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How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

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World Journal of Gastroenterology 2015年第40期21卷 11331-11342页

作者： Mark G Ward Peter M Irving Miles P sparrow Department of Gastroenterology The Alfred Hospital Department of Gastroenterology Guy’s and St. Thomas’ NHS Foundation Trust

In the last 15 years the management of inflammatory bowel disease has evolved greatly,largely through the increased use of immunomodulators and,especially,anti-tumor necrosis factor(anti-TNF) biologic agents. Within this time period,confidence in the use of anti-TNFs has increased,whilst,especially in recent years,the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines,combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease,especially those who are recently diagnosed. Concurrently,therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and antiTNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent,or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also,however there are few data to support this. similarly,the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention,including post hoc analyses of the pivotal registration trials,has focused on the optimization of anti-TNF agents,when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy,including an evaluation of recent data addressing unanswered questions regarding the optimal timing,dosage and duration of immunomodulator therapy in combination therapy patients.

关键词： Inflammatory bowel disease Thiopurines Drug monito

Double-layered covered stent for the treatment of malignant oesophageal obstructions: systematic review and meta-analysis

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World Journal of Gastroenterology 2016年第34期22卷 7841-7850页

作者： Zeiad Hussain Athanasios Diamantopoulos Miltiadis Krokidis Konstantinos Katsanos Department of Interventional Radiology Guy’s and St.Thomas’ HospitalsNHS Foundation Trust Department of Interventional Radiology Addenbrooke’s HospitalCambridge University Hospitals NHS Foundation Trust

AIM To investigate the efficacy of double-layered covered stent in the treatment of malignant oesophageal *** A systematic review and meta-analysis was performed following the PRIsMA process. Pub Med(Medline),EMBAsE(Excerpta Medical Database),AMED(Allied and Complementary medicine Database),scopus and online content,were searched for studies reporting on the Ni Ti-s polyurethane-covered double oesophageal stent for the treatment of malignant dysphagia. Weighted pooled outcomes were synthesized with a random effects model to account for clinical heterogeneity. All studies reporting the outcome of palliative management of dysphagia due to histologically confirmed malignant oesophageal obstruction using double-layered covered nitinol stent were included. The level of statistical significance was set at α = *** six clinical studies comprising 250 patients in total were identified. Pooled technical success of stent insertion was 97.2%(95%CI: 94.8%-98.9%; I2 = 5.8%). Pooled complication rate was 27.6%(95%CI: 20.7%-35.2%; I2 = 41.9%). Weighted improvement of dysphagia on a scale of 0-5 scoring system was-2.00 [95%CI:-2.29%-(-1.72%); I2 = 87%]. Distal stent migration was documented in 10 out of the 250 cases *** stent migration rate was 4.7%(95%CI: 2.5%-7.7%; I2 = 0%). Finally,tumour overgrowth was reported in 34 out of the 250 cases with pooled rate of tumour overgrowth of 11.2%(95%CI: 3.7%-22.1%; I2 = 82.2%). No funnel plot asymmetry to suggest publication bias(bias = 0.39,P = 0.78). In the sensitivity analysis all results were largely similar between the fixed and random effects *** The double-layered nitinol stent provides immediate relief of malignant dysphagia with low rates of stent migration and tumour

关键词： Double-layered covered stent Malignant oesophageal obstructions Dysphagia Double-layered nitinol stent

Hepatic, pancreatic and renal manifestations of a ciliopathy

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Hepatobiliary & Pancreatic Diseases International 2021年第4期20卷 394-395页

作者： sreelakshmi Kotha Philip Berry Department of Gastroenterology Guy’s and St Thomas’Foundation TrustLondonUK

Hepatorenal fibrocystic diseases are inherited disorders,characterized by developmental abnormalities and fibrocystic degeneration of the portobiliary system and kidneys^([1]).They are part of a larger group of disorders referred to as"ciliopathies"which affect 1 in 1000 *** kidney disease is the most common kidney manifestation,while others include nephronophthisis,glomerulocystic disease and cystic *** manifesta-tions include Caroli’s disease,congenital hepatic fibrosis and poly-cystic liver disease.

关键词： Hepatic kidney degeneration

Pancreatic cancer and depression

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World Journal of Clinical Cases 2023年第12期11卷 2631-2636页

作者： Kalliopi Michoglou Amsajini Ravinthiranathan saw san Ti saoirse Dolly Kiruthikah Thillai Department of Oncology Guy's and St Thomas'NHS Foundation TrustLondon Se19RTUnited Kingdom

Pancreatic cancer is a highly devastating disease with high mortality *** patients who undergo potential curative surgery have a high risk for *** incidence of depression and anxiety are higher in patients with cancer than the general ***,patients with pancreatic cancer are at most of risk of both depression and anxiety and there seems to be a biological *** some patients,depression seems to be a precursor to pancreatic *** this article we discuss the biological link between depression anxiety and hepatobiliary malignancies and discuss treatment strategies.

关键词： Pancreatic cancer Depression Anxiety Cytokines Gastrointestinal malignancies

Impact of tumour histological subtype on chemotherapy outcome in advanced oesophageal cancer

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World Journal of Gastrointestinal Oncology 2017年第8期9卷 333-340页

作者： Michael Davidson Ian Chau David Cunningham Komel Khabra Timothy Iveson Tamas Hickish Matthew seymour Naureen starling Royal Marsden hospital nhs Foundation trust London and Surrey southampton University hospital nhs trust and salisbury hospital nhs Foundation trust Department of Haematology and Oncology Bournemouth University and Poole Hospital NHS Trust st James’s Institute of Oncology St James’s Hospital

To investigate the impact of histology on outcome in advanced oesophageal cancer treated with first-line fluoropyrimidine-based chemotherapy. METHODsIndividual patient data were pooled from three randomised phase III trials of fluoropyrimidine-based chemotherapy ± platinum/anthracycline in patients with advanced, untreated gastroesophageal adenocarcinoma or squamous cell carcinoma (sCC) randomised between 1994 and 2005. The primary endpoint was overall survival of oesophageal cancer patients according to histology. secondary endpoints were response rates and a toxicity composite endpoint. REsULTsOf the total 1836 randomised patients, 973 patients (53%) were eligible (707 patients with gastric cancer were excluded), 841 (86%) had adenocarcinoma and 132 (14%) had sCC. There was no significant difference in survival between patients with adenocarcinoma and sCC, with median overall survivals of 9.5 mo vs 7.6 mo (HR = 0.85, 95%CI: 0.70-1.03, P = 0.09) and one-year survivals of 38.8% vs 28.2% respectively. The overall response rate to chemotherapy was 44% for adenocarcinoma vs 33% for sCC (P = 0.01). There was no difference in the frequency of the toxicity composite endpoint between the two groups. CONCLUsIONThere was no significant difference in survival between adenocarcinoma and sCC in patients with advanced oesophageal cancer treated with fluoropyrimidine-based chemotherapy despite a trend for worse survival and less chemo-sensitivity in sCC. Tolerance to treatment was similar in both groups. This analysis highlights the unmet need for sCC-specific studies in advanced oesophageal cancer and will aid in the design of future trials of targeted agents.

关键词： Oesophageal cancer Adenocarcinoma Chemotherapy squamous Pooled analysis

Outcomes after robot-assisted laparoscopic radical prostatectomy

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Asian Journal of Andrology 2009年第1期11卷 94-99页

作者： Declan G. Murphy Benjamin J. Challacombe Anthony J. Costello The Urology Centre Guy＇s ＆ St. Thomas ＇NHS Foundation Trust London SE1 9RT UK Department of Urology Royal Melbourne Hospital Melbourne VIC 3054 Australia

Robot-assisted laparoscopic radical prostatectomy （RALRP） using the da Vinci surgical system is now in widespread use in many countries where economic conditions allow the installation of this expensive technology. Controversy has surrounded the procedure since it was first performed in 2000, with many critics highlighting the lack of evidence to support its use. However, despite the lack of level I evidence, many large studies of patients have confirmed that the procedure is feasible and safe, with low morbidity. Available longer-term oncological data seem to show that outcomes from the robotic approach at least match those of traditional open radical prostatectomy. Functional outcomes also seem satisfactory, although randomized controlled trials are lacking. This paper reviews the current status of RALRP with respect to perioperative data and complications and oncologic and functional outcomes.

关键词： da Vinci laparoscopic outcomes prostate cancer radical prostatectomy robotic

Molecularly targeted therapy for advanced hepatocellular carcinoma-a drug development crisis?

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World Journal of Gastrointestinal Oncology 2016年第2期8卷 173-185页

作者： Kiruthikah Thillai Paul Ross Debashis sarker department of medical oncology guy’s and st thomas nhs trustLondon SE1 9RTUnited Kingdom division of cancer studies king’s college londonguy’s hospitalLondon SE1 9RTUnited Kingdom institute of liver studies king’s college hospital nhs trustLondon SE5 9RSUnited Kingdom

Hepatocellular carcinoma is the fastest growing cause of cancer related death globally. sorafenib,a multitargeted kinase inhibitor,is the only drug proven to improve outcomes in patients with advanced disease offering modest survival benefit. Although comprehensive genomic mapping has improved understanding of the genetic aberrations in hepatocellular cancer(HCC),this knowledge has not yet impacted clinical care. The last few years have seen the failure of several first and second line phase Ⅲ clinical trials of novel molecularly targeted therapies,warranting a change in the way new therapies are investigated in HCC. Potential reasons for these failures include clinical and molecular heterogeneity,trial design and a lack of biomarkers. This review discusses the current crisis in HCC drug development and how we should learn from recent trial failures to develop a more effective personalised treatment paradigm for patients with HCC.

关键词： Hepatocellular carcinoma Molecular targets Genomics sorafenib Tyrosine kinase inhibitors

Coronary artery anomalies overview: The normal and the abnormal

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World Journal of Radiology 2016年第6期8卷 537-555页

作者： Adriana DM Villa Eva sammut Arjun Nair Ronak Rajani Rodolfo Bonamini Amedeo Chiribiri Wellcome trust/EPsRC Medical Engineering Centre Division of Imaging SciencesGuy’s and St Thomas’ Hospital NHS Foundation Trust Department of Radiology Guy’s and St Thomas’ Hospital NHS Foundation Trust Department of Cardiology Guy’s and St Thomas’ Hospital NHS Foundation Trust Division of Cardiology Department of Medical SciencesUniversity of Turin

The aim of this review is to give a comprehensive and concise overview of coronary embryology and normal coronary anatomy, describe common variants of normal and summarize typical patterns of anomalous coronary artery anatomy. Extensive iconography supports the text, with particular attention to images obtained in vivo using non-invasive imaging. We have divided this article into three groups, according to their frequency in the general population: Normal, normal variant and anomaly. Although congenital coronary artery anomalies are relatively uncommon, they are the second most common cause of sudden cardiac death among young athletes and therefore warrant detailed review. Based on the functional relevance of each abnormality, coronary artery anomalies can be classified as anomalies with obligatory ischemia, without ischemia or with exceptional ischemia. The clinical symptoms may include chest pain, dyspnea, palpitations, syncope, cardiomyopathy, arrhythmia, myocardial infarction and sudden cardiac death. Moreover, it is important to also identify variants and anomalies without clinical relevance in their own right as complications during surgery or angioplasty can occur.

关键词： Coronary arteries Anomalies Variants Anatomy Heart

Recurrent missense mutation of GDF5 (p.R438L) causes proximal symphalangism in a British family

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World Journal of Orthopedics 2016年第12期7卷 839-842页

作者： Andreas Leonidou Melita Irving simon Holden Marcos Katchburian Department of Traumaand Orthopaedic surgery Maidstone and Tunbridge Wells NHSTrust Department of Clinical Genetics Guy’s and St Thomas’ NHS Foundation Trust Department of Clinical Genetics Addenbrookes Hospital

Proximal symphalangism(sYM1B)(OMIM 615298) is an autosomal dominant developmental disorder affecting joint fusion. It is characterized by variable fusions of the proximal interphalangeal joints of the hands,typically of the ring and little finger,with the thumb typically being spared. sYM1 is frequently associated with coalition of tarsal bones and conductive hearing loss. Molecular studies have identified two possible genetic aetiologies for this syndrome,NOG and GDF5. We herein present a British caucasian family with sYM1 B caused by a mutation of the GDF5 gene. A mother and her three children presented to the orthopaedic outpatient department predominantly for feet related problems. All patients had multiple tarsal coalitions and hand involvement in the form of either brachydactyly or symphalangism of the proximal and middle phalanx of the little fingers. Genetic testing in the eldest child and his mother identified a heterozygous missense mutation in GDF5 c.1313G>T(p.R438L),thereby establishing sYM1 B as the cause of the orthopaedic problems in this family. There were no mutations identified in the NOG gene. This report highlights the importance of thorough history taking,including a three generation family history,and detailed clinical examination of children with fixed planovalgus feet and other family members to detect rare skeletal dysplasia conditions causing pain and deformity,and provides details of the spectrum of problems associated with sYM1 B.

关键词： Proximal symphalangism GDF5