Surveillance after surgery for pancreatic cancer: a global scoping review of guidelines and a nordic Survey of contemporary practice.

OBJECTIVES: Most patients with pancreatic cancer who have undergone surgical resection eventually develop disease recurrence. |This study aimed to investigate whether there is evidence to support routine surveillance after pancreatic cancer surgery, with a secondary aim of analyzing the implementation of surveillance strategies in the Nordic countries. MATERIALS AND METHODS: A scoping review was conducted to identify clinical practice guidelines globally and research studies relating to surveillance after pancreatic cancer resection. This was followed by a survey among 20 pancreatic units from four Nordic countries to assess their current practice of follow-up for operated patients. RESULTS: Altogether 16 clinical practice guidelines and 17 research studies were included. The guidelines provided inconsistent recommendations regarding postoperative surveillance of pancreatic cancer. The clinical research data were mainly based on retrospective cohort studies with low level of evidence and lead-time bias was not addressed. Active surveillance was recommended in Sweden and Denmark, but not in Norway beyond the post-operative/adjuvant period. Finland had no national recommendations for surveillance. The Nordic survey revealed a wide variation in reported practice among the different units. About 75% (15 of 20 units) performed routine postoperative surveillance. Routine CA 19-9 testing was used by 80% and routine CT by 67% as part of surveillance. About 73% of centers continued follow-up until 5 years postoperatively. CONCLUSION: Evidence for routine long-term (i.e. 5 years) surveillance after pancreatic cancer surgery remains limited. Most pancreatic units in the Nordic countries conduct regular follow-up, but protocols vary.

Fast-track recovery after surgery for perforated peptic ulcer safely shortens hospital stay: A systematic review and meta-analysis of six randomized controlled trials and 356 patients.

BACKGROUND: Postoperative management after surgery for perforated peptic ulcer is still burdened by old traditions. All available data for fast-track recovery in this setting are either very unspecific or underpowered. The aim of this study was to evaluate fast-track recovery in this diagnosis-specific context in a larger sample. METHODS: Electronic data sources were searched. Eligible studies were randomized controlled trials (RCTs) comparing fast-track recovery and traditional management after surgery for perforated peptic ulcer in adults. A systematic review and meta-analysis was performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines regulated the process. Quality and risk of bias assessments of individual RCTs were performed by means of the Let Evidence Guide Every New Decision criteria and the Cochrane risk-of-bias tool. Primary endpoints were length of hospital stay and risk of complications. Random or fixed effects modeling were applied as indicated. Outcomes were measured by mean difference and risk difference. RESULTS: Six RCTs with a total cohort of 356 patients were included. Results of our meta-analysis showed significantly shortened length of hospital stay (mean difference -3.50 days [95% CI -4.51 to -2.49], p ≤ 0.00001), significantly less superficial and deep surgical-site infections (risk differences -0.12 [95% CI -0.20, -0.05], p = 0.002 and -0.03 [95% CI -0.09, 0.03], and p = 0.032, respectively), and significantly fewer pulmonary complications (risk difference -0.10 [95% CI -0.17, -0.03], p = 0.004) in the fast-track group. CONCLUSION: This systematic review and meta-analysis shows that fast-track recovery after surgery for perforated peptic ulcer significantly shortened hospital stay in the studied cohort without increasing the risk of postoperative complications.

Intraductal papillary neoplasms of the bile ducts: a comparative study of a rare disease in Europe and Nagoya, Japan.

BACKGROUND: Intraductal papillary neoplasm of the bile ducts (IPNB) is a rare disease in Western countries. The aim of this study was to compare tumor characteristics, management strategies, and outcomes between Western and Eastern patients who underwent surgical resection for IPNB. METHODS: A multi-institutional retrospective series of patients with IPNB undergoing surgery between January 2010 and December 2020 was gathered under the auspices of the European-African Hepato-Pancreato-Biliary Association (E-AHPBA), and at Nagoya University Hospital, Japan. RESULTS: A total of 85 patients (51% male; median age 66 years) from 28 E-AHPBA centers were compared to 91 patients (64% male; median age 71 years) from Nagoya. Patients in Europe had more multiple lesions (23% vs 2%, P < .001), less invasive carcinoma (42% vs 85%, P < .001), and more intrahepatic tumors (52% vs 24%, P < .001) than in Nagoya. Patients in Europe experienced less 90-day grade >3 Clavien-Dindo complications (33% vs 68%, P < .001), but higher 90-day mortality rate (7.0% vs 0%, P = .03). R0 resections (81% vs 82%) were similar. Overall survival, excluding 90-day postoperative deaths, was similar in both regions. DISCUSSION: Despite performing more extensive resections, the low perioperative mortality rate observed in Nagoya was probably influenced by a combination of patient-, tumor-, and surgery-related factors.

Ideal Outcome After Pancreatoduodenectomy: A Transatlantic Evaluation of a Harmonized Composite Outcome Measure.

OBJECTIVE: The aim of this study is to define and assess Ideal Outcome in the national or multicenter registries of North America, Germany, the Netherlands, and Sweden. BACKGROUND: Assessing outcomes after pancreatoduodenectomy among centers and countries requires a broad evaluation that cannot be captured by a single parameter. Previously, 2 composite outcome measures (textbook outcome and optimal pancreatic surgery) for pancreatoduodenectomy have been described from Europe and the United States. These composites were harmonized into ideal outcome (IO). METHODS: This analysis is a transatlantic retrospective study (2018-2020) of patients after pancreatoduodenectomy within the registries from North America, Germany, The Netherlands, and Sweden. After 3 consensus meetings, IO for pancreatoduodenectomy was defined as the absence of all 6 parameters: (1) in-hospital mortality, (2) severe complications-Clavien-Dindo ≥3, (3) postoperative pancreatic fistula-International Study Group of Pancreatic Surgery (ISGPS) grade B/C, (4) reoperation, (5) hospital stay >75th percentile, and (6) readmission. Outcomes were evaluated using relative largest difference (RLD) and absolute largest difference (ALD), and multivariate regression models. RESULTS: Overall, 21,036 patients after pancreatoduodenectomy were included, of whom 11,194 (54%) reached IO. The rate of IO varied between 55% in North America, 53% in Germany, 52% in The Netherlands, and 54% in Sweden (RLD: 1.1, ALD: 3%, P <0.001). Individual components varied with an ALD of 2% length of stay, 4% for in-hospital mortality, 12% severe complications, 10% postoperative pancreatic fistula, 11% reoperation, and 9% readmission. Age, sex, absence of chronic obstructive pulmonary disease, body mass index, performance status, American Society of Anesthesiologists (ASA) score, biliary drainage, absence of vascular resection, and histologic diagnosis were associated with IO. In the subgroup of patients with pancreatic adenocarcinoma, country, and neoadjuvant chemotherapy also was associated with improved IO. CONCLUSIONS: The newly developed composite outcome measure "Ideal Outcome" can be used for auditing and comparing outcomes after pancreatoduodenectomy. The observed differences can be used to guide collaborative initiatives to further improve the outcomes of pancreatic surgery.

Multisocietal European consensus on the terminology, diagnosis, and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE.

BACKGROUND: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases, with a focus on terminology, diagnosis, and management. METHODS: This project was a multiorganizational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis, and management. Statements were refined during an online Delphi process, and those with 70 per cent agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising 12 key statements. RESULTS: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term 'early metachronous metastases' applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour, the term 'late metachronous metastases' applies to those detected after 12 months. 'Disappearing metastases' applies to lesions that are no longer detectable on MRI after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards, and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways, including systemic chemotherapy, synchronous surgery, and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed. CONCLUSION: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.

Sex and gender differences in treatment intention, quality of life and performance status in the first 100 patients with periampullary cancer enrolled in the CHAMP study.

BACKGROUND: Periampullary cancer is a term for cancers arising in or in close proximity to the pancreas. Pancreatic cancer is the 3rd leading cause of cancer death for both sexes and while surgery is the only option for cure, chemotherapy is given in both the adjuvant and palliative settings. The aim of this study was to investigate any sex and gender differences in patients with pancreatic and other periampullary adenocarcinomas enrolled in a prospective, observational trial. METHODS: The study cohort consists of the first 100 patients, 49 women and 51 men, enrolled in the Chemotherapy, Host Response and Molecular dynamics in Periampullary cancer (CHAMP) study, an ongoing study of patients undergoing neoadjuvant, adjuvant or first-line palliative chemotherapy treatment. Twenty-five patients had surgery with curative intent and subsequent adjuvant treatment, and 75 patients were treated with palliative chemotherapy. Data regarding health-related quality of life (HRQoL, EORTC-QLQ-C30) at baseline, demographic and clinicopathological factors were examined and stratification by treatment intention according to sex. Overall survival (OS) was calculated through Kaplan-Meier analysis. RESULTS: There was a statistically significant difference between male and female patients treated with curative intent, with fewer women having undergone surgery (18 vs 7, p = 0.017), also after adjustment for age, tumor location and performance status. No statistical differences were found between the sexes regarding age, comorbidities, or clinicopathological factors. Before start of chemotherapy treatment, health-related quality of life (HRQoL) was lower in female than in male patients. However, HRQoL was not associated with performance status in female patients, whereas in male patients several HRQoL indicators were significantly positively associated with poorer performance status at baseline. CONCLUSIONS: This study shows no clear differences between the sexes regarding biological factors concluding that gender bias might be responsible for the discrepancy between men and women being offered curative surgery. The observed difference between women and men regarding the association between HRQoL and performance status is unprecedented. Altogether these findings underline the importance of taking gender into consideration when assessing eligibility for curative surgery in order to improve biological outcome and decrease suffering in both sexes. TRIAL REGISTRATION: NCT03724994.

The multi-societal European consensus on the terminology, diagnosis and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE.

BACKGROUND: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases with a focus on terminology, diagnosis and management. METHODS: This project was a multi-organisational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis and management. Statements were refined during an online Delphi process and those with 70% agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising twelve key statements. RESULTS: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term "early metachronous metastases" applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour with "late metachronous metastases" applied to those detected after 12 months. Disappearing metastases applies to lesions which are no longer detectable on MR scan after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways including systemic chemotherapy, synchronous surgery and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed. CONCLUSIONS: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.

Myocardial injury biomarkers at point of care for early identification of primary graft dysfunction after heart transplantation.

INTRODUCTION: Primary graft dysfunction (PGD) is a leading cause of 30-day mortality following heart transplantation, and early intervention in PGD may correlate to improved survival. Our analysis aimed to determine the feasibility of measuring cardiac biomarkers from the donor heart in the early phase for use as a predictor of PGD. METHODS: Blood samples from the coronary sinus were obtained at the time of transplantation in hearts preserved by cold static storage. The samples were analyzed for CK-MB and cTnI with a point-of-care method. The primary outcome was severe PGD or the need for veno-arterial extracorporeal membrane oxygenation within 7 days, referred to as severe graft dysfunction. RESULTS: Of the total cohort (n = 63), eight patients (13%) were diagnosed with severe graft dysfunction within 7 days. Patients with high CK-MB had an increased risk for severe graft dysfunction with unadjusted Odds Ratio (OR) of 4.5 (95%CI .96-21.11 P = .057) and adjusted OR of 7.4 (95%CI 1.13-48.46, P = .037. Similar but non significant trends were observed for cTnI. CONCLUSION: By measuring CK-MB from the coronary effluent in the donor heart, it may be possible to identify patients at increased risk for severe PGD after heart transplantation.

Nationwide trends and outcomes of neoadjuvant chemotherapy in pancreatic cancer - an analysis of the Swedish national pancreatic cancer registry.

OBJECTIVES: During the last decade, neoadjuvant therapy (NAT) for pancreatic cancer has become more frequent. Pathological response and overall survival are promising; however, various post-operative complications have been reported. Our primary aim was to compare the complication scenario of patients receiving NAT in borderline resectable and locally advanced disease with those who had upfront pancreatic surgery (UFS) for primarily resectable cancer. METHODS: From the Swedish National Pancreatic and Periampullary Cancer Registry, patients resected for pancreatic ductal adenocarcinoma (PDAC) between 2010 and 2018 were identified. Data on patient characteristics, neoadjuvant therapy, post-operative complications and survival were obtained. Comparisons between groups as well as survival analysis were performed. RESULTS: Within the total cohort of 13,948 patients, 1894 (median age 69 years, 51% men) were resected for PDAC. Among these, 112 (5.9%) patients received NAT followed by surgery. The patients who received NAT were younger (67 vs 70 years, p < .001), had a lower level of CA19-9 (47 vs 108, p = .001) and had to a larger extent vascular resection (58.9 vs 26.9%, p < .001) and total pancreatectomy performed (23.2 vs 9.1%, p < .001). No difference was found for major post-operative complications and there was no significant change in survival rate between the NAT and UFS groups (median 28 vs 26 months, p = .122). CONCLUSIONS: When analyzing data from a national registry, no difference in post-operative complications was found between resected patients receiving UFS and NAT for PDAC. Also, the survival was equal between groups. NAT is a feasible treatment option for patients with potentially curable pancreatic cancer.

Preoperative Risk Score for Early Mortality After Up-Front Pancreatic Cancer Surgery: A Nationwide Cohort Study.

BACKGROUND: Pancreatic ductal adenocarcinoma is a highly fatal malignancy. The aim was to identify preoperative factors for early mortality in up-front resectable patients following pancreatoduodenectomy (PD) and develop an early mortality risk score. METHODS: Patients registered in the Swedish National Registry for Pancreatic and Periampullary Cancer were included. Relevant preoperative factors (n = 21) were investigated. Early mortality was defined as death within 12 months after surgery. Based on the identified risk factor odds ratios (ORs), the Score Predicting Early Mortality (SPEM) was developed. RESULTS: In total, 2183 PDs were performed, and 926 patients met the study criteria. The mean age was 68 (SD ± 8.8) years, and 48% were female. A total of 233 (24%) patients died within 12 months. In the multivariable analyses, age > 75 years (OR 1.7; 95% CI 1.1-2.4; p = 0.008), CRP ≥ 15 mg/L (OR 2.0; 95% CI 1.3-3.1; p = 0.001), CA 19-9 > 500 U/mL (OR 1.8; 95% CI 1.0-3.2; p = 0.040), diabetes mellitus (OR 1.40; 95% CI 1.00-2.1; p = 0.042), and active smoking (OR 1.47; 95%CI 1.00-2.00; p = 0.050) were found to be independent risk factors for early mortality. CONCLUSION: Five independent preoperative risk factors for early mortality following PD were identified and together formed SPEM. The score might be a useful tool in establishing individualized treatment plans.

A scoring system for predicting malignancy in intraductal papillary mucinous neoplasms of the pancreas: a multicenter EUROPEAN validation.

PURPOSE: A preoperative estimate of the risk of malignancy for intraductal papillary mucinous neoplasms (IPMN) is important. The present study carries out an external validation of the Shin score in a European multicenter cohort. METHODS: An observational multicenter European study from 2010 to 2015. All consecutive patients undergoing surgery for IPMN at 35 hospitals with histological-confirmed IPMN were included. RESULTS: A total of 567 patients were included. The score was significantly associated with the presence of malignancy (p < 0.001). In all, 64% of the patients with benign IPMN had a Shin score < 3 and 57% of those with a diagnosis of malignancy had a score ≥ 3. The relative risk (RR) with a Shin score of 3 was 1.37 (95% CI: 1.07-1.77), with a sensitivity of 57.1% and specificity of 64.4%. CONCLUSION: Patients with a Shin score ≤ 1 should undergo surveillance, while patients with a score ≥ 4 should undergo surgery. Treatment of patients with Shin scores of 2 or 3 should be individualized because these scores cannot accurately predict malignancy of IPMNs. This score should not be the only criterion and should be applied in accordance with agreed clinical guidelines.

Risk factors and outcomes for patients with pancreatic cancer undergoing surgical exploration without resection due to metastatic disease: A national cohort study.

BACKGROUND: Unresectable disease is sometimes diagnosed during surgery in patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to identify preoperative risk factors for metastatic disease diagnosed at surgical exploration and to investigate and compare survival in resected and non-resected patients. METHODS: Patients were identified from the Swedish National Pancreatic and Periampullary Cancer Registry 2010-2018. Predictors of metastatic disease were evaluated with a multivariable logistic regression model, and survival was evaluated with Kaplan-Meier estimates and log-rank tests. RESULTS: In total, 1938 patients with PDAC were scheduled for surgery. An unresectable situation was diagnosed intraoperatively in 399 patients (20.6%), including 234 (12.1%) with metastasized disease. Independent risk factors for metastasis were involuntary weight loss (OR = 1.72; 95% CI: 1.27-2.33) and elevated carbohydrate antigen 19-9 (CA19-9) (35-599 U/mL, OR = 1.79, 95% CI: 1.11-2.89; ≥ 600 U/mL, OR = 3.24, 95% CI: 2.04-5.17). Overall survival was lower among patients with metastasized disease than that among patients with a resectable tumor (P < 0.001). CONCLUSIONS: Involuntary weight loss and an elevation of CA19-9 are preoperative risk factors for diagnosing metastasized disease during surgical exploration.

Heterogeneity of management practices surrounding operable gallbladder cancer - results of the OMEGA-S international HPB surgical survey.

BACKGROUND: Gallbladder cancer (GBC) is an aggressive, uncommon malignancy, with variation in operative approaches adopted across centres and few large-scale studies to guide practice. We aimed to identify the extent of heterogeneity in GBC internationally to better inform the need for future multicentre studies. METHODS: A 34-question online survey was disseminated to members of the European-African Hepatopancreatobiliary Association (EAHPBA), American Hepatopancreatobiliary Association (AHPBA) and Asia-Pacific Hepatopancreatobiliary Association (A-PHPBA) regarding practices around diagnostic workup, operative approach, utilization of neoadjuvant and adjuvant therapies and surveillance strategies. RESULTS: Two hundred and three surgeons responded from 51 countries. High liver resection volume units (>50 resections/year) organised HPB multidisciplinary team discussion of GBCs more commonly than those with low volumes (p < 0.0001). Management practices exhibited areas of heterogeneity, particularly around operative extent. Contrary to consensus guidelines, anatomical liver resections were favoured over non-anatomical resections for T3 tumours and above, lymphadenectomy extent was lower than recommended, and a minority of respondents still routinely excised the common bile duct or port sites. CONCLUSION: Our findings suggest some similarities in the management of GBC internationally, but also specific areas of practice which differed from published guidelines. Transcontinental collaborative studies on GBC are necessary to establish evidence-based practice to minimise variation and optimise outcomes.

Antibiotic prophylaxis in ERCP with failed cannulation.

OBJECTIVES: Endoscopic retrograde cholangiopancreatography (ERCP) with failed biliary cannulation is associated with a high rate of adverse events, but the role of prophylactic antibiotics remains unclear. The primary aim was to investigate if prophylactically administered antibiotics affect the frequency of overall adverse complications in patients where biliary cannulation fails during ERCP. The secondary aim was to investigate if specific infectious complications, also were affected by the antibiotic prophylaxis. MATERIALS AND METHODS: We analysed data from 96,818 ERCPs (2006-2018), from the Swedish National Quality Registry of Cholecystectomy and ERCP (GallRiks), excluding ERCPs with successful cannulation (n = 88,743), missing data (n = 2,014), or on-going antibiotic therapy (n = 1,062). RESULTS: In total 4,996 procedures were included, 2,124 received (42.5%) and 2,872 (57.5%) did not receive antibiotic prophylaxis. There were fewer overall complications in the group receiving prophylaxis (13.6% vs. 17.1%, p < .001), which corresponded to a 24% adjusted odds reduction in the multivariable analysis (odds ratio [OR] 0.76; 95% confidence interval [CI] 0.65-0.89). In the prophylaxis group, there was a lower overall rate of infectious complications (2.1% vs. 3.2%; p = .038; OR 0.68; 95% CI 0.47-0.98) and abscesses (0.8% vs. 1.4%; p = .040; OR 0.54; 95% CI 0.31-0.96). However, no significant differences were seen in the rate of cholangitis (1.3% vs. 1.7%; p = .182; OR 0.74; 95% CI 0.46-1.18). CONCLUSION: This national quality registry study of ERCPs with failed cannulation showed a significant reduction in overall and infectious complications when prophylactic antibiotics were administered.

An analysis of gender differences in treatment and outcome of periampullary tumours in Sweden - A national cohort study.

BACKGROUND: Little is known of possible gender differences in treatment of periampullary tumours and outcome after pancreatoduodenectomy (PD), and the aim of this study was therefore to investigate any variances from national multicentre perspective. METHODS: Data from the Swedish National Registry for Pancreatic and Periampullary Cancer for all patients diagnosed with a periampullary tumour from 2012 throughout 2017 was collected. The material was analysed in two groups, men and women, for palliative treatment and curative intended resection. RESULTS: A total of 5677 patients were included, 2906 (51%) men and 2771 (49%) women. Women were older than men, 72 (65-78) years vs. 70 (64-76), p < 0.001. A lesser proportion of women were planned for resection (1131 (41%) vs. 1288 (44%), p = 0.008), but after adjusting for age and tumour location no difference was seen. Postoperative morbidity was equal, but women had significantly better long-term survival than men. The survival was equal for palliative men and women. CONCLUSION: No gender bias could be established when analysing treatment for periampullary tumours in Sweden, even though less women were offered surgery. Data suggest that even though women were older they tolerate surgery well and hence offering PD at a higher age for women could be suggested.

Mass spectrometry-based analysis of formalin-fixed, paraffin-embedded distal cholangiocarcinoma identifies stromal thrombospondin-2 as a potential prognostic marker.

BACKGROUND: Distal cholangiocarcinoma is an aggressive malignancy with a dismal prognosis. Diagnostic and prognostic biomarkers for distal cholangiocarcinoma are lacking. The aim of the present study was to identify differentially expressed proteins between distal cholangiocarcinoma and normal bile duct samples. METHODS: A workflow utilizing discovery mass spectrometry and verification by parallel reaction monitoring was used to analyze surgically resected formalin-fixed, paraffin-embedded samples from distal cholangiocarcinoma patients and normal bile duct samples. Bioinformatic analysis was used for functional annotation and pathway analysis. Immunohistochemistry was performed to validate the expression of thrombospondin-2 and investigate its association with survival. RESULTS: In the discovery study, a total of 3057 proteins were identified. Eighty-seven proteins were found to be differentially expressed (q < 0.05 and fold change ≥ 2 or ≤ 0.5); 31 proteins were upregulated and 56 were downregulated in the distal cholangiocarcinoma samples compared to controls. Bioinformatic analysis revealed an abundance of differentially expressed proteins associated with the tumor reactive stroma. Parallel reaction monitoring verified 28 proteins as upregulated and 18 as downregulated in distal cholangiocarcinoma samples compared to controls. Immunohistochemical validation revealed thrombospondin-2 to be upregulated in distal cholangiocarcinoma epithelial and stromal compartments. In paired lymph node metastases samples, thrombospondin-2 expression was significantly lower; however, stromal thrombospondin-2 expression was still frequent (72%). Stromal thrombospondin-2 was an independent predictor of poor disease-free survival (HR 3.95, 95% CI 1.09-14.3; P = 0.037). CONCLUSION: Several proteins without prior association with distal cholangiocarcinoma biology were identified and verified as differentially expressed between distal cholangiocarcinoma and normal bile duct samples. These proteins can be further evaluated to elucidate their biomarker potential and role in distal cholangiocarcinoma carcinogenesis. Stromal thrombospondin-2 is a potential prognostic marker in distal cholangiocarcinoma.

The influence of ischemia and reperfusion time on outcome in heart transplantation.

Ischemia/reperfusion may lead to graft dysfunction in heart transplantation (HT). The purpose of this study was to evaluate the influence of ischemic and reperfusion time on acute cellular rejection (ACR) within the first-year post-HT and on long-term outcomes. Data were collected from 331 patients (mean age 49 ± 12 y, 28% females) who underwent HT 1988-2016. Endomyocardial biopsies obtained within the first year after HT were graded according to the 2004-ISHLT-WF. We classified the patients by ischemic time 4 hours, and of these, 31 (55%) patients had reperfusion with CPB ≥90 minutes. Ischemia >4 hours had an increased risk of ACR ≥ 2R during the first year (adjusted OR = 3.1, P = .016); however, an extended reperfusion ≥90 minutes reduced the risk (adjusted OR = 0.25, P = .024). The conditional probability of surviving 10 years post-transplant, given that the patients already survived first year, was inferior for recipients with ischemia ≥ 4 hours and reperfusion <90 minutes, 59%, compared with the other groups 83%, P = .016. Prolonged reperfusion appears to reduce the risk for ACR ≥ 2R and improve long-term survival.

Induction immunosuppression strategies and long-term outcomes after heart transplantation.

Although the use of induction therapy has reduced the risk of acute rejection after heart transplantation, its use may be associated with other adverse outcomes. We aimed to examine the effect of no induction (NoInd), induction with basiliximab (BAS), or induction with antithymocyte globulin (ATG) on outcome after heart transplantation. We analyzed data from the International Society for Heart and Lung Transplantation (ISHLT) registry for adult heart transplants performed between 2000 and 2013. The primary outcome was cumulative all-cause mortality, and the secondary outcome was cause-specific death. We identified 27 369 transplants whose recipients received NoInd (n = 15 688), ATG (n = 6830), or BAS (n = 4851). Over a median follow-up of 1497 days, overall 30-day mortality was 5% and 1-year mortality was 11%. Survival after transplant was similar in patients treated with NoInd compared with ATG. The survival was improved using NoInd compared with BAS (log-rank P = .040), adjustment HR = 1.11 (95% CI, 1.04-1.19). Compared to NoInd, BAS was associated with higher risk of graft failure-related deaths, HR = 1.27 (95% CI, 1.02-1.58), and ATG was associated with higher risk of malignancy-related deaths, HR = 1.18 (95% CI, 1.01-1.39). Survival of patients who received NoInd was similar to ATG and better compared with BAS. Further, the use of ATG may be associated with increased malignancy-related mortality, compared with NoInd.

Expression of peritumoral SPARC during distal cholangiocarcinoma progression and correlation with outcome.

Objectives: Distal cholangiocarcinoma (dCCA) is a malignancy with a dismal prognosis. One of the hallmarks is the presence of a rich desmoplastic stroma believed to contribute to tumor progression and treatment resistance. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein implicated in tumor-stroma interaction with prognostic correlation across several malignancies. The aim of the present study was to evaluate the expression pattern and prognostic significance of SPARC in resected dCCA and paired lymph node metastasis.Materials and methods: SPARC expression was evaluated in 59 resected dCCA samples and 25 paired lymph node metastases as well as 10 benign bile duct samples using immunohistochemistry. Stromal SPARC expression was scored semi quantitatively. Survival was estimated using the Kaplan-Meier method with associated log-rank test.Results: SPARC expression was absent in normal bile ducts. In dCCA, peritumoral stromal SPARC was detectable in 47/59 (80%) of samples with 40/59 (68%) classified as high stromal SPARC expression. There was a significantly lower proportion of SPARC positive stroma in paired lymph node metastasis 17/25 (68%) than the corresponding primary tumors 24/25 (96%) (p = .016). Stromal SPARC expression was associated with the presence of lymph node metastasis; high SPARC expression 31/40 (78%) versus low SPARC expression 9/19 (47%) (p = .013). In the present material there was no significant association between stromal SPARC expression and survival.Conclusions: Stromal SPARC expression occurs frequently in dCCA. Although significantly lower than in primary tumors stromal SPARC is frequently retained in paired lymph node metastasis suggesting a possible role in the metastatic process of dCCA.

Expression of fibroblast activation protein and the clinicopathological relevance in distal cholangiocarcinoma.

Objectives: The current survival of patients with distal cholangiocarcinoma (dCCA) is poor. There is a need to develop new prognostic and predictive biomarkers to improve the survival of patients. Fibroblast activation protein (FAP) expression has been associated with survival in several solid malignancies. The goal of this study was to evaluate the expression pattern and prognostic significance of FAP in dCCA.Materials and methods: FAP expression was examined in 57 resected dCCA specimens and 28 paired lymph node metastasis specimens, as well as 10 benign bile ducts using immunohistochemistry. FAP expression was scored in the epithelial and stromal component of the dCCA specimens. The association between FAP expression and prognosis was evaluated using univariable and multivariable statistical modeling.Results: FAP expression was absent in the benign controls. FAP expression was evident in the epithelial 43 (75%) and stromal compartment 34 (60%) of dCCA. There was no association between epithelial or stromal FAP expression and clinicopathological factors. Epithelial FAP expression (HR 0.4 95% CI 0.20-0.78; p=.007) but not stromal FAP expression was significantly associated with better survival in univariable and multivariable analysis.Conclusions: FAP overexpression is evident in dCCA. There was a positive association between epithelial FAP expression and better survival which merits further evaluation.