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Guidelines are increasingly determining the decision process in day-to-day clinical work. Guidelines describe the current best possible standard in diagnostics and therapy. They should be developed by an international panel of experts, whereby alongside individual experience, above all, the results of comparative studies are decisive. According to the results of high-ranking scientific studies published in peer-reviewed journals, statements and recommendations are formulated, and these are graded strictly according to the criteria of evidence-based medicine. Guidelines can therefore be valuable in helping particularly the young surgeon in his or her day-to-day work to find the best decision for the patient when confronted with a wide and confusing range of options. However, even experienced surgeons benefit because by virtue of a heavy workload and commitment, they often find it difficult to keep up with the ever-increasing published literature. All guidelines require regular updating, usually every 3 years, in line with progress in the field. The current Guidelines focus on technique and perioperative management of laparoscopic ventral hernia repair and constitute the first comprehensive guidelines on this topic. In this issue of Surgical Endoscopy, the first part of the Guidelines is published including sections on basics, indication for surgery, perioperative management, and key points of technique. The next part (Part 2) of the Guidelines will address complications and comparisons between open and laparoscopic techniques. Part 3 will cover mesh technology, hernia prophylaxis, technique-related issues, new technologic developments, lumbar and other unusual hernias, and training/education.
Guidelines are increasingly determining the decision process in day-to-day clinical work. Guidelines describe the current best possible standard in diagnostics and therapy. They should be developed by an international panel of experts, whereby alongside individual experience, above all, the results of comparative studies are decisive. According to the results of high-ranking scientific studies published in peer-reviewed journals, statements and recommendations are formulated, and these are graded strictly according to the criteria of evidence-based medicine. Guidelines can therefore be valuable in helping particularly the young surgeon in his or her day-to-day work to find the best decision for the patient when confronted with a wide and confusing range of options. However, even experienced surgeons benefit because by virtue of a heavy workload and commitment, they often find it difficult to keep up with the ever-increasing published literature. All guidelines require regular updating, usually every 3 years, in line with progress in the field. The current Guidelines focus on technique and perioperative management of laparoscopic ventral hernia repair and constitute the first comprehensive guidelines on this topic. In this issue of Surgical Endoscopy, the first part of the Guidelines is published including sections on basics, indication for surgery, perioperative management, and key points of technique. The next part (Part 2) of the Guidelines will address complications and comparisons between open and laparoscopic techniques. Part 3 will cover mesh technology, hernia prophylaxis, technique-related issues, new technologic developments, lumbar and other unusual hernias, and training/education.
Guidelines are increasingly determining the decision process in day-to-day clinical work. Guidelines describe the current best possible standard in diagnostics and therapy. They should be developed by an international panel of experts, whereby alongside individual experience, above all, the results of comparative studies are decisive. According to the results of high-ranking scientific studies published in peer-reviewed journals, statements and recommendations are formulated, and these are graded strictly according to the criteria of evidence-based medicine. Guidelines can therefore be valuable in helping particularly the young surgeon in his or her day-to-day work to find the best decision for the patient when confronted with a wide and confusing range of options. However, even experienced surgeons benefit because by virtue of a heavy workload and commitment, they often find it difficult to keep up with the ever-increasing published literature. All guidelines require regular updating, usually every 3 years, in line with progress in the field. The current Guidelines focus on technique and perioperative management of laparoscopic ventral hernia repair and constitute the first comprehensive guidelines on this topic. In this issue of Surgical Endoscopy, the first part of the Guidelines is published including sections on basics, indication for surgery, perioperative management, and key points of technique. The next part (Part 2) of the Guidelines will address complications and comparisons between open and laparoscopic techniques. Part 3 will cover mesh technology, hernia prophylaxis, technique-related issues, new technologic developments, lumbar and other unusual hernias, and training/education.
The prognosis of patients with locally advanced pancreatic cancer can be improved if secondary complete (R0) resection is possible. In patients initially staged as unresectable this may be achieved with neoadjuvant treatment which is usually chemoradiotherapy based. We report the case of a 46-year-old patient with an unresectable, locally advanced pancreatic cancer (pT4 Nx cM0 G2) who was treated with a sequential neoadjuvant chemotherapy regimen consisting of 2 cycles of nab-paclitaxel plus gemcitabine followed by 4 cycles of FOLFIRINOX. Neoadjuvant chemotherapy resulted in secondary resectability (R0 resection). After 2 cycles of nab-paclitaxel plus gemcitabine, the patient already had a complete metabolic remission as measured by integrated fludeoxyglucose ((18)F) positron emission tomography and computerized tomography. After a follow-up of 18 months the patient is alive without progression of disease. We propose to assess the clinical benefit of sequencing the combinations nab-paclitaxel plus gemcitabine and FOLFIRINOX as neoadjuvant therapy for patients with locally advanced and initially unresectable pancreatic cancer in a controlled clinical trial.
Purpose
Once open abdomen therapy has succeeded, the problem of closing the abdominal wall must be addressed. We present a new four-stage procedure involving the application of a two-component mesh and vacuum conditioning for abdominal wall closure of even large defects. The aim is to prevent the development of a giant ventral hernia and the eventual need for the repair of the abdominal wall.
Methods
Nineteen of 62 patients treated by open abdomen over a two-year period could not receive primary abdominal wall closure. To achieve closure in these patients, we applied the following four-stage procedure: stage 1: abdominal damage control and conditioning of the abdominal wall; stage 2: attachment of a tailored two-component mesh of polyglycolic acid (PGA) and large pore polypropylene (PP) in intraperitoneal position (IPOM) plus placement of a vacuum bandage; stage 3: vacuum therapy for 3–4 weeks to allow granulation of the mesh and optimization of dermatotraction; stage 4: final skin suture. During stage 3, eligible patients were weaned from respirator and mobilized.
Results
The abdominal wall gap in the 19 patients ranged in size from 240 cm2 to more than 900 cm2. An average of 3.44 vacuum dressing changes over 19 days were required to achieve 60–100 % granulation of the surface area, so final skin suture could be made. Already in stage 3, 14 patients (73.68 %) could be weaned from respirator an average of 6.78 days after placement of the two-component mesh; 6 patients (31.57 %) could be mobilized on the edge of the bed and/or to a bedside chair after an average of 13 days. No mesh-related hematomas, seromas, or intestinal fistulas were observed.
Conclusion
The four-stage procedure presented here is a viable option for achieving abdominal wall closure in patients treated with open abdomen, enabling us to avoid the development of planned giant ventral hernias. It has few complications and has the special advantage of allowing mobilization of the patients before final skin closure. Long-term course in a large number of patients must still confirm this result.
Balanced hydroxyethylstarch (HES 130/0.4) impairs kidney function in-vivo without inflammation
(2015)
Volume therapy is a standard procedure in daily perioperative care, and there is an ongoing discussion about the benefits of colloid resuscitation with hydroxyethylstarch (HES). In sepsis HES should be avoided due to a higher risk for acute kidney injury (AKI). Results of the usage of HES in patients without sepsis are controversial. Therefore we conducted an animal study to evaluate the impact of 6% HES 130/0.4 on kidney integrity with sepsis or under healthy conditions Sepsis was induced by standardized Colon Ascendens Stent Peritonitis (sCASP). sCASP-group as well as control group (C) remained untreated for 24 h. After 18 h sCASP+HES group (sCASP+VOL) and control+HES (C+VOL) received 50 ml/KG balanced 6% HES (VOL) 130/0.4 over 6h. After 24h kidney function was measured via Inulin- and PAH-Clearance in re-anesthetized rats, and serum urea, creatinine (crea), cystatin C and Neutrophil gelatinase-associated lipocalin (NGAL) as well as histopathology were analysed. In vitro human proximal tubule cells (PTC) were cultured +/- lipopolysaccharid (LPS) and with 0.1–4.0% VOL. Cell viability was measured with XTT-, cell toxicity with LDH-test. sCASP induced severe septic AKI demonstrated divergent results regarding renal function by clearance or creatinine measure focusing on VOL. Soleley HES (C+VOL) deteriorated renal function without sCASP. Histopathology revealed significantly derangements in all HES groups compared to control. In vitro LPS did not worsen the HES induced reduction of cell viability in PTC cells. For the first time, we demonstrated, that application of 50 ml/KG 6% HES 130/0.4 over 6 hours induced AKI without inflammation in vivo. Severity of sCASP induced septic AKI might be no longer susceptible to the way of volume expansion
Background
Up to 50% of septic patients develop acute kidney injury (AKI). The pathomechanism of septic AKI is poorly understood. Therefore, we established an innovative rodent model to characterize sepsis-induced AKI by standardized colon ascendens stent peritonitis (sCASP). The model has a standardized focus of infection, an intensive care set up with monitoring of haemodynamics and oxygenation resulting in predictable impairment of renal function, AKI parameters as well as histopathology scoring.
Methods
Anaesthetized rats underwent the sCASP procedure, whereas sham animals were sham operated and control animals were just monitored invasively. Haemodynamic variables and blood gases were continuously measured. After 24 h, animals were reanesthetized; cardiac output (CO), inulin and PAH clearances were measured and later on kidneys were harvested; and creatinine, urea, cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) were analysed. Additional sCASP-treated animals were investigated after 3 and 9 days.
Results
All sCASP-treated animals survived, whilst ubiquitous peritonitis and significantly deteriorated clinical and macrohaemodynamic sepsis signs after 24 h (MAP, CO, heart rate) were obvious. Blood analyses showed increased lactate and IL-6 levels as well as leucopenia. Urine output, inulin and PAH clearance were significantly decreased in sCASP compared to sham and control. Additionally, significant increase in cystatin C and NGAL was detected. Standard parameters like serum creatinine and urea were elevated and sCASP-induced sepsis increased significantly in a time-dependent manner. The renal histopathological score of sCASP-treated animals deteriorated after 3 and 9 days.
Conclusions
The presented sCASP method is a standardized, reliable and reproducible method to induce septic AKI. The intensive care set up, continuous macrohaemodynamic and gas exchange monitoring, low mortality rate as well as the opportunity of detailed analyses of kidney function and impairments are advantages of this setup. Thus, our described method may serve as a new standard for experimental investigations of septic AKI.
Background
Solitary metastases to the pancreas are rare. Therefore the value of resection in curative intention remains unclear. In the literature there are several promising reports about resection of solitary metastasis to the pancreas mainly of renal origin.
Case presentation
Here we report for the first time on the surgical therapy of a 1.5 cm solitary pancreatic metastasis of an adrenocortical carcinoma. The metastasis occurred almost 6 years after resection of the primary tumor. A partial pancreatoduodenectomy was performed and postoperatively adjuvant mitotane treatment was initiated. During the follow-up of 3 years after surgery no evidence of tumor recurrence occurred.
Conclusion
Resection of pancreatic tumors should be considered, even if the mass is suspicious for metastatic disease including recurrence of adrenocortical cancer.
Background
Comprehensive evidence on the incidence, time course and independent risk factors of metachronous peritoneal carcinomatosis (metaPC) in gastric cancer patients treated with curative intent in the context of available systemic combination chemotherapies is lacking.
Methods
Data from a prospectively collected single-institutional Center Cancer Registry with 1108 consecutive patients with gastric adenocarcinoma (GC), clinical, histological and survival data were analyzed for independent risk factors and prognosis with focus on the development of metaPC. Findings were then stratified to the time periods of treatment with surgery alone, 5-Fluorouracil-only and contemporary combined systemic perioperative chemotherapy strategies, respectively.
Results
Despite R0 D2 gastrectomy (n = 560), 49.6% (±5.4%) of the patients were diagnosed with tumour recurrence and 15.5% (±1.8%) developed metaPC after a median time of 17.7 (15.1-20.3) months after surgery resulting in a tumour related mortality of 100% with a median survival of 3.0 months (2.1 – 4.0). Independent risk factors for the development of metaPC were serosa positive T-category, nodal positive-status, signet cell and undifferentiated gradings (G3/G4). Contemporary systemic combination chemotherapy did not improve the incidence and prognosis of metaPC (p = 0.54).
Conclusions
Despite significant improvements in the overall survival for the complete cohort with gastric cancer over time, those patients with metaPC did not experience the same benefits. The lack of change in the incidence, and persistent poor prognosis of metaPC after curative surgery expose the need for further prevention and/or improved treatment options for this devastating condition.
Immunity, Inflammation and Cancer: The role of Foxp3, TLR7 and TLR8 in gastrointestinal cancer
(2015)
Regulatory T cells (Treg) expressing the transcription factor forkhead box protein P3 (Foxp3) have been demonstrated to mediate evasion from anti-tumor immune responses during tumor progression. Moreover, Foxp3 expression by tumor cells themselves may allow them to counteract effector T cell responses, resulting in a survival benefit of the tumor. For gastrointestinal cancers, in particular pancreatic and colorectal cancer (CRC), the clinical relevance of Foxp3 is not clear to date. Therefore the aim of this study was to analyze its impact in CRC and pancreatic cancer. To determine the relevance of Foxp3 for tumor progression and patient survival, gene and protein analysis of human pancreatic and colon cancer cell lines as well as tumor tissues from patients with CRC was performed. The results derived from the patients with CRC were correlated with clinicopathological parameters and patients’ overall survival. Cancer cell mediated Foxp3 expression in vitro was demonstrated in human pancreatic cancer cell lines PANC1, PaCa DD 135, PaCa DD 159 and PaCa DD 185 as well as in human colon cancer cell lines SW480 and SW620. Additionally, Foxp3 expressing cancer cells were found in ex vivo tumor tissue samples of patients with CRC. The percentage of Foxp3+ cancer cells increased from stages UICC I/II to UICC III/IV compared to normal tissue. Moreover, high tumor cell mediated Foxp3 expression was associated with poor prognosis compared to patients with low Foxp3 expression. In contrast, low and high Foxp3 level in tumor infiltrating Treg cells demonstrated no significant differences in patients’ overall survival. Correlation analysis demonstrated a significant association of Foxp3 cancer cell expression with the expression of immunosuppressive cytokines IL-10 and TGF-β. These findings suggest that Immunosuppressive cytokines such as IL-10 and TGF-β released by rather Foxp3+ cancer cells than Foxp3+ Treg cells may inhibit the activation of naive T cells, hence limiting antitumor immune responses and favoring tumorigenesis and progression.
Chronic inflammation has been shown to be an important epigenetic and environmental factor in numerous tumor entities. Recent data suggest that tumorigenesis and tumor progression may be associated with inflammation-triggered activation of Toll-like receptors (TLR). In this study, the specific impact of both TLR7 and TLR8 expression and signaling on tumor cell proliferation and chemoresistance is analyzed in inflammation linked CRC and pancreatic cancer. By gene and protein expression analysis of human pancreatic and colon cancer cell lines TLR7 and TLR8 expression was determined in vitro. Additionally, expression of TLR7/TLR8 in UICC stage I-IV pancreatic cancer, chronic pancreatitis and normal pancreatic tissue was examined. For in vitro/in vivo studies TLR7/TLR8 overexpressing PANC1 cell lines were generated and analyzed for effects of TLR expression and stimulation on tumor cell proliferation and chemoresistance. Cancer cell mediated TLR7 and TLR8 expression in vitro was demonstrated in human colon cancer cell lines SW480, SW620 and HT-29 as well as in primary pancreatic cancer cell lines PaCa DD 135, PaCa DD 159 and PaCa DD 185. Additionally, TLR7 and TLR8 expressing tumor cells were found in ex vivo tissue samples of patients with pancreatic cancer and chronic pancreatitis. Significantly elevated expression levels of TLR7 and TLR8 were found in advanced tumor stages (UICC III) compared to early tumor stages (UICC II) and chronic pancreatitis. No or occasionally low expression was detected in normal pancreatic tissue. In contrast to the tissues from patients with pancreatic cancer or chronic pancreatitis, established pancreatic tumor cell lines express only very low levels of TLR7 and TLR8. Therefore, for in vitro and xenograft studies TLR7 or TLR8 overexpressing PANC1 cells were generated. Proliferation promoting effects of TLR7 and TLR8 expression and stimulation with R848 were detected in vitro. Additionally, increased tumor growth of TLR expressing PANC1 cells was demonstrated in subcutaneously injected Balb/c nude mice. Interestingly, activation of TLR7 or TLR8 induced not only an increase in tumor cell proliferation but also a strong chemoresistance of PANC1 cells against 5-fluorouracil (5-FU). Moreover, treatment with R848 resulted in elevated expression levels of NF-κB, COX-2 and inflammatory cytokines IL-1β, IL-8 and TNF-α, suggesting TLR7/8 signaling to contribute to an inflammatory, anti-apoptotic and proliferation promoting tumor microenvironment. These findings emphasize the particular role of TLR7 and TLR8 in inflammation related cancers and their relevance as potential targets for cancer therapy.
Background
Although the repair of ventral abdominal wall hernias is one of the most commonly performed operations, many aspects of their treatment are still under debate or poorly studied. In addition, there is a lack of good definitions and classifications that make the evaluation of studies and meta-analyses in this field of surgery difficult.
Materials and methods
Under the auspices of the board of the European Hernia Society and following the previously published classifications on inguinal and on ventral hernias, a working group was formed to create an online platform for registration and outcome measurement of operations for ventral abdominal wall hernias. Development of such a registry involved reaching agreement about clear definitions and classifications on patient variables, surgical procedures and mesh materials used, as well as outcome parameters. The EuraHS working group (European registry for abdominal wall hernias) comprised of a multinational European expert panel with specific interest in abdominal wall hernias. Over five working group meetings, consensus was reached on definitions for the data to be recorded in the registry.
Results
A set of well-described definitions was made. The previously reported EHS classifications of hernias will be used. Risk factors for recurrences and co-morbidities of patients were listed. A new severity of comorbidity score was defined. Post-operative complications were classified according to existing classifications as described for other fields of surgery. A new 3-dimensional numerical quality-of-life score, EuraHS-QoL score, was defined. An online platform is created based on the definitions and classifications, which can be used by individual surgeons, surgical teams or for multicentre studies. A EuraHS website is constructed with easy access to all the definitions, classifications and results from the database.
Conclusion
An online platform for registration and outcome measurement of abdominal wall hernia repairs with clear definitions and classifications is offered to the surgical community. It is hoped that this registry could lead to better evidence-based guidelines for treatment of abdominal wall hernias based on hernia variables, patient variables, available hernia repair materials and techniques.
Purpose
Once open abdomen therapy has succeeded, the problem of closing the abdominal wall must be addressed. We present a new four-stage procedure involving the application of a two-component mesh and vacuum conditioning for abdominal wall closure of even large defects. The aim is to prevent the development of a giant ventral hernia and the eventual need for the repair of the abdominal wall.
Methods
Nineteen of 62 patients treated by open abdomen over a two-year period could not receive primary abdominal wall closure. To achieve closure in these patients, we applied the following four-stage procedure: stage 1: abdominal damage control and conditioning of the abdominal wall; stage 2: attachment of a tailored two-component mesh of polyglycolic acid (PGA) and large pore polypropylene (PP) in intraperitoneal position (IPOM) plus placement of a vacuum bandage; stage 3: vacuum therapy for 3–4 weeks to allow granulation of the mesh and optimization of dermatotraction; stage 4: final skin suture. During stage 3, eligible patients were weaned from respirator and mobilized.
Results
The abdominal wall gap in the 19 patients ranged in size from 240 cm2 to more than 900 cm2. An average of 3.44 vacuum dressing changes over 19 days were required to achieve 60–100 % granulation of the surface area, so final skin suture could be made. Already in stage 3, 14 patients (73.68 %) could be weaned from respirator an average of 6.78 days after placement of the two-component mesh; 6 patients (31.57 %) could be mobilized on the edge of the bed and/or to a bedside chair after an average of 13 days. No mesh-related hematomas, seromas, or intestinal fistulas were observed.
Conclusion
The four-stage procedure presented here is a viable option for achieving abdominal wall closure in patients treated with open abdomen, enabling us to avoid the development of planned giant ventral hernias. It has few complications and has the special advantage of allowing mobilization of the patients before final skin closure. Long-term course in a large number of patients must still confirm this result.
Objective: To determine whether rats reaching the same body mass, having been fed either a low-fat (LFD) or a high-fat diet (HFD), differ in white adipose tissue (WAT) deposition. Methods: In experiment 1, 22 Sprague-Dawley rats of the same age were divided into 11 rats with body mass below the batch median and fed a HFD, and 11 above the median and fed a LFD. In experiment 2, 20 Sprague-Dawley rats of the same age and starting body mass were randomised to either a HFD or LFD. When all groups reached similar final body mass, WAT was quantified using magnetic resonance imaging (MRI), dissection, and plasma leptin. Results: In experiment 1, both groups reached similar final body mass at the same age; in experiment 2 the HFD group reached similar final body mass earlier than the LFD group. There were no significant differences in WAT as assessed by MRI or leptin between the HFD and LFD groups in both experiments. Dissection revealed a trend for higher retroperitoneal and epididymal adiposity in the HFD groups in both experiments. Conclusions: We conclude that at similar body mass, adiposity is independent of the macronutrient composition of the feeding regimen used to achieve it. (C) 2014 S Karger GmbH, Freiburg
Die Auswertung des Patientenkollektivs von 2000 bis 2004 an der Chirurgischen Universitätsklinik Würzburg ergab 63 Patienten (Gruppe 1), die einer Minoramputation und
59 Patienten die einer Minor- mit konsekutiver Majoramputation (Gruppe 2) infolge pAVK unterzogen wurden. Eine Abhängigkeit zwischen Alter und Majornachamputationsrate konnte nicht festgestellt werden, jedoch eine Tendenz beim Einfluss von Comorbiditäten wie Diabetes mellitus und dialysepflichtiger Niereninsuffizienz auf die Wundheilung und Liegedauer.
Die Anzahl an durchgeführten gefäßchirurgischen Eingriffen wie PTA und Bypass-Operation lag in beiden Gruppen mit 65% bzw. 72% im Vergleich zur Literatur im Standardbereich.
Eine hohe Rate an gefäßmedizinischer Diagnostik und Therapie scheint auch bei fortgeschrittener pAVK (Grad IV) erforderlich, um die Notwendigkeit von Amputationen
insbesondere die Anzahl an Majoramputationen zu verringern. Bei hoher und mit Gruppe 1 vergleichbarer Interventionsrate in Gruppe 2 lässt sich allerdings auch erkennen, dass trotz Ausschöpfung dieser Massnahmen die Rate an Majoramputationen und damit des
Beinverlustes hoch ist.
Positiv zu werten ist, dass es bei über 50% der Amputierten ausgereicht hat, eine Amputation im Fussbereich (Minoramputation) durchzuführen. Bei diesen 63 Patienten, war bei 58 Patienten sogar nur ein Eingriff nötig. Ferner handelte es sich bei den Majoramputationen in der Mehrzahl um Unterschenkelamputation, und somit um einen nur partiellen Beinverlust . 76% der durchgeführten ersten Majoramputationen erfolgten in den ersten beiden Monaten nach vorausgegangener Minoramputation, die größte Anzahl innerhalb des ersten Monats. Auch die letzte Amputation, die definitive Versorgung, erfolgte
in den meisten Fällen innerhalb der ersten beiden Monate nach Primäreingriff. Somit ist ein nur unwesentlicher Aufschub bis zur definitiven Versorgung ersichtlich.
Der Versuch einer Konsolidierung der Ischämiefolgen (Gangrän) mittels Minoramputation scheint bei fortgeschrittener pAVK im Stadium IV nach Ausschöpfung der
gefäßmedizinischen Diagnostika und Interventionen somit immer gerechtfertigt, und sollte wenn möglich einer Majoramputation vorgezogen werden.
Die durchschnittliche Krankenhausverweildauer in der Gruppe der Minoramputationen lag bei 28 Tagen, in der Gruppe 2 der Majoramputationen bei 39 Tagen. Die Mortalitätsrate ergibt einen deutlich erhöhten Wert in der Gruppe der Majoramputationen. Die Dreijahresmortalität betrug in der Gruppe der Minoramputationen 20% und der Majoramputationen 58%. Es zeigte sich eine Zunahme der Mortalität mit zunehmender
Amputationshöhe und zunehmender Zahl der Amputationen. Diese Daten lassen sich mit 52 aktuellen Literaturangaben durchaus vergleichen und beweisen die schlechte Prognose für AVK-Patienten, bei denen eine Majoramputation unausweichlich ist.
Insgesamt ist es wichtig, dass ein Team aus Chirurgen, Gefäßchirurgen, Radiologen und Angiologen kooperativ zusammen arbeitet, um dem Patienten, eine für ihn
beste Versorgung anbieten zu können. Hier sollte auch nicht vor einem oft höheren Patientenalter zurückgeschreckt werden, denn häufig konnte gerade bei diesen Patienten durch eine Bypass-Operation eine sonst vermutlich unumgängliche Amputation im Unter- bzw.
Oberschenkelbereich verhindert werden.
Clinical prognosis of metastasized colorectal carcinoma (CRC) is still not at desired levels and novel drugs are needed. Here, we focused on the multi-tyrosine kinase inhibitor E7080 (Lenvatinib) and assessed its therapeutic efficacy against human CRC cell lines in vitro and human CRC xenografts in vivo. The effect of E7080 on cell viability was examined on 10 humanCRCcell lines and humanendothelial cells (HUVEC). The inhibitory effect of E7080 on VEGF-induced angiogenesis was studied in an ex vivo mouse aortic ring angiogenesis assay. In addition, the efficacy of E7080 against xenografts derived fromCRC cell lines and CRC patient resection specimenswithmutated KRASwas investigated in vivo. Arelatively low cytotoxic effect of E7080 on CRC cell viabilitywas observed in vitro. Endothelial cells (HUVEC)weremore susceptible to the incubation with E7080. This is in line with the observation that E7080 demonstrated an anti-angiogenic effect in a three-dimensional ex vivo mouse aortic ring angiogenesis assay. E7080 effectively disrupted CRC cell-mediated VEGF-stimulated growth of HUVEC in vitro. Daily in vivo treatment with E7080 (5 mg/kg) significantly delayed the growth of KRAS mutated CRC xenografts with decreased density of tumor-associated vessel formations and without tumor regression. This observation is in line with results that E7080 did not significantly reduce the number of Ki67-positive cells in CRC xenografts. The results suggest antiangiogenic activity of E7080 at a dosage thatwas well tolerated by nudemice. E7080 may provide therapeutic benefits in the treatment of CRC with mutated KRAS.
Ziel der vorliegenden Arbeit war, an den sechs gastrointestinalen Karzinomzelllinien CaCo, HCT116, HT29, SW620, WiDr und 23132/87 zu untersuchen, ob Ketonkörper den Anteil vitaler Zellen durch Hemmung der Zellteilung verringern. Hierzu wurden umfangreiche In-vitro-Experimente mit unterschiedlichen Konzentrationen an Sauerstoff (21, 5 und 1 %) und D-3-Hydroxybutyrat (0,25, 4,0, 8,0 und 20 mmol/l) durchgeführt. Zusätzlich wurde überprüft, ob Ketonkörper die Glykolyse beeinflussen. Hierzu wurden der Glukoseverbrauch und die Laktatproduktion bestimmt.
Die sechs humanen gastrointestinalen Karzinomzelllinien exprimieren die zur Ketolyse notwendigen Enzyme. Die Zellen oxidieren D-3-Hydroxybutyrat zwar eindeutig bei 21 % Sauerstoff, nicht aber bei physiologischen Sauerstoffkonzentrationen von 5 % und 1 % Sauerstoff.
Die Hemmung der Zellteilung durch Ketonkörper, wurde in der vorliegenden Arbeit für keine der vier Konzentrationen an D-3-Hydroxybutyrat bei keiner der drei Konzentrationen an Sauerstoff an den untersuchten Zellen beobachtet.
Auch war keine Beeinflussung der Glykolyse durch Ketonkörper nachzuweisen. Weder der Glukoseverbrauch noch die Laktatbildung wiesen signifikante Differenzen bei Inkubation der Zellen mit D-3-Hydroxy¬butyrat auf.
Dendritische Zellen stellen eine Gruppe morphologisch, phänotypisch und funktionell einzigartiger Leukozyten dar, die eine zentrale Rolle bei der Regu-lation des Immunsystems spielen. Als die mit Abstand effektivsten antigen-präsentierenden Zellen besteht ihre Funktion sowohl in der Auslösung als auch in der Verhinderung spezifischer Immunantworten, wobei diese Fähigkeiten von ihrem jeweiligen Reifungsstadium abhängig sind. In der vorliegenden Arbeit wurden Dendritische Zellen aus Milzen von Mäusen verschiedener Linien mit¬tels Dichtegradientenzentrifugation unter Verwendung von OptiPrep (Iodixanol) isoliert und phänotypisch sowie funktionell charakterisiert. Die gewonnenen Zellsuspensionen bestanden durchschnittlich zu 41 Prozent aus residenten konventionellen Dendritischen Zellen. Die isolierten Dendritischen Zellen waren unabhängig von der untersuchten Mauslinie bis zu 26 Prozent CD8α-positiv und bis zu 81 Prozent CD8α-negativ. Dendritische Zellen wiesen unmittelbar nach der Zellgewinnung einen unreifen Phänotyp auf mit starker Expression von MHC-Klasse-II, aber schwacher bis fehlender Expression der kostimulato¬rischen Moleküle CD80, CD86 und CD40. Eine 24- bzw. 48-stündige Kulti¬vierung in vitro führte zur Reifung der Dendritischen Zellen mit Zunahme der Expression von MHC-Klasse-II, CD80, CD86 und CD40 um den Faktor 2 bis 4. Diese Zellen wiesen zudem immunstimulatorische Eigenschaften in der gemischten (allogenen) Leukozytenkultur auf. Dendritische Zellen der Mauslinie NMRInude exprimierten nach der In-vitro-Kultur ebenfalls zahlreiche Ober¬flächenmarker, darunter die Reifungsmarker. Die Stärke der Expression war jedoch um bis zu 50 Prozent schwächer als bei Dendritischen Zellen der anderen Mauslinien. Dieser Befund weist auf potentielle Unterschiede zwischen Dendritischen Zellen der thymuslosen Mauslinie NMRInude und Dendritischen Zellen von Wildtyp-Mäusen hin. Es wurde gezeigt, dass OptiPrep zur Isolierung Dendritischer Zellen aus Mäusemilzen bei geringem Arbeitsaufwand und niedrigen Kosten verwendet werden kann. Die isolierten Dendritischen Zellen weisen die zu erwartenden phänotypischen und funktionellen Eigenschaften auf und scheinen somit für den Einsatz in weiterführenden Experimenten geeignet.
Einleitung: Eine präoperative Selektion adipöser Patienten anhand objektiver Kriterien soll entscheidend sein für den Gewichtsverlauf nach Implantation eines Magenbandes (Laparoscopic adjustable gastric banding, LAGB). Es ist unbekannt, ob die präoperative Selektion Auswirkungen auf das Langzeitergebnis des LAGB hat.
Material und Methoden: Die vorliegende Studie suchte nach objektiven Variablen mit signifikanter Vorhersagekraft für das Langzeitergebnis des LAGB. Hierfür wurde der Gewichtsverlauf nach LAGB in einem jährlichen Intervall analysiert. 166 Patienten (91,2 %) nahmen an der retrospektiven Studie teil (Lost to Follow-up 8,8 %). Das mediane Follow-up des gesamten Patientenguts betrug 83,1 Monate (Range 0,1 - 177,3 Monate) und endete am Tag des abschließenden Interviews mit den Studienteilnehmern, jedoch spätestens bei ersatzloser Explantation des Magenbandes (Studienende). Eine Per-Protokoll-Analyse untersuchte den Gewichtsverlauf von Patienten ohne ersatzlose Explantation des Magenbandes (N = 111).
Der prozentuale Verlust an Übergewicht (Excess Weight Loss, EWL %) am Studienende entschied über das Langzeitergebnis (Success: EWL ≥ 50,0 % mit LAGB, No Success: EWL < 50,0 % mit LAGB oder ersatzlose Explantation des LAGB; Failure: EWL < 20,0 % mit LAGB oder ersatzlose Explantation des LAGB, No Failure: EWL ≥ 20,0 % mit LAGB). Zur Abschätzung von prädiktiven Faktoren hinsichtlich der abhängigen Variablen Success und No Success sowie Failure und No Failure wurde eine binär logistische Regressionsanalyse durchgeführt. Folgende präoperative Kovariaten wurden auf ihren prädiktiven Langzeiteffekt analysiert: Alter, Body-Mass-Index, Übergewicht (Excess Weight), Geschlecht, Adipositas assoziierte Komorbiditäten (Diabetes Mellitus Typ II, arterieller Hypertonus, Schlafapnoe, Gelenkbeschwerden, Belastungsdyspnoe), Bandart (Swedish adjustable gastric banding, Lap Band), Operationstechnik (Pars flaccida, retrogastrisch).
Ergebnisse: In der vorliegenden Studie war der EWL (%) im Langzeitverlauf moderat. Der höchste mediane EWL (%) des gesamten Patientenguts wurde im 2. postoperativen Jahr erreicht und betrug 43,2 % (Range -34,1 - 178,8 %) (N = 155). Mit zunehmendem Follow-up sank der EWL (%). Im 5.-, 10.- und 14. postoperativen Jahr betrugen der mediane EWL 39,7 % (Range -39,7 - 162,0 %) (N = 126), 31,0 % (Range -37,6 - 139,7 %) (N = 65) und 31,9 % (Range -34,0 - 108,6 %) (N = 27). Am Studienende wurde am häufigsten ein EWL-Level von 30 - 40 % (12 %, N = 20) erreicht. Prüfkonforme Patienten erreichten am Studienende einen medianen EWL von 33,2 % (Range -81,4 - 116,7 %) (N = 111). Wie bereits in der Literatur berichtet nahmen mit zunehmendem Follow-up die Anteile an Success und No Failure ab. Im 2. postoperativen Jahr betrugen die Success- und No Success-Raten 38,0 % und 62,0 % (Failure: 24,7 %, No-Failure: 75,3 %). Bis zum 10. postoperativen Jahr reduzierte sich der Success-Anteil auf 17,2 % und der No Success-Anteil stieg auf 82,8 % (Failure: 60,9 %, No Failure: 39,1 %). Am Studienende erfüllten 18,7 % (N = 31) der Patienten das Kriterium Success und 81,3 % (N = 135) das Kriterium No Success (Failure: 52,4 %, N = 87; No Failure: 47,6 %, N = 79).
Die postoperative Komplikationsrate war hoch, jedoch vergleichbar mit aktuellen Langzeitstudien: 47,6 % (N = 79) der Patienten entwickelten postoperativ eine oder mehrere Band-assoziierte Komplikationen. Slippage (20,5 %, N = 34), Pouchdilatation (20,5 %, N = 34) und Portdislokation/Portdiskonnektion (12,7 %, N = 21) traten am häufigsten auf. 33,1 % (N = 55) der Magenbänder wurden ersatzlos entfernt nach einer medianen Zeit von 40,7 Monaten (Range 0,1 - 163,6 Monate). Diese Studie belegte die positiven Langzeiteffekte des LAGB auf Adipositas-assoziierte Komorbiditäten: 79,4 % (N = 54) der präoperativ hypertonen Patienten und 72,0 % (N = 18) der Patienten mit initialem Diabetes Mellitus Typ II erreichten am Studienende eine Remission und Heilung (Reduktion und Absetzen der Antihypertensiva bzw. Antidiabetika) ihrer Komorbidität.
In der Regressionsanalyse fanden sich keine objektiv fassbaren Parameter, die präoperativ ein erfolgreiches Langzeitergebnis nach Implantation eines Magenbandes vorhersagen konnten. Die wichtige präoperative Selektion der Patienten wird dadurch erschwert und basiert somit weiterhin auf eher subjektiven Parametern wie Eindruck der Patienten-Compliance, des patientenseitigen Verstehens der Prozedur sowie Patientenwunsch. LAGB ist heute kein bariatrischer Eingriff der ersten Wahl. Jedoch gibt es Patienten, die aufgrund der potentiellen Reversibilität und geringen Mortalität ein LAGB bevorzugen. Wird heute ein LAGB durchgeführt, erscheint auf Basis der klinischen Erfahrung eine engmaschige Anbindung der Patienten in der postoperativen Nachsorge notwendig, um ein optimales Ergebnis zu erreichen. Bei Versagen des Verfahrens (nicht zufriedenstellender Gewichtsverlauf und/oder Auftreten von Band-assoziierten Komplikationen) sind die Entfernung des Magenbandes und die Umwandlung in ein alternatives adipositaschirurgisches Verfahren zumindest zu diskutieren.
Background
The management of rectal cancer (RC) has substantially changed over the last decades with the implementation of neoadjuvant chemoradiotherapy, adjuvant therapy and improved surgery such as total mesorectal excision (TME). It remains unclear in which way these approaches overall influenced the rate of local recurrence and overall survival.
Methods
Clinical, histological and survival data of 658 out of 662 consecutive patients with RC were analyzed for treatment and prognostic factors from a prospectively expanded single-institutional database. Findings were then stratified according to time of diagnosis in patient groups treated between 1993 and 2001 and 2002 and 2010.
Results
The study population included 658 consecutive patients with rectal cancer between 1993 and 2010. Follow up data was available for 99.6% of all 662 treated patients. During the time period between 2002 and 2010 significantly more patients underwent neoadjuvant chemoradiotherapy (17.6% vs. 60%) and adjuvant chemotherapy (37.9% vs. 58.4%). Also, the rate of reported TME during surgery increased. The rate of local or distant metastasis decreased over time, and tumor related 5-year survival increased significantly with from 60% to 79%.
Conclusion
In our study population, the implementation of treatment changes over the last decade improved the patient’s outcome significantly. Improvements were most evident for UICC stage III rectal cancer.
Background
Reliable central venous access (CVC) is essential for hematology–oncology patients since frequent puncture of peripheral veins—e.g., for chemotherapy, antibiotic administration, repeated blood sampling, and monitoring—can cause unacceptable pain and psychological trauma, as well as severe side effects in cases of extravasation of chemotherapy drugs. However, CVC lines still carry major risk factors, including thrombosis, infection (e.g., entry site, tunnel, and luminal infections), and catheter dislocation, leakage, or breakage.
Methods
Here we performed a retrospective database analysis to determine the incidence of CVC-associated thrombosis in a single-center cohort of 448 pediatric oncologic patients, and to analyze whether any subgroup of patients was at increased risk and thus might benefit from prophylactic anticoagulation.
Results
Of the 448 patients, 269 consecutive patients received a CVC, and 55 of these 269 patients (20%) also had a thrombosis. Of these 55 patients, 43 had at least one CVC-associated thrombosis (total number of CVC-associated thrombosis: n = 52). Among all patients, the median duration of CVC exposure was 464 days. Regarding exposure time, no significant difference was found between patients with and without CVC-associated thrombosis. Subclavia catheters and advanced tumor stages seem to be the main risk factors for the development of CVC-associated thrombosis, whereas pharmacologic prophylaxis did not seem to have a relevant impact on the rate of thrombosis.
Conclusions
We conclude that pediatric surgeons and oncologists should pay close attention to ensuring optimal and accurate CVC placement, as this appears the most effective tool to minimize CVC-associated complications.