Pancreatic head resection for carcinoma of the ampulla vateri - better long-term prognosis, but more postoperative complications.

BACKGROUND: Pancreatoduodenectomies are complex surgical procedures with a considerable morbidity and mortality even in high-volume centers. However, postoperative morbidity and long-term oncological outcome are not only affected by the surgical procedure itself, but also by the underlying disease. The aim of our study is an analysis of pancreatoduodenectomies for patients with pancreatic ductal adenocarcinoma (PDAC) and ampullary carcinoma (CAMP) concerning postoperative complications and long-term outcome in a tertiary hospital in Germany. METHODS: The perioperative and oncological outcome of 109 pancreatic head resections performed for carcinoma of the ampulla vateri was compared to the outcome of 518 pancreatic head resections for pancreatic ductal adenocarcinoma over a 20 year-period from January 2002 until December 2021. All operative procedures were performed at the University Hospital Freiburg, Germany. Patient data was analyzed retrospectively, using a prospectively maintained SPSS database. Propensity score matching was performed to adjust for differences in surgical and reconstruction technique. Primary outcome of our study was long-term overall survival, secondary outcomes were postoperative complications and 30-day postoperative mortality. Postoperative complications like pancreatic fistula (POPF), postpancreatectomy hemorrhage (PPH) and delayed gastric emptying (DGE) were graded following current international definitions. Survival was estimated using Kaplan Meier curves and log-rank tests. A p-value < 0.05 was considered statistically significant. RESULTS: Operation time was significantly longer in PDAC patients (432 vs. 391 min, p < 0.001). The rate of portal vein resections was significantly higher in PDAC patients (p < 0.001). In CAMP patients, a pancreatogastrostomy as reconstruction technique was performed more frequently compared to PDAC patients (48.6% vs. 29.9%, p < 0.001) and there was a trend towards more laparoscopic surgeries in CAMP patients (p = 0.051). After propensity score matching, we found no difference in DGE B/C and PPH B/C (p = 0.389; p = 0.517), but a significantly higher rate of clinically relevant pancreatic fistula (CR-POPF) in patients with pancreatoduodenectomies due to ampullary carcinoma (30.7% vs. 16.8%, p < 0.001). Long-term survival was significantly better in CAMP patients (42 vs. 24 months, p = 0.003). CONCLUSION: Patients with pancreatoduodenectomies due to ampullary carcinomas showed a better long-term oncological survival, by reason of the better prognosis of this tumor entity. However, these patients often needed a more elaborated postoperative treatment due to the higher rate of clinically relevant pancreatic fistula in this group.

Single-cell deconvolution reveals high lineage- and location-dependent heterogeneity in mesenchymal multivisceral stage 4 colorectal cancer.

Metastasized colorectal cancer (CRC) is associated with a poor prognosis and rapid disease progression. Besides hepatic metastasis, peritoneal carcinomatosis is the major cause of death in Union for International Cancer Control (UICC) stage IV CRC patients. Insights into differential site-specific reconstitution of tumor cells and the corresponding tumor microenvironment are still missing. Here, we analyzed the transcriptome of single cells derived from murine multivisceral CRC and delineated the intermetastatic cellular heterogeneity regarding tumor epithelium, stroma, and immune cells. Interestingly, we found an intercellular site-specific network of cancer-associated fibroblasts and tumor epithelium during peritoneal metastasis as well as an autologous feed-forward loop in cancer stem cells. We furthermore deciphered a metastatic dysfunctional adaptive immunity by a loss of B cell-dependent antigen presentation and consecutive effector T cell exhaustion. Furthermore, we demonstrated major similarities of this murine metastatic CRC model with human disease and - based on the results of our analysis - provided an auspicious site-specific immunomodulatory treatment approach for stage IV CRC by intraperitoneal checkpoint inhibition.

Surgical complications requiring late surgical revisions after pancreatoduodenectomy increase postoperative morbidity and mortality.

BACKGROUND: Pancreatoduodenectomies are complex surgical procedures with considerable postoperative morbidity and mortality. Here, we describe complications and outcomes in patients requiring surgical revisions following pancreatoduodenectomy. METHODS: A total of 1048 patients undergoing a pancreatoduodenectomy at our institution between 2002 and 2019 were analyzed retrospectively. All patients with surgical revisions were included. Revisions were divided into early and late using a cut-off of 5 days after the first surgery. Statistical significance was examined by using chi-square tests and Fisher's exact tests. Survival analysis was performed using Kaplan-Meier curves and log-rank tests. RESULTS: A total of 150 patients with at least 1 surgical revision after pancreatoduodenectomy were included. Notably, 64 patients had a revision during the first 5 days and were classified as early revision. Compared with the 86 patients with late revisions, we found no differences concerning wound infections, delayed gastric emptying, or acute kidney failure. After late revisions, we found significantly more cases of sepsis (31.4% late versus 15.6% early, p = 0.020) and reintubation due to respiratory failure (33.7% versus 18.8%, p = 0.031). Postoperative mortality was significantly higher within the late revision group (23.2% versus 9.4%, p = 0.030). CONCLUSION: Arising complications after pancreatoduodenectomy should be addressed as early as possible as patients requiring late surgical revisions frequently developed septic complications and multiorgan failure.

Surgical pancreatic biopsies for cases with locally advanced pancreatic cancer with inconclusive histology after interventional biopsy.

Background: Histopathological confirmation of malignancy is mandatory in patients with unresectable pancreatic cancer before initiation of palliative chemotherapy. When interventional biopsy proves unsuccessful, laparoscopic or open surgical biopsies become necessary. Methods: 66 consecutive surgical biopsies of the pancreas performed at a single institution between 01/2010 and 04/2020 were analyzed retrospectively. We analyzed sensitivity of histopathological confirmation of malignancy as well as complication rates of laparoscopic and open surgical biopsies in patients with suspected advanced pancreatic cancer after unsuccessful interventional biopsies. Results: 8 complications were observed in 46 patients requiring only a pancreatic biopsy (17.4 %) while in 13 of 20 patients complications were observed when additional procedures were necessary (65 %). Major complications CD ≥ III were observed in the "biopsy +/- port" group in 4 of 46 patients and in the "biopsy + additional procedure" cohort in 9 of 20 patients (8.7 vs. 45 %, p < 0.001). Despite the trend to reduced perioperative complications in laparoscopic biopsies, the reduction did not reach statistical significance when compared to open resections (11.1 vs. 26.3 %, p = 0.18). Surgical pancreatic biopsies reached a sensitivity regarding the correct definite histopathological result of 90.32 %, specificity was 100 %. Conclusion: Both laparoscopic and open biopsies can be performed at acceptable complication rates CD ≥ III of 8.7 % and present a valuable option after failure of image-guided techniques for biopsy. Additional operative measures in locally advanced pancreatic carcinoma ought to be critically reflected due to a substantially higher complication rate CD ≥ III of 45 %. Key message: Laparoscopic and open surgical biopsies in patients with unresectable pancreatic cancer demonstrate a high diagnostic sensitivity at acceptable complication rates. This finding is important because it provides further support for surgical biopsies to avoid delay before initiation of palliative therapy.

Immune changes induced by periampullary adenocarcinoma are reversed after tumor resection and modulate the postoperative survival.

BACKGROUND: Tumor growth encompasses multiple immunologic processes leading to impaired immunity. Regarding cancer surgery, the perioperative period is characterized by additional immunosuppression, which may contribute to poorer outcomes. In this exploratory study, we assessed plasma parameters characterizing the perioperative immunity with a particular focus on their prognostic value. PATIENTS AND METHODS: 31 patients undergoing pancreatoduodenectomy were enrolled (adenocarcinoma of the pancreatic head and its periampullary region: n = 24, benign pancreatic diseases n = 7). Abundance and function of circulating immune cells and the plasma protein expression were analyzed in blood samples taken pre- and postoperatively using flow cytometry, ELISA and Proximity Extension Assay. RESULTS: Prior to surgery, an increased population of Tregs, a lower level of intermediate monocytes, a decreased proportion of activated T-cells, and a reduced response of T-cells to stimulation in vitro were associated with cancer. On the first postoperative day, both groups showed similar dynamics. The preoperative alterations did not persist six weeks postoperatively. Moreover, several preoperative parameters correlated with postoperative survival. CONCLUSION: Our data suggests systemic immunologic changes in adenocarcinoma patients, which are reversible six weeks after tumor resection. Additionally, the preoperative immune status affects postoperative survival. In summary, our results implicate prognostic and therapeutic potential, justifying further trials on the perioperative tumor immunity to maximize the benefit of surgical tumor therapy.

Clinical characteristics and long-term outcomes following pancreatic injury - An international multicenter cohort study.

Background: Trauma to the pancreas is rare but associated with significant morbidity. Currently available management guidelines are based on low-quality evidence and data on long-term outcomes is lacking. This study aimed to evaluate clinical characteristics and patient-reported long-term outcomes for pancreatic injury. Methods: A retrospective cohort study evaluating treatment for pancreatic injury in 11 centers across 5 European nations over >10 years was performed. Data relating to pancreatic injury and treatment were collected from hospital records. Patients reported quality of life (QoL), changes to employment and new or ongoing therapy due to index injury. Results: In all, 165 patients were included. The majority were male (70.9%), median age was 27 years (range: 6-93) and mechanism of injury predominantly blunt (87.9%). A quarter of cases were treated conservatively; higher injury severity score (ISS) and American Association for the Surgery of Trauma (AAST) pancreatic injury scores increased the likelihood for surgical, endoscopic and/or radiologic intervention. Isolated, blunt pancreatic injury was associated with younger age and pancreatic duct involvement; this cohort appeared to benefit from non-operative management. In the long term (median follow-up 93; range 8-214 months), exocrine and endocrine pancreatic insufficiency were reported by 9.3% of respondents. Long-term analgesic use also affected 9.3% of respondents, with many reported quality of life problems (QoL) potentially attributable to side-effects of opiate therapy. Overall, impaired QoL correlated with higher ISS scores, surgical therapy and opioid analgesia on discharge. Conclusions: Pancreatic trauma is rare but can lead to substantial short- and long-term morbidity. Near complete recovery of QoL indicators and pancreatic function can occur despite significant injury, especially in isolated, blunt pancreatic injury managed conservatively and when early weaning off opiate analgesia is achieved.

Preoperative risk assessment for postoperative pancreatic fistula (POPF): Image-based calculation of duct-to-parenchyma (D/P) ratio and an Alignment of Duct and Mucosa (ADAM) anastomosis may lead to a low POPF rate-results from 386 patients.

Background: Postoperative pancreatic fistula (POPF) is the most critical complication after pancreatoduodenectomy (PD). Preoperative identification of high-risk patients and optimal pancreatic reconstruction technique can be a way to reduce postoperative complications. Methods: A series of 386 patients underwent PD over a 10-year period (2009-2019). On routinely performed preoperative computed tomography (CT) images, the ventro-dorsal diameters of duct (D) and parenchyma (P) were measured in the cutting plane at the superior mesenteric vein. Then, the ratio of both values was calculated (D/P ratio) Double-layer pancreatojejunostomy with alignment of duct and mucosa (ADAM) by two monofilament threads (MFT) was performed in 359 patients and pancreatogastrostomy (PG) in 27 patients. The incidence of POPF was diagnosed according to the International Study Group for Pancreatic Fistula criteria. Results: The overall rate of POPF was 21% (n = 80), and the rate of clinically relevant type B/C fistulas 6.5% (n = 25). A D/P ratio of <0.2 was significantly associated with type B/C fistula (11%, p < 0.01). In low-risk patients (D/P ratio >0.2), type B/C fistula occurred only in 2%, and in high-risk patients (D/P ratio <0.2) in 9%. ADAM anastomosis was performed safely by two different surgeons. A PG anastomosis had double-digit POPF rates in all groups. Conclusion: Preoperative CT imaging with D/P measurement may predict the risk of POPF development. A cut off D/P ratio of <0.2 was significantly associated with clinical relevant POPF. ADAM anastomosis may be an option for pancreatojejunostomy. However, preoperative knowledge of the D/P ratio could guide decision-making for primary pancreatectomy when pancreatic reconstruction is critical.

Stent-Associated Infectious Complications After Pancreatoduodenectomies Can Be Prevented by Perioperative Antibiotic Therapy: An Analysis of Single-Center Standards.

OBJECTIVES: Perioperative morbidity after pancreatoduodenectomies is still high. One potentially responsible factor is the insertion of bile duct stents before surgery. In our single-center study, we evaluated the influence of preoperative bile duct stenting combined with perioperative antibiotic therapy versus primary surgery in carcinoma patients. METHODS: Clinical data of 973 patients undergoing pancreatoduodenectomy at the University Hospital Freiburg from 2002 to 2018 were explored retrospectively. Postoperative pancreatic fistula, delayed gastric emptying (DGE), and postpancreatectomy hemorrhage (PPH) were graded by current international definitions. Patients with pancreatic ductal adenocarcinoma or periampullary carcinoma were included. RESULTS: We included 634 patients of whom 372 (58.7%) were treated with preoperative bile duct stenting. No difference concerning postoperative pancreatic fistula was observed (P = 0.479). We found more wound infections (stent 18.4%, no stent 11.1%, P = 0.008) but a significantly lower rate of PPH and DGE in stented patients (PPH 7.5% vs 11.9%, P = 0.044; DGE 16.5% vs 22.5%, P = 0.039). Surprisingly, intra-abdominal abscesses were reduced in stented patients (9.4% vs 15.0%, P = 0.022), just as insufficiencies of the biliodigestive anastomosis (P = 0.021). CONCLUSIONS: Perioperative antibiotic therapy seems to reduce the risk for severe intra-abdominal infectious complications in stent-bearing patients.

Plasma biomarkers for prediction of early tumor recurrence after resection of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a disease with a very unfavorable prognosis. Surgical resection represents the only potentially curative treatment option, but recurrence after complete resection is almost certain. In an exploratory attempt we here aimed at identifying preoperative plasma protein biomarkers with the potential to predict early recurrence after resection of PDAC. Peripheral blood samples from 14 PDAC patients divided into three groups according to their time to tumor recurrence after curatively intended resection (early: < 6 months, medium: 6-12 months, late: > 12 months) underwent targeted proteome analysis. Proteins most strongly discriminating early and late recurrence were then examined in a number of established PDAC cell lines and their culture supernatants. Finally, PDAC organoid lines from primary tumors of patients with early and late recurrence were analyzed for confirmation and validation of results. In total, 23 proteins showed differential abundance in perioperative plasma from PDAC patients with early recurrence when compared to patients with late recurrence. Following confirmation of expression on a transcriptional and translational level in PDAC cell lines we further focused on three upregulated (MAEA, NT5E, AZU1) and two downregulated proteins (ATP6AP2, MICA). Increased expression of NT5E was confirmed in a subset of PDAC organoid cultures from tumors with early recurrence. MICA expression was heterogeneous and ATP6AP2 levels were very similar in both organoids from early and late recurrent tumors. Most strikingly, we observed high MAEA expression in all tested PDAC (n = 7) compared to a non-cancer ductal organoid line. MAEA also demonstrated potential to discriminate early recurrence from late recurrence PDAC organoids. Our study suggests that identification of plasma protein biomarkers released by tumor cells may be feasible and of value to predict the clinical course of patients. Prediction of recurrence dynamics would help to stratify up-front resectable PDAC patients for neoadjuvant chemotherapy approaches in an individualized fashion. Here, MAEA and NT5E were the most promising candidates for further evaluation.

Pancreatic Inflammation and Proenzyme Activation Are Associated With Clinically Relevant Postoperative Pancreatic Fistulas After Pancreas Resection.

OBJECTIVE: We investigated the activation of pancreatic proenzymes and signs of peripancreatic inflammation in patients with clinically relevant postoperative pancreatic fistulas (POPFs). SUMMARY BACKGROUND DATA: An increase of systemic amylase concentration was associated with POPFs. This suggested parallels in the pathomechanisms between the development of POPFs and pancreatitis. METHODS: Trypsinogen, procathepsin B, and IL-6 concentrations as well as cathepsin B, myeloperoxidase and trypsin activities were determined throughout the first 7 postoperative days in drain fluids of 128 consecutive patients after pancreas resection. Histology and immunohistochemistry were performed in pancreatic specimens after total pancreatectomy due to complications and after placing experimental pancreatic sutures in the pancreatic tail of C57/Bl6 mice. RESULTS: Trypsin activity, cathepsin B activity and myeloperoxidase activity on the first postoperative day were elevated and predictive for clinically relevant pancreatic fistulas. Drain fluid stabilized trypsin activity and prevented the activation of the cascade of digestive enzymes. Leukocytes were the source of cathepsin B in drain fluid. Findings differed between fistulas after distal pancreatectomy and pancreatoduodenectomy. Immunohistochemistry of the pancreatic remnant revealed an inflammatory infiltrate expressing cathepsin B, independent of the presence of pancreatic fistulas. The infiltrate could be reproduced experimentally by sutures placed in the pancreatic tail of C57/Bl6 mice. CONCLUSIONS: Trypsinogen activation, increased cathepsin B activity and inflammation around the pancreato-enteric anastomosis on post operative day 1 are associated with subsequent clinically relevant POPFs after pancreatoduodenectomy. The parenchymal damage seems to be induced by placing sutures in the pancreatic parenchyma during pancreatic surgery.