The Association Between Tobacco Use and Risk of COVID-19 Infection and Clinical Outcomes in Sweden: A Population-Based Study.

Background: The association between tobacco use and COVID-19 is controversial. During the early course of the pandemic, limited testing prevented studying a wide spectrum of clinical manifestations. Objective: To examine the potential causal association between tobacco use and COVID-19 during the second wave (1 October 2020-30 June 2021) of the pandemic in Stockholm, Sweden. Methods: A population-based cohort study was conducted in the Stockholm region of Sweden, with information on tobacco use collected prior to the pandemic. Adjusted relative risks (RR) of COVID-19 and 95% confidence intervals (CI) were calculated, contrasting current smokers and snus users to non-users of tobacco. Results: Compared with non-users of tobacco, current smokers had a lower risk of COVID-19 (RR 0.78, 95% CI = 0.75-0.81) and of hospitalisation for the disease. Current snus users had a higher risk of COVID-19. Heavy smokers and snus users had longer hospital stays than non-users of tobacco. Conclusion: Tobacco use may have a different impact on the risk of being infected with SARS-CoV-2 and the risk of developing severe clinical manifestations. Further research is needed to determine the underlying mechanisms.

Oxytocin versus a combination of tranexamic acid and ethamsylate in reducing intraoperative bleeding during abdominal myomectomy: a randomized clinical trial.

OBJECTIVE: Myomectomy is the preferred surgical approach to manage uterine fibroids. However, uterine fibroids are highly vascular tumors and, consequently, extremely susceptible to problems from myomectomy-related hemorrhage. Hence, we aim to compare oxytocin efficacy and safety profile versus tranexamic acid (TA) with ethamsylate for reducing bleeding during myomectomy. METHODS: This randomized, double-blinded multicenter study was performed between 20th August 2020 and 20th October 2020 at El-Galaa Teaching Hospital, El Hussein University Hospital, Al-Azhar University Hospitals of Assiut, and Al-Azhar University Hospitals of Damietta. One hundred and eighty patients were enrolled and divided into three groups: group (1) received an injection of 30 IU of oxytocin in 500 ml of normal saline; group (2) received injections of 1 g of TA, 250 mg of Ethamsylate, and 110 ml of normal saline IV; and group (3) received an injection of 110 ml of normal saline IV just before surgical incision. RESULTS: In 180 premenopausal women, oxytocin and TA with ethamsylate had no significant value in lowering intraoperative blood loss compared with the placebo for abdominal myomectomy (666.25 ± 183.03, 630.72 ± 145.83, and 646.67 ± 168.92, respectively (P = 0.506)). Non-significant trends were observed for a reduction in operation time (P = 0.760), intra/postoperative blood transfusion (P = 0.624), hospital stay (P = 0.986), postoperative fever (P = 0.659), and wound infection (P = 1). CONCLUSION: Oxytocin and TA with ethamsylate had no significant value in lowering intraoperative blood loss compared with the placebo for abdominal myomectomy which opens a new question about the role of the use of the hemostatic drug during myomectomy especially in centers with limited resources and had higher rates. TRIAL REGISTRATION: The study was registered on Pan African Clinical Trials Registry with the following number: PACTR202008739887429 and was approved on 24/08/2020.

Current tobacco use and COVID-19 diagnoses in a cohort of adult clients of public dental clinics in Sweden.

Smoking has been linked with both increased and decreased risk of COVID-19, prompting the hypothesis of a protective role of nicotine in the pathogenesis of the disease. Studies of the association between use of smokeless tobacco and COVID-19 would help refining this hypothesis. We analysed data from 424,386 residents in the Stockholm Region, Sweden, with information on smoking and smokeless tobacco (snus) use prior to the pandemic obtained from dental records. Diagnoses of COVID-19 between February and October 2020 were obtained from health-care registers. We estimated the risk of receiving a diagnosis of COVID-19 for current smokers and for current snus users relative to non-users of tobacco, adjusting for potential confounders (aRR). The aRR of COVID -19 was elevated for current snus users (1.09 ;95%CI = 0.99-1.21 among men and 1.15; 95%CI = 1.00-1.33 among women). The risk for women consuming more than 1 can/day was twice as high as among non-users of tobacco. Current smoking was negatively associated with risk of COVID-19 (aRR = 0.68; 95% CI = 0.61-0.75); including hospital admission (aRR = 0.60; 95% CI = 0.47-0.76) and intensive care (aRR = 0.43; 95% CI = 0.21-0.89). The hypothesis of a protective effect of tobacco nicotine on COVID-19 was not supported by the findings. The negative association between smoking and COVID-19 remains unexplained.

Radiographic comparison between Densah burs and osteotome for graftless internal sinus lifting with simultaneous implant placement: a randomized clinical trial.

Implant placement in the posterior maxilla is not an easy procedure, not only due to the low quality of bone, but also the physiological pneumatization, which decreases the remaining bone height to the maxillary sinus. Sinus lifting is an alternative for implant placement in these cases. The aim of this study was to radiographically compare the effect of Densah densifying burs versus osteotome in transcrestal sinus lifting. Twelve patients with missing premolars or molars and limited residual bone height were enrolled in the study and divided equally (by coin toss) into two groups: group A underwent densifying bur sinus lifting and group B underwent osteotome sinus lifting. Follow-up was performed over 6 months. Bone density (measured around the implant and at the implant apex) and bone height gain (measured using three reference points across the implant length) were measured using OnDemand 3D software. Bone density around the implant was found to be significantly higher for the densifying burs (P = 0.010); however, no significant difference in bone height gain (P = 0.985) or apical bone density (P = 0.337) was detected between the two groups. Densifying burs significantly improved bone density around dental implants, but did not prove to provide a significantly higher bone height gain or apical density compared to osteotomes in graftless internal sinus lifting. TRIAL REGISTRATION NUMBER: Clinical trial.gov registration ID #NCT04688957.

Cystic adrenal masses: spectrum of multimodality imaging features and pathological correlation.

Adrenal cystic lesions are generally rare and encompass a wide spectrum of benign and malignant entities. Increased utilisation of cross-sectional imaging has led to increased detection of incidentally discovered adrenal lesions. Many of these lesions are cystic or solid with cystic changes, and the majority are benign; however, some may represent malignant lesions and/or even metastases. Therefore, it is vital to characterise these lesions appropriately and follow-up with laboratory tests and imaging if necessary. Key imaging techniques include computed tomography (CT) and magnetic resonance imaging (MRI). Other supplemental imaging tools include metaiodobenzyl-guanidine (MIBG) scintigraphy and 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography (FDG-PET). Accurate diagnosis of adrenal cystic lesions is crucial in guiding appropriate evaluation and management of these patients. This review highlights the clinical presentations, pathological and imaging features, and management of cystic adrenal lesions.

Functional and Anatomical Characterization of Corticotropin-Releasing Factor Receptor Subtypes of the Rat Spinal Cord Involved in Somatic Pain Relief.

Corticotropin-releasing factor (CRF) orchestrates our body's response to stressful stimuli. Pain is often stressful and counterbalanced by activation of CRF receptors along the nociceptive pathway, although the involvement of the CRF receptor subtypes 1 and/or 2 (CRF-R1 and CRF-R2, respectively) in CRF-induced analgesia remains controversial. Thus, the aim of the present study was to examine CRF-R1 and CRF-R2 expression within the spinal cord of rats with Freund's complete adjuvant-induced unilateral inflammation of the hind paw using reverse transcriptase polymerase chain reaction, Western blot, radioligand binding, and immunofluorescence confocal analysis. Moreover, the antinociceptive effects of intrathecal (i.t.) CRF were measured by paw pressure algesiometer and their possible antagonism by selective antagonists for CRF-R1 and/or CRF-R2 as well as for opioid receptors. Our results demonstrated a preference for the expression of CRF-R2 over CRF-R1 mRNA, protein, binding sites and immunoreactivity in the dorsal horn of the rat spinal cord. Consistently, CRF as well as CRF-R2 agonists elicited potent dose-dependent antinociceptive effects which were antagonized by the i.t. CRF-R2 selective antagonist K41498, but not by the CRF-R1 selective antagonist NBI35965. In addition, i.t. applied opioid antagonist naloxone dose-dependently abolished the i.t. CRF- as well as CRF-R2 agonist-elicited inhibition of somatic pain. Importantly, double immunofluorescence confocal microscopy of the spinal dorsal horn showed CRF-R2 on enkephalin (ENK)-containing inhibitory interneurons in close opposition of incoming mu-opioid receptor-immunoreactive nociceptive neurons. CRF-R2 was, however, not seen on pre- or on postsynaptic sensory neurons of the spinal cord. Taken together, these findings suggest that i.t. CRF or CRF-R2 agonists inhibit somatic inflammatory pain predominantly through CRF-R2 receptors located on spinal enkephalinergic inhibitory interneurons which finally results in endogenous opioid-mediated pain inhibition.

Breast Angiosarcoma Surveillance Study: UK national audit of management and outcomes of angiosarcoma of the breast and chest wall.

BACKGROUND: Breast angiosarcomas are rare tumours of vascular origin. Secondary angiosarcoma occurs following radiotherapy for breast cancer. Angiosarcomas have high recurrence and poor survival rates. This is concerning owing to the increasing use of adjuvant radiotherapy for the treatment of invasive breast cancer and ductal cancer in situ (DCIS), which could explain the rising incidence of angiosarcoma. Outcome data are limited and provide a poor evidence base for treatment. This paper presents a national, trainee-led, retrospective, multicentre study of a large angiosarcoma cohort. METHODS: Data for patients with a diagnosis of breast/chest wall angiosarcoma between 2000 and 2015 were collected retrospectively from 15 centres. RESULTS: The cohort included 183 patients with 34 primary and 149 secondary angiosarcomas. Median latency from breast cancer to secondary angiosarcoma was 6 years. Only 78.9 per cent of patients were discussed at a sarcoma multidisciplinary team meeting. Rates of recurrence were high with 14 of 28 (50 per cent ) recurrences in patients with primary and 80 of 124 (64.5 per cent ) in those with secondary angiosarcoma at 5 years. Many patients had multiple recurrences: total of 94 recurrences in 162 patients (58.0 per cent). Median survival was 5 (range 0-16) years for patients with primary and 5 (0-15) years for those with secondary angiosarcoma. Development of secondary angiosarcoma had a negative impact on predicted breast cancer survival, with a median 10-year PREDICT prognostic rate of 69.6 per cent, compared with 54.0 per cent in the observed cohort. CONCLUSION: A detrimental impact of secondary angiosarcoma on breast cancer survival has been demonstrated. Although not statistically significant, almost all excess deaths were attributable to angiosarcoma. The increased use of adjuvant radiotherapy to treat low-risk breast cancer and DCIS is a cause for concern and warrants further study.

The NeST (Neoadjuvant systemic therapy in breast cancer) study: National Practice Questionnaire of United Kingdom multi-disciplinary decision making.

BACKGROUND: Neoadjuvant systemic therapy (NST) is increasingly used in the treatment of breast cancer, yet it is clear that there is significant geographical variation in its use in the UK. This study aimed to examine stated practice across UK breast units, in terms of indications for use, radiological monitoring, pathological reporting of treatment response, and post-treatment surgical management. METHODS: Multidisciplinary teams (MDTs) from all UK breast units were invited to participate in the NeST study. A detailed questionnaire assessing current stated practice was distributed to all participating units in December 2017 and data collated securely usingREDCap. Descriptive statistics were calculated for each questionnaire item. RESULTS: Thirty-nine MDTs from a diverse range of hospitals responded. All MDTs routinely offered neoadjuvant chemotherapy (NACT) to a median of 10% (range 5-60%) of patients. Neoadjuvant endocrine therapy (NET) was offered to a median of 4% (range 0-25%) of patients by 66% of MDTs. The principal indication given for use of neoadjuvant therapy was for surgical downstaging. There was no consensus on methods of radiological monitoring of response, and a wide variety of pathological reporting systems were used to assess tumour response. Twenty-five percent of centres reported resecting the original tumour footprint, irrespective of clinical/radiological response. Radiologically negative axillae at diagnosis routinely had post-NACT or post-NET sentinel lymph node biopsy (SLNB) in 73.0 and 84% of centres respectively, whereas 16% performed SLNB pre-NACT. Positive axillae at diagnosis would receive axillary node clearance at 60% of centres, regardless of response to NACT. DISCUSSION: There is wide variation in the stated use of neoadjuvant systemic therapy across the UK, with general low usage of NET. Surgical downstaging remains the most common indication of the use of NAC, although not all centres leverage the benefits of NAC for de-escalating surgery to the breast and/or axilla. There is a need for agreed multidisciplinary guidance for optimising selection and management of patients for NST. These findings will be corroborated in phase II of the NeST study which is a national collaborative prospective audit of NST utilisation and clinical outcomes.

Microcatheter-assisted circumferential trabeculotomy in primary congenital glaucoma.

PURPOSE: To study circumferential trabeculotomy for congenital glaucoma using Glaucolight illuminated microcatheter. METHODS: This was a prospective, uncontrolled, consecutive interventional study of 25 eyes of 25 patients with primary congenital glaucoma (PCG) underwent circumferential trabeculotomy done with an illuminated microcatheter through a period of 18-24 months in ophthalmology department, faculty of medicine, Minia University, Egypt. Patients' data of 12 months' follow-up were recorded. The primary target was the mean intraocular pressure (IOP) study in which complete success was defined as an IOP ≤21 mm Hg and at least a 30% reduction without the use of antiglaucoma drugs and a qualified success when medications were used to reach this aim. The secondary target was studying the corneal diameter and cup disc ratio change. RESULTS: The mean IOP (mm Hg) was reduced from 27.28 ± 3.46 preoperatively to 17.50 ± 5.09 at the final postoperative visit (P < 0.001). The mean follow-up period length was (18 months). A qualified success rate was reached to 88%, complete success in 76% and failure in 12%. No serious surgical complications were observed. CONCLUSION: Circumferential trabeculotomy accomplished by an illuminated microcatheter achieved a significant IOP lowering with either qualified or complete success in most of eyes with no significant ocular complications and it can be the first option in pediatric PCG surgery.

Does the Time of Starting Progesterone Luteal Support Affect Embryo Transfer in Long Agonist Protocol Downregulated ICSI Cycles? A Randomized Controlled Trial.

The aim of this study was to compare the effects of starting progesterone (P4) luteal support (LS) on day of egg retrieval (ER) or day of embryo transfer (ET) on the ratio of difficult ET and cycle outcome. This was a RCT ( ClinicalTrials.gov Identifier: NCT03040830) carried out at Mansoura Integrated Fertility Center (MIFC), Mansoura, Egypt, from November 2015 to January 2017. A total of 171 eligible long agonist ICSI cases were randomly allocated on day of ER into group A (86) starting LS as daily IM 100 mg P4 on day of ER and group B (85) starting P4-LS on day of ET. Difficult ET was defined as blood on ET catheter and/or sounding or dilating the cervix. Primary outcome was the overall ratio of difficult ET and ratios on day 3 and 5 ET. Secondary outcome was the ongoing pregnancy rate (OPR) and implantation rate (IR). The results are presented as % for groups A and B respectively: overall difficult ET (44.1, 24.7) (p = 0.009); day 3 difficult ET (23.2, 24.4) (p = 0.45); day 5 difficult ET (62.7, 25.6) (p = 0.001); overall OPR (38.3, 44.7) (p = 0.43); day 3 ET OPR (41.8, 33.3) (p = 0.51); day 5 ET OPR (34.8, 57.5) (p = 0.048); overall IR (20.0, 22.5) (p = 0.62); day 3 ET IR (17.8, 13.4) (p = 0.44); day 5 ET IR (22, 34.1) (p = 0.09). In conclusion, starting P4 luteal support on egg retrieval day is associated with significantly higher ratio of difficult embryo transfer and lower ongoing pregnancy rate and tendency to lower IR in day 5 ET, so starting P4-LS on day of ET is recommended.

Presentation and Outcomes of Hepatocellular Carcinoma in the Arabian Peninsula: A Review of a Single Institution Experience in the Sorafenib Era.

PURPOSE: There is a growing evidence showing that there are geographic differences in hepatocellular carcinoma (HCC). Little is known about the characteristics of hepatocellular carcinoma in the Arabian Peninsula. The present study examines the presentation and outcomes of HCC in a single institution. METHODS: A retrospective chart review of patients presented with advanced-stage HCC to Kuwait Cancer Control Center (KCCC) between 2008 and 2018 was conducted. Data collected included patients demographics, HCC risk factors, performance status, Child-Pugh score, pick up of sorafenib, and survival. RESULTS: About 111 cases were analyzed. The mean age of the cohort was 61.8 ± 11.4 years and 94 patients (84.7%) were males. HCV and diabetes were the most common risk factors for HCC and presented in 60 patients (54.1%) and 45 patients (40.5%), respectively. About 78 (70.3%) patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at presentation. Only 29 (26.1%) patients presented with Child-Pugh class A, while 42 (40.4%) patients received sorafenib. The median overall survival was only 3 months. CONCLUSIONS: In our cohort, HCV and diabetes were the main risk factors for HCC. The majority of patients was not amenable to sorafenib treatment and carries a very poor prognosis.

Prostanoid Receptor Subtypes and Its Endogenous Ligands with Processing Enzymes within Various Types of Inflammatory Joint Diseases.

A complex inflammatory process mediated by proinflammatory cytokines and prostaglandins commonly occurs in the synovial tissue of patients with joint trauma (JT), osteoarthritis (OA), and rheumatoid arthritis (RA). This study systematically investigated the distinct expression profile of prostaglandin E2 (PGE2), its processing enzymes (COX-2), and microsomal PGES-1 (mPGES-1) as well as the corresponding prostanoid receptor subtypes (EP1-4) in representative samples of synovial tissue from these patients (JT, OA, and RA). Quantitative TaqMan®-PCR and double immunofluorescence confocal microscopy of synovial tissue determined the abundance and exact immune cell types expressing these target molecules. Our results demonstrated that PGE2 and its processing enzymes COX-2 and mPGES-1 were highest in the synovial tissue of RA, followed by the synovial tissue of OA and JT patients. Corresponding prostanoid receptor, subtypes EP3 were highly expressed in the synovium of RA, followed by the synovial tissue of OA and JT patients. These proinflammatory target molecules were distinctly identified in JT patients mostly in synovial granulocytes, in OA patients predominantly in synovial macrophages and fibroblasts, whereas in RA patients mainly in synovial fibroblasts and plasma cells. Our findings show a distinct expression profile of EP receptor subtypes and PGE2 as well as the corresponding processing enzymes in human synovium that modulate the inflammatory process in JT, OA, and RA patients.

Optimum salinity for Nile tilapia (Oreochromis niloticus) growth and mRNA transcripts of ion-regulation, inflammatory, stress- and immune-related genes.

We aim to study the optimum salinity concentration for Nile tilapia, through the assessment of its growth performance and the expression of its related genes (Gh and Igf-1), as well as its salinity adaptation and immune status through the assessment of the gene expression of ion-regulation genes (Na+/K+-ATPase α-1a and α-1b), stress-related genes (GST, HSP27, and HSP70), inflammatory-related genes (IL1, IL8, CC, and CXC chemokine), and immune-related genes (IgMH TLR7, MHC, and MX) at the osmoregulatory organs (gills, liver, and kidney). Based on the least mortality percentage and the physical appearance of the fish, three salt concentrations (6, 16, and 20 ppt) were chosen following a 6-month preliminary study using serial salt concentrations ranged from 6 to 36 ppt, which were obtained by rearing the fish in gradual elevated pond salinity through daily addition of 0.5 ppt saline water. The fish size was 10.2-12 cm and weight was 25.5-26.15 g. No significant differences in the fish weight gain were observed among the studied groups. The group reared at 16-ppt salt showed better performance than that of 20 ppt, as they have lower morality % and higher expression of ion-regulated gene (Na+/K+-ATPase α1-b), stress-related genes (GST, HSP27, and HSP70) of the gills and also GST, inflammatory-related genes (IL-1ß and IL8), and TLR in the liver tissue. Higher expression of kidney-immune-related genes at 20-ppt salt may indicate that higher salinity predispose to fish infection and increased mortality. We concluded that 16-ppt salinity concentration is suitable for rearing O. niloticus as the fish are more adaptive to salinity condition without changes in their growth rate. Also, we indicate the use of immune stimulant feed additive to overcome the immune suppressive effect of hyper-salinity. Additionally, the survival of some fish at higher salinity concentrations (30-34 ppt) increase the chance for selection for salinity resistance in the Nile tilapia.

The NeST (neoadjuvant systemic therapy in breast cancer) study - Protocol for a prospective multi-centre cohort study to assess the current utilization and short-term outcomes of neoadjuvant systemic therapies in breast cancer.

INTRODUCTION: Neoadjuvant systemic therapy (NST) has several potential advantages in the treatment of breast cancer. However, there is currently considerable variation in NST use across the UK. The NeST study is a national, prospective, multicentre cohort study that will investigate current patterns of care with respect to NST in the UK. METHODS AND ANALYSIS: Phase 1 - a national practice questionnaire (NPQ) to survey current practice.Phase 2 - a multi-centre prospective cohort study of breast cancer patients, undergoing NST.Women undergoing NST as their MDT recommended primary breast cancer treatment between December 2017 and May 2018 will be included. The breast surgery and oncological professional associations and the trainee research collaborative networks will encourage participation by all breast cancer centres.Patient demographics, radiological, oncological, surgical and pathological data will be collected, including complications and the need for further intervention/treatment. Data will be collated to establish current practice in the UK, regarding NST usage and variability of access and provision of these therapies. Prospective data on 600 patients from ~50 centres are anticipated.Trial registration: ISRCTN11160072. ETHICS AND DISSEMINATION: Research ethics approval is not required for this study, as per the online Health Research Authority decision tool. The information obtained will provide valuable insights to help patients make informed decisions about their treatment. These data should establish current practice in the UK concerning NST, inform future service delivery as well as identifying further research questions.This protocol will be disseminated through the Mammary Fold Academic Research Collaborative (MFAC), the Reconstructive Surgery Trials Network and the Association of Breast Surgery. Participating units will have access to their own data and collective results will be presented at relevant conferences and published in appropriate peer-reviewed journals, as well as being made accessible to relevant patient groups.

The presentation, management and outcome of inflammatory breast cancer cases in the UK: Data from a multi-centre retrospective review.

OBJECTIVES: Inflammatory Breast cancer (IBC) is a rare but aggressive form of breast cancer. Its incidence and behaviour in the UK is poorly characterised. We collected retrospective data from hospitals in the UK and Ireland to describe the presentation, pathology, treatment and clinical course of IBC in the UK. MATERIALS AND METHODS: Patients with IBC diagnosed between 1997-2014 at fourteen UK and Irish hospitals were identified from local breast unit databases. Patient characteristics, tumour pathology and stage, and details of surgical, systemic and radiotherapy treatment and follow-up data were collected from electronic patient records and medical notes. RESULT: This retrospective review identified 445 patients with IBC accounting for 0.4-1.8% of invasive breast cancer cases. Median follow-up was 4.2 years. 53.2% of tumours were grade 3, 56.2% were oestrogen receptor positive, 31.3% were HER2 positive and 25.1% were triple negative. 20.7% of patients had distant metastases at presentation. Despite trimodality treatment in 86.4%, 40.1% of stage III patients developed distant metastases. Five-year overall survival (OS) was 61.0% for stage III and 21.4% for stage IV patients. CONCLUSIONS: This is the largest series of UK IBC patients reported to date. It indicates a lower incidence than in American series, but confirms that IBC has a high risk of recurrence with poor survival despite contemporary multi-modality therapy. A national strategy is required to facilitate translational research into this aggressive disease.

Systematic review of the impact of breast-conserving surgery on cancer outcomes of multiple ipsilateral breast cancers.

BACKGROUND: The clinical effectiveness of treating ipsilateral multifocal (MF) and multicentric (MC) breast cancers using breast-conserving surgery (BCS) compared with the standard of mastectomy is uncertain. Inconsistencies relate to definitions, incidence, staging and intertumoral heterogeneity. The primary aim of this systematic review was to compare clinical outcomes after BCS versus mastectomy for MF and MC cancers, collectively defined as multiple ipsilateral breast cancers (MIBC). METHODS: Comprehensive electronic searches were undertaken to identify complete papers published in English between May 1988 and July 2015, primarily comparing clinical outcomes of BCS and mastectomy for MIBC. All study designs were included, and studies were appraised critically using the Newcastle-Ottawa Scale. The characteristics and results of identified studies were summarized. RESULTS: Twenty-four retrospective studies were included in the review: 17 comparative studies and seven case series. They included 3537 women with MIBC undergoing BCS; breast cancers were defined as MF in 2677 women, MC in 292, and reported as MIBC in 568. Six studies evaluated MIBC treated by BCS or mastectomy, with locoregional recurrence (LRR) rates of 2-23 per cent after BCS at median follow-up of 59·5 (i.q.r. 56-81) months. BCS and mastectomy showed apparently equivalent rates of LRR (risk ratio 0·94, 95 per cent c.i. 0·65 to 1·36). Thirteen studies compared BCS in women with MIBC versus those with unifocal cancers, reporting LRR rates of 2-40 per cent after BCS at a median follow-up of 64 (i.q.r. 57-73) months. One high-quality study reported 10-year actuarial LRR rates of 5·5 per cent for BCS in 300 women versus 6·5 per cent for mastectomy among 887 women. CONCLUSION: The available studies were mainly of moderate quality, historical and underpowered, with limited follow-up and biased case selection favouring BCS rather than mastectomy for low-risk patients. The evidence was inconclusive, weakening support for the St Gallen consensus and supporting a future randomized trial.

NHS Breast Screening multidisciplinary working group guidelines for the diagnosis and management of breast lesions of uncertain malignant potential on core biopsy (B3 lesions).

Needle core biopsy is considered the histological diagnostic method of choice for screen-detected breast lesions. Although the majority are definitively diagnosed as normal, benign, or malignant, approximately 7% are categorised as B3, of uncertain malignant potential. These include a wide range of lesions with different risks of associated malignancy from <2% to approaching 40% from literature review in UK practice. Historically, these have typically been surgically excised as a diagnostic procedure but the majority are then proven to be benign. An alternative approach, for many of these lesions, is thorough sampling/excision by vacuum-assisted biopsy techniques to exclude the presence of co-existing carcinoma. This would potentially reduce the benign open biopsy rate whilst maintaining accuracy of cancer diagnosis. A group from the Radiology, Surgery, and Pathology NHS Breast Screening Programme Co-ordinating Committees and an additional co-opted expert were charged with review and development of guidelines for the clinical management of B3 lesions. The guidelines reflect suggested practice as stated by the NHS Breast Screening Programme and approved by the Royal College of Radiologists.

Evaluation of applying IHC4 as a prognostic model in the translational study of Intergroup Exemestane Study (IES): PathIES.

BACKGROUND: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and exemestane. PATIENTS AND METHODS: Primary tumour samples were available for 1274 patients (27% of IES population). Only patients for whom the IHC4 score could be calculated (based on oestrogen receptor, progesterone receptor, HER2 and Ki67) were included in this analysis (N = 430 patients). The clinical score (C) was based on age, grade, tumour size and nodal status. The association of clinicopathological parameters, IHC4(+C) scores and treatment effect with time to distant recurrence-free survival (TTDR) was assessed in univariable and multivariable Cox regression analyses. A modified clinical score (PathIEscore) (N = 350) was also estimated. RESULTS: Our results confirm the prognostic importance of the original IHC4, alone and in conjunction with clinical scores, but no significant difference with treatment effects was observed. The combined IHC4 + Clinical PathIES score was prognostic for TTDR (P < 0.001) with a hazard ratio (HR) of 5.54 (95% CI 1.29-23.70) for a change from 1st quartile (Q1) to Q1-Q3 and HR of 15.54 (95% CI 3.70-65.24) for a change from Q1 to Q4. CONCLUSION: In the PathIES population, the IHC4 score is useful in predicting long-term relapse in patients who remain disease-free after 2-3 years. This is a first trial to suggest the extending use of IHC4+C score for prognostic indication for patients who have switched endocrine therapies at 2-3 years and who remain disease-free after 2-3 years.

Modulation of d-galactosamine/lipopolysacharride-induced fulminant hepatic failure by nilotinib.

This investigation was undertaken to test the effect of nilotinib against d-galactosamine (GalN) and lipopolysaccharide (LPS)-induced fulminant hepatic failure (FHF). Male Swiss albino mice were orally treated with nilotinib for 3 days prior to GalN/LPS challenge. The results revealed that administration of GalN/LPS caused elevation in the mortality rate. GalN/LPS-induced severe hepatic injury was manifested by increased serum transaminases and alkaline phosphatase (ALP) levels as well as histopathological hepatic necrosis and inflammation. In addition, GalN/LPS increased the hepatic oxidative stress as indicated by increased malondialdehyde level, decreased glutathione content, and superoxide dismutase (SOD) activity. Furthermore, GalN/LPS increased nuclear factor kappa-B activation and the levels of tumor necrosis factor-alpha and interleukin-1ß. These biochemical and histopathological changes were markedly ameliorated by nilotinib pretreatment. On the other hand, the level of toll-like receptor-4 was increased upon GalN/LPS challenge, which was not alleviated by nilotinib pretreatment. These data demonstrate that nilotinib has hepatoprotective activity against GalN/LPS-mediated FHF in mice via anti-oxidative and anti-inflammatory effects.

Accessibility of axonal G protein coupled mu-opioid receptors requires conceptual changes of axonal membrane targeting for pain modulation.

The mechanisms of axonal trafficking and membrane targeting are well established for sodium channels, which are the principle targets for perineurally applied local anaesthetics. However, they have not been thoroughly investigated for G protein coupled receptors such as mu-opioid receptors (MOR). Focusing on these axonal mechanisms, we found that axonal MOR functionality is quite distinct in two different pain states, i.e. hindpaw inflammation and nerve injury. We observed axonal membrane MOR binding and functional G protein coupling exclusively at sites of CCI nerve injury. Moreover at these axonal membrane sites, MOR exhibited extensive co-localization with the membrane proteins SNAP and Na/K-ATPase as well as NGF-dependent enhanced lipid rafts and L1CAM anchoring proteins. Silencing endogenous L1CAM with intrathecal L1CAM specific siRNA, disrupting lipid rafts with the perineurial cholesterol-sequestering agent MßCD, as well as suppressing NGF receptor activation with the perineurial NGF receptor inhibitor K252a abrogated MOR axonal membrane integration, functional coupling, and agonist-elicited antinociception at sites of nerve injury. These findings suggest that local conceptual changes resulting from nerve injury are required for the establishment of functional axonal membrane MOR. Axonal integration and subsequent accessibility of functionally coupled MOR are of great relevance particularly for patients suffering from severe pain due to nerve injury or tumour infiltration.