Colorectal cancer remains one of the most important health challenges in our society. The development of cancer immunotherapies has fostered the need to better understand the anti-tumor immune ...mechanisms at play in the tumor microenvironment and the strategies by which the tumor escapes them. In this review, we provide an overview of the molecular interactions that regulate tumor inflammation. We particularly discuss immunomodulatory cell-cell interactions, cell-soluble factor interactions, cell-extracellular matrix interactions and cell-microbiome interactions. While doing so, we highlight relevant examples of tumor immunomodulation in colorectal cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
Pancreatic metastasis is a rare cause for pancreas surgery and often a sign of advanced disease no chance of curative-intent treatment. However, surgery for metastasis might be a promising ...approach to improve patients’ survival. The aim of this study was to analyze the surgical and oncological outcome after pancreatic resection of pancreatic metastasis.
Methods
This is a retrospective cohort analysis of a prospectively-managed database of patients undergoing pancreatic resection at the University of Freiburg Pancreatic Center from 2005 to 2017.
Results
In total, 29 of 1297 (2%) patients underwent pancreatic resection due to pancreatic metastasis. 20 (69%) patients showed metastasis of renal cell carcinoma (mRCC), followed by metastasis of melanoma (n = 5, 17%), colon cancer (n = 2, 7%), ovarian cancer (n = 1, 3%) and neuroendocrine tumor of small intestine (n = 1, 3%). Two (7%) patients died perioperatively. Median follow-up was 76.4 (range 21–132) months. 5-year and overall survival rates were 82% (mRCC 89% vs. non-mRCC 67%) and 70% (mRCC 78% vs. non-mRCC 57%), respectively. Patients with mRCC had shorter disease-free survival (14 vs. 22 months) than patients with other primary tumor entities.
Conclusion
Despite malignant disease, overall survival of patients after metastasectomy for pancreatic metastasis is acceptable. Better survival appears to be associated with the primary tumor entity. Further research should focus on molecular markers to elucidate the mechanisms of pancreatic metastasis to choose the suitable therapeutic approach for the individual patient.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The recommendation for postoperative chemotherapy in pancreatic ductal adenocarcinoma (PDAC) is based on prospective randomized trials. However, patients included in clinical trials do not often ...reflect the overall patient population treated in clinical practice.
A retrospective review of all patients undergoing pancreas resection for PDAC between 2001 and 2013 was performed. Follow-up data from oncologists, general practitioners, or hospital patient files were available for 92% of patients.
A total of 251 patients were included in our analysis. Chemotherapy was recommended for 223 patients, but 86 patients did not follow the recommendation. The application of the recommended chemotherapy, consisting of 6 cycles of gemcitabine, was only applied to 45 patients. Forty patients received the recommended number of cycles with dose reduction or prolonged intervals between cycles, and adjuvant chemotherapy was terminated prior to the intended completion of all 6 cycles in 54 patients. Survival of patients after adjuvant chemotherapy was increased compared to that of patients without chemotherapy (with recurrence 25.6 vs. 14.3 months, p = 0.001, and without recurrence 27.4 vs. 14.3 months, p < 0.001). Terminating chemotherapy prior to completion (p = 0.009) as well as a lower number of chemotherapy cycles (p = 0.026) was associated with a decreased survival.
Adjuvant chemotherapy improves overall and disease-free survival after curative pancreatic resection, but only a small fraction of patients completes the recommended 6 cycles of adjuvant chemotherapy. Our data indicates that performance status of patients after pancreas resections for PDAC requires not only highly biologically active but also well-tolerated adjuvant chemotherapy regimens.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Laparoscopic resections of the pancreatic head are increasingly performed. Several studies show that they are comparable to open operations in terms of postoperative morbidity. However, since a ...substantial proportion of pancreatic head resections are necessary for pancreatic adenocarcinoma the oncologic safety and outcome of minimally invasive operations is of interest. In this study we evaluated oncologic outcome and survival after laparoscopically assisted pancreatic head resection for ductal adenocarcinoma.
Perioperative and oncological outcome of sixty-two laparoscopically assisted pancreatic head resections for pancreatic ductal adenocarcinoma performed between 2010 and 2016 was compared to outcome of 278 open resections between 2001 and 2016 in a retrospective study. Data was continuously collected in a prospectively maintained database.
Operation time was significantly longer in the laparoscopic group (477 vs. 428 min. p < 0.001). Tumor size, lymph node yield and lymph node state and need of portal vein resection were comparable. There was a higher rate of free resection margins in the laparoscopic group (87% vs. 71%, p < 0.01). There was no difference in postoperative mortality and morbidity. Patients with laparoscopic resection stayed in hospital significantly shorter (median 14 vs. 16 days, p < 0.003). Postoperative survival after 5 years was not different in both groups.
Laparoscopically assisted resection of adenocarcinoma of the pancreatic head is equal to open resection concerning oncologic outcome and actuarial survival. However, minimally invasive resection shortened the hospital stay. However, further evaluations with a longer follow up time are needed.
•Laparoscopic resection of the pancreatic head is safe but associated with high conversion.•The oncological outcome after laparoscopic resection is equivalent to open resections.•Hospital stay is significantly reduced with the laparoscopic approach.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background It has been shown that crystalloid fluid-overload promotes anastomotic instability. As physiologic anastomotic healing requires the sequential infiltration of different cells, we ...hypothesized this to be altered by liberal fluid regimes and performed a histomorphological analysis. Methods 36 Wistar rats were randomized into 4 groups (n=8-10 rats/group) and treated with either liberal (+) or restrictive (−) perioperative crystalline (Jonosteril® = Cry) or colloidal fluid (Voluven® = Col). Anastomotic samples were obtained on postoperative day 4, routinely stained and histophathologically reviewed. Anastomotic healing was assessed using a semiquantitative score, assessing inflammatory cells, anastomotic repair and collagenase activity. Results Overall, the crystalloid overload group (Cry (+)) showed the worst healing score ( P < 0.01). A substantial increase of lymphocytes and macrophages was found in this group compared to the other three ( P < 0.01). Both groups that received colloidal fluid (Col (+) and Col (−)) as well as the group that received restricted crystalloid fluid resuscitation (Cry (−)) had better intestinal healing. Collagenase activity was significantly higher in the Cry (+) group. Conclusion Intraoperative infusion of high-volume crystalloid fluid leads to a pathological anastomotic inflammatory response with a marked infiltration of leukocytes and macrophages resulting in accelerated collagenolysis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Postoperative complications are a major problem occurring in up to 50% of patients undergoing major abdominal surgery. Occurrence of postoperative complications is associated with a significantly ...higher morbidity and mortality in affected patients. The most common postoperative complications are caused by an infectious genesis and include anastomotic leakage in case of gastrointestinal anastomosis and surgical site infections. Recent research highlighted the importance of gut microbiota in health and disease. It is plausible that the gut microbiota also plays a pivotal role in the development of postoperative complications. This narrative review critically summarizes results of recent research in this particular field. The review evaluates the role of gut microbiota alteration in postoperative complications, including postoperative ileus, anastomotic leakage, and surgical site infections in visceral surgery. We tried to put a special focus on a potential diagnostic value of pre- and post-operative gut microbiota sampling showing that recent data are inhomogeneous to identify a high-risk microbial profile for development of postoperative complications.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The perioperative morbidity after pancreatoduodenectomy (PD) is mostly influenced by intraabdominal complications which are often associated with infections. In patients with preoperative biliary ...drainage (PBD), the risk for postoperative infections may be even elevated. The aim of this study is to explore if isolated infectious complications without intraabdominal focus (iiC) can be observed after PD and if they are associated to PBD and antibiotic prophylaxis with potential conclusions for their treatment.
During a 10-year period from 2009 to 2019, all consecutive PD were enrolled prospectively in a database and analyzed retrospectively. Bacteriobilia (BB) and Fungibilia (FB) were examined by intraoperatively acquired smears. A perioperative antibiotic prophylaxis was performed by Ampicillin/Sulbactam. For this study, iiC were defined as postoperative infections like surgical site infection (SSI), pneumonia, unknown origin etc. Statistics were performed by Fisher's exact test and Mann Whitney U test.
A total of 426 PD were performed at the Vivantes Humboldt-hospital. The morbidity was 56% (n = 238). iiC occurred in 93 patients (22%) and accounted for 38% in the subgroup of patients with postoperative complications. They were not significantly related to BB and PBD but to FB. The subgroup of SSI, however, had a significant relationship to BB and FB with a poly microbial profile and an accumulation of E. faecalis, E. faecium, Enterobacter, and Candida. BB was significantly more frequent in longer lay of PBD. Resistance to standard PAP and co-existing resistance to broad spectrum antibiotics is frequently found in patients with iiC. The clinical severity of iiC was mostly low and non-invasive therapy was adequate. Their treatment led to a significant prolongation of the hospital stay.
iiC are a frequent problem after PD, but only in SSI a significant association to BB and FB can be found in our data. Therefore, the higher resistance of the bacterial species to routine PAP, does not justify broad spectrum prophylaxis. However, the identification of high-risk patients with BB and PBD (length of lay) is recommended. In case of postoperative infections, an early application of broad-spectrum antibiotics and adaption to microbiological findings from intraoperatively smears may be advantageous.
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.
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.
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 %.
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 %.
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.
•Laparoscopic and open pancreatic biopsy can be performed with reasonable morbidity.•They are a valuable option after failure of image-guided techniques for biopsy.•Surgical pancreatic biopsies confirm malignancy with high sensitivity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
Background
Bio‐absorbable sealants are widely used to reduce the rate and severity of postoperative pancreatic fistulas after distal pancreatectomy. However, numerous clinical trials have failed to ...demonstrate their clinical benefit. We therefore investigated stability and bio‐compatibility of absorbable sealants in vitro and in vivo.
Methods
In vitro, polymerized compounds were incubated in pancreatic juice before their stability was tested. In vivo, two compounds were used to seal the pancreatic stump after distal pancreatectomy in nine pigs. Burst pressure of the pancreatic stump, surgical outcome, histology of the pancreatic stump, systemic inflammation, and drain fluid was examined.
Results
Products based on fibrin or collagen were unstable in the presence of active pancreatic enzymes and completely dissolved within 2 h. Sealants using chemical cross‐linking of proteins showed improved stability for 7 days. In vivo, application of polyethylenglycol‐based sealant leads to complete closure of the pancreatic duct after 5 days, while a glutaraldehyde‐based sealant prevented physiological closure of the pancreatic main duct.
Conclusions
Many compounds used clinically to reinforce the pancreatic stump after distal pancreatectomy are inadequate due to instability in the presence of pancreatic enzymes. While selected bio‐absorbable sealants inhibited the natural healing of the pancreatic stump, polyethylenglycol‐based sealants should be tested in further clinical trials.
Highlight
Kühlbrey and colleagues describe the failure of most bio‐absorbable sealants for pancreatic stump reinforcement based on in vitro and in vivo experiments. Either complete dissolution of the products or inhibition of natural wound healing at the pancreatic remnant was found. Only one product was deemed adequate for further studies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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