Evaluating the potential utility of three-dimensional printed models in preoperative planning and patient consent in gastrointestinal cancer surgery.

INTRODUCTION: The Future of Surgery report from the Royal College of Surgeons of England acknowledges the important role that three-dimensional imaging will play in support of personalised surgical interventions. One component of this is preoperative planning. We investigated surgeons' and patients' perceptions of this evolving technology. MATERIALS AND METHODS: Ethical approval was obtained. From a normal computed tomography scan, three-dimensional models of the stomach, pancreas and rectum were rendered and printed on an Ultimaker™ three-dimensional printer. Semi-structured interviews were performed with surgeons and patients to explore perceived model effectiveness and utility. Likert scales were used to grade responses (1 = strongly disagree; 10 = strongly agree) and qualitative responses recorded. RESULTS: A total of 26 surgeons (9 rectal, 9 oesophagogastric, 8 pancreatic) and 30 patients (median age 62 years, interquartile range, IQR, 68-72 years; 57% male) were recruited. Median surgeon scores were effectiveness for preoperative planning, 6 (IQR 3-7), authenticity, 5 (IQR 3-6), likability, 6 (IQR 4-7), promoting learning, 7 (IQR 5-8), utility, 6 (IQR 5-7) and helping patients, 7 (IQR 5-8). Median patient scores were usefulness to the surgeon, 8 (IQR 7-9), authenticity, 8 (IQR 6-8), likability, 8 (IQR 7-8), helping understanding of condition, 8 (IQR 8-9), helping understanding of surgery, 8 (IQR 7-9) and feeling uncomfortable, 1 (IQR 1-4). Median overall decisional conflict score (0 = no; 100 = high) was 22 (IQR 19-28) and decision effectiveness was 25 (IQR 19-30). DISCUSSION: Overall, patients and surgeons considered that three-dimensional printed models were effective and had potential utility in education and, to a lesser extent, preoperative planning. Patient decisional conflict and effectiveness scores were weighted towards certainty in decision making but had room for improvement, which three-dimensional models may help to facilitate.

Endoscopic Botulinum toxin as a treatment for delayed gastric emptying following oesophagogastrectomy.

INTRODUCTION: The incidence of delayed gastric emptying (DGE) following oesophagogastrectomy with gastric conduit reconstruction is reported to be between 1.7% and 50%. This variation is due to differing practices of intraoperative pylorus drainage procedures, which increase the risk of postoperative biliary reflux and dumping syndrome, resulting in significant morbidity. The aim of our study was to establish rates of DGE in people undergoing oesophagogastrectomy without routine intraoperative drainage procedures, and to evaluate outcomes of postoperative endoscopically administered Botulinum toxin into the pylorus (EBP) for people with DGE resistant to systemic pharmacological treatment. METHODS: All patients undergoing oesophagogastrectomy between 1 January 2016 and 31 March 2018 at our unit were included. No intraoperative pyloric drainage procedures were performed, and DGE resistant to systemic pharmacotherapy was managed with EBP. RESULTS: Ninety-seven patients were included. Postoperatively, 29 patients (30%) were diagnosed with DGE resistant to pharmacotherapy. Of these, 16 (16.5%) were diagnosed within 30 days of surgery. The median pre-procedure nasogastric tube aspirate was 780ml; following EBP, this fell to 125ml (p<0.001). Median delay from surgery to EBP in this cohort was 13 days (IQR 7-16 days). Six patients required a second course of EBP, with 100% successful resolution of DGE before discharge. There were no procedural complications. CONCLUSIONS: This is the largest series of patients without routine intraoperative drainage procedures. Only 30% of patients developed DGE resistant to pharmacotherapy, which was managed safely with EBP in the postoperative period, thus minimising the risk of biliary reflux in people who would otherwise be at risk following prophylactic pylorus drainage procedures.

Kinetic studies of C1 and C2 Criegee intermediates with SO2 using laser flash photolysis coupled with photoionization mass spectrometry and time resolved UV absorption spectroscopy.

Recent, direct studies have shown that several reactions of stabilized Criegee intermediates (SCI) are significantly faster than indicated by earlier indirect measurements. The reaction of SCI with SO2 may contribute to atmospheric sulfate production, but there are uncertainties in the mechanism of the reaction of the C1 Criegee intermediate, CH2OO, with SO2. The reactions of C1, CH2OO, and C2, CH3CHOO, Criegee intermediates with SO2 have been studied by generating stabilized Criegee intermediates by laser flash photolysis (LFP) of RI2/O2 (R = CH2 or CH3CH) mixtures with the reactions being followed by photoionization mass spectrometry (PIMS). PIMS has been used to determine the rate coefficient for the reaction of CH3CHI with O2, k = (8.6 ± 2.2) × 10-12 cm3 molecule-1 s-1 at 295 K and 2 Torr (He). The yield of the C2 Criegee intermediate under these conditions is 0.86 ± 0.11. All errors in the abstract are a combination of statistical at the 1σ level and an estimated systematic contribution. For the CH2OO + SO2 reaction, additional LFP experiments were performed monitoring CH2OO by time-resolved broadband UV absorption spectroscopy (TRUVAS). The following rate coefficients have been determined at room temperature ((295 ± 2) K):CH2OO + SO2: k = (3.74 ± 0.43) × 10-11 cm3 molecule-1 s-1 (LFP/PIMS),k = (3.87 ± 0.45) × 10-11 cm3 molecule-1 s-1 (LFP/TRUVAS)CH3CHOO + SO2: k = (1.7 ± 0.3) × 10-11 cm3 molecule-1 s-1 (LFP/PIMS)LFP/PIMS also allows for the direction observation of CH3CHO production from the reaction of CH3CHOO with SO2, suggesting that SO3 is the co-product. For the reaction of CH2OO with SO2 there is no evidence of any variation in reaction mechanism with [SO2] as had been suggested in an earlier publication (Chhantyal-Pun et al., Phys. Chem. Chem. Phys., 2015, 17, 3617). A mean value of k = (3.76 ± 0.14) × 10-11 cm3 molecule-1 s-1 for the CH2OO + SO2 reaction is recommended from this and previous studies. The atmospheric implications of the results are briefly discussed.

Safety and effectiveness of antireflux surgery in obese patients.

Introduction The incidence of gastro-oesophageal reflux disease and obesity has increased significantly in recent years. The number of antireflux procedures being carried out on people with a higher body mass index (BMI) has been rising. Evidence is conflicting for outcomes of antireflux surgery in obese patients in terms of its safety and efficacy. Given the contradictory reports, this meta-analysis was undertaken to establish the outcomes of antireflux surgery (ARS) in obese patients and its associated safety. Methods A systematic electronic search was conducted using the PubMed, MEDLINE®, Ovid®, Cochrane Library and Google Scholar™ databases to identify studies that analysed the effect of BMI on the outcomes of ARS. A meta-analysis was performed using the random effects model. The intraoperative and postoperative outcomes that were examined included operative time, conversion to an open procedure, mean length of hospital stay, recurrence of acid reflux requiring reoperation and wrap migration. Results A total of 3,772 patients were included in 13 studies. There was no significant difference in procedure conversion rate, recurrence of reflux requiring reoperation or wrap migration between obese and non-obese patients. However, both the mean operative time and mean length of stay were longer for obese patients. Conclusions ARS in obese patients with gastro-oesophageal reflux disease is safe and outcomes are comparable with those in patients with a BMI in the normal range. A high BMI should therefore not be a deterrent to considering ARS for appropriate patients.

Assessing the quality of written information provision for surgical procedures: a case study in oesophagectomy.

OBJECTIVE: To examine the content and quality of written information provided by surgical centres for patients undergoing oesophagectomy for cancer. DESIGN: Cross-sectional study of the content of National Health Service (NHS) patient information leaflets (PILs) about oesophageal cancer surgery, using a modified framework approach. DATA SOURCES: Written information leaflets from 41 of 43 cancer centres undertaking surgery for oesophageal cancer in England and Wales (response rate 95.3%). ELIGIBILITY CRITERIA: All English language versions of PILs about oesophagectomy. RESULTS: 32 different PILs were identified, of which 2 were generic tools (Macmillan 'understanding cancer of the gullet' and EIDO 'oesophagectomy'). Although most PILs focused on describing in-hospital adverse events, information varied widely and was often misleading. Just 1 leaflet described survival benefits of surgery and 2 mentioned the possibility of disease recurrence. CONCLUSIONS: Written information provided for patients by NHS cancer centres undertaking oesophagectomy is inconsistent and incomplete. It is recommended that surgeons work together with patients to agree on standards of information provision of relevance to all stakeholders' needs.

Outcome reporting in bariatric surgery: an in-depth analysis to inform the development of a core outcome set, the BARIACT Study.

Outcome reporting in bariatric surgery needs a core outcome set (COS), an agreed minimum set of outcomes reported in all studies of a particular condition. The aim of this study was to summarize outcome reporting in bariatric surgery to inform the development of a COS. Outcomes reported in randomized controlled trials (RCTs) and large non-randomized studies identified by a systematic review were listed verbatim and categorized into domains, scrutinizing the frequency of outcome reporting and uniformity of definitions. Ninety studies (39 RCTs) identified 1,088 separate outcomes, grouped into nine domains with most (n = 920, 85%) reported only once. The largest outcome domain was 'surgical complications', and overall, 42% of outcomes corresponded to a theme of 'adverse events'. Only a quarter of outcomes were defined, and where provided definitions, which were often contradictory. Percentage of excess weight loss was the main study outcome in 49 studies, but nearly 40% of weight loss outcomes were heterogeneous, thus not comparable. Outcomes of diverse bariatric operations focus largely on adverse events. Reporting is inconsistent and ill-defined, limiting interpretation and comparison of published studies. Thus, we propose and are developing a COS for the surgical treatment of severe and complex obesity.

The role of ultrasound in the management of patients with occult groin hernias.

INTRODUCTION: Groin ultrasound scanning is commonly used to examine patients with obscure groin pain or swelling. A recent study has shown ultrasound has a poor positive predictive value (PPV) in diagnosing groin hernias although earlier studies reported PPV values as high as 100%. Our aims were to calculate ultrasound's accuracy in diagnosing occult groin hernias in symptomatic patients and assess how management of these patients is affected by ultrasound result. METHODS: We retrospectively analysed 375 symptomatic adult patients, who between February 2008 and March 2010, had ultrasound to diagnose groin hernias when clinical examination was inconclusive. Patients were identified on a prospective radiology database and all groin ultrasounds were performed by either one consultant radiologist or one radiographer. RESULTS: Ultrasound was positive in 199 patients, of which 118 underwent surgery. Using operative findings as the gold standard, ultrasound's PPV for groin hernias was 70% (95% CI: 62-78%). Ultrasound was equivocal in 42 patients of which hernias were diagnosed in 7 of the 10 who had surgery. Ultrasound was negative in 151 patients of which none were later diagnosed with hernias during 3 years' median follow-up. CONCLUSION: Ultrasound is poor in diagnosing occult groin hernias with a PPV of 70% suggesting a 30% chance of negative groin exploration. The equivocal ultrasound group requires careful follow-up as a considerable number were later diagnosed with hernia. The absence of subsequent hernia diagnosis in the negative ultrasound group suggests it may be a useful rule-out test to exclude occult groin hernias in symptomatic patients.

Meeting report: consensus recommendations for a research agenda in exercise in solid organ transplantation.

With improved survival rates in solid organ transplantation there has been an increased focus on long-term outcomes following transplant, including physical function, health-related quality-of-life and cardiovascular mortality. Exercise training has the potential to affect these outcomes, however, research on the optimal timing, type, dose of exercise, mode of delivery and relevant outcomes is limited. This article provides a summary of a 2-day meeting held in April 2013 (Toronto, Canada) in which a multi-disciplinary group of clinicians, researchers, administrators and patient representatives engaged in knowledge exchange and discussion of key issues in exercise in solid organ transplant (SOT). The outcomes from the meeting were the development of top research priorities and a research agenda for exercise in SOT, which included the need for larger scale, multi-center intervention studies, development of standardized outcomes for physical function and surrogate measures for clinical trials, examining novel modes of exercise delivery and novel outcomes from exercise training studies such as immunity, infection, cognition and economic outcomes. The development and dissemination of "expert consensus guidelines," synthesizing both the best available evidence and expert opinion was prioritized as a key step toward improving program delivery.

Laparotomy for blunt abdominal trauma in a civilian trauma service.

This report looks at the group of patients who required a laparotomy for blunt torso trauma at a busy metropolitan trauma service in South Africa. Methods. A prospective trauma registry is maintained by the surgical services of the Pietermaritzburg metropolitan complex. This registry is interrogated retrospectively. All patients who required admission for blunt torso trauma over the period September 2006 - September 2007 were included for review. Proformas documenting mechanism of injury, age, vital signs, blood gas, delay in presentation, length of hospital stay, intensive care unit stay and operative details were completed. Results. A total of 926 patients were treated for blunt trauma by the Pietermaritzburg metropolitan services during the period under consideration. A cohort of 65 (8%) required a laparotomy for blunt trauma during this period. There were 17 females in this group. The mechanisms of injury were motor vehicle accident (MVA) (27), pedestrian vehicle accident (PVA) (21), assault (5), fall from a height (3), bicycle accident (6), quad bike accident (1) and tractor-related accident (2). The following isolated injuries were discovered at laparotomy: liver (9), spleen (5), diaphragm (1), duodenum (2), small bowel (8), mesentery (8) bladder (10), gallbladder (1), stomach (2), colon/rectum (2) and retrohepatic vena cava (1). The following combined injuries were discovered: liver and diaphragm (2), spleen and pancreas (1), spleen and liver (2), spleen, aorta and diaphragm (1), spleen and bladder (1) and small bowel and bladder (2). Eighteen patients in the series (26%) required relaparotomy. In 10 patients temporary abdominal containment was needed. The mortality rate was 26% (18 patients). There were 6 deaths from massive bleeding, all within 6 hours of operation, and 3 deaths from renal failure; the remaining 9 patients died of multiple organ failure. There were 8 negative laparotomies (7%). In the negative laparotomy group false-positive computed tomography (CT) scan findings were a problem in 3 cases, in 1 case hypotension and a fractured pelvis on admission prompted laparotomy, and in the other cases clinical findings prompted laparotomy. All patients who underwent negative laparotomy survived. There were 10 pelvic fractures, 5 lower limb fractures, 2 spinal injuries, 4 femur fractures and 2 upper limb fractures. CT scans were done in 25 patients. In 20 patients the systolic blood pressure on presentation was <90 mmHg and in 41 the pulse rate was >110 beats/min. In 16 patients there was a base excess of <-4 on presentation. Conclusion. Laparotomy is needed in less than 10% of patients who sustain blunt abdominal trauma. Solid visceral injury requiring laparotomy presents with haemodynamic instability. Hollow visceral injury has a more insidious presentation and is associated with a delay in diagnosis. CT scan is the most widely used investigation in blunt abdominal trauma. It is both sensitive and specific for solid visceral injury, but its accuracy for the diagnosis of hollow visceral injury is less well defined. Clinical suspicion must be high, and hollow visceral injury needs to be actively excluded.

Variations in the pharmacological management of patients treated with carotid endarterectomy: a survey of European vascular surgeons.

OBJECTIVES: The peri-operative use of antiplatelet, anticoagulant and other drugs for patients undergoing carotid endarterectomy (CEA) is unclear and consensus is lacking. This study aimed to assess the current peri-operative practice of European vascular surgeons with respect to antiplatelet and other medications for patients undergoing CEA. DESIGN: Online questionnaire study. METHODS: Members of the Vascular Society of Great Britain & Ireland and European Society for Vascular Surgery were invited to complete an online survey in March 2008. Surgeons were asked about their preferences for the peri-operative administration of antiplatelet, statin and other medications for patients undergoing carotid endarterectomy. RESULTS: Partial or complete responses were received from 399/650 (61.4%) surgeons with a collective annual throughput of >11500 CEA procedures. For symptomatic and asymptomatic patients, 20/392 (5%) and 47/392 (12%) of surgeons would stop aspirin before surgery and 170/392 (43%) and 217/392 (55%) of surgeons would stop Clopidogrel prior to CEA. Of surgeons who would stop Clopidogrel, 84/170 (49%) and 124/217 (57%) would do so >7 days before surgery for symptomatic and asymptomatic patients respectively. 12/393 (3%) surgeons would prescribe one 75 mg dose of Clopidogrel on the evening before surgery. Intra-operative Dextran was used selectively by 40/395 (10%). Only 78/393 (20%) would delay surgery to commence a statin. Intra-operatively, 348/394 (88%) used intravenous heparin, which was reversed routinely by 47/348 (13%) and selectively by 60/348 (17%). CONCLUSIONS: There appears to be broad consensus between vascular surgeons in the pharmacological management of patients undergoing carotid endarterectomy, although some variations do exist. Further clinical studies may help clarify the optimum management strategy in this patient group.

Anticipation in familial pancreatic cancer.

BACKGROUND: Previous studies of anticipation in familial pancreatic cancer have been small and subject to ascertainment bias. Our aim was to determine evidence for anticipation in a large number of European families. PATIENTS AND METHODS: A total of 1223 individuals at risk from 106 families (264 affected individuals) were investigated. Generation G3 was defined as the latest generation that included any individual aged over 39 years; preceding generations were then defined as G2 and G1. RESULTS: With 80 affected child-parent pairs, the children died a median (interquartile range) of 10 (7, 14) years earlier. The median (interquartile range) age of death from pancreatic cancer was 70 (59, 77), 64 (57, 69), and 49 (44, 56) years for G1, G2, and G3, respectively. These indications of anticipation could be the result of bias. Truncation of Kaplan-Meier analysis to a 60 year period to correct for follow up time bias and a matched test statistic indicated significant anticipation (p=0.002 and p<0.001). To minimise bias further, an iterative analysis to predict cancer numbers was developed. No single risk category could be applied that accurately predicted cancer cases in every generation. Using three risk categories (low with no pancreatic cancer in earlier generations, high with a single earlier generation, and very high where two preceding generations were affected), incidence was estimated without significant error. Anticipation was independent of smoking. CONCLUSION: This study provides the first strong evidence for anticipation in familial pancreatic cancer and must be considered in genetic counselling and the commencement of secondary screening for pancreatic cancer.

Hereditary pancreatitis and secondary screening for early pancreatic cancer.

Hereditary pancreatitis is an autosomal dominant disease with incomplete penetrance (80%), accounting for approximately 1% of all cases of pancreatitis. It is characterized by the onset of recurrent attacks of acute pancreatitis in childhood and frequent progression to chronic pancreatitis. Whitcomb et al. identified the cationic trypsinogen gene (PRSS1) on chromosome 7q35 as the site of the mutation that causes hereditary pancreatitis. The European registry of hereditary pancreatitis and familial pancreatic cancer (EUROPAC) aims to identify and make provisions for those affected by hereditary pancreatitis and familial pancreatic cancer. The most common mutations in hereditary pancreatitis are R122H, N29I and A16V but many families have been described with clinically defined hereditary pancreatitis where there is no PRSS1 mutation. It is known that the cumulative lifetime risk (to age 70 years) of pancreatic cancer is 40% in individuals with hereditary pancreatitis. This subset of individuals form an ideal group for the development of a screening programme aimed at detecting pancreatic cancer at an early stage in an attempt to improve the presently poor long-term survival. Current screening strategies involve multimodality imaging (computed tomography, endoluminal ultrasound) and endoscopic retrograde cholangiopancreatography for pancreatic juice collection followed by molecular analysis of the DNA extracted from the juice. The potential benefit of screening (curative resection) must be balanced against the associated morbidity and mortality of surgery. Philosophically, the individual's best interest must be sought in light of the latest advances in medicine and science following discussions with a multidisciplinary team in specialist pancreatic centres.

Surgery in the treatment of acute pancreatitis--minimal access pancreatic necrosectomy.

Between 5% and 10% of patients with acute pancreatitis will develop infected pancreatic necrosis. Traditional open surgery for this condition carries a mortality rate of up to 50%, and therefore a number of less invasive techniques have been developed, including radiological drainage and a minimal access retroperitoneal approach. No randomised controlled trials have been published which compare these techniques. Indications for minimal access surgery are the same as for open surgery, i.e. infected pancreatic necrosis or failure to improve with extensive sterile necrosis. Access is obtained to the pancreatic necrosis via the left loin and necrosectomy performed using an operating nephroscope, and this often requires several procedures to remove all necrotic tissue. The cavity is continuously irrigated on the ward in between procedures. The results of this approach are encouraging, with less systemic upset to the patient, a lower incidence of post-operative organ failure when compared with open surgery, and a reduced requirement for ITU support. There is also a trend towards a lower mortality rate, although this does not reach statistical significance on the data published so far. Current evidence suggests that a minimal access approach to pancreatic necrosis is feasible, well tolerated and beneficial for the patient when compared with open surgery.

The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease.

BACKGROUND: Mutations in the PRSS1 gene explain most occurrences of hereditary pancreatitis (HP) but many HP families have no PRSS1 mutation. Recently, an association between the mutation N34S in the pancreatic secretory trypsin inhibitor (SPINK1 or PSTI) gene and idiopathic chronic pancreatitis (ICP) was reported. It is unclear whether the N34S mutation is a cause of pancreatitis per se, whether it modifies the disease, or whether it is a marker of the disease. PATIENTS AND METHODS: A total of 327 individuals from 217 families affected by pancreatitis were tested: 152 from families with HP, 108 from families with ICP, and 67 with alcohol related CP (ACP). Seven patients with ICP had a family history of pancreatitis but no evidence of autosomal dominant disease (f-ICP) compared with 87 patients with true ICP (t-ICP). Two hundred controls were also tested for the N34S mutation. The findings were related to clinical outcome. RESULTS: The N34S mutation was carried by five controls (2.5%; allele frequency 1.25%), 11/87 (13%) t-ICP patients (p=0.0013 v controls), and 6/7 (86%) affected (p<0.0001 v controls) and 1/9 (11%) unaffected f-ICP cases. N34S was found in 4/108 affected HP patients (p=0.724 v controls), in 3/27 (11%) with wild-type and in 1/81 (1%) with mutant PRSS1, and 4/67 ACP patients (all p>0.05 v controls). The presence of the N34S mutation was not associated with early disease onset or disease severity. CONCLUSIONS: The prevalence of the N34S mutation was increased in patients with ICP and was greatest in f-ICP cases. Segregation of the N34S mutation in families with pancreatitis is unexplained and points to a complex association between N34S and another putative pancreatitis related gene.

Molecular pathogenesis of pancreatic ductal adenocarcinoma and clinical implications.

Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer death worldwide. PDAC is also one of the best-studied cancers with regard to molecular pathogenesis. The chief risk factors associated with PDAC are smoking and pancreatitis, in addition genetic predisposition seems to play a major role. This genetic predisposition may in some cases be indirect, for example via the elevated risk of pancreatitis seen in patients with hereditary pancreatitis (HP). The elucidation of the molecular causes of PDAC has enabled the provision of secondary screening for PDAC in conditions such as HP. This review is concerned with the molecular pathogenesis of PDAC and the application of this basic scientific understanding into state-of-the-art clinical practice.

A new polymorphism for the RI22H mutation in hereditary pancreatitis.

BACKGROUND AND AIMS: Hereditary pancreatitis (HP) is a rare form of recurrent acute and chronic pancreatitis. Mutations in the cationic trypsinogen (protease serine 1, PRSS1) gene have been identified as causing HP. The R122H (previously known as R117H) mutation is the commonest and can be detected by a single and rapid polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) based technique using the AflIII enzyme. This test however may give a false negative result in the presence of a neutral polymorphism within the enzyme recognition site. The frequency of this event was examined by sequencing studies in patients with HP and in healthy controls. METHODS: Of 60 families identified by the UK and Ireland consortium of EUROPAC (European Registry for Hereditary Pancreatitis and Familial Pancreatic Cancer), 51 were screened for R122H, N29I, and A16V mutations using standard techniques, and by sequencing of all five exons of cationic trypsinogen. RESULTS: Twelve families had the N29I mutation, one family had A16V and, on standard testing, 15 families had the R122H mutation. An additional family with the R122H mutation was found on direct sequencing. The false negative result was due to a neutral polymorphism C-->T at the third base of the codon, not affecting the amino acid coded for, destroying the AflIII restriction site. This polymorphism was not observed in 50 DNA specimens (100 chromosomes) from controls nor from 50 individuals from PRSS1 mutation negative HP families. A novel mutation specific PCR was developed to avoid this pitfall. CONCLUSIONS: One of the 16 families with HP and an R122H mutation contained a polymorphism affecting the AflIII restriction site. Adoption of an alternative R122H assay is important for genetic studies in individuals with apparent HP.

Molecular diagnosis of early pancreatic ductal adenocarcinoma in high-risk patients.

The prevalence of pancreatic cancer in the general population is too low--even in high-prevalence areas such as Northern Europe and North America (8-12 per 10(5) population)--relative to the diagnostic accuracy of present detection methods to permit primary screening in the asymptomatic adult population. The recognition that the lifetime risk of developing pancreatic cancer for patients with hereditary pancreatitis (HP) is extremely high (20% by the age of 60 years and 40% by the age of 70 years) poses considerable challenges and opportunities for secondary screening in those patients without any clinical features of pancreatic cancer. Even for secondary screening, the detection of cancer at a biological stage that would be amenable to cure by surgery (total pancreatectomy) still requires diagnostic modalities with a very high sensitivity and specificity. Conventional radiological imaging methods such as endoluminal ultrasound and endoscopic retrograde pancreatography, which have proved to be valuable in the early detection of early neoplastic lesions in patients with familial pancreatic cancer, may well be applicable to patients with HP but only in those without gross morphological features of chronic pancreatitis (other than parenchymal atrophy). Unfortunately, most cases of HP also have associated gross features of chronic pancreatitis that are likely to seriously undermine the diagnostic value of these conventional imaging modalities. Pre-malignant molecular changes can be detected in the pancreatic juice of patients. Thus, the application of molecular screening in patients with HP is potentially the most powerful method of detection of early pancreatic cancer. Although mutant (mt) K-ras can be detected in the pancreatic juice of most patients with pancreatic cancer, it is also present in patients with non-inherited chronic pancreatitis who do not progress to pancreatic cancer (at least in the short to medium term), as well as increasingly in the older population without pancreatic disease. Nevertheless, the presence of mt-K-ras may identify a genuinely higher-risk group, enabling additional diagnostic imaging and molecular resources to be focussed on such a group. What is clear is that prospective multi-centre studies, such as that being pursued by the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC), are essential for the development of an effective secondary screening programme for these patients.

Screening for early pancreatic ductal adenocarcinoma in hereditary pancreatitis.

Patients with hereditary pancreatitis have a 40% lifetime risk of developing pancreatic ductal adenocarcinoma. Existing methods of diagnosing pancreatic cancer such as tumor markers, endoscopy, and radiological imaging lack the sensitivity and specificity for early diagnosis, particularly in a background of chronic pancreatitis. Molecular based strategies offer new avenues of screening for pancreatic ductal adenocarcinoma in these high-risk patients, which may allow the development of highly sensitive and specific diagnostic tests for the early detection of cancer.

Adjuvant therapy for pancreatic cancer.

Pancreatic cancer is a major cause of cancer death; and despite advances in the standards of surgery and supportive care, the median and long-term survival rates have not shown similar dramatic improvements. Techniques such as radical surgery alone cannot guarantee a cure. Previous work with conventional chemotherapy and radiotherapy in patients with advanced pancreatic cancer has indicated a role for adjuvant therapy for patients with resectable tumors. The main modalities that have been assessed are based on the Gastrointestinal Tumour Study Group (GITSG) results using 5-fluorouracil chemotherapy, external beam radiation therapy (EBRT), or both. Alternative approaches such as neoadjuvant therapy have been used, which may increase the number of patients suitable for resection; and regional therapy techniques have been used to increase the therapeutic potential by concentrating agents to the tumor bed. The results of single or combination therapy do show some improvement in survival but have been limited in most cases to retrospective nonrandomized series of patients. Therefore the results must be assessed as such. There are several large randomized trials that will deliver definitive answers in the near future as to whether conventional adjuvant therapy is effective. New approaches using novel agents for advanced disease are currently being assessed, and they may eventually identify the most appropriate and effective agents to use for pancreatic cancer in the adjuvant setting.