Defining the molecular pathology of pancreatic body and tail adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas. METHODS: Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study. RESULTS: Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole-genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial-to-mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer. CONCLUSION: PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.

Serum amylase and C-reactive protein in risk stratification of pancreas-specific complications after pancreaticoduodenectomy.

BACKGROUND: Pancreas-specific complications (PSCs), comprising postoperative pancreatic fistula, haemorrhage and intra-abdominal collections, are drivers of morbidity and mortality after pancreaticoduodenectomy (PD). A serum amylase concentration of 130 units/l or more on postoperative day (POD) 0 has been shown to be an objective surrogate of pancreatic texture, a determinant of PSCs. This study evaluated serial measurements of C-reactive protein (CRP) to refine PSC risk stratification. METHODS: Consecutive patients undergoing PD between 2008 and 2014, with vascular resection if required and without preoperative chemoradiotherapy, had serum investigations from the day before operation until discharge. Receiver operating characteristic (ROC) curve analysis was used to identify a threshold value of serum CRP with clinically relevant PSCs for up to 30 days after discharge as outcome measure. RESULTS: Of 230 patients, 95 (41·3 per cent) experienced a clinically relevant PSC. A serum CRP level of 180 mg/l or higher on POD 2 was associated with PSCs, prolonged critical care stay and relaparotomy (all P < 0·050). Patients with a serum amylase concentration of 130 units/l or more on POD 0 who developed a serum CRP level of at least 180 mg/l on POD 2 had a higher incidence of morbidity. Patients were stratified into high-, intermediate- and low-risk groups using these markers. The low-risk category was associated with a negative predictive value of 86·5 per cent for development of clinically relevant PSCs. There were no deaths among 52 patients in the low-risk group, but seven deaths among 79 (9 per cent) in the high-risk group. CONCLUSION: A serum amylase level below 130 units/l on POD 0 combined with a serum CRP level under 180 mg/l on POD 2 constitutes a low-risk profile following PD, and may help identify patients suitable for early discharge.

Prospective cohort study comparing transient EUS guided elastography to EUS-FNA for the diagnosis of solid pancreatic mass lesions.

BACKGROUND: Semiquantitative EUS-elastography has been introduced to distinguish between malignant and benign pancreatic lesions. This study investigated whether semiquantitative EUS-guided transient real time elastography increases the diagnostic accuracy for solid pancreatic lesions compared to EUS-FNA. PATIENTS AND METHODS: This single centre prospective cohort study included all patients with solitary pancreatic lesions on EUS during one year. Patients underwent EUS-FNA and semiquantitative EUS-elastography during the same session. EUS and elastography results were compared with final diagnosis which was made on the basis of tissue samples and long-term outcome. RESULTS: 91 patients were recruited of which 68 had pancreatic malignancy, 17 showed benign disease and 6 had cystic lesions and were excluded from further analysis. Strain ratios from malignant lesions were significantly higher (24.00; 8.01-43.94 95% CI vs 44.00; 32.42-55.00 95% CI) and ROC analysis indicated optimal cut-off of 24.82 with resulting sensitivity, specificity and accuracy of 77%, 65% and 73% respectively. B-mode EUS and EUS-FNA had an accuracy for the correct diagnosis of malignant lesions of 87% and 85%. When lowering the cut-off strain ratio for elastography to 10 the sensitivity rose to 96% with specificity of 43% and accuracy of 84%, resulting in the least accurate EUS-based method. This was confirmed by pairwise comparison. CONCLUSION: Semiquantitative EUS-elastography does not add substantial value to the EUS-based assessment of solid pancreatic lesions when compared to B-mode imaging.

Exploiting inflammation for therapeutic gain in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC.

Congenital diaphragmatic hernia in Minnesota. Impact of antenatal diagnosis on survival.

OBJECTIVE: We characterized the natural history and true mortality of congenital diaphragmatic hernia (CDH) in newborn patients by identifying all infants born with this condition in a fixed geographic region over a 2-year period. We examined this population to determine the frequency of intrauterine diagnosis, the outcome of prenatally diagnosed infants, and the impact of deaths in infants with an unsuspected diagnosis (the "hidden mortality") on the overall outcome of this condition. DESIGN: This was a retrospective population survey of all infants born with CDH in Minnesota between June 1988 and June 1990. SETTING: All Minnesota birth and death records were reviewed to identify patients with the diagnosis of CDH. A separate survey of all level 3 intensive care nurseries was conducted and the record of each identified patient was reviewed. Extracorporeal membrane oxygenation was available throughout the study period. MAIN OUTCOME MEASURE: Survival to hospital discharge and short-term morbidity were examined for each patient. RESULTS: Survival was 60% (29/48). Eleven of 19 deaths occurred in patients born prematurely and/or with coexisting major anomalies. Eight percent (4/48) of patients died within the first hour of life prior to diagnosis (hidden mortality). Intrauterine diagnosis of CDH was made in 15 patients. Survival was 60% (9/15) in infants whose conditions were diagnosed in utero, a rate identical to that for infants whose conditions were diagnosed in the postnatal period (61% [20/33]). There was no relationship between age at fetal diagnosis and mortality. CONCLUSIONS: The hidden mortality of CDH was low. Almost half of the total mortality for CDH was associated with coexisting, additional anomalies. Patients who were not offered extracorporeal membrane oxygenation owing to prematurity, other major anomalies, or birth at a center that did not offer extracorporeal membrane oxygenation accounted for 84% (16/19) of deaths. These data will be useful for determining the impact of new therapeutic strategies on the mortality of CDH.

The significance of involved tumour bed biopsy following wide local excision of breast cancer.

AIM: Following wide local excision of breast cancer approximately 25% of patients have residual disease in the tumour bed. The aim of this study was to determine whether positive bed biopsy correlated with either local recurrence or overall survival. METHOD: Following wide excision bed biopsies were taken at four separate sites from the tumour bed. Histopathological assessment of the bed biopsies was made and compared to features within the primary tumour. Patients were followed-up over a median period of 6.17 years and local recurrence and survival data documented. RESULTS: Two hundred and sixty-eight patients were included in the study and 63 had positive bed biopsies. In all, 85 patients had a recurrence of breast cancer and 69 died. Kaplan-Meier plots showed no evidence of a difference in survival between bed biopsy positive and negative patients. Bed biopsy positive patients were at greater risk of local recurrence. CONCLUSIONS: These findings suggest that positive bed biopsy is associated with an increase in local recurrence rates but has no effect on overall survival following wide excision of breast cancer.

Staging of acute pancreatitis. Is it important?

Staging of acute pancreatitis is important for selection of patients for clinical trials, comparison of results between centers, and the early identification of patients who may benefit from therapeutic intervention or transfer to a specialist unit. The APACHE-II score and other multiple-factor scoring systems are widely used for the first two indications, and of these, the APACHE-II score provides the best accuracy at an early stage in the course of the illness. Presently, however, no system provides sufficient predictive power to facilitate clinical decision making. At a time of increasing pressure to involve specialist units at an early stage in the management of these complex patients, a pressing need to identify a system for accurate early staging of acute pancreatitis remains.

Pediatric cardiac care consortium. Demonstrated value of a physician-directed quality assessment system.

A quality assessment system for analyzing the results of inpatient care of children with cardiac abnormalities is described. Three Minnesota institutions (the Mayo Clinic, Minneapolis Children's Medical Center, and the University of Minnesota) participate with 15 other similar centers elsewhere in the United States in this system. Patient data are analyzed and adjusted for case mix to allow for differences in patient populations and referral patterns. The statistical methods used are shown for two conditions: ventricular septal defect and aortic valvotomy. Data presented show reduction in length of stay for cardiac catheterization. This change occurred as physicians annually reviewed and discussed the data and, as a result, instituted changes. This physician-directed program seeks improvement in patient care through physician education.

The role of endoscopic ultrasound in the management of intraductal papillary mucinous neoplasms.

As the use of cross-sectional imaging increases so does the incidence of asymptomatic pancreatic cysts. Pancreatic neoplastic cysts can be broadly grouped into mucinous lesions and solid pseudopapillary neoplasms, which have malignant potential and serous lesions, which have negligible malignant potential. Non-neoplastic pancreatic cysts such as pseudocysts are not associated with malignant potential. It is important to identify those mucinous lesions with the highest potential of malignancy as identifying these lesions may allow prevention or early treatment of pancreatic carcinoma. The preoperative diagnosis of these cysts remains challenging with imaging alone often proving inadequate at making the diagnosis. Endoscopic ultrasound (EUS) can assess the morphology of cysts including identification of malignant characteristics of cysts as well as allowing aspiration of cyst fluid, which can be analysed for cytology, mucin, tumour markers, amylase and DNA analysis. Intraductal papillary mucinous neoplasms (IPMNs) can be subdivided into main duct IPMNs (MD-IPMN), branch duct IPMNs (BD-IPMN) and mixed type IPMNs which have feature of both the aforementioned. MD-IPMNs have the highest malignant potential and are often easier to identify on cross-sectional imaging due to the involvement of the main pancreatic duct. BD-IPMNs however can be difficult to distinguish from non-mucinous lesions such as pseudocysts, serous cyst adenomas and other benign cysts such as duplication cysts and in this group of lesions EUS is a valuable tool both to aid diagnosis and to identify BD-IPMNs, which should be considered for surgical resection.

Photon doses in NPL standard neutron fields.

Standard neutron fields are invariably accompanied by a photon component due to the neutron-generating reactions and secondary neutron interactions in the surrounding environment. A set of energy-compensated Geiger-Müller (GM) tubes and electronic personal dosemeters (EPDs) have been used to measure the photon dose rates in a number of standard radionuclide and accelerator-based neutron fields. The GM tubes were first characterised in standard radioisotope and X-ray photon fields and then modelled using MCNP to determine their photon dose response as a function of energy. Values for the photon-to-neutron dose equivalent ratios are presented and compared with other published values.

Long-term follow-up of endoscopic Histoacryl glue injection for the management of gastric variceal bleeding.

BACKGROUND: Variceal bleeding is an acute medical emergency with high mortality. Although less common than oesophageal variceal haemorrhage, gastric variceal bleeding is more severe and more difficult to control. The optimal therapy for gastric variceal bleeding remains unclear although endoscopic injection of N-Butyl-2-Cyanoacrylate (Histoacryl) glue is often used. However, its long-term efficacy is poorly described. We studied the immediate and long-term effects of Histoacryl glue injection as treatment for bleeding gastric varices in a large UK hospital. METHOD: Endoscopy records and case notes were used to identify patients receiving Histoacryl injection for gastric variceal bleeding over a 4-year period. RESULTS: Thirty-one patients received Histoacryl for gastric variceal bleeding. Seventy-four per cent patients had alcohol-related liver disease and 61% of cirrhotics were Childs Pugh grade B or C. Fifty-eight per cent were actively bleeding during the procedure with 100% haemostasis rates achieved. Two patients developed pyrexia within 24 h of injection settling with antibiotics. No other complications were encountered. Mean overall follow-up was 35 months, with mean follow-up of survivors 57 months. Forty-eight per cent patients had endoscopic ultrasound assessment of varices during follow-up with no effect on rebleeding rates. Thirteen per cent required subsequent transjugular intrahepatic portosystemic shunt placement. Gastric variceal rebleeding rate was 10% at 1 year and 16% in total. One- and two-year mortality was 23% and 35%, respectively. CONCLUSION: Endoscopic injection of Histoacryl glue appears to be a safe and effective treatment for gastric variceal bleeding. Further data are required to compare it with other therapies in this situation.

Incarcerated small bowel within a spontaneous lumbar hernia.

Lumbar hernias are rare, resulting from protrusion through the posterior abdominal wall that may be congenital, acquired or spontaneous. They very rarely present with acute bowel obstruction. We present a case of incarcerated small bowel within a spontaneous inferior (Petit's) lumbar hernia, treated by early open repair with mesh insertion. This case highlights the importance of thorough clinical examination and a high index of suspicion, even in the absence of previous surgery around the anatomical site of the suspected hernia, in order to effect an early repair before the onset of ischaemia in incarcerated contents.

Identification of mixed-symmetry states in an odd-mass nearly spherical nucleus.

The low-spin structure of 93Nb has been studied using the (n,n'gamma) reaction at neutron energies ranging from 1.5 to 3 MeV and the 94Zr(p,2ngamma)93Nb reaction at bombarding energies from 11.5 to 19 MeV. States at 1779.7 and 1840.6 keV, respectively, are proposed as mixed-symmetry states associated with the pi2p(1/2)-1x(2(1),MS+,94Mo) coupling. These assignments are derived from the observed M1 and E2 transition strengths to the 2p(1/2)-1x(2(1)+,94Mo) symmetric one-phonon states, energy systematics, spins and parities, and comparison with shell model calculations.

Systemic inflammatory response predicts outcome in patients undergoing resection for ductal adenocarcinoma head of pancreas.

The aim of the present study was to examine the relationship between the clinicopathological status, the pre- and postoperative systemic inflammatory response and survival in patients undergoing potentially curative resection for ductal adenocarcinoma of the head of the pancreas. Patients (n = 65) who underwent resection of ductal adenocarcinoma of the head of pancreas between 1993 and 2001, and had pre- and postoperative measurements of C-reactive protein, were included in the study. The majority of patients had stage III disease (International Union Against Cancer Criteria, IUCC), positive circumferential margin involvement (R1), tumour size greater than 25 mm with perineural and lymph node invasion and died within the follow-up period. On multivariate analysis, tumour size (hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.20-3.68, P = 0.009), vascular invasion (HR 2.58, 95% CI 1.48-4.50, P < 0.001) and postoperative C-reactive protein (HR 2.00, 95% CI 1.14-3.52, P = 0.015) retained independent significance. Those patients with a postoperative C-reactive protein < or = 10 mg l(-1) had a median survival of 21.5 months compared with 8.4 months in those patients with a C-reactive protein >10 mg l(-1) (P < 0.001). The results of the present study indicate that, in patients who have undergone potentially curative resection for ductal adenocarcinoma of the head of pancreas, the presence of a systemic inflammatory response predicts poor outcome.

A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis.

BACKGROUND: After 50 yr in which nasoenteric feeding was considered contraindicated in acute pancreatitis (AP), several clinical studies have shown that early nasojejunal (NJ) feeding can be achieved in most patients. A pilot study of early nasogastric (NG) feeding in patients with objectively graded severe AP proved that this approach was also feasible. A randomized study comparing NG versus NJ feeding has been performed. METHODS: A total of 50 consecutive patients with objectively graded severe AP were randomized to receive either NG or NJ feeding via a fine bore feeding tube. The end points were markers of the acute phase response APACHE II scores and C-reactive protein (CRP) measurements, and pain patterns by visual analogue score (VAS) and analgesic requirements. Complications were monitored and comparisons made of both total hospital and intensive-care stays. RESULTS: A total of 27 patients were randomized to NG feeding and 23 to NJ. One of those in the NJ group had a false diagnosis, thereby reducing the number to 22. Demographics were similar between the groups and no significant differences were found between the groups in APACHE II score, CRP measurement, VAS, or analgesic requirement. Clinical differences between the two groups were not significant. Overall mortality was 24.5% with five deaths in the NG group and seven in the NJ group. CONCLUSIONS: The simpler, cheaper, and more easily used NG feeding is as good as NJ feeding in patients with objectively graded severe AP. This appears to be a useful and practical therapeutic approach to enteral feeding in the early management of patients with severe AP.

Natural history of organ failure in acute pancreatitis.

The majority of deaths from acute pancreatitis are a consequence of multiple organ dysfunction syndrome (MODS). In order to influence the outcome of this condition, we need to have a better understanding of the natural history of acute pancreatitis, particularly when complicated by MODS. This paper reviews the recent literature dealing with the natural history of acute pancreatitis and the relationship between MODS, pancreatic necrosis and mortality.

The scientific basis of medical therapy of acute pancreatitis. Could it work, and is there a role for lexipafant?

For a 30-year period beginning in 1958, the general basis of medical therapy of acute pancreatitis had as its focus the provision of supplementary antiprotease therapy usually given intravenously. This concept was based on the belief that the body's natural antiprotease defense mechanism, which relies heavily on alpha 2-macroglobulin, together with alpha 1-antiprotease (alpha 1-antitrypsin), was inadequate to cope with the vast enzyme release that occurred with the onset of the more severe forms of the disease. This article examines recent studies and emerging theories on the medical therapy of acute pancreatitis.