Estrogen Receptor Expression in Pancreatic Adenocarcinoma: Time to Reconsider Evidence

Pancreatic adenocarcinoma remains a chemotherapy-resistant and refractory malignancy with high mortality, unaffected by recent progress in anticancer treatment. Expression of estrogen receptors was detected almost 50 years ago, in both benign and malignant pancreatic cells. However, early preclinical studies in pancreatic cancer led to contradictory findings, and most clinical studies failed to demonstrate an effect with tamoxifen treatment. The identification of a second form of estrogen receptor seems to provide some explanation for these discrepancies. Predominantly expressed in malignant cells and structurally different from what was considered the only estrogen receptor, estrogen receptor β was recognized as a negative prognostic factor and a possible therapeutic target in pancreatic ductal adenocarcinoma. Therefore, findings of research before the identification of estrogen receptor β should be reconsidered, and further studies should be designed to reassess the expression and effect of this specific estrogen receptor type in pancreatic cancer

Μελέτη της έκφρασης των υποδοχέων των φυλετικών ορμονών στα παγκρεατικά νεοπλάσματα, και συσχέτισή της με κλινικοπαθολογικά δεδομένα

Υπόβαθρο Η ανακάλυψη των δύο μορφών των οιστρογονικών υποδοχέων, κατέστησε απαραίτητη την επανεξέταση των ευρημάτων παλαιότερων μελετών και τον επανέλεγχο της έκφρασης των υποδοχέων σε όγκους που παλαιότερα θεωρούνταν αρνητικοί. Η μελέτη αυτή στόχευσε στην εκτίμηση της έκφρασης των δύο τύπων οιστρογονικών υποδοχέων ανάμεσα σε καλοήθεις και κακοήθεις παγκρεατικές βλάβες. Μέθοδος Διεξήχθη μελέτη αντιστοίχισης περιστατικών μεταξύ καλοηθών και καοηθών παγκρεατικών βλαβών σε ασθενείς με όμοια ηλικία, φύλο και μέγεθος όγκου. Η έκφραση του ER-α και ER-β αξιολογήθηκε με μεθόδους ανοσοϊστοχημείας και βαθμολογήθηκε με βάση δύο καθιερωμένα συστήματα βαθμολόγησης. Στατιστική ανάλυση πραγματοποιήθηκε μεταξύ των δύο υποομάδων καθώς και με άλλους ιστολογικούς παράγοντες κι ογκολογικά αποτελέσματα. Αποτελέσματα Δεκαέξι καλοήθεις βλάβες και 32 κακοήθεις βλάβες αναλύθηκαν. Ο ER-α ανιχνεύθηκε στο 31,25% των καλοηθών βλαβών και σε καμία κακοήθη βλάβη (p=0,003). Ο ER-β ανιχνεύθηκε στο 31,25% των καλοηθών βλαβών και στο 37,5% των κακοηθών βλαβών (p=0,757). Δεν ανευρέθηκε στατιστικά σημαντική διαφορά μεταξύ της έκφρασης του ER-β κι άλλων ιστολογικών ή κλινικών παραμέτρων. Συμπεράσματα Τα παγκρεατικά αδενοκαρκινώματα δεν εκφράζουν τον ER-α, γεγονός που μπορεί να εξηγεί γιατί παλαιότερες σχετικές κλινικές μελέτες απέτυχαν, αλλά εκφράζουν τον ER-β σε αξιοσημείωτο ποσοστό, γεγονός που υποστηρίζει την ανάγκη για περαιτέρω μελέτες στο πεδίο.Background The discovery of two forms of estrogen receptors, has mandated to reconsider findings of earlier studies and re-examine their expression in tumours that were previously thought negative. This study aimed to assess the expression of the two estrogen receptor types in benign and malignant pancreatic lesions. Methods A case-matched study was performed between benign and malignant pancreatic lesions of patients with similar age, gender and tumour size. ER-α and ER-β expression was assessed by immunohistochemistry and scored using two established scoring systems. Statistical analysis was performed between the two groups as well as with other histological factors and oncological outcomes. Results Sixteen benign lesions and 32 malignant lesions were analysed. ER-α was detected in 31,25% of benign tumours but in no malignant tumour (p=0,003). ER-β was positive in 31,25% of benign and 37,5% of malignant tumours (p=0,757). No statistically significant correlation was found between ER-β expression and other histological or clinical parameters. Conclusions Pancreatic adenocarcinomas do not express ER-α, which might explain failure of relevant earlier clinical trials, but do express ER-β at a considerable rate, which supports the need for further targeted studies

Treatment challenges in and outside a specialist network setting: Pancreatic neuroendocrine tumours

Pancreatic Neuroendocrine Neoplasms comprise a group of rare tumours with special biology, an often indolent behaviour and particular diagnostic and therapeutic requirements. The specialized biochemical tests and radiological investigations, the complexity of surgical options and the variety of medical treatments that require individual tailoring, mandate a multidisciplinary approach that can be optimally achieved through an organized network. The present study describes currents concepts in the management of these tumours as well as an insight into the challenges of delivering the pathway in and outside a Network

Bilirubin is a specific marker for the diagnosis of acute appendicitis

Total serum bilirubin and other biochemical parameters have been associated with acute appendicitis, mainly in complicated cases. The present study aimed to evaluate the role of biochemical parameters in the diagnosis of acute appendicitis, and to further investigate the role of bilirubin as a diagnostic marker irrespective of the severity of the pathology. All recorded cases of appendicectomies in a 1-year period in a single institution were reviewed. The median values of white cell count, C-reactive protein and total serum bilirubin on admission were associated with final histology, and their respective rates of abnormal and normal values were compared between patients who were proven to have negative histology and patients who were proven to have acute appendicitis. A total of 300 patients were studied. Median total serum bilirubin, white cell count and C-reactive protein on admission were significantly associated with acute appendicitis (P<0.001). Respective rates of normal and abnormal values were significantly associated with final histology (P<0.001). Total serum bilirubin demonstrated higher specificity (0.88) but lower sensitivity (0.26) and diagnostic accuracy (0.40) for acute appendicitis. In conclusion, total serum bilirubin on admission should be considered in the diagnostic workup to confirm rather than exclude appendicitis, without focusing on subgroups of specific severity of the disease. White cell count and C-reactive protein may also contribute to the diagnostic work-up, although with limited accuracy

Optimal extent of initial parathyroid resection in patients with multiple endocrine neoplasia syndrome type 1: A meta-analysis

BACKGROUND: Hyperparathyroidism is an almost universal feature of multiple endocrine neoplasia type 1 syndrome. We present a systematic review and meta-analysis of the postoperative outcomes of patients undergoing initial operative treatment of primary hyperparathyroidism complicating multiple endocrine neoplasia 1. METHODS: A comprehensive literature search was performed with a priori defined exclusion criteria for studies comparing total parathyroidectomy, subtotal parathyroidectomy, and less than subtotal parathyroidectomy. RESULTS: Twenty-one studies incorporating 1,131 patients (272 undergoing total parathyroidectomy, 510 subtotal parathyroidectomy, and 349 less than subtotal parathyroidectomy) were identified. Pooled results revealed increased risk for long-term hypoparathyroidism in total parathyroidectomy patients (relative risk 1.61; 95% confidence interval, 1.12-2.31; P = .009) versus those undergoing subtotal parathyroidectomy. In the less than subtotal parathyroidectomy or subtotal parathyroidectomy comparison group, a greater risk for recurrence of hyperparathyroidism (relative risk 1.37; 95% confidence interval, 1.05-1.79; P = .02), persistence of hyperparathyroidism (relative risk 2.26; 95% confidence interval, 1.49-3.41; P = .0001), and reoperation for hyperparathyroidism (relative risk 2.48; 95% confidence interval, 1.65-3.73; P < .0001) was noted for less than subtotal parathyroidectomy patients, albeit with lesser risk for long-term for hypoparathyroidism (relative risk 0.47; 95% confidence interval, 0.29-0.75; P = .002). CONCLUSION: Subtotal parathyroidectomy compares favorably to total parathyroidectomy, exhibiting similar recurrence and persistence rates with a decreased propensity for long-term postoperative hypoparathyroidism. The benefit of the decreased risk of hypoparathyroidism in less than subtotal parathyroidectomy is negated by the increase in the risk for recurrence, persistence, and reoperation. Future studies evaluating the performance of less than subtotal parathyroidectomy in specific multiple endocrine neoplasia 1 phenotypes should be pursued in an effort to delineate a patient-tailored, operative approach that optimizes long-term outcomes

Current evidence on laparoscopic vs. open resection for gastric stromal tumours

Although the use of laparoscopic surgery is increasing, controversy still surrounds its application for malignant conditions. Gastrointestinal stromal tumours (GISTs) are less demanding in terms of lymphadenectomy, meaning that laparoscopic resection might have a more defined benefit when compared with open resection. To the best of our knowledge, no randomized study exists that compares the laparoscopic and open resection of GISTs. The current study aimed to examine the relevant literature by means of a systematic review. A systematic literature search was performed individually by two authors, in which three independent databases were searched using specific search-terms. Titles, abstracts and full texts were screened, as well as references to relevant articles, in order to comprise a comprehensive list of studies. Data were extracted using a detailed pre-agreed spreadsheet. Studies were evaluated according to the modified MINORS criteria. A total of 10 studies were included in the present review, yielding a total of 14 entries. The majority of studies reported significantly improved perioperative outcomes for the laparoscopic approach, including improved duration of operation, blood loss and length of hospital stay. Only four studies reported long-term outcomes and findings that were controversial, with some studies detecting no statistically significant differences, one reporting improved and one reporting worse disease-free and overall survival for the laparoscopic group. Three studies were deemed to be good quality, two of which had not reported significantly different long-term outcomes, while the third had reported significantly improved outcomes in the open resection group. While there is a clear benefit for performing laparoscopic surgery in patients with GIST with regards to perioperative outcomes, when it comes to long-term oncological outcomes, uncertainty over its application remains. The lack of randomized trials, as well as the poor reporting of retrospective studies, limits the amount of evidence that is currently available. Laparoscopic surgery for GIST is certainly safe, feasible and likely cost-effective; however, further studies are required to inform on whether this technique is superior to open resection

Global Consequences of Liver Ischemia/Reperfusion Injury

Liver ischemia/reperfusion injury has been extensively studied during the last decades and has been implicated in the pathophysiology of many clinical entities following hepatic surgery and transplantation. Apart from its pivotal role in the pathogenesis of the organ’s post reperfusion injury, it has also been proposed as an underlying mechanism responsible for the dysfunction and injury of other organs as well. It seems that liver ischemia and reperfusion represent an event with “global” consequences that influence the function of many remote organs including the lung, kidney, intestine, pancreas, adrenals, and myocardium among others. The molecular and clinical manifestation of these remote organs injury may lead to the multiple organ dysfunction syndrome, frequently encountered in these patients. Remote organ injury seems to be in part the result of the oxidative burst and the inflammatory response following reperfusion. The present paper aims to review the existing literature regarding the proposed mechanisms of remote organ injury after liver ischemia and reperfusion

Outcomes After Distal Pancreatectomy with Celiac Axis Resection for Pancreatic Cancer: A Pan-European Retrospective Cohort Study

BACKGROUND: Western multicenter studies on distal pancreatectomy with celiac axis resection (DP-CAR), also known as the Appleby procedure, for locally advanced pancreatic cancer are lacking. We aimed to study overall survival, morbidity, mortality and the impact of preoperative hepatic artery embolization (PHAE). METHODS: Retrospective cohort study within the European-African Hepato-Pancreato-Biliary-Association, on DP-CAR between 1-1-2000 and 6-1-2016. Primary endpoint was overall survival. Secondary endpoints were radicality (R0-resection), 90-day mortality, major morbidity, and pancreatic fistulae (grade B/C). RESULTS: We included 68 patients from 20 hospitals in 12 countries. Postoperatively, 53% of patients had R0-resection, 25% major morbidity, 21% an ISGPS grade B/C pancreatic fistula, and 16% mortality. In total, 82% received (neo-)adjuvant chemotherapy and median overall survival in 62 patients with pancreatic ductal adenocarcinoma patients was 18 months (CI 10-37). We observed no impact of PHAE on ischemic complications. CONCLUSIONS: DP-CAR combined with chemotherapy for locally advanced pancreatic cancer is associated with acceptable overall survival. The 90-day mortality is too high and should be reduced. Future studies should investigate to what extent increasing surgical volume or better patient selection can improve outcomes

IL-22BP controls the progression of liver metastasis in colorectal cancer

BackgroundThe immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown.MethodsWe used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages.ResultsOur data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice.ConclusionsWe here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC

Study of the expression of sex hormones in pancreatic neoplasms, and correlation with clinical and pathological data

Background: The discovery of two forms of estrogen receptors, has mandated to reconsider findings of earlier studies and re-examine their expression in tumours that were previously thought negative. This study aimed to assess the expression of the two estrogen receptor types in benign and malignant pancreatic lesions. Methods: A case-matched study was performed between benign and malignant pancreatic lesions of patients with similar age, gender and tumour size. ER-α and ER-β expression was assessed by immunohistochemistry and scored using two established scoring systems. Statistical analysis was performed between the two groups as well as with other histological factors and oncological outcomes. Results: Sixteen benign lesions and 32 malignant lesions were analysed. ER-α was detected in 31,25% of benign tumours but in no malignant tumour (p=0,003). ER-β was positive in 31,25% of benign and 37,5% of malignant tumours (p=0,757). No statistically significant correlation was found between ER-β expression and other histological or clinical parameters. Conclusions: Pancreatic adenocarcinomas do not express ER-α, which might explain failure of relevant earlier clinical trials, but do express ER-β at a considerable rate, which supports the need for further targeted studies.Υπόβαθρο: Η ανακάλυψη των δύο μορφών των οιστρογονικών υποδοχέων, κατέστησε απαραίτητη την επανεξέταση των ευρημάτων παλαιότερων μελετών και τον επανέλεγχο της έκφρασης των υποδοχέων σε όγκους που παλαιότερα θεωρούνταν αρνητικοί. Η μελέτη αυτή στόχευσε στην εκτίμηση της έκφρασης των δύο τύπων οιστρογονικών υποδοχέων ανάμεσα σε καλοήθεις και κακοήθεις παγκρεατικές βλάβες. Μέθοδος: Διεξήχθη μελέτη αντιστοίχισης περιστατικών μεταξύ καλοηθών και καοηθών παγκρεατικών βλαβών σε ασθενείς με όμοια ηλικία, φύλο και μέγεθος όγκου. Η έκφραση του ER-α και ER-β αξιολογήθηκε με μεθόδους ανοσοϊστοχημείας και βαθμολογήθηκε με βάση δύο καθιερωμένα συστήματα βαθμολόγησης. Στατιστική ανάλυση πραγματοποιήθηκε μεταξύ των δύο υποομάδων καθώς και με άλλους ιστολογικούς παράγοντες κι ογκολογικά αποτελέσματα. Αποτελέσματα: Δεκαέξι καλοήθεις βλάβες και 32 κακοήθεις βλάβες αναλύθηκαν. Ο ER-α ανιχνεύθηκε στο 31,25% των καλοηθών βλαβών και σε καμία κακοήθη βλάβη (p=0,003). Ο ER-β ανιχνεύθηκε στο 31,25% των καλοηθών βλαβών και στο 37,5% των κακοηθών βλαβών (p=0,757). Δεν ανευρέθηκε στατιστικά σημαντική διαφορά μεταξύ της έκφρασης του ER-β κι άλλων ιστολογικών ή κλινικών παραμέτρων. Συμπεράσματα: Τα παγκρεατικά αδενοκαρκινώματα δεν εκφράζουν τον ER-α, γεγονός που μπορεί να εξηγεί γιατί παλαιότερες σχετικές κλινικές μελέτες απέτυχαν, αλλά εκφράζουν τον ER-β σε αξιοσημείωτο ποσοστό, γεγονός που υποστηρίζει την ανάγκη για περαιτέρω μελέτες στο πεδίο