Genetic alterations in primary melanoma in Taiwan.

BACKGROUND: Acral melanoma (AM) is the most common histopathological subtype of malignant melanoma in Asians. However, differences in the mutational profiles underlying AM and nonacral cutaneous melanoma (NAM) in Asians are not well understood. OBJECTIVES: To augment the understanding of the prevalence, patterns and associations of various mutations between different subtypes of melanoma. METHODS: We performed comprehensive genomic profiling of 409 cancer-associated genes, using next-generation sequencing, in 66 primary melanomas comprised of 45 AMs and 21 NAMs. RESULTS: Most of the AMs (n = 27/45; 60%), but only five of 21 (24%) NAMs, were triple wild-type (triple-WT) tumours. Compared with AMs, NAMs exhibited a significantly higher frequency of BRAF mutations. The frequencies of NRAS/KRAS mutations, cell-cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and gains of receptor tyrosine kinase genes were significantly higher in AMs. Ulceration was found at significantly higher rates in the AMs and NAMs with cell-cycle aberrations and gains of receptor tyrosine kinase genes. Notably, cell-cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma-specific survival in the 66 patients with melanoma and especially in the 45 patients with AM. Multivariate analysis showed that lymph node metastasis and cell-cycle aberrations were independent prognostic factors of melanoma-specific survival. CONCLUSIONS: This study strengthens our understanding of the patterns and clinical associations of oncogenic mutations in AMs and NAMs in Asians. What's already known about this topic? Mutation frequencies of driver genes vary between melanoma subtypes. Acral melanoma is the most common subtype of melanoma in Asians. KIT mutations and copy number variations occur more frequently in the acral subtype of melanoma than in the nonacral subtype What does this study add? NRAS/KRAS mutations, cell-cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and amplifications of receptor tyrosine kinase genes were significantly enriched in acral melanoma and could be potential targets for treatment. Melanomas with cell-cycle aberrations and gains in receptor tyrosine kinase genes were significantly more likely to contain ulceration. What is the translational message? Cell-cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma-specific survival. These observations should be explored further for future drug development.

Does Tumour Contrast Retention on CT Immediately Post Chemoembolization Predict Tumour Metabolic Response on FDG-PET in Patients with Hepatic Metastases from Colorectal Cancer?

PURPOSE: The exact mechanism of action of chemoembolization with drug eluting beads loaded with irinotecan (DEBIRI) in colorectal cancer is undetermined. Posttreatment tumour contrast retention often seen on CT immediately post procedure is of indeterminate significance. This study is aimed at assessing if metabolic response on PET-CT can be related to posttreatment tumour contrast retention. MATERIALS AND METHODS: In this retrospective study, a total of 17 patients with a total of 55 marker lesions were recruited. RESULTS: The area of tumour contrast retention can be matched to a hypometabolic area on subsequent PET-CT in over 36 lesions (65.5%). Out of the 55 lesions, a total of 38 marker lesions in 11 patients who also had pre-DEBIRI PET-CT were analyzed for disease response. 10 out of 10 lesions that had a complete response on PET-CT were found to demonstrate contrast retention throughout the tumour. 12 out of 13 (92.3%) tumours that had a partial metabolic response on PET-CT were found to demonstrate contrast uptake in the hypometabolic area only. In the 15 lesions that had progression/no response, 13 (86.6%) demonstrated no relationship between tumour contrast retention and tumour response. There was a significant correlation between contrast retention and disease response (P < 0.001). CONCLUSION: Our study showed that PET-CT response can be associated with post embolization contrast retention. The data suggests blood stasis, for which tumour contrast retention is a surrogate marker, is important for the PET-CT metabolic response. The authors propose that tumour contrast retention is an important embolization endpoint in DEBIRI.

Real-Time Quantitative Measurements of Foot Perfusion in Patients With Critical Limb Ischemia.

INTRODUCTION: Current methods of evaluating adequacy of endovascular procedures are imperfect and do not always predict which patients will do well. The purpose of this study was to evaluate the role of real-time quantitative measurements of perfusion among patients with critical limb ischemia. MATERIALS AND METHODS: Thirty-four patients with critical limb ischemia undergoing endovascular treatment were recruited. Perfusion Images of the foot were obtained pre and post successful angioplasty using an SPY Elite System (Novadaq Technologies, Ontario, Canada). Patients were followed for 6 months. Subsequently a logistic regression was performed to determine whether intraprocedural perfusion parameters predicted the odds of wound healing. RESULTS: Twenty-nine patients had successful angioplasty. Median age was 69.5% ± 8.3; 75% were men and 64% were diabetic. Rutherford stages were (4%-39%, 5%-57%, 6%-4%), and the average target limb ankle-brachial index (ABI) was 0.58 (SD 2.24). There was no significant correlation between the ABI and perfusion parameters. Inflow perfusion rate correlated significantly with Rutherford stage (Spearman rho 0.398, P = .036). After successful angioplasty 39% had a decrease in inflow rate and 57% had a decreased total inflow. In all, 25 patients completed 6 months of follow-up. Resolution of rest pain and/or healing of the ischemic wound occurred in 10 (40%) patients at 1 month, 4 (16%) at 3 months, and 2 (8%) at 6 months. One patient underwent a major amputation at 2 months. Eight (32%) patients never healed or had persistent rest pain. None of the real-time perfusion variables were significant predictors of wound healing. CONCLUSION: Many patients experience a paradoxical decrease in perfusion following successful angioplasty suggesting perfusion may not correlate with angiographic outcome, possibly due to microemboli, microvascular disease, or vasospasm. Real-time perfusion imaging following intra-arterial infusion of indocyanine green does not predict the odds of wound healing.

A case of pulmonary tuberculosis masquerading as lung carcinoma.

Tuberculosis is a nimble chameleon. It can manifest itself in various ways with atypical clinical and radiographic findings. In this report we discuss the importance of radiographic findings (nodular or mass-like forms) requiring a correlation with microbiological and histopathological results to differentiate lung cancer from TB.

Ordering of mutations in acute myeloid leukemia with partial tandem duplication of MLL (MLL-PTD).

Partial tandem duplication of MLL (MLL-PTD) characterizes acute myeloid leukemia (AML) patients often with a poor prognosis. To understand the order of occurrence of MLL-PTD in relation to other major AML mutations and to identify novel mutations that may be present in this unique AML molecular subtype, exome and targeted sequencing was performed on 85 MLL-PTD AML samples using HiSeq-2000. Genes involved in the cohesin complex (STAG2), a splicing factor (U2AF1) and a poorly studied gene, MGA were recurrently mutated, whereas NPM1, one of the most frequently mutated AML gene, was not mutated in MLL-PTD patients. Interestingly, clonality analysis suggests that IDH2/1, DNMT3A, U2AF1 and TET2 mutations are clonal and occur early, and MLL-PTD likely arises after these initial mutations. Conversely, proliferative mutations (FLT3, RAS), typically appear later, are largely subclonal and tend to be unstable. This study provides important insights for understanding the relative importance of different mutations for defining a targeted therapeutic strategy for MLL-PTD AML patients.

Prediction of margin involvement and local recurrence after skin-sparing and simple mastectomy.

UNLABELLED: Skin-sparing mastectomy (SSM) facilitates immediate breast reconstruction. We investigated locoregional recurrence rates after SSM compared with simple mastectomy and the factors predicting oncological failure. METHODS: Patients with early breast cancer that underwent mastectomy between 2000 and 2005 at a single institution were studied to ascertain local and systemic recurrence rates between groups. Kaplan-Meier curves and log-rank test were used to evaluate disease-free survival. RESULTS: Patients (n = 577) underwent simple mastectomy (80%) or SSM (20%). Median follow up was 80 months. Patients undergoing SSM were of younger average age, less often had involved lymph nodes (22% vs 44%, p < 0.001), more often had DCIS present (79% vs 53%, p < 0.001) and involved margins (29% vs 15%, p = 0.001). Involved surgical margins were associated with large size (p = 0.001). The 8-year local recurrence (LR) rates were 7.9% for SSM and 5% for simple mastectomy respectively (p = 0.35). Predictors of locoregional recurrence were lymph node involvement (HR 8.0, for >4 nodes, p < 0.001) and involved surgical margins (HR 3.3, p = 0.002). In node negative patients, SSM was a predictor of locoregional recurrence (HR 4.8 [1.1, 19.9], p = 0.033). CONCLUSION(S): Delayed reconstruction is more appropriate for node positive early breast cancer after post-mastectomy radiotherapy. Re-excision of involved margins is essential to prevent local recurrence after mastectomy.

Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

Internal Iliac Aneurysm Repair Outcomes Using a Modification of the Iliac Branch Graft.

OBJECTIVES: Iliac branch grafts (IBGs) are a validated option for the treatment of aorto-iliac aneurysms preserving internal iliac artery (IIA) flow. IIA aneurysm (IIAA) is a relative contraindication to IBG placement. The goal of this study was to review experience in managing aorto-iliac aneurysms with concomitant IIAAs with extension of the IIA branch stent graft into the superior gluteal artery (SGA). METHODS: This retrospective study between May 2009 and November 2014 includes consecutive patients who underwent placement of an IBG (Cook, Bloomington, IN, USA) with extension of the internal iliac component of the branch stent graft into the SGA because of aneurysmal IIA (>15 mm). The stent grafts used were Viabahn (Gore, Karlsruhe, Germany), Fluency (Bard, Flagstaff, AZ, USA), or iCast (Atrium, Hudson, NH, USA) proximally. Imaging follow up was with computed tomography angiography (CTA) within 30 days of device insertion and then annually. RESULTS: The procedure was performed on 15 patients with a mean age of 76.8 years (SD 6.1 years). Twenty IIAAs were treated with a mean IIA and common iliac artery (CIA) diameter of 33 mm (SD 13 mm) and 35 mm (SD 11 mm) respectively. Technical success rate was 100%. One patient who underwent simultaneous IBG and three vessel fenestrated endovascular aneurysm repair died of mesenteric ischemia 2 days after the procedure. Mean imaging follow up with CTA was 18.3 months (SD 15.1 months). Primary patency of the SGA stent grafts was 100%. There was one case of type II endoleak. All patients were free from buttock claudication at follow up (mean: 19.7 months). Two patients who had IIA embolization contralateral to the IBG placement suffered from unilateral lower limb monoparesis. CONCLUSIONS: Extension of the internal iliac component of IBGs into the SGA for distal seal is feasible and safe in the endovascular treatment of aorto-iliac aneurysms with concomitant IIAs. Long-term results are needed to further validate this technique.

Consensus statement: the 16th Annual Western Canadian Gastrointestinal Cancer Consensus Conference; Saskatoon, Saskatchewan; September 5-6, 2014.

The 16th annual Western Canadian Gastrointestinal Cancer Consensus Conference was held in Saskatoon, Saskatchewan, September 4-5, 2014. The Consensus Conference is an interactive, multidisciplinary event attended by health care professionals from across western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) involved in the care of gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals participated in presentation and discussion sessions for the purposes of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancer.

Bedside Continuous Irrigation and Drainage as an Interim Local Treatment for Septic Arthritis of the Knee in the Medically Unstable Patient: A Case Report.

Septic arthritis is a surgical emergency. Prompt diagnosis and immediate treatment reduce the destruction of articular cartilage and give better outcome. We describe a simple, minimally invasive closed tube irrigation system for the initial treatment of septic arthritis of the knee in a patient with complex medical problems who was unfit to undergo surgery.

Clinical utility of ultrasound versus magnetic resonance imaging for deciding to proceed with uterine artery embolization for presumed symptomatic fibroids.

AIM: To compare the diagnostic utility of pelvic ultrasound (US) and magnetic resonance imaging (MRI) on the clinical decision to proceed with uterine artery embolization (UAE). MATERIALS AND METHODS: Over 2 years, 180 consecutive women (mean age 43) sought consultation for UAE, 116 underwent pelvic US and MRI before possible UAE. US was performed prior to MRI. Imaging was analysed for leiomyoma quantity, size and location, uterine volume, and the presence of potential contraindications to UAE. Discrepancies between imaging methods and cases where discrepancies could have altered management, were recorded. RESULTS: For the 116 patients who completed imaging, the average uterine volume was 701 cm(3) using MRI versus 658 cm(3) using US (p=0.48). The average dominant leiomyoma volume was 292 cm(3) using MRI versus 253 cm(3) using US (p=0.16). In 14 (12.1%) patients US did not correctly quantify or localize leiomyomas compared with MRI (p=0.0005). Thirteen patients did not undergo UAE (patient preference n=9, pre-procedural imaging findings n=4). In the four cases where UAE was not performed due to imaging findings, relevant findings were all diagnosed by MRI compared with two by US (p=0.5). The two cases not detected by ultrasound were adenomyosis and a pedunculate subserosal leiomyoma. Of the 103 patients who underwent UAE, 14 were treated (without complication) despite the presence of a relative contraindication; all 14 relative contraindications were identified by MRI compared with 13 by US (p=1.0). CONCLUSION: MRI is more accurate than US for characterizing uterine leiomyomas. In a small but statistically insignificant number of cases, MRI identified findings that were missed by US, which changed management. For patients that are unsuitable to be assessed with MRI, ultrasound alone is sufficient for pre-UAE assessment.

Characterization of hyaluronan and TSG-6 in skin scarring: differential distribution in keloid scars, normal scars and unscarred skin.

BACKGROUND: Hyaluronan (HA) is a major component of the extracellular matrix (ECM) with increased synthesis during tissue repair. Tumour necrosis factor-stimulated gene-6 (TSG-6) is known to catalyze the covalent transfer of heavy chains (HC1 and HC2) from inter-α-inhibitor (IαI) onto HA, and resultant HC•HA complexes have been implicated in physiological and pathological processes related to remodelling and inflammation. OBJECTIVE: The aims of this study were to determine the expression of HA, TSG-6 and the IαI polypeptides in unscarred skin, normal scars and keloid scars. METHODS: Formalin-fixed paraffin-embedded sections of unscarred skin, normal scars and keloid scars were prepared from patient samples collected during scar revision surgery. Haematoxylin and eosin, as well as immunofluorescent staining for HA, TSG-6 and the three polypeptide chains of IαI (i.e. HC1, HC2 and bikunin) were performed. RESULTS: All skin types stained positive for TSG-6, HC1, HC2 and bikunin, associated with keratinocytes, fibroblasts and skin appendages all in close proximity to HA. Keloid lesions showed altered HA organization patterns compared with unscarred skin and normal scars. TSG-6 staining was significantly more intense in the epidermis compared with the dermis of all sample types. There was a significant reduction in TSG-6 levels within keloid lesions compared with the dermis of unscarred skin (P=0.017). CONCLUSION: TSG-6 is expressed in unscarred skin, where its close association with HA and IαI could give rise to TSG-6-mediated HC•HA formation within this tissue. A reduction in the beneficial effects of TSG-6, caused by diminished protein levels in keloid lesions, could contribute to this abnormal scarring process.

Tumour necrosis factor-α expression is associated with increased severity of periprosthetic breast capsular contracture.

BACKGROUND: The pathogenesis of periprosthetic capsular contracture following breast implant surgery is unclear. The aim of this study was to identify the expression of tumour necrosis factor-α (TNF-α), collagen type III α(1) (COL3A1), transforming growth factor-ß(1) (TGF-ß(1)) and connective tissue growth factor (CTGF) in different Baker grades of breast capsular contracture. METHODS: Seven periprosthetic breast capsule specimens were collected from 6 patients. TNF-α, COL3A1, TGF-ß(1) and CTGF gene expression were analysed using real-time quantitative polymerase chain reaction. Immunohistolocalisation of TNF-α was performed on paraffin-embedded sections. Significant correlations were analysed using the Pearson correlation coefficient. RESULTS: TNF-α expression was associated with increased Baker grade of capsular contracture (Pearson correlation, r = 0.558; p = 0.02). COL3A1 gene expression was reduced with increasing severity of contracture (r = -0.490; p = 0.05). There were no significant correlations between TGF-ß(1) and CTGF expression with Baker grade. Positive TNF-α staining in breast capsules was localised to fibroblasts, macrophages, and extracellularly close to the prosthesis. CONCLUSION: The increased expression of TNF-α may play a key role in the inflammatory response associated with capsular contracture. The corresponding decrease in COL3A1 may contribute to the change in capsular physical properties seen in capsular contracture.

Frontal fibrosing alopecia: clinical presentations and prognosis.

BACKGROUND: Frontal fibrosing alopecia is an uncommon condition characterized by progressive frontotemporal recession due to inflammatory destruction of hair follicles. Little is known about the natural history of this disease. OBJECTIVES: To determine the clinical features and natural history of frontal fibrosing alopecia. METHODS: We studied the cases notes of patients diagnosed with frontal fibrosing alopecia from 1993 to 2008 at the Royal Hallamshire Hospital, Sheffield. RESULTS: There were 18 patients aged between 34 and 71 years. Three were premenopausal. All had frontotemporal recession with scarring. This was associated with partial or complete loss of eyebrows in 15 patients while four had hair loss at other sites. One had keratosis pilaris-like papules on the face, and one had follicular erythema on the cheeks. Three patients had oral lichen planus, of whom two also had cutaneous lichen planus affecting other sites of the body. Treatments given included intralesional triamcinolone acetonide, 0.1% tacrolimus ointment and oral hydroxychloroquine. Progression of frontotemporal recession was seen in some patients, but not all. In one patient the hair line receded by 30 mm over 72 months, whereas in another patient there was no positional change in the hair line after 15 years. CONCLUSIONS: Frontal fibrosing alopecia is more common in postmenopausal women, but it can occur in younger women. It may be associated with mucocutaneous lichen planus. Recession of the hair line may progress inexorably over many years but this is not inevitable. It is not clear whether or not treatment alters the natural history of the disease - the disease stabilized with time in most of the patients with or without continuing treatment.

Renal vascular injuries following nephron-sparing surgery and their endovascular management.

INTRODUCTION: This study aims to describe renal vascular injuries following nephron-sparing surgery and the efficacy of transcatheter embolisation in management of these complications. METHODS: A retrospective review was performed on 96 patients who underwent nephron-sparing surgery from 2001 to 2005. Selective angiography was performed on all patients referred for significant postoperative haematuria and internal bleeding, followed by embolisation where indicated. Patient presentation, type of vascular injury, embolisation technique and treatment outcome were reviewed in each case. Efficacy of embolisation in preservation of renal function was assessed. RESULTS: Seven arterial lesions were identified in four patients (three male and one female; age range 47-70 years). Three patients developed pseudoaneurysms (mean size 2.1 cm, range 1.5-3 cm). One patient revealed four separate areas of active contrast extravasations. All patients were successfully treated with coil embolisation with complete symptomatic relief within one to three days. Renal function was preserved in all patients over a follow-up period of 90 days. CONCLUSION: Renal arterial injuries, especially pseudoaneurysms, are an important though uncommon cause of haematuria following nephron-sparing surgery. Coil embolisation is an effective treatment for management of these iatrogenic injuries.

The benefits of combined anti-platelet treatment in carotid artery stenting.

OBJECTIVE: To assess the benefits of a combined anti-platelet regime of aspirin and clopidogrel in carotid artery stenting. METHODS: A randomised controlled trial was performed comparing aspirin and 24-h heparin with aspirin and clopidogrel for patients undergoing carotid artery stenting. Outcome measures included 30-day bleeding and neurological complications and 30-day stenosis rates. RESULTS: Bleeding complications (groin haematoma or excessive bleeding at the groin site) occurred in 17% of the heparin and 9% of the clopidogrel group (p=0.35; n.s). The neurological complication rate in the 24-h heparin group was 25% compared to 0% in the clopidogrel group (p=0.02). The 30-day 50-100% stenosis rates were 26% in the heparin group and 5% in the clopidogrel group (p=0.10; n.s). CONCLUSIONS: The dual anti-platelet regime has a significant impact on reducing adverse neurological outcomes without an additional increase in bleeding complications. This study was terminated prematurely due to an unacceptable level of complications in the heparin arm of the trial.

Clinically apparent atherosclerotic disease in diabetes is associated with an increase in platelet microparticle levels.

BACKGROUND: The commonest cause of mortality in patients with Type 2 diabetes is atherothrombosis, which can be related to abnormalities in the coagulation and fibrinolytic pathways, as well as in platelet function. Platelet microparticles (PMPs) may contribute to the prothrombotic state and may promote the progression of atherosclerosis. We hypothesized that PMPs are elevated in Type 2 diabetes and that patients with Type 2 diabetes and clinically apparent atherosclerosis would have the highest levels. Similarly, we hypothesized that soluble plasma P-selectin (sPsel) and CD40L (both molecules which are released by activated platelets), as well as %CD62P (P-selectin) and %CD63 positivity on platelets quantified by flow cytometry, would be highest in patients with Type 2 diabetes and clinically apparent atherosclerotic disease, and might be correlated to PMP levels. METHODS: Venous blood was obtained from 21 Type 2 diabetic patients without atherosclerotic complications, 18 diabetic patients with clinically apparent atherosclerotic disease and 21 non-diabetic control subjects. PMPs, as well as %CD62P and %CD63 positivity on platelets, were quantified by flow cytometry. sPsel and CD40L were measured using ELISA. RESULTS: Patients with Type 2 diabetes and clinically apparent atherosclerotic disease had the highest PMP (P=0.045) and sPsel (P=0.046) levels, compared with patients without complications (who had intermediate PMP levels) and control subjects. Control subjects had the lowest CD40L levels (P<0.001) when compared with patients with Type 2 diabetes, with no difference in sCD40L levels between the two diabetic subgroups. %CD62P and %CD63 positivity did not differ between the groups. PMP levels correlated with %CD62P positivity (P=0.026) but not to %CD63 positivity (P=0.089), sCD40L (P=0.407) or sP-sel (P=0.163); sCD40L levels did not correlate with any other marker of platelet activation. CONCLUSION: PMPs are elevated in Type 2 diabetes. In addition, patients with clinically apparent atherosclerosis had the highest levels of PMPs and sPsel. Thus, PMPs may be a marker of symptomatic atherosclerotic vascular disease in Type 2 diabetes, and may both represent a useful risk stratification tool as well as a novel therapeutic target for anti-thrombotic drugs.