Pancreatic neuroendocrine neoplasms are a rare and complex group of neoplastic lesions that develop from pancreatic islet cells.Their incidence has dramatically increased during the last two decades.Due to its complex...Pancreatic neuroendocrine neoplasms are a rare and complex group of neoplastic lesions that develop from pancreatic islet cells.Their incidence has dramatically increased during the last two decades.Due to its complex nature and pathophysiological behaviour,surgical management continues to evolve.Surgery remains the cornerstone of treatment for most non-functional and functional pancreatic neuroendocrine tumours,while lymphadenectomy remains a controversial subject.Different techniques,such as pancreas-preserving and minimally invasive approaches,continue to evolve and offer the same overall outcomes as open surgery.This comprehensive review describes in detail the current and most up-todate classification and staging of pancreatic neuroendocrine tumours,explores the rationale for nonsurgical and surgical management,and focuses on surgical treatment and more specifically,on minimally invasive approaches.展开更多
Ascites remain the commonest complication of decompensated cirrhosis. Spontaneous bacterial peritonitis (SBP) is defined as the infection of ascitic fluid (AF) in the absence of a contiguous source of infection and/or...Ascites remain the commonest complication of decompensated cirrhosis. Spontaneous bacterial peritonitis (SBP) is defined as the infection of ascitic fluid (AF) in the absence of a contiguous source of infection and/or an intraabdominal inflammatory focus. An AF polymorphonuclear (PMN) leucocyte count ≥ 250/mm 3 -irrespective of the AF culture resultis universally accepted nowadays as the best surrogate marker for diagnosing SBP. Frequently the results of the manual or automated PMN count do not reach the hands of the responsible medical personnel in a timely manner. However, this is a crucial step in SBP management. Since 2000, 26 studies (most of them published as full papers) have checked the validity of using leukocyte esterase reagent strips (LERS) in SBP diagnosis. LERS appear to have low sensitivity for SBP, some LERS types more than others. On the other hand, though, LERS have consistently given a high negative predictive value (> 95% in the majority of the studies) and this supports the use of LERS as a preliminary screening tool for SBP diagnosis. Finally, an AF-tailored dipstick has been developed. Within the proper setting, it is set to become the mainstream process for handling AF samples.展开更多
Acute liver failure is a rare and devastating clinical condition. At present, emergency liver transplantation is the only life-saving therapy in advanced cases, yet the feasibility of transplantation is affected by th...Acute liver failure is a rare and devastating clinical condition. At present, emergency liver transplantation is the only life-saving therapy in advanced cases, yet the feasibility of transplantation is affected by the presence of systemic inflammation, infection and resultant multiorgan failure. The importance of immune dysregulation and acquisition of infection in the pathogenesis of acute liver failure and its associated complications is now recognised. In this review we discuss current thinking regarding the role of infection and inflammation in the pathogenesis of and outcome in human acute liver failure, the implications for the management of such patients and suggest directions for future research.展开更多
AIM:To evaluate the efficacy of human thrombin in the treatment of bleeding gastric and ectopic varices.METHODS:Retrospective observational study in a Tertiary Referral Centre.Between January 1999-October 2005,we iden...AIM:To evaluate the efficacy of human thrombin in the treatment of bleeding gastric and ectopic varices.METHODS:Retrospective observational study in a Tertiary Referral Centre.Between January 1999-October 2005,we identified 37 patients who were endoscopically treated with human thrombin injection therapy for bleeding gastric and ectopic varices.Patient details including age,gender and aetiology of liver disease/segmental portal hypertension were documented.The thrombin was obtained from the Scottish National Blood Transfusion Service and prepared to give a solution of 250 IU/mL which was injected via a standard injection needle.All patient case notes were reviewed and the total dose of thrombin given along with the number of endoscopy sessions was recorded.Initial haemostasis rates,rebleeding rates and mortality were catalogued along with the incidence of any immediate complications which could be attributable to the thrombin therapy.The duration of follow up was also listed.The study was conducted according to the United Kingdom research ethics guidelines.RESULTS:Thirty-seven patients were included.33 patients(89%) had thrombin(250 U/mL) for gastric varices,2(5.4%) for duodenal varices,1 for rectal varices and 1 for gastric and rectal varices.(1) Gastric varices,an average of 15.2 mL of thrombin was used per patient.Re-bleeding occurred in 4 patients(10.8%),managed in 2 by a transjugular intrahepatic portosystemic shunt(TIPSS)(one unsuccessfully who died) and in other 2 by a distal splenorenal shunt;(2) Duodenal varices(or type 2 isolated gastric varices),an average of 12.5 mL was used per patient over 2-3 endoscopy sessions.Re-bleeding occurred in one patient,which was treated by TIPSS;and(3) Rectal varices,an average of 18.3 mL was used per patient over 3 endoscopy sessions.No re-bleeding occurred in this group.CONCLUSION:Human thrombin is a safe,easy to use and effective therapeutic option to control haemorrhage from gastric and ectopic varices.展开更多
AIM: To characterise expression of known E-cadherin repressors; Snail, Slug and Twist in the development of esophageal adenocarcinoma. METHODS: E-cadherin, Slug, Snail and Twist mRNA expression in Barrett's metapl...AIM: To characterise expression of known E-cadherin repressors; Snail, Slug and Twist in the development of esophageal adenocarcinoma. METHODS: E-cadherin, Slug, Snail and Twist mRNA expression in Barrett's metaplasia and esophageal adenocarcinoma specimens was examined by real-time reverse transcription-polymerase chain reaction (RT-PCR). Semi-quantitative immunohistochemistry was used to examine cellular localisation and protein levels. The effect of Slug on epithelial mesenchymal transition (EMT) markers was examined by transfection of Slug into an adenocarcinoma line OE33.RESULTS: Cellular localisation of Slug in Barrett's metaplasia was largely cytoplasmic whilst in adenocarcinoma it was nuclear. Semi-quantitative analysis indicated that Slug was more abundant in adenocarcinoma compared to matched Barrett's metaplastic specimens. Snail and Twist were expressed in adenocarcinoma but were cytoplasmic in location and not induced compared to Barrett's mucosa. These observations were supported by mRNA studies where only Slug mRNA was shown to be over-expressed in adenocarcinoma and inversely correlated to E-cadherin expression. Overexpression of Slug in OE33 mediated E-cadherin repression and induced the mesenchymal markers vimentin and fibronectin.CONCLUSION: Progression to adenocarcinoma is associated with increased Slug expression and this may represent a mechanism of E-cadherin silencing.展开更多
Pancreatic cancer is difficult to diagnose at an early stage and is associated with a very poor survival.Ten percent of pancreatic cancers result from genetic susceptibility and/or familial aggregation.Individuals fro...Pancreatic cancer is difficult to diagnose at an early stage and is associated with a very poor survival.Ten percent of pancreatic cancers result from genetic susceptibility and/or familial aggregation.Individuals from families with multiple affected first-degree relatives and those with a known cancer-causing genetic mutation have been shown to be at much higher risk of developing pancreatic cancer.Recent efforts have focused on detecting disease at an earlier stage to improve survival in these high-risk groups.This article reviews high-risk groups,screening methods,and current screening programs and their results.展开更多
This editorial reviews and summarises the current evidence(meta-analyses and Cochrane reviews) relating to the use of hip hemi-arthroplasty for neck of femur fractures. Regarding the optimal surgical approach,two rece...This editorial reviews and summarises the current evidence(meta-analyses and Cochrane reviews) relating to the use of hip hemi-arthroplasty for neck of femur fractures. Regarding the optimal surgical approach,two recent meta-analyses have found that posterior approaches are associated with: higher rates of dislocation compared to lateral and anterior approaches; and higher rates of re-operation compared to lateral approaches. Posterior approaches should therefore be avoided when performing hip hemi-arthroplasty procedures. Assessing the optimal prosthesis head component,three recent meta-analyses and one Cochrane review have found that while unipolar hemiarthroplasty can be associated with increased rates of acetabular erosion at short-term follow-up(up to 1 year),there is no significant difference between the unipolar hemi-arthroplasty and bipolar hemi-arthroplasty for surgical outcome,complication profile,functional outcome and acetabular erosion rates at longer-term follow-up(2 to 4 years). With bipolar hemi-arthroplasty being the more expensive prosthesis,unipolar hemi-arthroplasty is the recommended option. With regards to the optimal femoral stem insertion technique,three recent metaanalyses and one Cochrane Review have found that,while cemented hip hemi-arthroplasties are associated with a longer operative time compared to uncemented Hip Hemi-arthroplasties,cemented prostheses have lower rates of implant-related complications(particularly peri-prosthetic femoral fracture) and improved postoperative outcome regarding residual thigh pain and mobility. With no significant difference found between the two techniques for medical complications and mortality,cemented hip hemi-arthroplasty would appear to be the superior technique. On the topic of wound closure,one recent meta-analysis has found that,while staples can result in a quicker closure time,there is no significant difference in post-operative infections rates or wound healing outcomes when comparing staples to sutures. Therefore,either suture or staple wound closure techniques appear equally appropriate for hip hemiarthroplasty procedures.展开更多
AIM:To evaluate the three-dimensional(3-D)representation performance of 4 publicly available Shapefrom-Shading(SfS)algorithms in small-bowel capsule endoscopy(SBCE).METHODS:SfS techniques recover the shape of objects ...AIM:To evaluate the three-dimensional(3-D)representation performance of 4 publicly available Shapefrom-Shading(SfS)algorithms in small-bowel capsule endoscopy(SBCE).METHODS:SfS techniques recover the shape of objects using the gradual variation of shading.There are4 publicly available SfS algorithms.To the best of our knowledge,no comparative study with images obtained during clinical SBCE has been performed to date.Three experienced reviewers were asked to evaluate 54 twodimensional(2-D)images(categories:protrusion/inflammation/vascular)transformed to 3-D by the aforementioned SfS 3-D algorithms.The best algorithm was selected and inter-rater agreement was calculated.RESULTS:Four publicly available SfS algorithms were compared.Tsai’s SfS algorithm outperformed the rest(selected as best performing in 45/54 SBCE images),followed by Ciuti’s algorithm(best performing in 7/54images)and Torre o’s(in 1/54 images).In 26/54 images;Tsai’s algorithm was unanimously selected as the best performing 3-D representation SfS software.Tsai’s 3-D algorithm superiority was independent of lesion category(protrusion/inflammatory/vascular;P=0.678)and/or CE system used to obtain the 2-D images(MiroCam/PillCam;P=0.558).Lastly,the interobserver agreement was good(kappa=0.55).CONCLUSION:3-D representation software offers a plausible alternative for 3-D representation of conventional capsule endoscopy images(until optics technology matures enough to allow hardware enabled-"real"3-D reconstruction of the gastrointestinal tract).展开更多
The goal of therapy in chronic hepatitis C virus(HCV) infection is sustained virological response(SVR) which reflects HCV eradication. Treatment against HCV has dramatically improved with the recent availability of di...The goal of therapy in chronic hepatitis C virus(HCV) infection is sustained virological response(SVR) which reflects HCV eradication. Treatment against HCV has dramatically improved with the recent availability of direct-acting antivirals(DAAs) including sofosbuvir, simeprevir, daclatasvir, ledipasvir/sofosbuvir, paritaprevir/ombitasvir and dasabuvir. Carefully selected combinations of these DAAs offer the potential for highly effective all-oral safe regimens even for patients with decompensated cirrhosis or liver transplant(LT) recipients. Like all current protease inhibitors, simeprevir and paritaprevir should not be used in patients with Child C cirrhosis, while sofosbuvir and ledipasvir/sofosbuvir should not be given in patients with severe renal impairment and glomerular filtration rate less than 30 m L/min. Drug-drug interactions may still occur with the current DAAs particularly in postLT patients, in whom simeprevir should not be coadministered with cyclosporine and dose adjustments of calcineurin inhibitors are required in case of regimens including the ritonavir boosted paritaprevir. Phase Ⅱ clinical trials and real life cohort studies have shown that sofosbuvir based combinations are safe and can achieve improvements of clinical status, high SVR rates and even prevention of post-LT HCV recurrence in patients with decompensated cirrhosis or LT-candidates. In the post-LT setting, sofosbuvir based regimens and the combination of paritaprevir/ombitasvir and dasabuvir have been reported to be safe and achieve high SVR rates, similar to those in non-transplantpatients, being effective even in cases with cholestatic fibrosing hepatitis. Ongoing clinical trials and rapidly emerging real life data will further clarify the safety and efficacy of the new regimens in these settings.展开更多
Microscopic colitis(MC) is considered an "umbrella term",comprising two subtypes,i.e.,collagenous colitis(CC) and lymphocytic colitis(LC).They are classically associated with normal or unremarkable colonosco...Microscopic colitis(MC) is considered an "umbrella term",comprising two subtypes,i.e.,collagenous colitis(CC) and lymphocytic colitis(LC).They are classically associated with normal or unremarkable colonoscopy.In the last few years,reports have been published revealing findings that are thought to be characteristic or pathognomonic of MC,especially CC.A systematic electronic and manual search of PubMed and EMBASE(to December 2010),for publications on distinct endoscopic findings in MC,resulted in 42 relevant reports for inclusion in this review.Eighty eight patients with collagenous colitis were presented.Only one publication describing a distinct endoscopic pattern in LC was found.Typical findings in CC are alteration of the vascular mucosal pattern,mucosal nodularity,a sequence of change from mucosal defects to mucosal cicatricial lesions,and perhaps(although of doubtful relevance) mucosal pseudomembranes.A causal connection of mucosal defects with the use of lansoprazole seems to exist.Adoption of the proposed lesion description herein is recommended in order to improve homogeneity of future reports.展开更多
Pancreatic ductal adenocarcinoma is characterised by poor oncological outcomes with curative treatment only possible for a minority.Symptoms are dependent on the stage of the disease and location within the pancreas w...Pancreatic ductal adenocarcinoma is characterised by poor oncological outcomes with curative treatment only possible for a minority.Symptoms are dependent on the stage of the disease and location within the pancreas with constitutional decline often prominent.Patients require biochemical investigations and accurate imaging with CT to determine stage of disease and local resectability.CT-PET and endoscopic ultrasound are increasingly used preoperatively.Surgery remains the cornerstone of curative management and can be performed using minimally invasive approaches.Vascular resection and combination treatment with chemoradiotherapy are also utilised for suitable patients.Perioperative outcomes may be optimised using enhanced recovery pathways.Quality standards have been defined for individual clinicians and units to benchmark their clinical outcomes.The developments described hold promise in improving outcomes from pancreatic ductal adenocarcinoma.展开更多
Duplicate publication can introduce significant bias into a meta-analysis if studies are inadvertently included more than once. Many studies are published in more than one journal to maximize readership and impact of ...Duplicate publication can introduce significant bias into a meta-analysis if studies are inadvertently included more than once. Many studies are published in more than one journal to maximize readership and impact of the study findings. Inclusion of multiple publications of the same study within a meta-analysis affords inappropriate weight to the duplicated data if reports of the same study are not linked together. As studies which have positive findings are more likely to be published in multiple journals this leads to a potential overestimate of the benefits of an intervention. Recent advances in immunosuppression strategies following liver transplantation have led to many studies investigating immunosuppressive regimes including immunosuppression monotherapy. In this letter we focus on a recently published meta-analysis by Lan et al investigating studies assessing immunosuppression monotherapy for liver transplantation. The authors claim to have identified fourteen separate randomised studies investigating immunosuppression monotherapy. Seven of the references appear to relate to only three studies which have been subject to duplicate publication. Several similarities can be identified in each of the duplicate publications including similar authorship, identical immunosuppression regimes, identical dates of enrolment and citation of the original publication in the subsequent manuscripts. We discuss the evidence of the duplicate publication inclusion in the meta-analysis.展开更多
The first generation direct antiviral agents(DAAs) highlighted substantial prognosis improvement among liver transplant(LT) candidates and recipients with recurrent hepatitis C virus(HCV) infection. During2014, second...The first generation direct antiviral agents(DAAs) highlighted substantial prognosis improvement among liver transplant(LT) candidates and recipients with recurrent hepatitis C virus(HCV) infection. During2014, second generation DAAs are associated with high sustained virological response rates(> 95%), shortened duration courses and relatively few toxicities. In keeping with the currently available data, patients with decompensated cirrhosis awaiting LT is preferable to be treated with interferon-free, new generation DAAs, with or without ribavirin combinations. Although data about the safety of new DAAs combinations in this patient population are limited, sofosbuvir and daclatasvir pharmacokinetics do not appear to change significantly in moderate or severe liver impairment, while other new DAAs(simeprevir, asunaprevir) seem to be contraindicated in patients with severe liver impairment(Child-Pugh class C). On the other hand, sofosbuvir should not be given in patients with glomerular filtration rate ≤ 30 m L/min, but ongoing trials will clarify better this issue. With the objective that newer antiviral combinations will yield safer and more efficient manipulation of HCV recurrence posttransplant, the European Association for the Study of the Liver has recently updated its recommendations towards this direction. Nevertheless the new antivirals' high cost may be the biggest challenge to their implementation worldwide.展开更多
In capsule endoscopy(CE), there is research to develop hardware that enables ‘‘real'' three-dimensional(3-D) video. However, it should not be forgotten that ‘‘true'' 3-D requires dual video images....In capsule endoscopy(CE), there is research to develop hardware that enables ‘‘real'' three-dimensional(3-D) video. However, it should not be forgotten that ‘‘true'' 3-D requires dual video images. Inclusion of two cameras within the shell of a capsule endoscope though might be unwieldy at present. Therefore, in an attempt to approximate a 3-D reconstruction of the digestive tract surface, a software that recovers information-using gradual variation of shading-from monocular two-dimensional CE images has been proposed. Light reflections on the surface of the digestive tract are still a significant problem. Therefore, a phantom model and simulator has been constructed in an attempt to check the validity of a highlight suppression algorithm. Our results confirm that 3-D representation software performs better with simultaneous application of a highlight reduction algorithm. Furthermore, 3-D representation follows a good approximation of the real distance to the lumen surface.展开更多
AIM To describe the epidemiology of sport-related open fractures from one centre's adult patient population over a 15-year period. METHODS A retrospective review of a prospectively-collected database was performed...AIM To describe the epidemiology of sport-related open fractures from one centre's adult patient population over a 15-year period. METHODS A retrospective review of a prospectively-collected database was performed: The database contained information all sport-related open fractures, sustained from 1995 to 2009 in the Edinburgh, Mid and East Lothian Populations.RESULTS Over the 15-year period, there were 85 fractures recorded in 84 patients. The annual incidence of open sport-related fractures was 0.01 per 1000 population. The mean age at injury was 29.2 years(range 15-67). There were 70(83%) males and 14 females(17%).The 6 most common sports were soccer(n = 19, 22%), rugby(n = 9, 11%), cycling(n = 8, 9%), hockey(n = 8, 9%); horse riding(n = 6, 7%) and skiing(n = 6, 7%). The five most common anatomical locations were finger phalanges(n = 30, 35%); tibial diaphysis(n = 19, 23%); forearm(n = 12, 14%); ankle(n = 7, 8%) and metacarpals(n = 5, 6%). The mean injury severity score was 7.02. According to the Gustilo-Anderson classification system, 45(53%) fractures were grade 1; 28(33%) fractures were grade 2; 8(9%) fractures were grade 3a; and 4(5%) fractures were grade 3b. Out of the total number of fractures, 7(8%) required plastic surgical intervention as part of management. The types of flaps used were split skin graft(n = 4), fasciocutaneous flaps(n = 2); and adipofascial flap(n = 1). CONCLUSION We analysed the epidemiology of open fractures secondary to sport in one centre over a 15-year period. Soccer and rugby were the most common causative sports while fractures of the finger phalanx and of the tibial diaphysis were the most common sites. Open fractures are uncommon in sport; however, when they are sustained they usually occur on muddy sport fields or forest tracks and therefore must be treated appropriately. It is important that clinicians and sports therapists have knowledge of these injuries, in order to ensure they are managed optimally.展开更多
The combination of hepatitis B immune globulin with entecavir or tenofovir(at least for a certain period of time) seems to be the most reasonable prophylaxis against recurrent hepatitis B after liver transplantation. ...The combination of hepatitis B immune globulin with entecavir or tenofovir(at least for a certain period of time) seems to be the most reasonable prophylaxis against recurrent hepatitis B after liver transplantation. Entecavir represents an attractive option for treatment of na?ve kidney transplant recipients, because of its high efficacy and the low rates of resistance. However antiviral treatment should be individualized in the view of kidney function and the previous resistance. To date, new captivating therapeutic strategies could make interferon-free regimens viable for treatment of hepatitis C virus positive liver transplant recipients. The recent combinations of sofosbuvir with simeprevir or daclatasvir or ledipasvir plus/minus ribavirin have boosted the on treatment and sustained virological response to rates approaching 100% within liver transplant recipients with recurrent chronic hepatitis C(CHC). Preliminary data showed that the second generation direct oral antivirals could result to high treatment rates of recurrent CHC in kidney transplant recipients as well. Ongoing studies will clarify the optimal treatment of recurrent CHC in kidney transplant recipients.展开更多
Objective:Surgical resection of pancreatic cancer remains the only potentially curative treatment for pancreatic ductal adenocarcinoma.The robotic platform has been introduced to surgical practice and recent large stu...Objective:Surgical resection of pancreatic cancer remains the only potentially curative treatment for pancreatic ductal adenocarcinoma.The robotic platform has been introduced to surgical practice and recent large studies from national registries have demonstrated similar or improved peri-operative outcomes compared to the standard open approach.Neo-adjuvant chemotherapy is increasingly being offered to patients with borderline resectable/locally advanced disease but this has led to more challenging resections.Numbers of patients undergoing minimally invasive resection following neo-adjuvant chemotherapy remain low.The aim of this review is to assess the current evidence for the peri-operative safety and long-term oncological outcomes associated with minimally invasive pancreatic resection following neo-adjuvant chemotherapy.Methods:Medline,Embase and Cochrane Central Register for Clinical Trials were searched up until 31st October 2021.The search terms include“minimally invasive”,“robotic”,“laparoscopic”,“pancreatectomy”,“pancreatic resection”,“whipple's pancreaticoduodenectomy”,“distal pancreatectomy”,“chemotherapy”,“neo-adjuvant chemotherapy”,“radiotherapy”,“neo-adjuvant chemoradiotherapy”,“induction therapy”,and“conversion surgery”.All studies including patients undergoing pancreatic resections were included.Studies which did not clearly state the approach to resection(minimally invasive or open)were excluded.Results:Seventy-eight studies were identified of which 8 compared open and minimally invasive resection following neo-adjuvant chemotherapy.There was insufficient data to perform a meta-analysis.Robotic surgery was associated with lower blood loss and shorter length of hospital stay.Three-year overall survival rates were similar between patients who underwent robotic or open resection however the robotic approach was associated with higher lymph node yield and a lower R1 resection rate.Conclusion:Currently the evidence for minimally invasive surgery following neo-adjuvant chemotherapy is limited.Long-term oncological outcomes are similar to patients undergoing open resection and there is some evidence to suggest superior peri-operative outcomes.As numbers are limited,future studies analysing national and international databases on minimally invasive pancreatic resection are required to provide sufficient evidence to support the use of minimally invasive pancreatic resection following neo-adjuvant chemotherapy in high-risk groups.展开更多
Good perioperative analgesia following total knee arthroplasty facilitates rehabilitation and may reduce hospital stay. We present the patient analgesic requirements and rehabilitation of a prospective single surgeon ...Good perioperative analgesia following total knee arthroplasty facilitates rehabilitation and may reduce hospital stay. We present the patient analgesic requirements and rehabilitation of a prospective single surgeon series after the introduction of a multimodal drug injection during his total knee arthroplasty. Basic epidemiological data as well as analgesic, antiemetic requirements and time to straight leg raised was collected on 27 consecutive patients (group 1) whom received the multimodal drug injection, consisting of levobupivacaine, ketorolac and adrenaline at the time of their total knee arthroplasty under spinal anaesthesia. Their rehabilitation was compared to a retrospective review of patients who were case matched by age and sex (group 2n = 26), whom had received the unit standard of spinal anaesthetic and a femoral and sciatic block at the time of their operation. Patients in group 1 had significantly lower analgesic and antiemetic requirements than group 2. Group 1 also had a significantly shorter hospital stay. We have demonstrated that periarticular multimodal drug injection can improve perioperative analgesia and mobilisation following total knee arthroplasty as well as reducing opioid requirements and side effects.展开更多
Background/Aims: High-resolution oesophageal manometry utilises water swallows to evaluate oesophageal function. However, small volumes of water are not representative of normal eating and as a result often produce no...Background/Aims: High-resolution oesophageal manometry utilises water swallows to evaluate oesophageal function. However, small volumes of water are not representative of normal eating and as a result often produce normal manometry studies in patients with dysphagia. This study sets out to establish optimal diagnostic thresholds for semi-solid solid swallows and evaluate their ability to uncover motility abnormalities in patients with motility disorders. Method: Manometry was performed using ten 5-mL single water swallows followed by two semi-solid and two solid swallows in the upright position. Normative values for the adjunctive tests were obtained from patient controls while patients with major motility disorders were used to establish the optimal diagnostic thresholds. Diagnostic thresholds identified were prospectively tested in patients with normal water swallows but oesophagus related symptoms and in those with minor and major motility disorders. Results: Normal values for semi-solid and solid were determined in patient controls (n = 100). Development of diagnostic thresholds included 120 patients with major motility disorders. Optimal diagnostic thresholds identified for oesophagogastric junction dysfunction in semi-solid and solid swallows (IRP > 15.5 mmHg). Hypercontractilty and spasm used existing thresholds (>8000 mmHg-s-cm and < 4.5 s, respectively) but modified frequency of ≥50% of adjunctive swallows. Diagnostic thresholds were applied to symptomatic patients with normal water swallows (n = 70) identifying 12/70 (17%) to have abnormal adjunctive swallows. One of 30 patients (3%) with ineffective motility had abnormal adjunctive swallow and 12 patients with oesophageal spasm, oesophagogastric junction obstruction, and hypercontractility had abnormal adjunctive swallows that moved them up the motility disorder hierarchy. Conclusions: Semi-solid and solid challenge increase diagnostic yield of motility disorders.展开更多
T cells engineered to express chimeric antigen receptors (CARs) combining an external antibody binding domain with the CD3ζ T cell receptor (TCR) signaling domain for triggering cell activation are being used for imm...T cells engineered to express chimeric antigen receptors (CARs) combining an external antibody binding domain with the CD3ζ T cell receptor (TCR) signaling domain for triggering cell activation are being used for immunotherapeutic targeting of tumor cells in a non-HLA restricted manner. In this study we transduced T cells with a CD19-CAR construct containing a truncated CD34 gene (tCD34) marker and used these to target the B cell antigen CD19 on the surface of a Hodgkin’s lymphoma (HL) cell line (L591) both in vitro and in vivo. Levels of tCD34 expression in transduced peripheral blood mononuclear cells (PBMCs) ranged from 6% - 20% and this was increased to 82% after selection for transduced tCD34+ cells. In vitro cytotoxicity testing on a CD19+ HL cell line (L591) showed specific cell lysis initiated by the CD19-CAR transduced PBMCs. Importantly, CD19-CAR T cells prevented the growth of L591 HL tumor cells when co-injected subcutaneously (sc) in 6/6 severe combined immunodeficient (SCID) mice. There was no evidence of anti-tumor activity when CD19-CAR T cells were infused intravenously (iv) at the same time as L591 HL tumor cells were injected sc. However, 3/6 SCID mice showed tumor rejection within 83 days after iv infusion of CD19-CAR T cells 3 - 9 days after establishment of L591 HL tumors, while all control animals succumbed to tumors within 60 days. Interestingly, immuno-histochemical analysis of L591 HL tumors demonstrated that CD19-CAR T cells were detected not earlier than 11 days after infusion within the tumor mass. These results suggest that CD19 is a potentially attractive target for the immunotherapy of HL.展开更多
文摘Pancreatic neuroendocrine neoplasms are a rare and complex group of neoplastic lesions that develop from pancreatic islet cells.Their incidence has dramatically increased during the last two decades.Due to its complex nature and pathophysiological behaviour,surgical management continues to evolve.Surgery remains the cornerstone of treatment for most non-functional and functional pancreatic neuroendocrine tumours,while lymphadenectomy remains a controversial subject.Different techniques,such as pancreas-preserving and minimally invasive approaches,continue to evolve and offer the same overall outcomes as open surgery.This comprehensive review describes in detail the current and most up-todate classification and staging of pancreatic neuroendocrine tumours,explores the rationale for nonsurgical and surgical management,and focuses on surgical treatment and more specifically,on minimally invasive approaches.
文摘Ascites remain the commonest complication of decompensated cirrhosis. Spontaneous bacterial peritonitis (SBP) is defined as the infection of ascitic fluid (AF) in the absence of a contiguous source of infection and/or an intraabdominal inflammatory focus. An AF polymorphonuclear (PMN) leucocyte count ≥ 250/mm 3 -irrespective of the AF culture resultis universally accepted nowadays as the best surrogate marker for diagnosing SBP. Frequently the results of the manual or automated PMN count do not reach the hands of the responsible medical personnel in a timely manner. However, this is a crucial step in SBP management. Since 2000, 26 studies (most of them published as full papers) have checked the validity of using leukocyte esterase reagent strips (LERS) in SBP diagnosis. LERS appear to have low sensitivity for SBP, some LERS types more than others. On the other hand, though, LERS have consistently given a high negative predictive value (> 95% in the majority of the studies) and this supports the use of LERS as a preliminary screening tool for SBP diagnosis. Finally, an AF-tailored dipstick has been developed. Within the proper setting, it is set to become the mainstream process for handling AF samples.
文摘Acute liver failure is a rare and devastating clinical condition. At present, emergency liver transplantation is the only life-saving therapy in advanced cases, yet the feasibility of transplantation is affected by the presence of systemic inflammation, infection and resultant multiorgan failure. The importance of immune dysregulation and acquisition of infection in the pathogenesis of acute liver failure and its associated complications is now recognised. In this review we discuss current thinking regarding the role of infection and inflammation in the pathogenesis of and outcome in human acute liver failure, the implications for the management of such patients and suggest directions for future research.
文摘AIM:To evaluate the efficacy of human thrombin in the treatment of bleeding gastric and ectopic varices.METHODS:Retrospective observational study in a Tertiary Referral Centre.Between January 1999-October 2005,we identified 37 patients who were endoscopically treated with human thrombin injection therapy for bleeding gastric and ectopic varices.Patient details including age,gender and aetiology of liver disease/segmental portal hypertension were documented.The thrombin was obtained from the Scottish National Blood Transfusion Service and prepared to give a solution of 250 IU/mL which was injected via a standard injection needle.All patient case notes were reviewed and the total dose of thrombin given along with the number of endoscopy sessions was recorded.Initial haemostasis rates,rebleeding rates and mortality were catalogued along with the incidence of any immediate complications which could be attributable to the thrombin therapy.The duration of follow up was also listed.The study was conducted according to the United Kingdom research ethics guidelines.RESULTS:Thirty-seven patients were included.33 patients(89%) had thrombin(250 U/mL) for gastric varices,2(5.4%) for duodenal varices,1 for rectal varices and 1 for gastric and rectal varices.(1) Gastric varices,an average of 15.2 mL of thrombin was used per patient.Re-bleeding occurred in 4 patients(10.8%),managed in 2 by a transjugular intrahepatic portosystemic shunt(TIPSS)(one unsuccessfully who died) and in other 2 by a distal splenorenal shunt;(2) Duodenal varices(or type 2 isolated gastric varices),an average of 12.5 mL was used per patient over 2-3 endoscopy sessions.Re-bleeding occurred in one patient,which was treated by TIPSS;and(3) Rectal varices,an average of 18.3 mL was used per patient over 3 endoscopy sessions.No re-bleeding occurred in this group.CONCLUSION:Human thrombin is a safe,easy to use and effective therapeutic option to control haemorrhage from gastric and ectopic varices.
基金Supported by City Hospital Trust Fundthe University of Birmingham Scientific Project Grant
文摘AIM: To characterise expression of known E-cadherin repressors; Snail, Slug and Twist in the development of esophageal adenocarcinoma. METHODS: E-cadherin, Slug, Snail and Twist mRNA expression in Barrett's metaplasia and esophageal adenocarcinoma specimens was examined by real-time reverse transcription-polymerase chain reaction (RT-PCR). Semi-quantitative immunohistochemistry was used to examine cellular localisation and protein levels. The effect of Slug on epithelial mesenchymal transition (EMT) markers was examined by transfection of Slug into an adenocarcinoma line OE33.RESULTS: Cellular localisation of Slug in Barrett's metaplasia was largely cytoplasmic whilst in adenocarcinoma it was nuclear. Semi-quantitative analysis indicated that Slug was more abundant in adenocarcinoma compared to matched Barrett's metaplastic specimens. Snail and Twist were expressed in adenocarcinoma but were cytoplasmic in location and not induced compared to Barrett's mucosa. These observations were supported by mRNA studies where only Slug mRNA was shown to be over-expressed in adenocarcinoma and inversely correlated to E-cadherin expression. Overexpression of Slug in OE33 mediated E-cadherin repression and induced the mesenchymal markers vimentin and fibronectin.CONCLUSION: Progression to adenocarcinoma is associated with increased Slug expression and this may represent a mechanism of E-cadherin silencing.
文摘Pancreatic cancer is difficult to diagnose at an early stage and is associated with a very poor survival.Ten percent of pancreatic cancers result from genetic susceptibility and/or familial aggregation.Individuals from families with multiple affected first-degree relatives and those with a known cancer-causing genetic mutation have been shown to be at much higher risk of developing pancreatic cancer.Recent efforts have focused on detecting disease at an earlier stage to improve survival in these high-risk groups.This article reviews high-risk groups,screening methods,and current screening programs and their results.
文摘This editorial reviews and summarises the current evidence(meta-analyses and Cochrane reviews) relating to the use of hip hemi-arthroplasty for neck of femur fractures. Regarding the optimal surgical approach,two recent meta-analyses have found that posterior approaches are associated with: higher rates of dislocation compared to lateral and anterior approaches; and higher rates of re-operation compared to lateral approaches. Posterior approaches should therefore be avoided when performing hip hemi-arthroplasty procedures. Assessing the optimal prosthesis head component,three recent meta-analyses and one Cochrane review have found that while unipolar hemiarthroplasty can be associated with increased rates of acetabular erosion at short-term follow-up(up to 1 year),there is no significant difference between the unipolar hemi-arthroplasty and bipolar hemi-arthroplasty for surgical outcome,complication profile,functional outcome and acetabular erosion rates at longer-term follow-up(2 to 4 years). With bipolar hemi-arthroplasty being the more expensive prosthesis,unipolar hemi-arthroplasty is the recommended option. With regards to the optimal femoral stem insertion technique,three recent metaanalyses and one Cochrane Review have found that,while cemented hip hemi-arthroplasties are associated with a longer operative time compared to uncemented Hip Hemi-arthroplasties,cemented prostheses have lower rates of implant-related complications(particularly peri-prosthetic femoral fracture) and improved postoperative outcome regarding residual thigh pain and mobility. With no significant difference found between the two techniques for medical complications and mortality,cemented hip hemi-arthroplasty would appear to be the superior technique. On the topic of wound closure,one recent meta-analysis has found that,while staples can result in a quicker closure time,there is no significant difference in post-operative infections rates or wound healing outcomes when comparing staples to sutures. Therefore,either suture or staple wound closure techniques appear equally appropriate for hip hemiarthroplasty procedures.
文摘AIM:To evaluate the three-dimensional(3-D)representation performance of 4 publicly available Shapefrom-Shading(SfS)algorithms in small-bowel capsule endoscopy(SBCE).METHODS:SfS techniques recover the shape of objects using the gradual variation of shading.There are4 publicly available SfS algorithms.To the best of our knowledge,no comparative study with images obtained during clinical SBCE has been performed to date.Three experienced reviewers were asked to evaluate 54 twodimensional(2-D)images(categories:protrusion/inflammation/vascular)transformed to 3-D by the aforementioned SfS 3-D algorithms.The best algorithm was selected and inter-rater agreement was calculated.RESULTS:Four publicly available SfS algorithms were compared.Tsai’s SfS algorithm outperformed the rest(selected as best performing in 45/54 SBCE images),followed by Ciuti’s algorithm(best performing in 7/54images)and Torre o’s(in 1/54 images).In 26/54 images;Tsai’s algorithm was unanimously selected as the best performing 3-D representation SfS software.Tsai’s 3-D algorithm superiority was independent of lesion category(protrusion/inflammatory/vascular;P=0.678)and/or CE system used to obtain the 2-D images(MiroCam/PillCam;P=0.558).Lastly,the interobserver agreement was good(kappa=0.55).CONCLUSION:3-D representation software offers a plausible alternative for 3-D representation of conventional capsule endoscopy images(until optics technology matures enough to allow hardware enabled-"real"3-D reconstruction of the gastrointestinal tract).
文摘The goal of therapy in chronic hepatitis C virus(HCV) infection is sustained virological response(SVR) which reflects HCV eradication. Treatment against HCV has dramatically improved with the recent availability of direct-acting antivirals(DAAs) including sofosbuvir, simeprevir, daclatasvir, ledipasvir/sofosbuvir, paritaprevir/ombitasvir and dasabuvir. Carefully selected combinations of these DAAs offer the potential for highly effective all-oral safe regimens even for patients with decompensated cirrhosis or liver transplant(LT) recipients. Like all current protease inhibitors, simeprevir and paritaprevir should not be used in patients with Child C cirrhosis, while sofosbuvir and ledipasvir/sofosbuvir should not be given in patients with severe renal impairment and glomerular filtration rate less than 30 m L/min. Drug-drug interactions may still occur with the current DAAs particularly in postLT patients, in whom simeprevir should not be coadministered with cyclosporine and dose adjustments of calcineurin inhibitors are required in case of regimens including the ritonavir boosted paritaprevir. Phase Ⅱ clinical trials and real life cohort studies have shown that sofosbuvir based combinations are safe and can achieve improvements of clinical status, high SVR rates and even prevention of post-LT HCV recurrence in patients with decompensated cirrhosis or LT-candidates. In the post-LT setting, sofosbuvir based regimens and the combination of paritaprevir/ombitasvir and dasabuvir have been reported to be safe and achieve high SVR rates, similar to those in non-transplantpatients, being effective even in cases with cholestatic fibrosing hepatitis. Ongoing clinical trials and rapidly emerging real life data will further clarify the safety and efficacy of the new regimens in these settings.
文摘Microscopic colitis(MC) is considered an "umbrella term",comprising two subtypes,i.e.,collagenous colitis(CC) and lymphocytic colitis(LC).They are classically associated with normal or unremarkable colonoscopy.In the last few years,reports have been published revealing findings that are thought to be characteristic or pathognomonic of MC,especially CC.A systematic electronic and manual search of PubMed and EMBASE(to December 2010),for publications on distinct endoscopic findings in MC,resulted in 42 relevant reports for inclusion in this review.Eighty eight patients with collagenous colitis were presented.Only one publication describing a distinct endoscopic pattern in LC was found.Typical findings in CC are alteration of the vascular mucosal pattern,mucosal nodularity,a sequence of change from mucosal defects to mucosal cicatricial lesions,and perhaps(although of doubtful relevance) mucosal pseudomembranes.A causal connection of mucosal defects with the use of lansoprazole seems to exist.Adoption of the proposed lesion description herein is recommended in order to improve homogeneity of future reports.
文摘Pancreatic ductal adenocarcinoma is characterised by poor oncological outcomes with curative treatment only possible for a minority.Symptoms are dependent on the stage of the disease and location within the pancreas with constitutional decline often prominent.Patients require biochemical investigations and accurate imaging with CT to determine stage of disease and local resectability.CT-PET and endoscopic ultrasound are increasingly used preoperatively.Surgery remains the cornerstone of curative management and can be performed using minimally invasive approaches.Vascular resection and combination treatment with chemoradiotherapy are also utilised for suitable patients.Perioperative outcomes may be optimised using enhanced recovery pathways.Quality standards have been defined for individual clinicians and units to benchmark their clinical outcomes.The developments described hold promise in improving outcomes from pancreatic ductal adenocarcinoma.
文摘Duplicate publication can introduce significant bias into a meta-analysis if studies are inadvertently included more than once. Many studies are published in more than one journal to maximize readership and impact of the study findings. Inclusion of multiple publications of the same study within a meta-analysis affords inappropriate weight to the duplicated data if reports of the same study are not linked together. As studies which have positive findings are more likely to be published in multiple journals this leads to a potential overestimate of the benefits of an intervention. Recent advances in immunosuppression strategies following liver transplantation have led to many studies investigating immunosuppressive regimes including immunosuppression monotherapy. In this letter we focus on a recently published meta-analysis by Lan et al investigating studies assessing immunosuppression monotherapy for liver transplantation. The authors claim to have identified fourteen separate randomised studies investigating immunosuppression monotherapy. Seven of the references appear to relate to only three studies which have been subject to duplicate publication. Several similarities can be identified in each of the duplicate publications including similar authorship, identical immunosuppression regimes, identical dates of enrolment and citation of the original publication in the subsequent manuscripts. We discuss the evidence of the duplicate publication inclusion in the meta-analysis.
文摘The first generation direct antiviral agents(DAAs) highlighted substantial prognosis improvement among liver transplant(LT) candidates and recipients with recurrent hepatitis C virus(HCV) infection. During2014, second generation DAAs are associated with high sustained virological response rates(> 95%), shortened duration courses and relatively few toxicities. In keeping with the currently available data, patients with decompensated cirrhosis awaiting LT is preferable to be treated with interferon-free, new generation DAAs, with or without ribavirin combinations. Although data about the safety of new DAAs combinations in this patient population are limited, sofosbuvir and daclatasvir pharmacokinetics do not appear to change significantly in moderate or severe liver impairment, while other new DAAs(simeprevir, asunaprevir) seem to be contraindicated in patients with severe liver impairment(Child-Pugh class C). On the other hand, sofosbuvir should not be given in patients with glomerular filtration rate ≤ 30 m L/min, but ongoing trials will clarify better this issue. With the objective that newer antiviral combinations will yield safer and more efficient manipulation of HCV recurrence posttransplant, the European Association for the Study of the Liver has recently updated its recommendations towards this direction. Nevertheless the new antivirals' high cost may be the biggest challenge to their implementation worldwide.
文摘In capsule endoscopy(CE), there is research to develop hardware that enables ‘‘real'' three-dimensional(3-D) video. However, it should not be forgotten that ‘‘true'' 3-D requires dual video images. Inclusion of two cameras within the shell of a capsule endoscope though might be unwieldy at present. Therefore, in an attempt to approximate a 3-D reconstruction of the digestive tract surface, a software that recovers information-using gradual variation of shading-from monocular two-dimensional CE images has been proposed. Light reflections on the surface of the digestive tract are still a significant problem. Therefore, a phantom model and simulator has been constructed in an attempt to check the validity of a highlight suppression algorithm. Our results confirm that 3-D representation software performs better with simultaneous application of a highlight reduction algorithm. Furthermore, 3-D representation follows a good approximation of the real distance to the lumen surface.
文摘AIM To describe the epidemiology of sport-related open fractures from one centre's adult patient population over a 15-year period. METHODS A retrospective review of a prospectively-collected database was performed: The database contained information all sport-related open fractures, sustained from 1995 to 2009 in the Edinburgh, Mid and East Lothian Populations.RESULTS Over the 15-year period, there were 85 fractures recorded in 84 patients. The annual incidence of open sport-related fractures was 0.01 per 1000 population. The mean age at injury was 29.2 years(range 15-67). There were 70(83%) males and 14 females(17%).The 6 most common sports were soccer(n = 19, 22%), rugby(n = 9, 11%), cycling(n = 8, 9%), hockey(n = 8, 9%); horse riding(n = 6, 7%) and skiing(n = 6, 7%). The five most common anatomical locations were finger phalanges(n = 30, 35%); tibial diaphysis(n = 19, 23%); forearm(n = 12, 14%); ankle(n = 7, 8%) and metacarpals(n = 5, 6%). The mean injury severity score was 7.02. According to the Gustilo-Anderson classification system, 45(53%) fractures were grade 1; 28(33%) fractures were grade 2; 8(9%) fractures were grade 3a; and 4(5%) fractures were grade 3b. Out of the total number of fractures, 7(8%) required plastic surgical intervention as part of management. The types of flaps used were split skin graft(n = 4), fasciocutaneous flaps(n = 2); and adipofascial flap(n = 1). CONCLUSION We analysed the epidemiology of open fractures secondary to sport in one centre over a 15-year period. Soccer and rugby were the most common causative sports while fractures of the finger phalanx and of the tibial diaphysis were the most common sites. Open fractures are uncommon in sport; however, when they are sustained they usually occur on muddy sport fields or forest tracks and therefore must be treated appropriately. It is important that clinicians and sports therapists have knowledge of these injuries, in order to ensure they are managed optimally.
文摘The combination of hepatitis B immune globulin with entecavir or tenofovir(at least for a certain period of time) seems to be the most reasonable prophylaxis against recurrent hepatitis B after liver transplantation. Entecavir represents an attractive option for treatment of na?ve kidney transplant recipients, because of its high efficacy and the low rates of resistance. However antiviral treatment should be individualized in the view of kidney function and the previous resistance. To date, new captivating therapeutic strategies could make interferon-free regimens viable for treatment of hepatitis C virus positive liver transplant recipients. The recent combinations of sofosbuvir with simeprevir or daclatasvir or ledipasvir plus/minus ribavirin have boosted the on treatment and sustained virological response to rates approaching 100% within liver transplant recipients with recurrent chronic hepatitis C(CHC). Preliminary data showed that the second generation direct oral antivirals could result to high treatment rates of recurrent CHC in kidney transplant recipients as well. Ongoing studies will clarify the optimal treatment of recurrent CHC in kidney transplant recipients.
文摘Objective:Surgical resection of pancreatic cancer remains the only potentially curative treatment for pancreatic ductal adenocarcinoma.The robotic platform has been introduced to surgical practice and recent large studies from national registries have demonstrated similar or improved peri-operative outcomes compared to the standard open approach.Neo-adjuvant chemotherapy is increasingly being offered to patients with borderline resectable/locally advanced disease but this has led to more challenging resections.Numbers of patients undergoing minimally invasive resection following neo-adjuvant chemotherapy remain low.The aim of this review is to assess the current evidence for the peri-operative safety and long-term oncological outcomes associated with minimally invasive pancreatic resection following neo-adjuvant chemotherapy.Methods:Medline,Embase and Cochrane Central Register for Clinical Trials were searched up until 31st October 2021.The search terms include“minimally invasive”,“robotic”,“laparoscopic”,“pancreatectomy”,“pancreatic resection”,“whipple's pancreaticoduodenectomy”,“distal pancreatectomy”,“chemotherapy”,“neo-adjuvant chemotherapy”,“radiotherapy”,“neo-adjuvant chemoradiotherapy”,“induction therapy”,and“conversion surgery”.All studies including patients undergoing pancreatic resections were included.Studies which did not clearly state the approach to resection(minimally invasive or open)were excluded.Results:Seventy-eight studies were identified of which 8 compared open and minimally invasive resection following neo-adjuvant chemotherapy.There was insufficient data to perform a meta-analysis.Robotic surgery was associated with lower blood loss and shorter length of hospital stay.Three-year overall survival rates were similar between patients who underwent robotic or open resection however the robotic approach was associated with higher lymph node yield and a lower R1 resection rate.Conclusion:Currently the evidence for minimally invasive surgery following neo-adjuvant chemotherapy is limited.Long-term oncological outcomes are similar to patients undergoing open resection and there is some evidence to suggest superior peri-operative outcomes.As numbers are limited,future studies analysing national and international databases on minimally invasive pancreatic resection are required to provide sufficient evidence to support the use of minimally invasive pancreatic resection following neo-adjuvant chemotherapy in high-risk groups.
文摘Good perioperative analgesia following total knee arthroplasty facilitates rehabilitation and may reduce hospital stay. We present the patient analgesic requirements and rehabilitation of a prospective single surgeon series after the introduction of a multimodal drug injection during his total knee arthroplasty. Basic epidemiological data as well as analgesic, antiemetic requirements and time to straight leg raised was collected on 27 consecutive patients (group 1) whom received the multimodal drug injection, consisting of levobupivacaine, ketorolac and adrenaline at the time of their total knee arthroplasty under spinal anaesthesia. Their rehabilitation was compared to a retrospective review of patients who were case matched by age and sex (group 2n = 26), whom had received the unit standard of spinal anaesthetic and a femoral and sciatic block at the time of their operation. Patients in group 1 had significantly lower analgesic and antiemetic requirements than group 2. Group 1 also had a significantly shorter hospital stay. We have demonstrated that periarticular multimodal drug injection can improve perioperative analgesia and mobilisation following total knee arthroplasty as well as reducing opioid requirements and side effects.
文摘Background/Aims: High-resolution oesophageal manometry utilises water swallows to evaluate oesophageal function. However, small volumes of water are not representative of normal eating and as a result often produce normal manometry studies in patients with dysphagia. This study sets out to establish optimal diagnostic thresholds for semi-solid solid swallows and evaluate their ability to uncover motility abnormalities in patients with motility disorders. Method: Manometry was performed using ten 5-mL single water swallows followed by two semi-solid and two solid swallows in the upright position. Normative values for the adjunctive tests were obtained from patient controls while patients with major motility disorders were used to establish the optimal diagnostic thresholds. Diagnostic thresholds identified were prospectively tested in patients with normal water swallows but oesophagus related symptoms and in those with minor and major motility disorders. Results: Normal values for semi-solid and solid were determined in patient controls (n = 100). Development of diagnostic thresholds included 120 patients with major motility disorders. Optimal diagnostic thresholds identified for oesophagogastric junction dysfunction in semi-solid and solid swallows (IRP > 15.5 mmHg). Hypercontractilty and spasm used existing thresholds (>8000 mmHg-s-cm and < 4.5 s, respectively) but modified frequency of ≥50% of adjunctive swallows. Diagnostic thresholds were applied to symptomatic patients with normal water swallows (n = 70) identifying 12/70 (17%) to have abnormal adjunctive swallows. One of 30 patients (3%) with ineffective motility had abnormal adjunctive swallow and 12 patients with oesophageal spasm, oesophagogastric junction obstruction, and hypercontractility had abnormal adjunctive swallows that moved them up the motility disorder hierarchy. Conclusions: Semi-solid and solid challenge increase diagnostic yield of motility disorders.
文摘T cells engineered to express chimeric antigen receptors (CARs) combining an external antibody binding domain with the CD3ζ T cell receptor (TCR) signaling domain for triggering cell activation are being used for immunotherapeutic targeting of tumor cells in a non-HLA restricted manner. In this study we transduced T cells with a CD19-CAR construct containing a truncated CD34 gene (tCD34) marker and used these to target the B cell antigen CD19 on the surface of a Hodgkin’s lymphoma (HL) cell line (L591) both in vitro and in vivo. Levels of tCD34 expression in transduced peripheral blood mononuclear cells (PBMCs) ranged from 6% - 20% and this was increased to 82% after selection for transduced tCD34+ cells. In vitro cytotoxicity testing on a CD19+ HL cell line (L591) showed specific cell lysis initiated by the CD19-CAR transduced PBMCs. Importantly, CD19-CAR T cells prevented the growth of L591 HL tumor cells when co-injected subcutaneously (sc) in 6/6 severe combined immunodeficient (SCID) mice. There was no evidence of anti-tumor activity when CD19-CAR T cells were infused intravenously (iv) at the same time as L591 HL tumor cells were injected sc. However, 3/6 SCID mice showed tumor rejection within 83 days after iv infusion of CD19-CAR T cells 3 - 9 days after establishment of L591 HL tumors, while all control animals succumbed to tumors within 60 days. Interestingly, immuno-histochemical analysis of L591 HL tumors demonstrated that CD19-CAR T cells were detected not earlier than 11 days after infusion within the tumor mass. These results suggest that CD19 is a potentially attractive target for the immunotherapy of HL.
