versus 96% without. A significant difference in reporting rates, but not PPV, was found between radiologists. CONCLUSION: Accurate colonic investigation using CTC can be delivered safely to a high-risk patient population at a single centre. Faecal tagging and an intravenous spasmolytic improve diagnostic performance.

Localized argyria caused by metallic silver aortic grafts: a unique adverse effect.

INTRODUCTION: Silver-coated grafts are designed to prevent vascular graft infections. Silver is a safe element but toxic effects have been reported. We describe two cases of possible localized argyria after silver graft implantation. REPORT: Two patients presented with perigraft groin collections after implantation of silver grafts. During reoperation, an ashen-grey necrotic substance was seen surrounding the grafts. The grafts were explanted and lower limb perfusion restored. Cultures were negative and both patients had uneventful recoveries. DISCUSSION: Our cases are highly suggestive of a possible unique adverse effect: a combination of localized silver toxicity and neutrophilic mediated tissue destruction.

MRI-based anatomical landmarks for the identification of thoracic vertebral levels.

AIM: To identify soft-tissue and bony anatomical landmarks on dedicated thoracic spine magnetic resonance imaging (MRI), and to assess their detectability, reproducibility, and accuracy in predicting specific thoracic vertebral levels. MATERIALS AND METHODS: One hundred dedicated thoracic MRI studies were retrospectively analysed by two radiologists independently. Ten bone and soft-tissue landmarks were localized to the adjacent vertebral level. The true numerical thoracic vertebral level was subsequently determined and recorded by cross referencing with a sagittal cervico-thoracic "counting scan". RESULTS: Six landmarks were defined in ≥98% cases; however, there was a low interobserver percentage agreement for the defined vertebral levels (>70% for only one landmark). The most useful landmark for defining a specific vertebral level was the most superior rib (98% detection, 95% interobserver agreement, 98% at a single vertebral level, 0.07 SD). Eight landmarks localized to a specific thoracic segment in only 16-44% of cases, with a standard deviation of >0.5 vertebral levels and with a range which was greater than four vertebral levels. CONCLUSION: The C2 vertebra must be identified and cross referenced to the dedicated thoracic spine MRI, as other MRI-based anatomical landmarks are unreliable in determining the correct thoracic vertebral level.

Acoustic radiation force impulse quantification: repeatability of measurements in selected liver segments and influence of age, body mass index and liver capsule-to-box distance.

OBJECTIVE: To assess the inter- and intra-observer variability of acoustic radiation force impulse (ARFI) quantification in liver segments with influence of age, body mass index (BMI) and liver capsule-to-box (CB) distance. METHODS: 10 healthy volunteers were examined twice, by three experienced operators, separated by a 1-week interval. 10 readings were obtained, from segments 3, 5/6 and 7/8. Age, BMI and the CB distance were noted. The Cronbach α statistic for analysis of reliability was performed for the inter- and intra-observer studies. Multivariate linear regression models determined significance of the other parameters. RESULTS: 1800 velocity measurements were recorded. Mean values±standard deviation: segment 3, 1.31±0.19 m s(-1); segment 5/6, 1.12±0.22 m s(-1); segment 7/8, 1.12±0.17 m s(-1). For both the inter- and intra-observer study, the Cronbach α statistic was ≥0.7 (reliable) when taken from segments 5/6 and 7/8 but <0.7 (unreliable) for segment 3. BMI and age showed significant (p<0.0001) but contrasting correlation (segment 5/6: BMI r=0.02, age r=-0.02; segment 7/8: BMI r=-0.01, age r=0.01) with ARFI velocities when analysed for the segments deemed reliable. A weak negative correlation between ARFI velocities and liver CB distance was demonstrated for both assessed segments (segment 5/6, r=-0.08; segment 7/8, r=-0.06; p<0.001). CONCLUSION: With trained operators, ARFI is a reliable and reproducible method of liver stiffness quantification in segments 5/6 and 7/8 but acquisition of measurements from segment 3 should be avoided. Values obtained deeper to the liver capsule allow more reliable liver stiffness quantification.

Vascular occlusion as a late complication of the Angio-Seal closure device. A review of literature.

Although early vascular complications of the Angio-Seal closure device have been well described, little is known about late vascular complications due to this device. The aim of this paper is to discuss late femoral stenosis associated with the use of the Angio-Seal closure device. A literature search was performed using Medline', Embase' and The Cochrane Library' to identify relevant articles published up to the first of May 2007. Late occlusion was defined as an occlusion after approximately one week after Angio-Seal deployment. All together, eleven relevant papers were available. The reported prevalence of late vascular stenosis associated with Angio-Seal use varies between 1/961 and 4/175. Claudication was the most frequently reported complaint. In most cases, late stenosis due to the use of the Angio-Seal required surgery. Vascular obstruction due to the device has been reported up to 6 months after placement. In conclusion, vascular stenosis due to the use an Angio-Seal closure device is a complication that not only occurs in the first few days after placement, but also in the following months. In every patient developing complaints of arterial insufficiency after using an Angio-Seal, local arterial stenosis due to the device should be considered in the differential diagnosis. It therefore is important to register the use of the device in the patient chart.