A systematic review of economic evaluation in pancreatic cystic neoplasms.

Clinical Management of Pancreatic Premalignant Lesions

Hedgehog (Hh) signaling is an important mediator of tumorigenesis of pancreatic ductal adenocarcinoma (PA). It is intriguing to explore whether Hh signaling is also involved in pancreatic cystic neoplasms, which are phenotypically different from PA. Patients with solid and pseudopapillary tumor (SPT; n = 12), mucinous cystic neoplasm (MCN; n = 18), intraductal papillary mucinous neoplasm (IPMN; n = 18), and PA (n = 20) were studied. Expression of Hh signaling molecules including sonic Hh (sHh), smoothened (Smo), patched 1 (Ptc1), and Gli were determined using immunohistochemistry and/or Western blotting. Cell cycle-regulator genes, including cyclin A, B, C, and D1 messenger RNA, were determined using ribonuclease protection assay. Six of 12 SPT, 8 of 18 MCN, 17 of 18 IPMN, and 20 of 20 PA displayed Hh signaling using immunohistochemistry. Sonic Hh was predominantly expressed in stromal cells neighboring to the neoplastic cells of SPT and IPMN; in contrast, sHh was expressed in both stromal cells and neoplastic epithelial cells of MCN and PA. The quantitative expression of sHh signaling detected by Western blotting showed that expression of Ptc1 and Gli, but not Smo, corresponded to the magnitude of sonic hedgehog ligand. The expression of cyclin D1 messenger RNA was highest in PA, followed by MCN, IPMN, and SPT, which matches with Ptc1 and Gli. Hedgehog signaling pathway might play a role during tumorigenesis of SPT, MCN, IPMN, and PA. Mucinous cystic neoplasm and PA exhibit an autocrine regulation of sHh, whereas SPT and IPMN do not. Overexpression of Ptc1 and Gli, reflected by cyclin D1, might represent proliferative potential of various pancreatic neoplasms.

Objective To investigate the manifestations and diagnostic value of imaging examinations in pancreatic cystic neoplasm. Methods Clinical data of 95 patients with pancreatic cystic neoplasm who were admitted to the Second Affiliated Hospital, College of Medical Sciences, Zhejiang University between January 2014 and December 2015 were retrospectively analyzed. Among the patients, 37 were males and 58 were females, aged 10-80 years old with a median age of 54 years old. Sixteen cases were diagnosed with serous cystic neoplasm (SCN), 11 with mutinous cystic neoplasm (MCN), 21 with intraductal papillary mucinous neoplasm (IPMN), 12 with cystic solid pseudopapillary neoplasm (SPN), 24 with cystic pancreatic neuroendocrine neoplasm (PNEN) and 11 with cystic pancreatic adenocarcinoma. The informed consents of all patients were obtained and the local ethical committee approval was received. Computed tomography (CT) and magnetic resonance imaging (MRI) manifestations of the patients with pancreatic cystic neoplasm were analyzed, and the diagnostic accuracy was calculated. Results SCN was characterized with multiple small cysts. MCN was characterized with a clear border, single lumen and thick wall lesion, mainly occurred in the pancreatic body and tail. IPMN was characterized with lesions connected to the main pancreatic duct. Dilation of varying degrees in the main and branch pancreatic duct dilation were observed. Cystic SPN was characterized with gradual enhancement, but the enhancement intensity was lower than that of pancreatic parenchyma. Cystic PNEN was characterized with evident enhancement in arterial phase. Cystic pancreatic adenocarcinoma was characterized with insufficient blood supply complicated with surrounding tissue invasiveness or distal metastasis. The diagnostic accuracy of CT and MRI was the lowest for SCN (29% for CT and 14% for MRI), and highest for cystic PNEN (89% for CT and 100% for MRI). Conclusions Due to the nonspecific clinical manifestations of pancreatic cystic neoplasm, imaging examination remains the main method for the diagnosis. It has high value for the diagnosis of most pancreatic cystic neoplasms and the differential diagnosis between benign and malignant tumors. Key words: Pancreatic cyst; Neoplasms, cystic, mucinous, and serous; Diagnosis, differential

Guidelines on Pancreatic Cystic Neoplasms: Major Inconsistencies With Available Evidence and Clinical Practice— Results From an International Survey

Preoperative staging and evaluation of resectability in pancreatic ductal adenocarcinoma

Pancreatic Cystic Neoplasms: Management and Unanswered Questions

To investigate the imaging features of pancreatic ductal adenocarcinoma (PDAC) with histological large duct pattern. Our study included 37 patients (mean age, 66.5 years; 22 women) with surgically proven PDAC with histological large duct pattern, whose imaging features were classified into four types: Type I, solid mass; Type II, predominantly cystic mass with intracystic solid components; Type III, predominantly solid mass with intratumoral cysts; and Type IV, solid mass with peritumoral retention cysts or pseudocysts. Two radiologists independently analyzed both CT and MRI images for the morphological type, presence of abrupt main pancreatic duct (MPD) cutoff, adjacent vascular invasion, diffusion restriction, and reached consensus. On CT, 26 patients (70.3%) had Type I tumors, five (13.5%) had Type II, three (8.1%) had Type III, and three (8.1%) had Type IV. Among the 26 patients with Type I tumors on CT, 16 had tumors with multiple intratumoral cysts within the solid mass on MRI and were subsequently classified as Type III. Accordingly, 10 patients (27.0%) were classified as Type I, five (13.5%) as Type II, 19 (51.7%) as Type III, and three (8.1%) as Type IV on MRI. Of the 37 patients, 27 (73.0%) had an abrupt MPD cutoff, 15 (40.5%) had adjacent vascular invasion, and 25 (67.6%) had diffusion restriction on MRI. Predominantly solid pancreatic masses with small intratumoral cysts visualized on MRI may be a characteristic imaging finding of PDAC with histological large duct pattern, and differentiate it from conventional PDAC or other cystic pancreatic tumors. Radiologists should be familiar with the various imaging features of PDAC with histological large duct pattern and should be aware that it may mimic other solid or cystic tumors of the pancreas. Imaging features of pancreatic ductal adenocarcinoma with histological large duct pattern can be classified into four types. This pathology more frequently appears as a predominantly solid masswith intratumoral cysts on MRI than on CT. Adding MRI to CT may help identify pancreatic ductal adenocarcinoma with histological large duct pattern.

<div>Abstract<p>The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of <i>Myc</i> in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells <i>in vivo</i> is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this <i>Myc</i>-driven PDAC switch is completely and immediately reversible: <i>Myc</i> deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible <i>Myc</i> switch.</p>Significance:<p>We show that <i>Myc</i> activation in indolent <i>Kras</i><sup>G12D</sup>-induced PanIN epithelium acts as an immediate pleiotropic switch, triggering tissue-specific signals that instruct all the diverse signature stromal features of spontaneous human PDAC. Subsequent <i>Myc</i> deactivation or inhibition immediately triggers a program that coordinately disassembles PDAC back to PanIN.</p><p><i>See related commentary by English and Sears, p. 495</i>.</p></div>

<div>Abstract<p>The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of <i>Myc</i> in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells <i>in vivo</i> is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this <i>Myc</i>-driven PDAC switch is completely and immediately reversible: <i>Myc</i> deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible <i>Myc</i> switch.</p>Significance:<p>We show that <i>Myc</i> activation in indolent <i>Kras</i><sup>G12D</sup>-induced PanIN epithelium acts as an immediate pleiotropic switch, triggering tissue-specific signals that instruct all the diverse signature stromal features of spontaneous human PDAC. Subsequent <i>Myc</i> deactivation or inhibition immediately triggers a program that coordinately disassembles PDAC back to PanIN.</p><p><i>See related commentary by English and Sears, p. 495</i>.</p></div>

The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of Myc in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells in vivo is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this Myc-driven PDAC switch is completely and immediately reversible: Myc deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible Myc switch. SIGNIFICANCE: We show that Myc activation in indolent Kras G12D-induced PanIN epithelium acts as an immediate pleiotropic switch, triggering tissue-specific signals that instruct all the diverse signature stromal features of spontaneous human PDAC. Subsequent Myc deactivation or inhibition immediately triggers a program that coordinately disassembles PDAC back to PanIN.See related commentary by English and Sears, p. 495.

To the Editor, The prevalence of pancreatic cystic neoplasm (PCN) has been increasing due to advances in diagnostic technology, including ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography and endoscopic ultrasound. When PCN is found incidentally, pancreatic cystic lesions may represent a malignant or premalignant neoplasm and require diagnostic evaluation [1]. Generally, cystic mucin-producing pancreatic neoplasms do not communicate with the pancreatic duct and are classified as benign adenomas or borderline, low-grade malignant and non-invasive or invasive carcinomas according to the grade of epithelial dysplasia. These tumors occur almost exclusively in females aged 50 to 60 years [1]. Mucinous cystic neoplasms (MCNs) are characterized by an ovarian-type stroma that typically forms a band of densely packed spindle-shaped cells beneath the malignant epithelium [1]. Although there are several hypotheses of their origin, the pathogenesis of pancreatic MCNs remains unclear because MCNs are rare and molecular studies are difficult since the tumors often contain only a small number of malignant cells [2]. Clonorchiasis is a parasitic disease common in Far Eastern countries, such as Korea and China. Its symptoms are diverse, although the majority of patients are asymptomatic. The parasite may damage bile duct epithelial cells, causing cholangitis and cholangiocarcinoma. The severity of the disease is proportionate to the number of the infectious parasites and the infection period [3]. Infection with a large number of parasites can result in invasion of the pancreatic duct [3] and the parasites may damage ductal epithelial cells and cause inflammation in the pancreas and the bile duct, leading to clonorchiasis-induced pancreatitis. There are reports associating clonorchiasis and pancreatic malignancies with biliary malignancies, including one case of clonorchiasis-associated pancreatic adenocarcinoma [4]; however, clonorchiasis-associated pancreatic MCN has not been reported. Here, we report a case of pancreatic mucinous cystadenoma of borderline malignancy infested with Clonorchis sinensis found incidentally in a 53-yearold male with rectal cancer. The patient presented with lower abdominal pain and hematochezia lasting 3 months. The patient often ate freshwater fish and was not a heavy drinker. His medical history was unremarkable except for chronic hepatitis B reactivation treated with 0.5 mg/day entecavir for 1 month. His mother also had chronic hepatitis B patient and succumbed to hepatocellular carcinoma. On admission, the patient's body temperature, heart rate, respiratory rate, and blood pressure were 37.1℃ 70/min, 22/min, and 100/60 mmHg, respectively. Physical examination of the neck, chest, and abdomen showed no abnormal findings. Digital rectal examination revealed a non-tender, fixed, hard mass at the posterior rectum, 6 cm from the anal verge. An initial complete blood count revealed a hemoglobin count of 13.3 g/dL, a platelet count of 245,000/µL, and a white cell count of 5,700/µL. Biochemical testing showed a blood urea nitrogen of 11 mg/dL, creatinine of 0.6 mg/dL, total protein of 7.1 g/dL, albumin of 3.4 g/dL, aspartate amino transferase of 41 IU/L, alanine transaminase of 37 IU/L, alkaline phosphatase of 69 IU/L, uric acid of 4.4 mg/dL, total calcium of 8.7 mg/dL, phosphorus of 5.1 mg/dL, lactate dehydrogenase of 233 IU/L, carcinoembryonic antigen of 1.4 ng/mL, carbohydrate antigen 19-9 22.0 U/mL, and α-fetoprotein of 62.9 ng/mL. A chest X-ray evaluation showed no specific findings. Gastroscopic examination showed no specific abnormality. Colonoscopic examination revealed a large ulcerofungating mass at the distal rectum, and he was diagnosed with adenocarcinoma of the rectum. Abdomen and pelvis CT showed an asymmetric contrast enhancement in the posterior wall of the distal rectum. In addition, a 4.3-cm, heterogeneous, solid and cystic mass on the distal pancreas was found incidentally (Fig. 1A and 1B). Abdominal MRI showed a multi-septated cystic tumor in the pancreas tail and a fibrotic component was found with mild contrast enhancement after gadolinium injection (Fig. 1C and 1D). There was no dilatation of the pancreatic duct in the tail portion, and there was no dilatation of the common bile duct or the intrahepatic bile duct. On day 2 of hospitalization, an ultra-lower anterior resection and distal pancreatectomy was performed. Gross examination of the resected pancreas presented a well-circumscribed cystic mass, measuring 4.4 × 4.4 × 3.7 cm. Sectioning revealed a multilocular cyst filled with mucinous and necrotic material (Fig. 2). Microscopically, the multilocular cyst was lined by tall-columnar, mucin-secreting cells with stratification and papillary growth, and mild to moderate nuclear atypia, without stromal invasion. These findings were consistent with a mucinous cystadenoma of borderline malignancy. In addition, there was a papillary growing, nodular lesion embedded in the myxoid and fibrotic stroma with numerous eggs, morphologically considered to be C. sinensis, The eggs were surrounded by epithelioid histiocytes or found within multinucleated giant cells (Fig. 3). The rectal sample obtained from the low anterior resection showed moderately differentiated adenocarcinoma invading the muscle layer, but without lymph node metastasis. Figure 1 Contrast-enhanced computed tomography and magnetic resonance imaging. (A) There was a 3.6-cm cystic mass with a suspicious biloculation in the pancreatic tail that extended to the spleen. (B) No pancreatic ductal dilatation was observed. (C) In the inferior ... Figure 2 Macroscopic appearance of the resected pancreas (4.4 × 4.4 × 3.7 cm). Sectioning revealed a multilocular cyst filled with mucinous and necrotic material was found. Figure 3 Microscopic appearance of the resected pancreas. The cyst wall was lined by tall columnar mucin-secreting epithelium with stratification and papillary growth (H&E, ×40). A nodular lesion within the cyst contained numerous parasitic eggs ... On day 6 after surgery, the patient complained of abdominal pain because of leakage at the surgical area. An exploratory laparotomy was performed and the area washed and drained. After this procedure, the patient showed satisfactory improvement and left the hospital on 15 days after surgery. He is undergoing follow-up care in the Department of Surgery and Hepatology. Clonorchiasis is caused by eating raw freshwater fish, which are the intermediary hosts of the metacercariae of C. sinensis. The metacercariae is stripped of its cyst by gastric acid, and the larva passes through the ampulla of Vater to mature in the bile duct. Clonorchiasis is associated with cholangitis, biliary stones, and cholangiocarcinoma; the prevalence of clonorchiasis is much higher in patients with cholangiocarcinoma [3]. In Pusan, an area with an extremely high prevalence of C. sinensis, flukes increase the risk of cholangiocarcinoma 6-fold. Animal experiments have also show a strong association between clonorchiasis and cholangiocarcinoma. Therefore, C. sinensis is believed to have malignant potential in the bile duct. As the larva move to the bile duct, some pass through the main pancreatic duct to branch pancreatic ducts, causing pancreatic disorders [3]. Invasion of the pancreas may result in pancreatitis. Two mechanisms have been proposed by which C. sinensis causes pancreatitis: mechanical obstruction resulting in chemical stimuli by the mixture of the stagnant pancreatic fluid and the metabolites produced by C. sinensis, or inflammation and fibrosis caused by C. sinensis resulting in a back-current of bile into the pancreatic duct [5]. There have been few reports on the association between clonorchiasis and pancreatic neoplasms. A case of pancreatic adenocarcinoma associated with C. sinensis has been reported [4], while cases of clonorchiasiscombined pancreatic MCN have not. In the former reports, an ultrasonogram showed marked dilatation of the intrahepatic and extrahepatic bile ducts. Biopsies of the pancreatic lesion revealed well differentiated ductal adenocarcinoma, but C. sinensis was detected in the common bile duct. Therefore, a direct association between pancreatic adenocarcinoma and C. sinensis could not be proven. However, in this case, C. sinensis was present in a mucinous cystadenoma, suggesting an association between this parasite and MCN. Although parasitic mechanical irritation and chemical injury may be involved in the pathogenesis of pancreatic mucinous cystadenoma by inducing molecular changes, similar to clonorchiasis-associated cholangiocarcinoma, we could not determine pancreatic ductal dilation and inflammatory changes, representing mechanical obstruction, and parasitic irritations. Therefore, we concluded that C. sinensis was associated with pancreatic mucinous neoplasm.

Systematic reviews of studies of effectiveness are the centrepiece of evidence-based medicine and policy making. Increasingly, systematic reviews of economic evaluations are also an expected input into much evidence-based policy making, with some health economists even calling for 'an economics approach to systematic review'. This paper questions the value of conducting systematic reviews of economic evaluations to inform decision making in health care. It argues that the value of systematic reviews of economic evaluations is usually undermined by three things. Firstly, compared with effectiveness studies, there is a much wider range of factors that limit the generalisability of cost-effectiveness results, over time and between health systems and service settings, including the context-dependency of resource use and opportunity costs, and different decision contexts and budget constraints. Secondly, because economic evaluations are more explicitly intended to be decision-informing, the requirements for generalisability take primacy, and considerations of internal validity become more secondary. Thirdly, since one of the two main forms of economic evaluation - decision analytic modelling - is itself a well-developed method of evidence synthesis, in most cases the need for a comprehensive systematic review of previous economic evaluations of a particular health technology or policy choice is unwarranted. I conclude that apparent 'meta-analytic expectations' for clear and widely applicable cost-effectiveness conclusions from systematic reviews of economic evaluations are optimistic and generally futile. For more useful insights and knowledge from previous economic studies in evidence-based policy making, a more limited range of reasons for conducting systematic reviews of health economic studies is proposed.

Can We Predict the Progression of Premalignant Pancreatic Cystic Tumours to Ductal Adenocarcinoma? A Literature Reviewa New Parenchyma-Sparing Procedures for Deep-Located Hepatic Tumors

Simple SummaryPancreatic cancer has a poor prognosis, even in patients that can be surgically treated with curative intent. An interesting subgroup of resected pancreatic cancers are those associated with pancreatic cystic neoplasms (PCN), since overall survival might differ from pancreatic cancer not associated with PCN. Although several single-center studies published conflicting data on this topic, nationwide studies are lacking. In this nationwide, registry-based study, we aimed to compare the overall survival between patients with PCN-associated pancreatic cancers to those with pancreatic cancer not associated with PCN. We found that 12% of resected pancreatic cancers patients were PCN-associated. Overall survival was better in patients with PCN-associated pancreatic cancer as compared to those not associated with PCN. Future prospective studies should focus on the impact of these findings, such as the impact of (neo)adjuvant treatment regimens in this specific patient group.Background: Outcome after resection of pancreatic ductal adenocarcinoma associated with pancreatic cystic neoplasms (PCN-PDAC) might differ from PDAC not associated with PCN. This nationwide, registry-based study aimed to compare the overall survival (OS) in these patients. Methods: Data from consecutive patients after pancreatic resection for PDAC between 2013 and 2018 were matched with the corresponding pathology reports. Primary outcome was OS for PCN-PDAC and PDAC including 1-year and 5-year OS. Cox regression analysis was used to correct for prognostic factors (e.g., pT-stage, pN-stage, and vascular invasion). Results: In total, 1994 patients underwent resection for PDAC including 233 (12%) with PCN-PDAC. Median estimated OS was better in patients with PCN-PDAC (34.5 months [95%CI 25.6 to 43.5]) as compared to PDAC not associated with PCN (18.2 months [95%CI 17.3 to 19.2]; hazard ratio 0.53 [95%CI 0.44–0.63]; p < 0.001). The difference in OS remained after correction for prognostic factors (adjusted hazard ratio 1.58 [95%CI 1.32−1.90]; p < 0.001). Conclusions: This nationwide registry-based study showed that 12% of resected PDAC were PCN-associated. Patients with PCN-PDAC had better OS as compared to PDAC not associated with PCN.

BACKGROUNDPatients with pancreatic cystic neoplasms (PCN), without surgical indication at the time of diagnosis according to current guidelines, require lifetime image-based surveillance follow-up. In these patients, the current European evidenced-based guidelines advise magnetic resonance imaging (MRI) scanning every 6 mo in the first year, then annually for the next five years, without reference to any role for trans-abdominal ultrasound (US). In this study, we report on our clinical experience of a follow-up strategy of image-based surveillance with US, and restricted use of MRI every two years and for urgent evaluation whenever suspicious changes are detected by US.AIMTo report the results and cost-efficacy of a US-based surveillance follow-up for known PCNs, with restricted use of MRI.METHODSWe retrospectively evaluated the records of all the patients treated in our institution with non-surgical PCN who received follow-up abdominal US and restricted MRI from the time of diagnosis, between January 2012 and January 2017. After US diagnosis and MRI confirmation, all patients underwent US surveillance every 6 mo for the first year, and then annually. A MRI scan was routinely performed every 2 years, or at any stage for all suspicious US findings. In this communication, we reported the clinical results of this alternative follow-up, and the results of a comparative cost-analysis between our surveillance protocol (abdominal US and restricted MRI) and the same patient cohort that has been followed-up in strict accordance with the European guidelines recommended for an exclusive MRI-based surveillance protocol.RESULTSIn the 5-year period, 200 patients entered the prescribed US-restricted MRI surveillance follow-up. Mean follow-up period was 25.1 ± 18.2 mo. Surgery was required in two patients (1%) because of the appearance of suspicious features at imaging (with complete concordance between the US scan and the on-demand MRI). During the follow-up, US revealed changes in PCN appearance in 28 patients (14%). These comprised main pancreatic duct dilatation (n = 1), increased size of the main cyst (n = 14) and increased number of PNC (n = 13). In all of these patients, MRI confirmed US findings, without adding more information. The bi-annual MRI identified evolution of the lesions not identified by US in only 11 patients with intraductal papillary mucinous neoplasms (5.5%), largely consisting of an increased number of very small PCN (P = 0.14). The overall mean cost of surveillance, based on a theoretical use of the European evidenced-based exclusive MRI surveillance in the same group of patients, would have been 1158.9 ± 798.6 € per patient, in contrast with a significantly lower cost of 366.4 ± 348.7 € (P < 0.0001) incurred by the US-restricted MRI surveillance used at our institution.CONCLUSIONIn patients with non-surgical PCN at the time of diagnosis, US surveillance could be a safe complementary approach to MRI, delaying and reducing the numbers of second level examinations and therefore reducing the costs.