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.
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.
Parastomal hernia (PH) is the most common complication after ostomy formation. Prophylactic mesh placement may be effective in reducing the rate of PH at the stoma site. The aims of this systematic ...review were to summarize the evidence with regard to the safety and effectiveness in comparison with the standard procedure without mesh placement and to identify important risk constellations.
A systematic literature search was performed in PubMed, EMBASE and the Cochrane library with no language or date restrictions. Randomized (RCTs) and non-randomized controlled trials (nRCTs) were included. The main outcomes of interest were PH (primary outcome) rate and stoma-related complications (secondary outcomes) such as stenosis or fistula. Statistical analysis included meta-analyses of pooled data and subgroup analyses.
Eleven trials (eight RCTs; three nRCTs) with a total of 755 patients were included. PH rate varied from 0% to 59% in the intervention and from 20% to 94% in the control group. RCTs showed a significant reduction of PH rate in the mesh group (OR 0.24; 95% CI 0.10 to 0.58, p = 0.034), whereas included nRCTs did not. No significant differences were observed in postoperative complication rates. Subgroup analyses showed superiority of non-absorbable meshes and sublay mesh positioning in open surgery.
Prophylactic mesh placement is safe and reduces PH rate. A recommendation for prophylactic non-absorbable meshes in a sublay position can be made for patients undergoing open colorectal operations with end-ostomies. Further research endeavors should focus on patient-oriented outcomes, not only PH rate, with respect to tailored treatment in specific patient populations.
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.
Systemic administration of the local anaesthetic lidocaine is antinociceptive in both acute and chronic pain states, especially in acute postoperative and chronic neuropathic pain. These effects ...cannot be explained by its voltage-gated sodium channel blocking properties alone, but the responsible mechanisms are still elusive. This narrative review focuses on available experimental evidence of the molecular mechanisms by which systemic lidocaine exerts its clinically documented analgesic effects. These include effects on the peripheral nervous system and CNS, where lidocaine acts via silencing ectopic discharges, suppression of inflammatory processes, and modulation of inhibitory and excitatory neurotransmission. We highlight promising objectives for future research to further unravel these antinociceptive mechanisms, which subsequently may facilitate the development of new analgesic strategies and therapies for acute and chronic pain.
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.
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.
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.
•Mature landfill leachate nitrogen removal via nitrite pathway at low DO was achieved.•Excellent NH4+-N removal and nitrite accumulation was obtained at DO of 0.3–0.5mg/L.•Actual HRT of the first ...oxic reactor mainly decided the operational limit.•High-throughput sequencing analysis was used for bacterial community variation.•Genus Nitrosomonas was responsible for NH4+-N removal and nitrite accumulation.
Controlling of low dissolved oxygen (DO) levels (0.1–0.5mg/L), a cost-effective strategy, was applied to a pilot-scale anoxic-oxic-oxic-anoxic process for partial nitrification and denitrification of mature landfill leachate. High ammonium removal efficiency, stable nitrite accumulation rate and total nitrogen removal efficiency was higher than 95.0%, 90.0% and 66.4%, respectively, implying potential application of this process for nitrogen removal of mature landfill leachate. Efficient nitrite accumulation in the first oxic reactor depended on low DO conditions and sufficient alkalinity. However, operational limit was mainly decided by actual hydraulic retention time (AHRT) of the first oxic reactor and appeared with AHRT less than 13.9h under DO of 0.3–0.5mg/L. High-throughput sequencing analysis demonstrated significant change of bacterial diversity in the first oxic reactor after a long-term operation and dominant bacteria genus Nitrosomonas was shown to be responsible for NH4+-N removal and nitrite accumulation under low DO levels.
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.
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