| 1. |
- Ateeb, Zeeshan
(författare)
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Improvement of the diagnosis and management of cystic tumors of the pancreas
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pancreatic cancer is on its course on becoming the second cause of cancer related mortality. Although improvements have been made in the treatment arsenal, still only a minority of patients are able to receive treatment with curative intention. This can be attributed to the fact that most of the pancreatic cancers are diagnosed at a later stage when curative therapy is no longer possible. Thus, efforts are being made to find pancreatic cancer and its precursor lesions at an earlier stage. Intraductal papillary mucinous neoplasms (IPMN) is the most common type of cystic lesion which has the potential for malignant transformation. Hence, an accurate and early diagnosis of this entity could contribute to reverse the dismal trend of pancreatic cancer. Study I & II Aim: To identify and correlate risk factors for advanced histological findings in IPMN patients. Methods: These were retrospective studies in which patients undergoing resection for IPMN during 2008-2015 (study I) and 2004-2017 (study II) were included. Patients characteristics, radiological and histological data were prospectively collected. Results: One-hundred-fifty-two patients were included in study I and 796 patients in study II. In study I, main pancreatic duct (MPD) dilatation of 6-9.9 mm and >10 mm were associated with an increased risk of advanced IPMN histology, such as high grade dysplasia (HGD) and cancer, at odds of 2.92 (CI 1.38–6.20, p=0.005) and 2.65 (CI 1.12–6.25, p=0.02), respectively. In addition, jaundice and elevated levels of CA 19-9 were also associated with higher risk for HGD/cancer at odds of 15.36 (CI 1.94–121.22, p=0.009) and 4.15 (CI 1.90–9.05, p=0.0003), respectively. These associations remained significant at uni- and multivariable regression analysis. In study II, the results showed MPD-dilatation to be the lone significant variable associated with increased probability of HGD or IPMN-cancer at both uni- and multivariable analysis. MPD dilatation of 5-9.9 mm was associated with odds of 2.74 (CI 1.80–4.16) and 4.42 (CI 2.55–7.66) for HGD and IPMN-cancer respectively. MPD-dilatation over 10 mm was associated with greater odds of 6.57 (CI 3.94–10.98) and 15.07 (CI 8.21–27.65) for HGD and IPMN-cancer, respectively. A 5-7 mm diameter of the MPD was determined as the cut-off value to best discriminate between the lesions with low risk of malignancy to those with a high risk. Conclusions: Even a smaller dilatation of the MPD is associated with increased risk of HGD and IPMN-cancer. Dilatation of the MPD and elevated levels of CA 19-9 are important diagnostic markers of advanced histology, thereby facilitating proper selection of patients most suitable for surgery. Study III & IV Aim: To define and validate the metabolic profile of patients with IPMN and serous cystic neoplasm (SCN) and to correlate the metabolite levels to histology and grade of dysplasia. Methods: Plasma and cyst fluid were prospectively collected from patients undergoing resection for IPMN and SCN. Targeted and untargeted analysis of metabolites and lipids species were performed and correlated to histology and clinical parameters. Results: From a cohort of 35 patients in study III and 57 patients in study IV several metabolites and lipids were identified in both cyst fluid and plasma. In study III, the metabolic profile showed significant alterations in the lipid pathways. An integrated metabolomic and lipidomic analysis model was able to discriminate IPMN from SCN up to 100% accuracy. The results in study IV not only validated the results from study III but also found novel metabolites able to discriminate non-cancerous lesions (low-grade IPMN and SCN) from malignant (HGD and cancer). Furthermore, specific metabolites correlated to presence of bacteria sequences in the cyst fluid. Conclusion: Analysis of the metabolic profile in cyst fluid and plasma from IPMN patients has been able to discriminate IPMN from SCN with high accuracy and also to predict the degree of dysplasia within IPMN. This method has shown potential of clinical application which in turn could improve the diagnosis of pancreatic cystic lesions. Study V Aim: To investigate the rate of new recurrence and progression of known IPMNs in the remnant pancreas after pancreatic surgery and to investigate if the grade of dysplasia at first histology affects the risk of recurrence. Methods: This was a retrospective study in which patients undergoing an elective partial pancreatic resection between 2008 and 2017 were included. Patients who underwent total pancreatectomy and/or had less than 2 years of follow-up were excluded. Patient characteristics and data of radiology, histology and recurrence was collected prospectively. Clinical significant recurrence was defined as findings resulting in a change in the management of the lesion. Results: Overall 224 patients were included in the study. The overall recurrence rate was 44.6% (100/224), whereas the clinical significant recurrence rate was 30.8% (69/224). Patients older than 65 years presented 4.4 odds (CI 1.5-13.1) of recurrence and patients with “known IPMN left in remnant” had 2.6 odds (CI 1.12-5.9) of recurrence. Patients with LGD and HGD at first histology without concomitant PDAC had a clinical significant recurrence rate of 11.1% (15/135). No differences regarding risk of recurrence could be found when comparing patients with LGD to HGD (HR 1.1 [CI 0.5-2.2]). Conclusion: Patients with LGD and HGD at first histology harbor a not negligible risk of future malignant transformation and should not be overlooked. The risk is further increased if the patient is older and/or have a previously known IPMN in the remnant. The overall conclusion of the thesis is that the included studies have increased the knowledge on several aspects in the diagnosis and management of cystic tumors of the pancreas. A known radiological diagnostic marker, the dilatation of the main pancreatic duct, has been studied where the results show that even smaller dilatations over 5 mm may indicate malignancy. An upcoming field in metabolomics has been applied on pancreatic cystic neoplasms and has shown great potential as a future diagnostic method. Lastly, the post-operative management of IPMN patients has been studied where the results highlight the need for continued clinical surveillance due the risk of recurrence even after surgery.
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| 2. |
- Crippa, Stefano, et al.
(författare)
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A tug-of-war in intraductal papillary mucinous neoplasms management : Comparison between 2017 International and 2018 European guidelines
- 2021
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Ingår i: Digestive and Liver Disease. - : Elsevier. - 1590-8658 .- 1878-3562. ; 53:8, s. 998-1003
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: 2017 International and 2018 European guidelines are the most recent guidelines for intraductal papillary mucinous neoplasms management.AIM: to evaluate the diagnostic accuracy of these guidelines in identifying malignant IPMN.METHODS: data from resected patients with IPMN were collected in two referral centers. Features of risk associated to cancerous degeneration described in International and European guidelines were retrospectively applied. Sensitivity, specificity, positive and negative predictive value in detecting malignant disease were calculated.RESULTS: the study includes 627 resected patients. European guidelines suggest resection in any patient with at least one feature of moderate-risk. International guidelines suggest that patients with moderate-risk features undergo endoscopic ultrasound before surgery. European guidelines had a higher sensitivity (99.2% vs. 83%) but a lower positive predictive value (59.5% vs. 65.8%) and Specificity (2% vs. 37.5%). European guidelines detected almost all malignancies, but 40% of resected patients had low-grade dysplasia. 297 patients underwent endoscopic ultrasound before surgery. 31/116 (26.7%) tumors radiologically classified as "worrisome features" were reclassified as "high-risk stigmata" by endoscopic ultrasound and 24/31 were malignant IPMN.CONCLUSIONS: European and International guidelines have a relatively low diagnostic accuracy, being European guidelines more aggressive. Endoscopic ultrasound can improve guidelines accuracy in patients with moderate-risk features.
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| 3. |
- Halimi, Asif, et al.
(författare)
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Isolation of pancreatic microbiota from cystic precursors of pancreatic cancer with intracellular growth and DNA damaging properties
- 2021
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Ingår i: Gut microbes. - : Taylor & Francis Group. - 1949-0976 .- 1949-0984. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Emerging research suggests gut microbiome may play a role in pancreatic cancer initiation and progression, but cultivation of the cancer microbiome remains challenging. This pilot study aims to investigate the possibility to cultivate pancreatic microbiome from pancreatic cystic lesions associated with invasive cancer. Intra-operatively acquired pancreatic cyst fluid samples showed culture-positivity mainly in the intraductal papillary mucinous neoplasm (IPMN) group of lesions. MALDI-TOF MS profiling analysis shows Gammaproteobacteria and Bacilli dominate among individual bacteria isolates. Among cultivated bacteria, Gammaproteobacteria, particularly Klebsiella pneumoniae, but also Granulicatella adiacens and Enterococcus faecalis, demonstrate consistent pathogenic properties in pancreatic cell lines tested in ex vivo co-culture models. Pathogenic properties include intracellular survival capability, cell death induction, or causing DNA double-strand breaks in the surviving cells resembling genotoxic effects. This study provides new insights into the role of the pancreatic microbiota in the intriguing link between pancreatic cystic lesions and cancer.
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| 4. |
- Morgell, Ann, et al.
(författare)
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Metabolic Characterization of Plasma and Cyst Fluid from Cystic Precursors to Pancreatic Cancer Patients Reveal Metabolic Signatures of Bacterial Infection
- 2021
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3907 .- 1535-3893. ; 20:5, s. 2725-2738
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, with a 5 year survival rate as low as 9%. One factor complicating the management of pancreatic cancer is the lack of reliable tools for early diagnosis. While up to 50% of the adult population has been shown to develop precancerous pancreatic cysts, limited and insufficient approaches are currently available to determine whether a cyst is going to progress into pancreatic cancer. Recently, we used metabolomics approaches to identify candidate markers of disease progression in patients diagnosed with intraductal papillary mucinous neoplasms (IPMNs) undergoing pancreatic resection. Here, we enrolled an independent cohort to verify the candidate markers from our previous study with orthogonal quantitative methods in plasma and cyst fluid from serous cystic neoplasm and IPMN (either low- or high-grade dysplasia or pancreatic ductal adenocarcinoma). We thus validated these markers with absolute quantitative methods through the auxilium of stable isotope-labeled internal standards in a new independent cohort. Finally, we identified novel markers of IPMN status and disease progression - including amino acids, carboxylic acids, conjugated bile acids, free and carnitine-conjugated fatty acids, purine oxidation products, and trimethylamine-oxide. We show that the levels of these metabolites of potential bacterial origin correlated with the degree of bacterial enrichment in the cyst, as determined by 16S RNA. Overall, our findings are interesting per se, owing to the validation of previous markers and identification of novel small molecule signatures of IPMN and disease progression. In addition, our findings further fuel the provoking debate as to whether bacterial infections may represent an etiological contributor to the development and severity of the disease in pancreatic cancer, in like fashion to other cancers (e.g., Helicobacter pylori and gastric cancer).
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| 5. |
- Stoop, Thomas F., et al.
(författare)
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Surgical Outcomes After Total Pancreatectomy : A High-Volume Center Experience
- 2021
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Ingår i: Annals of Surgical Oncology. - : Springer. - 1068-9265 .- 1534-4681. ; 28:3, s. 1543-1551
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Tidskriftsartikel (refereegranskat)abstract
- Background: The impact of high-volume care in total pancreatectomy (TP) is barely explored since annual numbers are mostly low. This study evaluated surgical outcomes after TP over time in a high-volume center.Methods: All adult patients (age >= 18 years) who underwent an elective single-stage TP at Karolinska University Hospital were retrospectively analysed (2008-2017). High volume was defined as > 20 TPs/year.Results: Overall, 145 patients after TP were included, including 86 (59.3%) extended resections. Major morbidity was 34.5% (50/145) and 90-day mortality 5.5% (8/145). The relative use of TP within all pancreatectomies increased from 5.4% (63/1175) in 2008-2015 to 17.3% (82/473) in 2016-2017 (p < 0.001). Over time, TP was more often performed to achieve radicality (n = 11, 17.5% ton = 31, 37.8%;p = 0.007). In multivariable logistic regression analysis, an annual TP-volume of > 20 was associated with reduced major morbidity (odds ratio [OR] = 0.225, 95% confidence interval [CI], 0.097-0.521;p < 0.001). In the high-volume years (2016-2017), major morbidity (n = 31, 49.2% ton = 19, 23.2%;p = 0.001) and relaparotomy rate (n = 13, 20.6% ton = 5, 6.1%;p = 0.009) improved. Improvements occurred mainly after extended TP, including lower major morbidity (n = 22, 57.9% ton = 12, 25.0%;p = 0.002) and in-hospital mortality (n = 3, 7.9% ton = 0, 0%;p = 0.082).Conclusions: In a single, high-volume center study, an increase in surgical volume of TP was associated with improved perioperative outcomes, especially for extended resections.
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| 6. |
- van Hilst, Jony, et al.
(författare)
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Minimally Invasive versus Open Distal Pancreatectomy for Ductal Adenocarcinoma (DIPLOMA)
- 2019
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Ingår i: Annals of Surgery. - : Lippincott Williams & Wilkins. - 0003-4932 .- 1528-1140. ; 269:1, s. 10-17
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC).Background: Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent international surveys, however, revealed that surgeons have concerns about the oncological outcomes of MIDP for PDAC.Methods: This is a pan-European propensity score matched study including patients who underwent MIDP (laparoscopic or robot-assisted) or ODP for PDAC between January 1, 2007 and July 1, 2015. MIDP patients were matched to ODP patients in a 1:1 ratio. Main outcomes were radical (R0) resection, lymph node retrieval, and survival.Results: In total, 1212 patients were included from 34 centers in 11 countries. Of 356 (29%) MIDP patients, 340 could be matched. After matching, the MIDP conversion rate was 19% (n = 62). Median blood loss [200 mL (60–400) vs 300 mL (150–500), P = 0.001] and hospital stay [8 (6–12) vs 9 (7–14) days, P < 0.001] were lower after MIDP. Clavien-Dindo grade ≥3 complications (18% vs 21%, P = 0.431) and 90-day mortality (2% vs 3%, P > 0.99) were comparable for MIDP and ODP, respectively. R0 resection rate was higher (67% vs 58%, P = 0.019), whereas Gerota's fascia resection (31% vs 60%, P < 0.001) and lymph node retrieval [14 (8–22) vs 22 (14–31), P< 0.001] were lower after MIDP. Median overall survival was 28 [95% confidence interval (CI), 22–34] versus 31 (95% CI, 26–36) months (P = 0.929).Conclusions: Comparable survival was seen after MIDP and ODP for PDAC, but the opposing differences in R0 resection rate, resection of Gerota's fascia, and lymph node retrieval strengthen the need for a randomized trial to confirm the oncological safety of MIDP.
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