Improvements in Glucose Regulation in Children and Young People with Cystic Fibrosis-Related Diabetes following Initiation of Elexacaftor/Tezacaftor/Ivacaftor.

INTRODUCTION: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are increasingly used in children and young people with cystic fibrosis (CF). Data in adults show there may be an impact on glycaemic control in those with CF-related diabetes (CFRD). Paediatric data are rare. Case Series/Presentation: Children aged >12 years with CFRD, who were eligible for elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) were commenced on treatment. Glucose monitoring via the FreeStyle Libre system was commenced prior to, immediately after, and several months after commencing ELX/TEZ/IVA. Glycaemic control, shown by time in range (3-10 mmol/L), percentage of time spent hypoglycaemic (<3 mmol/L), and percentage of time spent hyperglycaemic (>10 mmol/L) on Insulin doses were recorded. Following ELX/TEZ/IVA, four of seven children stopped insulin, two required substantially reduced doses of insulin, one showed no response. Glycaemic control remained similar on lower doses or no insulin. Hypoglycaemia was detected in those not requiring insulin. CONCLUSION: ELX/TEZ/IVA has a positive impact on glycaemic control and insulin requirements in children with CFRD. Close monitoring is required when commencing treatment. Children with CFRD need counselling regarding possible reductions in insulin requirement and re-education regarding symptoms, signs, and management of hypoglycaemia.

Hybrid Closed-Loop with Faster Insulin Aspart Compared with Standard Insulin Aspart in Very Young Children with Type 1 Diabetes: A Double-Blind, Multicenter, Randomized, Crossover Study.

We evaluated the use of hybrid closed-loop (HCL) insulin delivery with faster insulin aspart (Fiasp) in very young children with type 1 diabetes (T1D). In a double-blind, multicenter, randomized, crossover study, children aged 2-6 years with T1D underwent two 8-week periods of HCL using CamAPS FX with Fiasp and standard insulin aspart (IAsp), in random order. Primary endpoint was between-treatment difference in time in target range 3.9-10.0 mmol/L. We randomized 25 participants: mean (±standard deviation) age 5.1 ± 1.3 years, baseline HbA1c 55 ± 9 mmol/mol. Time in range was not significantly different between interventions (64% ± 9% vs. 65% ± 9% for HCL with Fiasp vs. IAsp; mean difference -0.33% [95% confidence interval: -2.13 to 1.47; P = 0.71]). There was no significant difference in time with glucose <3.9 mmol/L. No post-randomization severe hypoglycemia or diabetic ketoacidosis events occurred. Use of Fiasp with CamAPS FX HCL demonstrated no significant difference in glycemic outcomes compared with IAsp in very young children with T1D. Clinical trials registration: NCT04759144.

Factors Associated With Diabetic Ketoacidosis at Onset of Type 1 Diabetes Among Pediatric Patients: A Systematic Review.

Importance: Presenting with diabetic ketoacidosis (DKA) at onset of type 1 diabetes (T1D) remains a risk. Following a 2011 systematic review, considerable additional articles have been published, and the review required updating. Objective: To evaluate factors associated with DKA at the onset of T1D among pediatric patients. Evidence Review: In this systematic review, PubMed, Embase, Scopus, CINAHL, Web of Science, and article reference lists were searched using the population, intervention, comparison, outcome search strategy for primary research studies on DKA and T1D onset among individuals younger than 18 years that were published from January 2011 to November 2021. These studies were combined with a 2011 systematic review on the same topic. Data were pooled using a random-effects model. Findings: A total of 2565 articles were identified; 149 were included, along with 46 from the previous review (total 195 articles). Thirty-eight factors were identified and examined for their association with DKA at T1D onset. Factors associated with increased risk of DKA were younger age at T1D onset (<2 years vs ≥2 years; odds ratio [OR], 3.51; 95% CI, 2.85-4.32; P < .001), belonging to an ethnic minority population (OR, 0.40; 95% CI, 0.21-0.74; P = .004), and family history of T1D (OR, 0.46; 95% CI, 0.37-0.57; P < .001), consistent with the 2011 systematic review. Some factors that were not associated with DKA in the 2011 systematic review were associated with DKA in the present review (eg, delayed diagnosis: OR, 2.27; 95% CI, 1.72-3.01; P < .001). Additional factors associated with risk of DKA among patients with new-onset T1D included participation in screening programs (OR, 0.35; 95% CI, 0.21-0.59; P < .001) and presentation during the COVID-19 pandemic (OR, 2.32; 95% CI, 1.76-3.06; P < .001). Conclusions and Relevance: In this study, age younger than 2 years at T1D onset, belonging to an ethnic minority population, delayed diagnosis or misdiagnosis, and presenting during the COVID-19 pandemic were associated with increased risk of DKA. Factors associated with decreased risk of DKA included greater knowledge of key signs or symptoms of DKA, such as a family history of T1D or participation in screening programs. Future work should focus on identifying and implementing strategies related to these factors to reduce risk of DKA among new patients with T1D.

Outcomes for non-operatively managed fracture neck of femur patients: A single-institution study.

BACKGROUND: The majority of neck of femur (NOF) fractures are treated operatively in the United Kingdom. The literature reports the advantages of operative management for these patients. However, whilst a subset is treated non-operatively, there is currently no clear guidance for the selection and subsequent management of these patients. This study aims to explore the incidence, demographics, inpatient stay, use of imaging and outcomes of patients who have non-operatively managed NOF fractures. METHODS: A 6-year retrospective review (2013-2019) of all non-operatively managed NOF fractures at a tertiary teaching hospital and major trauma centre was conducted. Electronic patient records, radiographs and National Hip Fracture Database (NHFD) data were used to obtain information. We noted demographic details, fracture classification, rationale for non-operative management, mortality, clinical frailty score (CFS), use of imaging and analgesia requirements. Patients who were repatriated or transferred to other sites for specialist surgery were excluded. RESULTS: 3.2% (99/3132) of NOF fractures were managed non-operatively. The two commonest reasons for non-operative management were either 'comfortable mobilisation' (n = 44) or 'patient frailty/medically unwell' (n = 50). 74% (37/50) of the patients in whom operative risk was thought to outweigh benefit died within the 30 days of admission and 1-year mortality for this group was 92% (46/50). Of the "comfortable mobilisation" subgroup only 18% (8/44) of this patient subgroup subsequently required surgical intervention for failed non-operative management. The 30-day mortality for this cohort was 6.8% with a 1-year mortality rate of 25% (11/44). CONCLUSION: For a select group of patients whose fractures are stable enough to allow them to mobilise comfortably, non-operative management resulted in a 25% 1-year mortality rate and average length of stay of 10.1 days. This is comparable to statistics for overall NOF fracture management in the literature according to the NHFD January 2021 report. 82% of this group of patients were successfully managed without an operation indicating that there is a place for the consideration of non-operative management in a small select subgroup of hip fracture patients with minimally displaced, stable fractures. Further analysis is necessary to assess the functional outcomes of this subgroup, as well as the potential cost implications.

Update and harmonisation of guidance for the management of diabetic ketoacidosis in children and young people in the UK.

Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes mellitus. Careful and timely intervention is required to optimise glycaemic control and reduce the risk of mortality and devastating complications. Of these, cerebral oedema is the leading cause of death, with a mortality rate of approximately 25%. This article highlights the recent updates to UK fluid therapy guidelines for DKA and provides clinical context for the benefit of paediatricians and junior doctors in light of this new guidance.

Splenic preservation versus splenectomy in laparoscopic distal pancreatectomy: a propensity score-matched study.

BACKGROUND: The laparoscopic approach in distal pancreatectomy is associated with higher rates of splenic preservation compared to open surgery. Although favorable postoperative short-term outcomes have been reported in open spleen-preserving distal pancreatectomy when compared to distal pancreatectomy with splenectomy, it is unclear whether this observation applies to the laparoscopic approach. The aim of this study is to compare laparoscopic spleen-preserving distal pancreatectomy (LSPDP) with laparoscopic distal pancreatectomy with splenectomy (LDPS). STUDY DESIGN: This is a UK wide, propensity score-matched study, including patients who underwent LSPDP or LDPS between 2006 and 2016. Short-term outcomes were compared between LSPDP and LDPS according to intention to treat. Additionally, risk factors for unplanned splenectomy were explored. RESULTS: A total of 456 patients were included from eleven centers (229 LSPDP and 227 LDPS). We were able to match 173 LSPDP cases to 173 LDPS cases, according to intention to treat. No differences were seen in postoperative morbidity between the groups. The only identified risk factor for unplanned splenectomy was tumor size ≥ 30 mm. CONCLUSIONS: Preserving the spleen during laparoscopic distal pancreatectomy is not associated with a lower postoperative morbidity compared to sacrificing the spleen. Tumor size is a risk factor for unplanned splenectomy.

The Impact of Positive Resection Margins on Survival and Recurrence Following Resection and Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma.

OBJECTIVE AND BACKGROUND: Local and distant disease recurrence are frequently observed following pancreatic cancer resection, but an improved understanding of resection margin assessment is required to aid tailored therapies. METHODS: Analyses were carried out to assess the association between clinical characteristics and margin involvement as well as the effects of individual margin involvement on site of recurrence and overall and recurrence-free survival using individual patient data from the European Study Group for Pancreatic Cancer (ESPAC)-3 randomized controlled trial. RESULTS: There were 1151 patients, of whom 505 (43.9%) had an R1 resection. The median and 95% confidence interval (CI) overall survival was 24.9 (22.9-27.2) months for 646 (56.1%) patients with resection margin negative (R0 >1 mm) tumors, 25.4 (21.6-30.4) months for 146 (12.7%) patients with R1<1 mm positive resection margins, and 18.7 (17.2-21.1) months for 359 (31.2%) patients with R1-direct positive margins (P < 0.001). In multivariable analysis, overall R1-direct tumor margins, poor tumor differentiation, positive lymph node status, WHO performance status ≥1, maximum tumor size, and R1-direct posterior resection margin were all independently significantly associated with reduced overall and recurrence-free survival. Competing risks analysis showed that overall R1-direct positive resection margin status, positive lymph node status, WHO performance status 1, and R1-direct positive superior mesenteric/medial margin resection status were all significantly associated with local recurrence. CONCLUSIONS: R1-direct resections were associated with significantly reduced overall and recurrence-free survival following pancreatic cancer resection. Resection margin involvement was also associated with an increased risk for local recurrence.

Long-Term Retrospective Analysis of Gene Therapy with Alipogene Tiparvovec and Its Effect on Lipoprotein Lipase Deficiency-Induced Pancreatitis.

Alipogene tiparvovec (Glybera) is a gene therapy product approved in Europe under the "exceptional circumstances" pathway as a treatment for lipoprotein lipase deficiency (LPLD), a rare genetic disease resulting in chylomicronemia and a concomitantly increased risk of acute and recurrent pancreatitis, with potentially lethal outcome. This retrospective study analyzed the frequency and severity of pancreatitis in 19 patients with LPLD up to 6 years after a single treatment with alipogene tiparvovec. An independent adjudication board of three pancreas experts, blinded to patient identification and to pre- or post-gene therapy period, performed a retrospective review of data extracted from the patients' medical records and categorized LPLD-related acute abdominal pain events requiring hospital visits and/or hospitalizations based on the adapted 2012 Atlanta diagnostic criteria for pancreatitis. Both entire disease time period data and data from an equal time period before and after gene therapy were analyzed. Events with available medical record information meeting the Atlanta diagnostic criteria were categorized as definite pancreatitis; events treated as pancreatitis but with variable levels of laboratory and imaging data were categorized as probable pancreatitis or acute abdominal pain events. A reduction of approximately 50% was observed in all three categories of the adjudicated post-gene therapy events. Notably, no severe pancreatitis and only one intensive care unit admission was observed in the post-alipogene tiparvovec period. However, important inter- and intraindividual variations in the pre- and post-gene therapy incidence of events were observed. There was no relationship between the posttreatment incidence of events and the number of LPL gene copies injected, the administration of immunosuppressive regimen or the percent triglyceride decrease achieved at 12 weeks (primary end point in the prospective clinical studies). Although a causal relationship cannot be established and despite the limited number of individuals evaluated, results from this long-term analysis suggest that alipogene tiparvovec was associated with a lower frequency and severity of pancreatitis events, and a consequent overall reduction in health care resource use up to 6 years posttreatment.

Knee dislocation and vascular injury: 4 year experience at a UK Major Trauma Centre and vascular hub.

INTRODUCTION: Knee dislocation is a rare but potentially devastating injury. Quoted rates of associated vascular compromise vary dramatically between 3.3% and 64%, and the best approach to investigate and diagnose such an injury remains controversial. We aim to evaluate our own 4-year experience of knee dislocation and vascular injury as a UK Major Trauma Centre and vascular hub. METHODS: Knee dislocation was defined as disruption of at least two major stabilising ligaments of the knee and gross instability requiring an operation. Patients were identified from the Department of Trauma and Orthopaedics patient database across a 4 year period from 2010 to 2014. Electronic patient records, imaging and hard notes were retrieved and reviewed retrospectively and relevant information recorded. RESULTS: Twenty-five cases of knee dislocation were identified. Male to female ratio was 11.5:1 with a mean age of 33 years (range 17-71). One patient had a vascular injury which ultimately required a femoro-popliteal bypass graft. Twenty-four patients had documented examination findings pertaining to the vascular status of the limb. Seventeen patients had specific reference to the presence or absence of pedal pulses. The remaining seven cases were documented as either "warm well perfused" or "neurovascularly in-tact". Nine patients were discharged directly from the emergency department with outpatient follow up. All admitted cases had documented vascular examination findings the following day. Two patients had additional adjunctive non-invasive investigations. No patients were examined with duplex ultrasound, although two patients had pulses confirmed with hand-held doppler ultrasound. Three patients had an angiogram. Four cases have a documented discussion with or review from a vascular surgeon. DISCUSSION AND CONCLUSIONS: Our rates of vascular injury are in line with the most recent and largest study to date. Non-invasive investigation and selective angiography has been safe in identifying significant vascular compromise, however, there is inconsistency in management pathways, and too much reassurance attributed to the presence of pedal pulses on initial examination. Safety and consistency could be improved with the introduction of a formalised evidence-based protocol for the initial evaluation of knee dislocation and vascular injury.

Long-term effectiveness of cholecystectomy and endoscopic sphincterotomy in the management of gallstone pancreatitis.

BACKGROUND: Gallstone pancreatitis (GSP) is a common condition, accounting for 30-40 % of all pancreatitis cases. All GSP patients should undergo definitive treatment to prevent further attacks. This study aimed to investigate the long-term outcome after definitive treatment in England by cholecystectomy, endoscopic sphincterotomy (ES), or both. METHODS: Hospital episode statistics data were used to identify patients admitted for the first time with GSP between January and December 2005. These patients were followed for 18 months to identify those who underwent definitive treatment. Treatment groups then were followed until December 2010 to identify readmissions with a further GSP attack as an emergency or admissions with complications of gallstone disease. RESULTS: 5,079 patients admitted with a first bout of GSP between January and December 2005. The in-hospital mortality rate was 7.8 %. Of those who survived the initial attack, 2,511 went on to have a cholecystectomy, 419 had an ES alone, and 496 had ES followed by cholecystectomy. Recurrent pancreatitis after definitive treatment was more common among patients treated with ES (6.7 %) than among those treated with cholecystectomy (4.4 %) or ES followed by cholecystectomy (1.2 %) (p < 0.05). Admissions with other complications attributable to gallstones in patients treated with ES alone were similar to those seen in patients who had received no definitive treatment (12.2 vs. 9.4 %). CONCLUSIONS: Cholecystectomy offers better protection than ES against further bouts of pancreatitis in patients with GSP, but ES is an acceptable alternative. Interval cholecystectomy in patients treated initially with ES was the most effective method of preventing further pancreatitis, and the patients who underwent treatment by ES alone remained at risk of readmission with gallstone-related problems. Patients who have undergone ES and are fit for surgery should have a cholecystectomy.

Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial.

BACKGROUND: Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection. METHODS: Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided. RESULTS: Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)1= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)1 = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)1 = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients. CONCLUSIONS: Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.

Laparoscopic versus open repair of inguinal hernia: a longitudinal cohort study.

BACKGROUND: Traditionally, repair of an inguinal hernia has been by an open method, but laparoscopic techniques have recently been introduced and are increasing in popularity. This study aimed to compare early and late outcomes following laparoscopic and open repair of inguinal hernia. METHODS: We performed an analysis of inpatient Hospital Episode Statistics. Early-outcome criteria studied include in-hospital mortality, length of hospital stay, complications (infection, bleeding, injury to an organ, and urinary retention), and readmission. Late outcome was assessed by the need for a further inguinal hernia repair on the same side. RESULTS: Between April 2002 and April 2004 there were 125,342 patients who underwent inguinal hernia repair and were included in the analysis. They were followed until April 2009. There were no differences in postoperative stay between the laparoscopic and open groups except for the laparoscopic bilateral hernia repair patients who had a shorter stay than the open group. Infection and bleeding were more common following open repair, whilst urinary retention and injury to an organ were more frequent after laparoscopic repair. Reoperation for another inguinal hernia was more common after laparoscopic (4.0 %) than after open repair of primary inguinal hernia (2.1 %), mostly in the first year after surgery. There was no difference in reoperation rate following repair of a recurrent inguinal hernia. Consultant caseload was strongly inversely correlated with reoperation following laparoscopic but not open repair of primary inguinal hernia. CONCLUSIONS: Reoperation is more common after laparoscopic than after open repair of primary but not recurrent inguinal hernia. Surgeons with a low laparoscopic hernia repair caseload have an increased reoperation rate following laparoscopic repair of primary inguinal hernia. The increase in reoperation rate following laparoscopic repair is seen in the first year or two following the initial surgery.

A unique peri-prosthetic fracture pattern in well fixed femoral stems with polished, tapered, collarless design of total hip replacement.

Peri-prosthetic fractures (PPF) are a recognised complication following hip arthroplasty. Prosthesis design and type influence PPF pattern. Surgeons rely on classification systems, such as the Vancouver, to aid treatment planning. This study highlights a specific fracture pattern that occurs with cemented well-fixed polished, tapered, collarless (PTC) stems. We reviewed a consecutive series of 21 PPF around well fixed PTC stems. The majority of the fractures were classified pre-operatively as Vancouver B2 (14/21), but there were also B1 (6/21) and A type fractures. The B2 fractures had common radiological and intra-operative findings: a spiral fracture with extensive fragmentation of bone and cement, debonding of cement from the implant, cement fracture, and a well-fixed cement-bone interface. Reconstruction of these fractures was more difficult than suggested by the radiographs. Two of the six patients who were considered to have a Vancouver B1 fracture underwent open reduction and internal fixation (ORIF), and had treatment-related complications. Retrospective review of the radiographs showed subtle features, such as subsidence of the stem into the centraliser, that are characteristic of a B2 fracture pattern. In summary, it is important to recognise this fracture pattern around secure PTC stems in order to prevent misinterpretation of the fracture as a Vancouver B1 rather than a B2, leading to failure of treatment, and to alert the surgeon that complex reconstruction will be required because of the extensive fragmentation.

WITHDRAWN: Inhaled insulin in diabetes mellitus.

BACKGROUND: Insulin therapy often relies on multiple daily injections of insulin. However this is a considerable burden to many people with diabetes and adherence to such an insulin regimen can be difficult to maintain, hence compromising optimal glycaemic control. Also, short acting injected insulin is absorbed more slowly than insulin released by the normal pancreas in response to a meal. Inhaled insulin has the potential to reduce the number of injections to perhaps one long-acting insulin per day, and provide a closer match to the natural state, by more rapid absorption from the lung. OBJECTIVES: To compare the efficacy, adverse effects and patient acceptability of inhaled versus injected insulin. SEARCH STRATEGY: A sensitive search strategy for randomised controlled or cross-over trials was combined with key terms for inhaled insulins. Databases searched were: The Cochrane Library, MEDLINE, PubMed, EMBASE, Science Citation Index, BIOSIS, Web of Science Proceedings, National Research Register UK, Current Controlled Trials, ClinicalTrials.gov, Conference Papers Index, LexisNexis, and web sites of the ADA and EASD were searched for recent meeting abstracts. Reference lists and journals were handsearched. There were no language restrictions on searching. Manufacturers of inhaled insulin were also contacted. Date of last search October 2002. SELECTION CRITERIA: Only randomised controlled trials with parallel groups or controlled cross-over trials, including type 1 or type 2 diabetic patients of any age treated with insulin, were considered eligible. The minimum trial duration considered was 10 weeks, as this is the time taken for glycated haemoglobin to reliably reflect changes in glycaemic control. DATA COLLECTION AND ANALYSIS: Trial selection and evaluation of study quality was performed independently by two reviewers. The quality of reporting of each trial was assessed according to a modification of the criteria outlined in Centre for Reviews and Dissemination (CRD) Report 4, Spitzer; and Jadad. MAIN RESULTS: Six randomised controlled trials were found and the overall number of participants was 1191. Three trials included patients with type 1 diabetes and three with type 2 diabetes. Three trials had a duration of 24 weeks, and three of 12 weeks. All were open label. There was insufficient information to determine the study quality. Results for HbA1c were similar for all trials, in that all showed comparable glycaemic control for inhaled insulin compared to an entirely subcutaneous regimen. All trials that reported patient satisfaction and quality of life showed that these were significantly greater in the inhaled insulin group. Overall there was no difference in total hypoglycaemic episodes between the groups, but one trial showed a statistically significant increase in severe hypoglycaemic episodes for the inhaled insulin group. No adverse pulmonary effects were observed in any of the studies, but longer follow-up will be required to be sure that there are no adverse side-effects. Cavets include: few studies published in full (so quality could not be assessed), and only two studies used the same basal regimen in both the inhaled and injected groups. AUTHORS' CONCLUSIONS: Inhaled insulin taken before meals, in conjunction with an injected basal insulin, has been shown to maintain glycaemic control comparable to that of patients taking multiple daily injections. The key benefit appears to be that patient satisfaction and quality of life are significantly improved, presumably due to the reduced number of daily injections required. However, the patient satisfaction data is based on five trials, of which only two have been published in full; also the three trials containing quality of life data are all only published in abstract form at present. In addition, longer term pulmonary safety data are still needed. Also, the lower bioavailability, and hence higher doses of inhaled insulin required, may make it less cost-effective than injected insulin.

Evaluation of the role of laparoscopic ultrasonography in the staging of oesophagogastric cancers.

INTRODUCTION: The role of laparoscopic ultrasound (LUS) during staging laparoscopy for pancreatic cancers is established but remains debatable in evaluating oesophagogastric cancers. METHODS: A retrospective consecutive case series consisting of patients undergoing staging laparoscopy in two centres (centre A and B) was carried out over a 5-year period (2000-2005). Patients in centre B underwent LUS following laparoscopic assessment using a 7.5-MHz probe. Staging laparoscopy in both centres was performed using a standardised three-port protocol using a 30 degrees laparoscope. All suspicious lesions were sent for histological assessment for confirmation of malignancy. RESULTS: There were 201 patients in centre A (83 gastric, 138 lower oesophageal/junctional cancers) and 119 patients in centre B (51 and 68, respectively). There were no differences between the two centres for patient demographics and tumour site. There was no difference between the two centres for the detection of metastatic disease using laparoscopic assessment alone (A 13% versus B 20%, p = 0.12). However, there was a significant difference (13% versus 28%, p = 0.001) with the additional use of LUS in centre B. The findings in the additional 8% (n = 9) were para-aortic lymphadenopathy (n = 5), liver metastasis (n = 3) and local extension (n = 1). Five had gastric and four lower oesophageal/junctional cancers. The negative predictive value was 6.4% for centre A and 4.5% for centre B. CONCLUSION: The addition of LUS increased the detection rate of metastasis by 8% but there was little impact on the false-negative rate. LUS is useful in detecting metastatic lymphadenopathy beyond the limits of curative resection and liver metastasis.

Comparison between open and laparoscopic repair of perforated peptic ulcer disease.

BACKGROUND: The place of laparoscopic repair of perforated peptic ulcer followed by peritoneal toilet has been established, although it is not routinely practiced. This prospective study compared laparoscopic and open repair of perforated peptic ulcer disease. We evaluated whether the early results from laparoscopic repair resulted in improved patient outcome compared with conventional open repair. METHODS: All patients who underwent repair of perforated peptic ulcer disease during a 12-month period in our unit were included in the study. The primary end points that were evaluated were total operative time, nasogastric tube utilisation, intravenous fluid requirement, total time of urinary catheter and abdominal drainage usage, time taken to return to normal diet, intravenous/intramuscular opiate use, time to full mobilization, and total in-patient hospital stay. RESULTS: Thirty-three patients underwent surgical repair of perforated peptic ulcer disease (19 laparoscopic repairs and 14 open repairs; mean age, 54.2 (range, 32-82) years). There was no increase in total operative time in patients who had undergone laparoscopic repair (mean: 61 minutes laparoscopic versus 57 minutes open). There was significantly less requirement for intravenous/intramuscular opiate analgesia in patients who had undergone laparoscopic repair (mean time to oral analgesia: 1.2 days laparoscopic versus 3.8 days open). In addition there was a significant decrease in the time that the nasogastric tube (mean: 2.1 days laparoscopic versus 3.1 days open), urinary catheter (mean: 2.3 days laparoscopic versus 3.7 days open) and abdominal drain (mean: 2.2 days laparoscopic versus 3.8 days open) were required during the postoperative period. Patients who had undergone laparoscopic repair required less intravenous fluids (mean: 1.4 days laparoscopic versus 3.1 days open) and returned to normal diet (mean: 2.3 days laparoscopic versus 4.8 days open) and full mobilization significantly earlier than those who had undergone open repair (mean: 2.3 days laparoscopic versus 3.3 days open). In addition, patients who had undergone laparoscopic repair required a shorter in-patient hospital stay (mean: 3.1 days laparoscopic versus 4.3 days open). CONCLUSIONS: Laparoscopic repair is a viable and safe surgical option for patients with perforated peptic ulcer disease and should be considered for all patients, providing that the necessary expertise is available.

Primary colorectal tumors fail to express the proapoptotic mediator PTAG and its reexpression augments drug-induced apoptosis.

Genes implicated in tumor evolution and progression, including those in apoptotic pathways, are associated with methylation-associated gene silencing in different tumor types. By exploiting differential methylation we recently isolated a novel pituitary tumor derived apoptosis gene (PTAG) that augments drug-induced apoptosis. The importance of PTAG was determined in other tumor types, and these studies show that the majority of primary colorectal tumors fail to express the PTAG gene, indicating an important role for PTAG in colorectal tumorigenesis. The effects of expression of PTAG were examined through stable transfection of the colorectal cell lines HCT116 and SW480. Expression of PTAG, per se, had no discernible effects on cell viability or cell kinetics. In contrast to these findings, in cells subject to drug challenges that engaged either a death-receptor mediated or mitochondrial pathway, all of the experiments indicated a role for PTAG in the intrinsic pathway of apoptosis. Loss of PTAG therefore contributes to a blunted apoptotic response and is likely to predispose cells toward malignant transformation and resistance to chemotherapeutic interventions.

Polymorphisms in the glutathione S-transferase mu cluster are associated with tumour progression and patient outcome in colorectal cancer.

Glutathione S-transferase (GST) enzymes catalyse the detoxification of by-products of reactive oxygen species and are thus important in cellular defence mechanisms. The GSTs are polymorphic with allelic variants encoding isoforms with functional differences. GST polymorphism has been associated with susceptibility and clinical outcome in patients with cancer. In this retrospective cohort, we have investigated associations between common GSTM1, GSTM3 and GSTP1 polymorphisms with factors known to influence clinical out-come and patient survival in colorectal cancer. Significant linkage disequilibrium was demonstrated between GSTM1 and GSTM3 alleles (P< or =0.001). We identified no significant associations between the GSTP1(Ile105Val105) polymorphism and any clinical outcome parameters or patient survival. However significant associations were demonstrated with mu class GSTs. Those patients who were GSTM1 null presented less frequently with poorly-differentiated tumours (P=0.038). Furthermore, patients who were GSTM3 AA were less likely to present with advanced stage tumours (T-stage, P=0.036 and Dukes' classifications, P=0.012) or distant metastases (P=0.017) when examined alone. Upon further examination of the effect of linkage disequilibrium, we found that, in GSTM1 null individuals, GSTM3 AA (compared with other GSTM3 genotypes combined) had longer disease-free survival (HR=0.54, 95% CI 0.30-0.98, P=0.044). Thus, the GSTM3 AA genotype is associated with improved prognosis especially in those with GSTM1 null. Our findings suggest that the GST mu gene cluster mediates tumour characteristics and survival in patients with colorectal cancer.

Suture strength and angle of load application in a suture anchor eyelet.

PURPOSE: To assess the effect of suture material, anchor orientation, and anchor eyelet design on the static loading properties of suture anchors. TYPE OF STUDY: Biomechanical bench study. METHODS: Two metallic suture anchors, Mitek GII (Mitek, Westwood, MA) and Corkscrew (Arthrex, Naples, FL) and a bioabsorbable anchor (Biocorkscrew; Arthrex) were tested with single strand of No. 2 Ethibond (Ethicon, Norderstedt, Germany) or No. 2 FiberWire (Arthrex) suture. Suture pull angle was varied through 0 degrees, 45 degrees, and 90 degrees with the anchor rotation angle in either a sagittal or coronal plane. Constructs were tested to failure using an MTS 858 Bionix testing machine (Material Testing Systems, Eden Prairie, MN). Peak loads, stiffness, energy to peak load, and failure modes were determined for all samples. RESULTS: FiberWire showed superior static mechanical properties when compared with single-strand Ethibond over all testing conditions (P < .05). Suture pull angle had a significant effect on load to failure with both metallic anchors but not on the bioabsorbable anchor (P < .05). CONCLUSIONS: Suture pull angle and anchor rotation angle play an important role in the failure load of suture when placed in an eyelet. The polyaxial nature of the Biocorkscrew eyelet allows for increased degrees of freedom but introduces failure of the suture eyelet as a new failure mode. CLINICAL RELEVANCE: The loading direction and placement of the suture anchor plays a role in the performance of the suture anchor-suture complex.

Inequity of upper gastrointestinal cancer distribution and survival with socioeconomic deprivation: a population-based study.

BACKGROUND: It is postulated that patients with upper gastrointestinal cancers from affluent classes have better survival outcomes than those from deprived backgrounds. We aimed to analyze the incidence, mortality, and survival trends of esophageal, gastric, and pancreatic cancers in West Midlands, England, from 1986 to 2000 in terms of socioeconomic deprivation. METHODS: A well-validated demographic score, the Townsend Band, was employed as a measure of socioeconomic status. Data were collated from a cancer registry database; the individuals were allocated to 1 of 5 Townsend bands by using the postcodes at diagnosis. Relative survival rates were calculated by using stratified actuarial life tables, regression trend analysis at 1 and 5 years was performed, and the P value was derived from a t test statistic. RESULTS: An increase in esophageal cancer incidence was more marked in the affluent categories (127%), compared with the deprived categories (57%). Gastric cancer incidence fell preferentially by 31% and 47% in the most-deprived men and women, respectively, but remained relatively unchanged in the affluent groups. A marginal overall decrease in pancreatic cancer incidence masked preferential increases in the most-affluent men (39%) and women (41%). Small increases in 1- and 5-year survival were noted in affluent subgroups, with the 1-year survival advantage for esophageal cancer achieving significant levels in the most-affluent categories (P = .05). CONCLUSIONS: The esophageal cancer incidence increased preferentially in the affluent groups but with a marginally better survival rate. The gastric cancer incidence decreased noticeably in the most-deprived groups, suggesting that improvements in hygiene with consequent reduction in Helicobacter pylori primarily could be responsible. Pancreatic cancer trends were unrelated to social deprivation and warrant further studies.