Pancreatic cancer is likely to become the second most frequent cause of cancer-associated mortality within the next decade. Surgical resection with adjuvant systemic chemotherapy currently provides ...the only chance of long-term survival. However, only 10-20% of patients with pancreatic cancer are diagnosed with localized, surgically resectable disease. The majority of patients present with metastatic disease and are not candidates for surgery, while surgery remains underused even in those with resectable disease owing to historical concerns regarding safety and efficacy. However, advances made over the past decade in the safety and efficacy of surgery have resulted in perioperative mortality of around 3% and 5-year survival approaching 30% after resection and adjuvant chemotherapy. Furthermore, owing to advances in both surgical techniques and systemic chemotherapy, the indications for resection have been extended to include locally advanced tumours. Many aspects of pancreatic cancer surgery, such as the management of postoperative morbidities, sequencing of resection and systemic therapy, and use of neoadjuvant therapy followed by resection for tumours previously considered unresectable, are rapidly evolving. In this Review, we summarize the current status of and new developments in pancreatic cancer surgery, while highlighting the most important research questions for attempts to further optimize outcomes.
Late diagnosis contributes to pancreatic cancer (PaCa) dismal prognosis, urging for reliable, early detection. Serum‐exosome protein and/or miRNA markers might be suitable candidates, which we ...controlled for patients with PaCa. Protein markers were selected according to expression in exosomes of PaCa cell line culture supernatants, but not healthy donors' serum‐exosomes. miRNA was selected according to abundant recovery in microarrays of patients with PaCa, but not healthy donors' serum‐exosomes and exosome‐depleted serum. According to these preselections, serum‐exosomes were tested by flow cytometry for the PaCa‐initiating cell (PaCIC) markers CD44v6, Tspan8, EpCAM, MET and CD104. Serum‐exosomes and exosome‐depleted serum was tested for miR‐1246, miR‐4644, miR‐3976 and miR‐4306 recovery by qRT‐PCR. The majority (95%) of patients with PaCa (131) and patients with nonPa‐malignancies reacted with a panel of anti‐CD44v6, ‐Tspan8, ‐EpCAM and ‐CD104. Serum‐exosomes of healthy donors' and patients with nonmalignant diseases were not reactive. Recovery was tumor grading and staging independent including early stages. The selected miR‐1246, miR‐4644, miR‐3976 and miR‐4306 were significantly upregulated in 83% of PaCa serum‐exosomes, but rarely in control groups. These miRNA were also elevated in exosome‐depleted serum of patients with PaCa, but at a low level. Concomitant evaluation of PaCIC and miRNA serum‐exosome marker panels significantly improved sensitivity (1.00, CI: 0.95–1) with a specificity of 0.80 (CI: 0.67–0.90) for PaCa versus all others groups and of 0.93 (CI: 0.81–0.98) excluding nonPa‐malignancies. Thus, the concomitant evaluation of PaCIC and PaCa‐related miRNA marker panels awaits retrospective analyses of larger cohorts, as it should allow for a highly sensitive, minimally‐invasive PaCa diagnostics.
What's new?
Tumor exosomes—membrane vesicles of endocytic origin abundantly secreted by tumor cells and readily detected in body fluids—have recently emerged as a potential, non‐invasive diagnostic tool. This study shows that the serum of pancreatic cancer (PaCa) patients contains detectable amounts of PaCa stem cell marker‐expressing exosomes. Furthermore, the miRNA profile of serum exosomes in PaCa patients differs significantly from that of healthy donors and patients with non‐malignant disease. A blinded screening study of PaCa patients' serum exosomes revealed a combined evaluation of a panel of PaCa‐associated miRNA and stem cell biomarkers to provide a highly sensitive, minimally‐invasive diagnostic tool.
Leukemia immunotherapy frequently does not meet expectation, one of the handicaps being tumor exosome (TEX)‐promoted immunosuppression. We here asked, using the mouse myeloid leukemia WEHI3B and the ...renal cell carcinoma line RENCA, whether dendritic cell (DC) vaccination suffices to counterregulate TEX‐induced immunosuppression and whether TEX could serve as tumor antigen for DC‐loading. DC‐vaccination significantly prolonged the survival time of WEHI3B‐bearing mice, TEX‐loaded DC (DC‐TEX) being superior to lysate‐loaded DC (DC‐lys), even an excess of TEX not interfering with immune response induction. The superior response to DC‐TEX was accompanied by an increase in WEHI3B‐specific CD4+ T cells, evaluated by trogocytosis and proliferation. Similar findings accounted for DC loaded with RENCA TEX. TEX was efficiently taken‐up by DC and TEX uptake supported CD11c, MHCII and IL12 upregulation in DC. Importantly, TEX was partly recruited into the MHCII‐loading compartment such that “TEX” presentation time and recovery in T cells significantly exceeded that of tumor‐lysate. Thus, TEX did not drive DC into a suppressive phenotype and were a superior antigen due to higher efficacy of TEX‐presentation that is supported by prolonged persistence, preferential processing in the MHCII‐loading compartment and pronounced trogocytosis by T helper cells. TEX is present in tumor patients' sera. TEX, recovered and enriched from patients' sera, might well provide an optimized, individual‐specific antigen source for DC‐loading and vaccination.
What's new?
Dendritic cells (DCs) are of great therapeutic interest, owing to their ability to induce immune responses against tumor cells. So far, however, DC‐based vaccines have shown limited therapeutic effectiveness, which may be due, in part, to immune interference by tumor exosomes. Here, tumor exosomes were harnessed as a possible antigen source for DC vaccination. Survival time in tumor‐bearing mice was found to be prolonged following vaccination with tumor exosome‐loaded DCs. As an antigen source, tumor exosomes were superior to tumor lysate. DC loading using tumor exosomes recovered from patients could allow for individualized tumor immunotherapy.
Summary Over the past several decades, research on the action of bioactive constituents of plants has focused predominantly on their cancer-preventive properties. Today it can be explained why the ...consumption of fruits and vegetables may lead to a reduced frequency of certain cancer entities and why certain foods have therapeutic effects. Secondary plant products and especially glucosinolates from vegetables of the cruciferae family are supposed to have anti-carcinogenic potential. The present article gives an overview about secondary plant products in general and focuses to mechanisms of preventive and therapeutic effects of cruciferae, particular the brassica family and their famous member broccoli. Also, this article summarizes our knowledge of safety, tolerance and metabolism of glucosinolates and their therapeutic active degradation products isothiocyanates in animals and clinical studies.
Tumor-exosomes being reported to suppress or promote a cancer-directed immune response, we used exosomes of the rat pancreatic adenocarcinoma BSp73ASML (ASML) to evaluate, whether and which steps in ...immune response induction can be affected by tumor-exosomes and how the impaired responsiveness can be circumvented.
ASML-exosomes bind to and are taken up by all leukocyte subpopulations in vivo and in vitro, uptake by CD11b+ leukocytes exceeding that by T and B cells. ASML-exosomes affect leukocyte proliferation via reduced CD44v6 up-regulation and lck, ZAP70 and ERK1,2 phosphorylation, which can be compensated by dendritic cells (DC). ASML-exosomes do not support Treg. Yet, impaired activation of anti-apoptotic signals is accompanied by slightly increased apoptosis susceptibility. IgM secretion is unaffected; NK and CTL activity are strengthened, ASML-exosomes co-operating with DC in CTL activation. ASML-exosomes transiently interfere with leukocyte migration by occupying migration-promoting receptors CD44, CD49d, CD62L and CD54 during binding/internalization.
ASML-exosomes might well serve as adjuvant in immunotherapy as they support leukocyte effector functions and have only a minor impact on leukocyte activation, which can be overridden by DC. However, exosome-induced modulation of immune cells relies, at least in part, on exosome uptake and message transfer. This implies that depending on the individual tumor's exosome composition, exosomes may distinctly affect the immune system. Nonetheless, whether immunotherapy can profit from using tumor-exosomes as adjuvant can easily be settled beforehand in vitro.
Background Laparoscopic distal pancreatectomy is regarded as a feasible and safe surgical alternative to open distal pancreatectomy for lesions of the pancreatic tail and body. The aim of the present ...systematic review was to provide recommendations for clinical practice and research on the basis of surgical morbidity, such as pancreas fistula, delayed gastric empting, safety, and clinical significance of laparoscopic versus open distal pancreatectomy for malignant and nonmalignant diseases of the pancreas. Methods A systematic literature search (MEDLINE) was performed to identify all types of studies comparing laparoscopic distal pancreatectomy and open distal pancreatectomy. Random effects meta-analyses were calculated after critical appraisal of the included studies and presented as odds ratios or mean differences each with corresponding 95% confidence intervals. Results A total of 4,148 citations were retrieved initially; available data of 29 observational studies (3,701 patients overall) were included in the meta-analyses. Five systematic reviews on the same topic were found and critically appraised. Meta-analyses showed superiority of laparoscopic distal pancreatectomy in terms of blood loss, time to first oral intake, and hospital stay. All other parameters of operative morbidity and safety showed no difference. Data on oncologic radicality and effectiveness are limited. Conclusion Laparoscopic distal pancreatectomy seems to be a safe and effective alternative to open distal pancreatectomy. No more nonrandomized trials are needed within this context. A large, randomized trial is warranted and should focus on oncologic effectiveness, defined end points, and cost-effectiveness.
Background
The aim of the present study was to determine empirically which electronic databases contribute best to a literature search in surgical systematic reviews.
Methods
For ten published ...systematic reviews, the systematic literature searches were repeated in the databases MEDLINE, Web of Science, CENTRAL, and EMBASE. On the basis of these reviews, a gold standard set of eligible articles was created. Recall (%), precision (%), unique contribution (%), and numbers needed to read (NNR) were calculated for each database, as well as for searches of citing references and of the reference lists of related systematic reviews (hand search).
Results
CENTRAL yielded the highest recall (88.4%) and precision (8.3%) for randomized controlled trials (RCT), MEDLINE for non-randomized studies (NRS; recall 92.6%, precision 5.2%). The most effective combination of two databases plus hand searching for RCT was MEDLINE/CENTRAL (98.6% recall, NNR 97). Adding EMBASE marginally increased the recall to 99.3%, but with an NNR of 152. For NRS, the most effective combination was MEDLINE/Web of Science (99.5% recall, NNR 60).
Conclusions
For surgical systematic reviews, the optimal literature search for RCT employs MEDLINE and CENTRAL. For surgical systematic reviews of NRS, Web of Science instead of CENTRAL should be searched. EMBASE does not contribute substantially to reviews with a surgical intervention.
Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, and surgical resection is a requirement for a potential cure. However, the majority of patients are diagnosed with ...advanced-stage disease, either metastatic (50%) or locally advanced cancer (30%). Although palliative chemotherapy is the standard of care for patients with metastatic disease, management of locally advanced adenocarcinoma is controversial. Several treatment options, including extended surgical resections, neoadjuvant therapy with subsequent resections, as well as palliative radiotherapy and/or chemotherapy, should be considered. However, there is little evidence available to support treatment options for locally advanced disease. As valid predictive biomarkers for stratification of therapy are not available today, future trials need to define the role of the different treatment options. This Review summarizes the current evidence and discusses available treatment options for both locally advanced and metastatic pancreatic adenocarcinoma.
To investigate the perioperative and oncologic long-term outcomes of patients with LAPC after surgical resection at a high-volume center for pancreatic surgery.
The role of surgery in LAPC with ...arterial involvement is controversial.
We analyzed 385 consecutive patients undergoing PAR (n = 195) or PAD (n = 190) of the encased artery for LAPC between January 1, 2003 and April 30, 2019.
There were 183 total pancreatectomies, 113 partial pancreatoduodenectomies, 79 distal pancreatectomies, and 10 resections for tumor recurrences, including 121 multivisceral resections and 171 venous resections. Forty-three patients (11.4%) had resectable oligometastatic disease. All of the 190 patients undergoing PAD (100%) and 95 of the 195 patients undergoing PAR (48.7%) received neoadjuvant chemotherapy. The R0 (circumferential resection margin negative) resection rate was 28%. The median hospital stay was 15 days (range: 3-236). The median survival after surgery for LAPC was 20.1 months and the overall 5-year survival rate 12.5%. In-hospital mortality was 8.8% for the entire patient cohort (n = 385). With increasing case load and growing expertise, there was a significant reduction of in-hospital mortality to 4.8% (n = 186) after 2013 (P = 0.005). The learning curve of experienced pancreatic surgeons for PAR was 15 such procedures.
Our data demonstrate that an arterial surgical approach is effective in LAPC with promising long-term survival. PAD after neoadjuvant treatment is safe. PAR is a technically demanding procedure and requires a high level of expertise.
Summary Surgery is the only potential hope of cure for patients with pancreatic cancer. Advantageous tumour characteristics and complete tumour resection are the factors most relevant for a positive ...prognosis, so detection of premalignant or early invasive lesions, combined with safe and oncologically adequate surgery, is an important goal. The experience and volume of both the individual surgeon and hospital are of paramount importance to achieve low morbidity and adequate management of complications. Most pancreatic cancers are locally advanced or metastatic when diagnosed and need multimodal therapy. With increasing evidence on surgical and perioperative aspects of pancreatic cancer therapy, short-term and long-term outcomes of resectable and borderline resectable pancreatic cancer are improving.
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