Thrombospondin-2 as a diagnostic biomarker for distal cholangiocarcinoma and pancreatic ductal adenocarcinoma

PurposeDistal cholangiocarcinoma and pancreatic ductal adenocarcinoma are malignancies with poor prognoses that can be difficult to distinguish preoperatively. Thrombospondin-2 has been proposed as a novel diagnostic biomarker for early pancreatic ductal adenocarcinoma. The aim of the present study was to evaluate thrombospondin-2 as a diagnostic and prognostic biomarker in combination with current biomarker CA 19-9 for distal cholangiocarcinoma and pancreatic ductal adenocarcinoma.MethodsThrombospondin-2 was measured in prospectively collected serum samples from patients who underwent surgery with a histopathological diagnosis of distal cholangiocarcinoma (N = 51), pancreatic ductal adenocarcinoma (N = 52) and benign pancreatic diseases (N = 27) as well as healthy blood donors (N = 52) using an enzyme-linked immunosorbent assay.ResultsThrombospondin-2 levels (ng/ml) were similar in distal cholangiocarcinoma 55 (41–77) and pancreatic ductal adenocarcinoma 48 (35–80) (P = 0.221). Thrombospondin-2 + CA 19-9 had an area under the curve of 0.92 (95% CI 0.88–0.97) in differentiating distal cholangiocarcinoma and pancreatic ductal adenocarcinoma from healthy donors which was superior to CA 19-9 alone (P < 0.001). The diagnostic value of adding thrombospondin-2 to CA 19-9 was larger in early disease stages. Thrombospondin-2 did not provide additional value to CA 19-9 in differentiating the benign disease group; however, heterogeneity was notable in the benign cohort. Three of five patients with autoimmune pancreatitis patients had greatly elevated thrombospondin-2 levels. Thrombospondin-2 levels had no correlation with prognoses.ConclusionsSerum thrombospondin-2 in combination with CA 19-9 has potential as a biomarker for distal cholangiocarcinoma and pancreatic cancer.

Thrombospondin-2 as a diagnostic biomarker for distal cholangiocarcinoma and pancreatic ductal adenocarcinoma.

PURPOSE: Distal cholangiocarcinoma and pancreatic ductal adenocarcinoma are malignancies with poor prognoses that can be difficult to distinguish preoperatively. Thrombospondin-2 has been proposed as a novel diagnostic biomarker for early pancreatic ductal adenocarcinoma. The aim of the present study was to evaluate thrombospondin-2 as a diagnostic and prognostic biomarker in combination with current biomarker CA 19-9 for distal cholangiocarcinoma and pancreatic ductal adenocarcinoma. METHODS: Thrombospondin-2 was measured in prospectively collected serum samples from patients who underwent surgery with a histopathological diagnosis of distal cholangiocarcinoma (N = 51), pancreatic ductal adenocarcinoma (N = 52) and benign pancreatic diseases (N = 27) as well as healthy blood donors (N = 52) using an enzyme-linked immunosorbent assay. RESULTS: Thrombospondin-2 levels (ng/ml) were similar in distal cholangiocarcinoma 55 (41-77) and pancreatic ductal adenocarcinoma 48 (35-80) (P = 0.221). Thrombospondin-2 + CA 19-9 had an area under the curve of 0.92 (95% CI 0.88-0.97) in differentiating distal cholangiocarcinoma and pancreatic ductal adenocarcinoma from healthy donors which was superior to CA 19-9 alone (P < 0.001). The diagnostic value of adding thrombospondin-2 to CA 19-9 was larger in early disease stages. Thrombospondin-2 did not provide additional value to CA 19-9 in differentiating the benign disease group; however, heterogeneity was notable in the benign cohort. Three of five patients with autoimmune pancreatitis patients had greatly elevated thrombospondin-2 levels. Thrombospondin-2 levels had no correlation with prognoses. CONCLUSIONS: Serum thrombospondin-2 in combination with CA 19-9 has potential as a biomarker for distal cholangiocarcinoma and pancreatic cancer.

Sulcation of the intraparietal sulcus is related to symbolic but not non-symbolic number skills.

Understanding the constraints, including biological ones, that may influence mathematical development is of great importance because math ability is a key predictor of career success, income and even psychological well-being. While research in developmental cognitive neuroscience of mathematics has extensively studied the key functional regions for processing numbers, particularly the horizontal segment of intraparietal sulcus (HIPS), few studies have investigated the effects of early cerebral constraints on later mathematical abilities. In this pre-registered study, we investigated whether variability of the sulcal pattern of the HIPS, a qualitative feature of the brain determined in-utero and not affected by brain maturation and learning, accounts for individual difference in symbolic and non-symbolic number abilities. Seventy-seven typically developing school-aged children and 21 young adults participated in our study. We found that the HIPS sulcal pattern, (a) explains part of the variance in participant's symbolic number comparison and math fluency abilities, and (b) that this association between HIPS sulcal pattern and symbolic number abilities was found to be stable from childhood to young adulthood. However, (c) we did not find an association between participant's non-symbolic number abilities and HIPS sulcal morphology. Our findings suggest that early cerebral constraints may influence individual difference in math abilities, in addition to the well-established neuroplastic factors.

Domain-general and domain-specific influences on emerging numerical cognition: Contrasting uni-and bidirectional prediction models.

Domain-general skills such as executive functions (EFs), and domain-specific skills such as non-symbolic number sense and symbolic understanding are often pitted against each other as predictors of emerging maths. Here we aimed to investigate early childhood relations between these foundational skills with a balanced, longitudinal design. One hundred and seventy 3- and 4-year-old-children were tested at two time points, 5 months apart, on four domain-general executive and five domain-specific numeracy tasks. A latent EF factor was a strong predictor of symbolic maths and of their growth. In addition, stronger symbolic maths at Time 1 was correlated with later stronger EF, but symbolic maths did not predict EF growth. Our findings provide novel insights into dynamic interplay between general and specific cognitive skills contributing to preschool maths.

Surgical Infections and Antibiotic Stewardship: In Need for New Directions.

BACKGROUND AND AIMS: Patients undergoing surgery are prone to infections, either at the site of surgery (superficial or organ-space) or at remote sites (e.g. pneumonia or urinary tract). Surgical site infections are associated with substantial morbidity and mortality, increased length of hospital stay and represent a huge burden to the health economy across all healthcare systems. Here we discuss recent advances and challenges in the field of surgical site infections. MATERIAL AND METHODS: Review of pertinent English language literature. RESULTS: Numerous guidelines and recommendations have been published in order to prevent surgical site infections. Compliance with these evidence-based guidelines vary and has not resulted in any major decrease in the surgical site infection rate. To date, most efforts to reduce surgical site infection have focused on the role of the surgeon, but a more comprehensive approach is necessary. CONCLUSION: Surgical site infections need to be addressed in a structured way, including checklists, audits, monitoring, and measurements. All stakeholders, including the medical profession, the society, and the patient, need to work together to reduce surgical site infections. Most surgical site infections are preventable-and we need a paradigm shift to tackle the problem.

Potential biomarkers for early detection of pancreatic ductal adenocarcinoma.

Pancreatic cancer has the highest mortality amongst all major organ cancers. Early detection is key to reduce deaths related to pancreatic cancer. However, early detection has been challenged by the lack of non-invasive biomarkers with enough sensitivity and specificity to allow for screening. The gold standard is still carbohydrate antigen (CA 19-9), against which all new biomarkers must be evaluated. In this paper, we describe recent progress in the development of new pancreatic cancer biomarkers, focusing on proteins, metabolites, and genetic and epigenetic biomarkers. Although several promising biomarkers have been identified, they are all derived from retrospective studies and additional prospective studies are needed to confirm their clinical validity.

The Dilemma of Drains after Pancreatoduodenectomy: Still an Issue?

BACKGROUND AND AIMS: Routine drainage after pancreatoduodenectomy is a controversial issue. In this article, we present and discuss the current evidence on abdominal drains in pancreatic surgery. MATERIAL AND METHODS: Review of the pertinent English-language literature. RESULTS: There is a growing body of evidence showing a lack of benefit of prophylactic drainage after pancreatoduodenectomy. Randomized trials have reported similar outcomes with or without routine drains. If drains were used, early removal was found to be superior to late removal in patients with a low risk of postoperative pancreatic fistula. Consequently, criteria for early drain removal have been developed based on the measurement of drain amylase levels. On the contrary, there exists a subgroup of patients where drains may have a role. In patients with high risk of pancreatic fistula formation, such as those having a soft pancreatic texture, small pancreatic duct and high body mass index, the placement of drains may give sentinel information about future clinical deterioration. The drain may thus help reduce failure-to-rescue rates. CONCLUSION: Despite much research, there are many unanswered questions regarding drains in pancreatic surgery. It is evident that routine drainage should be abandoned for a more selective strategy. Furthermore, what is needed is a postoperative warning score that early on can identify patients at risk of a pancreatic fistula, without the routine placement of drains.

Sustainability of an Enhanced Recovery Program for Pancreaticoduodenectomy with Pancreaticogastrostomy.

BACKGROUND:: Enhanced recovery program for pancreaticoduodenectomy have become standard care. Little is known about adherence rates and sustainability of the program, especially when pancreaticogastrostomy is used in reconstruction. The aim of this study was, therefore, to evaluate adherence rates and continued outcome, after implementation of an enhanced recovery program. METHODS:: Consecutive patients undergoing pancreaticoduodenectomy at the Department of Surgery, Skåne University Hospital, Lund, Sweden were followed, after implementation of enhanced recovery program, October 2012. In April 2015, some items in the enhanced recovery program were modified, namely earlier removal of nasogastric tubes and abdominal drain. The patients were analyzed in three groups, the implementation group (control) and two post-implementation groups; intermediate and modified group. Sustainability was assessed according to length of stay and adherence rate. RESULTS:: In total, 160 patients were identified. The overall protocol adherence rate increased from 65% to 72%, p = 0.035. While the pre- and intraoperative protocol items were fulfilled to more than >90%, the postoperative were lower, but increasing over time; 48%, 50%, and 58%, p = 0.033. Postoperative complications and hospital length of stay did not change significantly. CONCLUSION:: The positive outcome of an enhanced recovery program for pancreaticoduodenectomy was reasonably well sustained. Compliance with the protocol has increased, but strict adherence remains a challenge, especially with the postoperative items.

Intraductal Papillary Mucinous Neoplasms of The Pancreas: A Nationwide Registry-Based Study.

BACKGROUND AND AIMS:: To investigate the paraclinical and pathological features of surgically resected intraductal papillary mucinous neoplasms in Sweden. MATERIALS AND METHODS:: A review of prospectively collected data on patients undergoing pancreatic resection for a histopathologically verified intraductal papillary mucinous neoplasm between 2010 and 2016 was performed using the Swedish National Registry for Pancreatic and Periampullary Cancer. RESULTS:: A total of 3038 pancreatic resections were performed during the study period, of which 251 (8.3%) were due to intraductal papillary mucinous neoplasms. The intraductal papillary mucinous neoplasm cases comprised 227 noninvasive and 24 invasive lesions. There was an annual increase in the number of resected intraductal papillary mucinous neoplasms, from 13 in 2010 to 56 in 2016, and an increase in the proportion of intraductal papillary mucinous neoplasm to the total number of pancreatic resections (4.7%-11%). Biliary obstruction was the only independent predictor of invasive disease, with odds ratio 3.106 (p = 0.030). There was no difference in survival between low-, intermediate-, and high-grade dysplastic lesions (p = 0.417). However, once invasive, the prognosis was severely impacted (p < 0.001). Three-year survival was 90% for noninvasive intraductal papillary mucinous neoplasm and 39% for invasive intraductal papillary mucinous neoplasm. Survival was better in lymph node negative invasive intraductal papillary mucinous neoplasm (p = 0.021), but still dismal compared to noninvasive lesions (p < 0.001). CONCLUSION:: The number of surgically resected intraductal papillary mucinous neoplasms is increasing in Sweden. Biliary obstruction is associated with invasive disease. Low-to-high-grade dysplastic intraductal papillary mucinous neoplasm has an excellent prognosis, while invasive intraductal papillary mucinous neoplasm has a poor survival rate.

Relationship between tumour size and outcome in pancreatic ductal adenocarcinoma.

BACKGROUND: The size of pancreatic ductal adenocarcinoma (PDAC) at diagnosis is an indicator of outcome. Previous studies have focused mostly on patients with resectable disease. The aim of this study was to investigate the relationship between tumour size and risk of metastasis and death in a large PDAC cohort, including all stages. METHODS: Patients diagnosed with PDAC between 1988 and 2013 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Tumour size was defined as the maximum dimension of the tumour as provided by the registry. Metastatic spread was assessed, and survival was calculated according to size of the primary tumour using the Kaplan-Meier method. Cox proportional regression modelling was used to adjust for known confounders. RESULTS: Some 58 728 patients were included. There were 187 patients (0·3 per cent) with a tumour size of 0·5 cm or less, in whom the rate of distant metastasis was 30·6 per cent. The probability of tumour dissemination was associated with tumour size at the time of diagnosis. The association between survival and tumour size was linear for patients with localized tumours, but stochastic in patients with regional and distant stages. In patients with resected tumours, increasing tumour size was associated with worse tumour-specific survival, whereas size was not associated with survival in patients with unresected tumours. In the adjusted Cox regression analysis, the death rate increased by 4·1 per cent for each additional 1-cm increase in tumour size. CONCLUSION: Pancreatic cancer has a high metastatic capacity even in small tumours. The prognostic impact of tumour size is restricted to patients with localized disease.

Hemorrhage after Major Pancreatic Resection: Incidence, Risk Factors, Management, and Outcome.

BACKGROUND AND AIMS: Hemorrhage is a rare but dreaded complication after pancreatic surgery. The aim of this study was to examine the incidence, risk factors, management, and outcome of postpancreatectomy hemorrhage in a tertiary care center. MATERIALS AND METHODS: A retrospective observational study was conducted on 500 consecutive patients undergoing major pancreatic resections at our institution. Postpancreatectomy hemorrhage was defined according to the International Study Group of Pancreatic Surgery criteria. RESULTS: A total of 68 patients (13.6%) developed postpancreatectomy hemorrhage. Thirty-four patients (6.8%) had a type A, 15 patients (3.0%) had a type B, and the remaining 19 patients (3.8%) had a type C bleed. Postoperative pancreatic fistula Grades B and C and bile leakage were significantly associated with severe postpancreatectomy hemorrhage on multivariable logistic regression. For patients with postpancreatectomy hemorrhage Grade C, the onset of bleeding was in median 13 days after the index operation, ranging from 1 to 85 days. Twelve patients (63.2%) had sentinel bleeds. Surgery lead to definitive hemostatic control in six of eight patients (75.0%). Angiography was able to localize the bleeding source in 8/10 (80.0%) cases. The success rate of angiographic hemostasis was 8/8. (100.0%). The mortality rate among patients with postpancreatectomy hemorrhage Grade C was 2/19 (10.5%), and both fatalities occurred late as a consequence of eroded vessels in association with pancreaticogastrostomy. CONCLUSION: Delayed hemorrhage is a serious complication after major pancreatic surgery.Sentinel bleed is an early warning sign. Postoperative pancreatic fistula and bile leakage are important risk factors for severe postpancreatectomy hemorrhage.

On the ordinality of numbers: A review of neural and behavioral studies.

The last several years have seen steady growth in research on the cognitive and neuronal mechanisms underlying how numbers are represented as part of ordered sequences. In the present review, we synthesize what is currently known about numerical ordinality from behavioral and neuroimaging research, point out major gaps in our current knowledge, and propose several hypotheses that may bear further investigation. Evidence suggests that how we process ordinality differs from how we process cardinality, but that this difference depends strongly on context-in particular, whether numbers are presented symbolically or nonsymbolically. Results also reveal many commonalities between numerical and nonnumerical ordinal processing; however, the degree to which numerical ordinality can be reduced to domain-general mechanisms remains unclear. One proposal is that numerical ordinality relies upon more general short-term memory mechanisms as well as more numerically specific long-term memory representations. It is also evident that numerical ordinality is highly multifaceted, with symbolic representations in particular allowing for a wide range of different types of ordinal relations, the complexity of which appears to increase over development. We examine the proposal that these relations may form the basis of a richer set of associations that may prove crucial to the emergence of more complex math abilities and concepts. In sum, ordinality appears to be an important and relatively understudied facet of numerical cognition that presents substantial opportunities for new and ground-breaking research.

Systematic review of immunohistochemical biomarkers to identify prognostic subgroups of patients with pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis. There is a need to identify prognostic subtypes of PDAC to predict clinical and therapeutic outcomes accurately, and define novel therapeutic targets. The purpose of this review was to provide a systematic summary and review of available data on immunohistochemical (IHC) prognostic and predictive markers in patients with PDAC. METHODS: Relevant articles in English published between January 1990 and June 2010 were obtained from PubMed searches. Other articles identified from cross-checking references and additional sources were reviewed. The inclusion was limited to studies evaluating IHC markers in a multivariable setting. RESULTS: Database searches identified 76 independent prognostic and predictive molecular markers implicated in pancreatic tumour growth, apoptosis, angiogenesis, invasion and resistance to chemotherapy. Of these, 11 markers (Ki-67, p27, p53, transforming growth factor ß1, Bcl-2, survivin, vascular endothelial growth factor, cyclo-oxygenase 2, CD34, S100A4 and human equilibrative nucleoside transporter 1) provided independent prognostic or predictive information in two or more separate studies. CONCLUSION: None of the molecular markers described can be recommended for routine clinical use as they were identified in small cohorts and there were inconsistencies between studies. Their prognostic and predictive values need to be validated further in prospective multicentre studies in larger patient populations. A panel of molecular markers may become useful in predicting individual patient outcome and directing novel types of intervention.

Major haemorrhagic complications of acute pancreatitis.

BACKGROUND: Haemorrhage is a rare, potentially fatal complication in acute pancreatitis (AP). The aim was to investigate the incidence, management and outcome related to this complication. METHODS: The medical records of all patients with AP who presented to a single hospital between January 1994 and July 2009 were reviewed retrospectively. Patients who developed at least one in-hospital episode of major haemorrhage were selected. The aetiology, patient characteristics, occurrence of sentinel bleeding, clinical management and outcome were recorded. RESULTS: Fourteen (1.0 per cent) of 1356 patients diagnosed with AP developed major haemorrhage. Angiography established the diagnosis in four of six patients. Embolization was successful in one patient. Surgery was performed in two patients. Sentinel bleeding occurred in three of four patients with major postoperative bleeding. The overall mortality rate was 36 per cent (5 of 14 patients). Haemorrhage presenting after more than 7 days was associated with a higher mortality rate of 80 per cent (4 of 5 patients). A fatal outcome was at least three times more likely in patients with severe AP and haemorrhagic complications than in those with severe AP but no bleeding. CONCLUSION: Major haemorrhagic complications of AP are rare, but clinically important. Major postoperative bleeding is often preceded by sentinel bleeding. Intra-abdominal haemorrhage presenting more than 1 week after disease onset is a highly fatal complication.

Structure-function relationships underlying calculation: a combined diffusion tensor imaging and fMRI study.

Both neuropsychological and functional neuroimaging studies have identified brain regions that are critical for the neurocognitive processes related to the calculation of arithmetic problems. In particular, the left angular gyrus (lAG) has been repeatedly implicated in arithmetic problem solving and found to be most activated during the retrieval of arithmetic facts. While significant progress has been made in determining the functional role of specific grey matter areas underlying calculation, very little is known about the relationship between these activated regions and their underlying white matter structures. In this study, we collected both diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) data while participants performed a mental arithmetic task. Fractional anisotropy (FA) values were extracted from predefined, hypothesis-driven, white matter regions and correlated with fMRI activation values, which were extracted from anatomically defined grey matter regions. Results indicated structure-function relationships on multiple levels. Specifically, a link between the integrity of the left superior corona radiata (SCR) and neural activity in the lAG during calculation was observed, which was found to be particularly strong for problems that have a high probability of being solved via the retrieval of arithmetic facts (problems with a relatively small problem size). The findings reported provide a link between functional activation and structural integrity of grey and white matter regions in the left temporoparietal cortex, thereby contributing to our understanding of the role of both the function and structure of this brain region in calculation.

Plasma BDNF concentration, Val66Met genetic variant and depression-related personality traits.

Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurogenesis, and BDNF plasma and serum levels have been associated with depression, Alzheimer's disease, and other psychiatric and neurodegenerative disorders. In a relatively large community sample, drawn from the Baltimore Longitudinal Study of Aging (BLSA), we examine whether BDNF plasma concentration is associated with the Val66Met functional polymorphism of the BDNF gene (n = 335) and with depression-related personality traits assessed with the NEO-PI-R (n = 391). Plasma concentration of BDNF was not associated with the Val66Met variant in either men or women. However, in men, but not in women, BDNF plasma level was associated with personality traits linked to depression. Contrary to the notion that low BDNF is associated with negative outcomes, we found lower plasma levels in men who score lower on depression and vulnerability to stress (two facets of Neuroticism) and higher on Conscientiousness and Extraversion. These findings challenge the prevailing hypothesis that lower peripheral levels of BDNF are a marker of depression.

Stroke rehabilitation: application and analysis of the modified Barthel index in an Arab community.

PURPOSE: The primary aim was to provide experience with a functional evaluation instrument (modified Barthel index MBI) that assures the quality of work and identify its deficiencies, familiarize our staff with the feasibility of its application on our local inpatients and educate our personnel in the field of stroke rehabilitation. The secondary aim was to collect data that are measurable and reproducible, identify specific local factors that adversely affect outcomes and serve as a feedback system to our national organizations. METHODS: In this prospective/retrospective study we evaluated 80 hemiplegic patients with completed stroke, admitted to hospital during the year 1989 1990. They were assessed by a neurologist, physiatrist and physiotherapist on admission and discharge using the MBI. All patients received comprehensive inpatient rehabilitation. The study was interrupted at the beginning of the Gulf crisis. However, the data were revived and retrospectively studied in the year 1994-1995. RESULTS: The MBI proved to be fully acceptable and easily applicable in our community. The rehabilitation staff became rapidly familiarized with its application and the reproduction of its data. The goals of rehabilitation were achieved through the reduction in the number of individuals in the more severe MBI scores and the increase in the number of individuals in the less severe ones. Significant improvements occurred in dressing of the upper and lower body, washing, grooming, care of perineum, transfer chair, toilet and walking on a level of 50 yards (p < or = 0.0005). CONCLUSIONS: We conclude that MBI is simple, convenient, efficient, gives exact and accurate information about daily activities and ambulation and could be used in inpatient follow up sittings, in the Arab and culturally similar Middle East countries.

Synergistic cooperation of TFE3 and smad proteins in TGF-beta-induced transcription of the plasminogen activator inhibitor-1 gene.

Members of the TGF-beta superfamily influence a broad range of biological activities including stimulation of wound healing and inhibition of cell growth. TGF-beta signals through type I and II receptor serine/ threonine kinases and induces transcription of many genes including plasminogen activator inhibitor-1 (PAI-1). To identify proteins that participate in TGF-beta-induced gene expression, we developed a novel retrovirus-mediated expression cloning strategy; and using this approach, we established that transcription factor microE3 (TFE3) is involved in TGF-beta-induced activation of the PAI-1 promoter. We showed that TFE3 binds to an E-box sequence in PE2, a 56-bp promoter fragment of the PAI-1 promoter, and that mutation of this sequence abolishes both TFE3 binding as well as TGF-beta-dependent activation. TFE3 and Smad3 synergistically activate the PE2 promoter and phosphorylated Smad3 and Smad4 bind to a sequence adjacent to the TFE3-binding site in this promoter. Binding of both TFE3 and the Smad proteins to their cognate sequences is indispensable for TGF-beta-inducible activation of the PE2 promoter. Hence, TFE3 is an important transcription factor in at least one TGF-beta-activated signal transduction pathway.