Background A prognostic benefit of additive chemotherapy in patients following resection of metac... more Background A prognostic benefit of additive chemotherapy in patients following resection of metachronous colorectal liver metastases (CRLM) remains controversial. Therefore, the goal of this retrospective study was to investigate the impact of perioperative chemotherapy on disease-free survival (DFS) and overall survival (OS) of patients after curative resection of metachronous CRLM. Methods In a retrospective single-centre study, patients after curative resection of metachronous CRLM were included and analysed for DFS and OS with regard to the administration of additive chemotherapy. The Kaplan-Meier method was applied to compare DFS and OS while Cox regression models were used to identify independent prognostic variables. Results Thirty-four of 75 patients were treated with additive 5-FU based chemotherapy. OS was significantly prolonged in this patient subgroup (62 vs 57 months; p = 0.032). Additive chemotherapy significantly improved 10-year survival rates (42% vs 0%, p = 0.023)...
Jaynes (1957a,b) formulates the maximum entropy (ME) principle as the search for a distribution m... more Jaynes (1957a,b) formulates the maximum entropy (ME) principle as the search for a distribution maximizing a given entropy under some given constraints. Kapur (1984) and Kesavan & Kapur (1989) introduce the generalized maximum entropy principle as the derivation of an entropy for which a given distribution has the maximum entropy property under some given constraints. Both principles will be considered for cumulative entropies. Such entropies depend either on the distribution (direct) or on the survival function (residual) or on both (paired). Maximizing this entropy without any constraint gives a extremely U-shaped (= bipolar) distribution. Under the constraint of fixed mean and variance. maximizing the cumulative entropy tries to transform a distribution in the direction of a bipolar distribution as far as it is allowed by the constraints. A bipolar distribution represents so-called contradictory information in contrast to minimum or no information. Only a few maximum entropy dist...
Purpose Traditionally, previous wound infection was considered a contraindication to secondary sk... more Purpose Traditionally, previous wound infection was considered a contraindication to secondary skin closure; however, several case reports describe successful secondary wound closure of wounds “preconditioned” with negative pressure wound therapy (NPWT). Although this has been increasingly applied in daily practice, a systematic analysis of its feasibility has not been published thus far. The aim of this study was to evaluate secondary skin closure in previously infected abdominal wounds following treatment with NPWT. Methods Single-center retrospective analysis of patients with infected abdominal wounds treated with NPWT followed by either secondary skin closure referenced to a group receiving open wound therapy. Endpoints were wound closure rate, wound complications (such as recurrent infection or hernia), and perioperative data (such as duration of NPWT or hospitalization parameters). Results One hundred ninety-eight patients during 2013–2016 received a secondary skin closure aft...
Background 40-50% of patients with colorectal cancer (CRC) will develop liver metastases (CRLM) d... more Background 40-50% of patients with colorectal cancer (CRC) will develop liver metastases (CRLM) during the course of the disease. One third of these patients will additionally develop pulmonary metastases. Methods 137 consecutive patients with CRLM, were analyzed regarding survival data, clinical, histological data and treatment. Results were stratified according to the occurrence of pulmonary metastases and metastases resection.
The purpose of this study was to evaluate the clinical and long-term outcome of patients who unde... more The purpose of this study was to evaluate the clinical and long-term outcome of patients who underwent covered stent treatment because of late-onset postpancreatectomy hemorrhage in a greater number of patients. A secondary study goal was to compare embolization techniques with covered stents regarding differences in early and late clinical outcome, rebleeding, and vessel patency. Between December 2008 and June 2015, 27 consecutive patients suffering from major hemorrhage after pancreatic surgery underwent either covered stent placement or embolization of the affected visceral artery. The patients' medical reports and radiologic images were retrospectively reviewed. The main study end point was technical and clinical success, including survival and complications; the secondary end points were perfusion distal to the target vessel and, for covered stent placement, patency of the affected artery. Covered stent placement was successful in 14 of 16 patients (88%); embolization was s...
Interactions between the liver and CD8+ T cells can lead to tolerance, due in part to CD8+ T cell... more Interactions between the liver and CD8+ T cells can lead to tolerance, due in part to CD8+ T cell death. To test whether this was the case in an extrahepatic infection, we investigated the fate and effector capacity of intrahepatic CD8+ T cells during lung-restricted influenza infection in mice. Virus-specific T cells accumulated in livers without detectable intrahepatic presentation of viral Ags, and this accumulation was not restricted to the contraction phase, but was apparent as early as day 5. Intrahepatic influenza-specific cells were functionally similar to those recovered from the bronchioalveolar lavage, based on ex vivo cytokine production and specific target lysis. Both adoptive transfer of liver lymphocytes and orthotopic liver transplant of organs containing accumulated effector T cells revealed that activated CD8s from the liver were viable, expanded during reinfection, and generated a memory population that trafficked to lymphoid organs. Thus, intrahepatic CD8+ T cell...
The transplanted liver elicits systemic tolerance, and the underlying mechanism may also account ... more The transplanted liver elicits systemic tolerance, and the underlying mechanism may also account for the persistence of liver infections, such as malaria and viral hepatitis. These phenomena have led to the hypothesis that antigen presentation within the liver is abortive, leading to T cell tolerance or apoptosis. Here we test this hypothesis in an optimized orthotopic liver transplantation model. In direct contradiction to this model, the liver itself induces full CD8+ T cell activation and differentiation. The effects of microchimerism were neutralized by bone marrow transplantation in the liver donor, and the lack of liver-derived antigen-presenting cells was documented by eight-color flow cytometry and by sensitive functional assays. We conclude that local antigen presentation cannot explain liver tolerance. On the contrary, the liver may be an excellent priming site for naive CD8+ T cells.
Activated CD8؉ T cells migrate to the liver at the end of an immune response and go through apopt... more Activated CD8؉ T cells migrate to the liver at the end of an immune response and go through apoptosis there, but this mechanism is impaired in mice lacking Toll-like receptor-4. This allowed us to test the importance of liver trapping in an ongoing immune response. In the absence of Toll-like receptor-4, reduced liver accumulation was associated with an increase in the circulating CD8؉ T cell pool, more long-lived memory T cells and increased CD8؉ T cell memory responses. Using experimental orthotopic liver transplantation, we showed that the effect of Toll-like receptor-4 on the formation of the CD8؉ T cell memory resides in the liver. Conclusion: These studies reveal a new function for the liver, which is to regulate the magnitude of T cell memory responses through a Toll-like receptor-4-dependent mechanism. (HEPATOLOGY 2007;45:178-186.) Materials and Methods Animals. C57BL/10SnJ mice (with normal TLR-4, referred to as WT) and C57BL/10ScN mice (which lack
Kupffer cells form a large intravascular macrophage bed in the liver sinusoids. The differentiati... more Kupffer cells form a large intravascular macrophage bed in the liver sinusoids. The differentiation history and diversity of Kupffer cells is disputed; some studies argue that they are derived from blood monocytes, whereas others support a local origin from intrahepatic precursor cells. In the present study, we used both flow cytometry and immunohistochemistry to distinguish 2 subsets of Kupffer cells that were revealed in the context both of bone marrow transplantation and of orthotopic liver transplantation. One subset was radiosensitive and rapidly replaced from hematogenous precursors, whereas the other was relatively radioresistant and long-lived. Both were phagocytic but only the former population was recruited into inflammatory foci in response to CD8+ T-cell activation. We propose the name “sessile” for the radioresistant Kupffer cells that do not participate in immunoinflammatory reactions. However, we found no evidence that these sessile Kupffer cells arise from immature i...
Background: The management of rectal cancer (RC) has substantially changed over the last decades ... more 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 International consensus criteria (ICC) have redefined borderline resectability for pan... more Background International consensus criteria (ICC) have redefined borderline resectability for pancreatic ductal adenocarcinoma (PDAC) according to three dimensions: anatomical (BR-A), biological (BR-B), and conditional (BR-C). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumour and vessels but that biological and conditional dimensions also are important. Methods Patients’ tumours were retrospectively defined borderline resectable according to ICC. The study cohort was grouped into either BR-A or BR-B and compared with patients considered primarily resectable (R). Differences in postoperative complications, pathological reports, overall (OS), and disease-free survival were assessed. Results A total of 345 patients underwent resection for PDAC. By applying ICC in routine preoperative assessment, 30 patients were classified as stage BR-A and 62 patients as stage BR-B. In total, 253 patients were considered R. The cohort...
Background: Liver resection is the most effective available therapy for patients with hepatocellu... more Background: Liver resection is the most effective available therapy for patients with hepatocellular carcinoma (HCC). The accurate selection of patients for surgery requires determination of technical resectability and the risk of recurrence, as well as assessment of liver function and functional reserve to avoid postoperative liver failure. Previous studies have underlined the effectiveness and reliability of the LiMAx® test to evaluate liver function preoperatively. Nevertheless, data concerning HCC evaluation are lacking. Methods: From 2014 to 2019, 92 patients with HCC underwent additional assessment of liver function using the LiMAx test prior to decision for or against liver resection. Preoperative LiMAx results were compared between cirrhotic and noncirrhotic liver. The clinical decision for surgery was evaluated applying the various liver function parameters available. Results: Forty-six patients underwent liver resection. The LiMAx results were higher in resected patients (...
The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transpla... more The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8 T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis...
Liver Anesthesiology and Critical Care Medicine, 2012
Organ allocation for donor livers in the USA follows an algorithm of medical urgency determined b... more Organ allocation for donor livers in the USA follows an algorithm of medical urgency determined by 3-month mortality risk based on objective laboratory values. However, a framework of local and regional distribution units is superimposed on the prioritization of organ recipients resulting in significant geographical differences with regard to waiting time and severity of disease at the time of transplant. Changes in the current allocation and distribution policies are evaluated but have to balance increased cold ischemia times and cost efficiency with equity. While the number of “standard criteria” deceased organ donors has remained relatively stable over the last decade, there was an increase of primarily older donors, donors with comorbidities, and donations after cardiac death. These so-called expanded criteria donors together with the use of donors with steatotic livers have broadened the donor pool, but bear an increased risk of organ dysfunction to the liver recipient. Currently clinical outcome research focuses on which patient population will benefit the most from which type of expanded criteria organ. In the United States, living donor liver transplantation has not evolved into a significant proportion of the total number of liver transplantations and remains an option predominantly for pediatric recipients and recipients who are not prioritized in the current allocation system.
Background A prognostic benefit of additive chemotherapy in patients following resection of metac... more Background A prognostic benefit of additive chemotherapy in patients following resection of metachronous colorectal liver metastases (CRLM) remains controversial. Therefore, the goal of this retrospective study was to investigate the impact of perioperative chemotherapy on disease-free survival (DFS) and overall survival (OS) of patients after curative resection of metachronous CRLM. Methods In a retrospective single-centre study, patients after curative resection of metachronous CRLM were included and analysed for DFS and OS with regard to the administration of additive chemotherapy. The Kaplan-Meier method was applied to compare DFS and OS while Cox regression models were used to identify independent prognostic variables. Results Thirty-four of 75 patients were treated with additive 5-FU based chemotherapy. OS was significantly prolonged in this patient subgroup (62 vs 57 months; p = 0.032). Additive chemotherapy significantly improved 10-year survival rates (42% vs 0%, p = 0.023)...
Jaynes (1957a,b) formulates the maximum entropy (ME) principle as the search for a distribution m... more Jaynes (1957a,b) formulates the maximum entropy (ME) principle as the search for a distribution maximizing a given entropy under some given constraints. Kapur (1984) and Kesavan & Kapur (1989) introduce the generalized maximum entropy principle as the derivation of an entropy for which a given distribution has the maximum entropy property under some given constraints. Both principles will be considered for cumulative entropies. Such entropies depend either on the distribution (direct) or on the survival function (residual) or on both (paired). Maximizing this entropy without any constraint gives a extremely U-shaped (= bipolar) distribution. Under the constraint of fixed mean and variance. maximizing the cumulative entropy tries to transform a distribution in the direction of a bipolar distribution as far as it is allowed by the constraints. A bipolar distribution represents so-called contradictory information in contrast to minimum or no information. Only a few maximum entropy dist...
Purpose Traditionally, previous wound infection was considered a contraindication to secondary sk... more Purpose Traditionally, previous wound infection was considered a contraindication to secondary skin closure; however, several case reports describe successful secondary wound closure of wounds “preconditioned” with negative pressure wound therapy (NPWT). Although this has been increasingly applied in daily practice, a systematic analysis of its feasibility has not been published thus far. The aim of this study was to evaluate secondary skin closure in previously infected abdominal wounds following treatment with NPWT. Methods Single-center retrospective analysis of patients with infected abdominal wounds treated with NPWT followed by either secondary skin closure referenced to a group receiving open wound therapy. Endpoints were wound closure rate, wound complications (such as recurrent infection or hernia), and perioperative data (such as duration of NPWT or hospitalization parameters). Results One hundred ninety-eight patients during 2013–2016 received a secondary skin closure aft...
Background 40-50% of patients with colorectal cancer (CRC) will develop liver metastases (CRLM) d... more Background 40-50% of patients with colorectal cancer (CRC) will develop liver metastases (CRLM) during the course of the disease. One third of these patients will additionally develop pulmonary metastases. Methods 137 consecutive patients with CRLM, were analyzed regarding survival data, clinical, histological data and treatment. Results were stratified according to the occurrence of pulmonary metastases and metastases resection.
The purpose of this study was to evaluate the clinical and long-term outcome of patients who unde... more The purpose of this study was to evaluate the clinical and long-term outcome of patients who underwent covered stent treatment because of late-onset postpancreatectomy hemorrhage in a greater number of patients. A secondary study goal was to compare embolization techniques with covered stents regarding differences in early and late clinical outcome, rebleeding, and vessel patency. Between December 2008 and June 2015, 27 consecutive patients suffering from major hemorrhage after pancreatic surgery underwent either covered stent placement or embolization of the affected visceral artery. The patients' medical reports and radiologic images were retrospectively reviewed. The main study end point was technical and clinical success, including survival and complications; the secondary end points were perfusion distal to the target vessel and, for covered stent placement, patency of the affected artery. Covered stent placement was successful in 14 of 16 patients (88%); embolization was s...
Interactions between the liver and CD8+ T cells can lead to tolerance, due in part to CD8+ T cell... more Interactions between the liver and CD8+ T cells can lead to tolerance, due in part to CD8+ T cell death. To test whether this was the case in an extrahepatic infection, we investigated the fate and effector capacity of intrahepatic CD8+ T cells during lung-restricted influenza infection in mice. Virus-specific T cells accumulated in livers without detectable intrahepatic presentation of viral Ags, and this accumulation was not restricted to the contraction phase, but was apparent as early as day 5. Intrahepatic influenza-specific cells were functionally similar to those recovered from the bronchioalveolar lavage, based on ex vivo cytokine production and specific target lysis. Both adoptive transfer of liver lymphocytes and orthotopic liver transplant of organs containing accumulated effector T cells revealed that activated CD8s from the liver were viable, expanded during reinfection, and generated a memory population that trafficked to lymphoid organs. Thus, intrahepatic CD8+ T cell...
The transplanted liver elicits systemic tolerance, and the underlying mechanism may also account ... more The transplanted liver elicits systemic tolerance, and the underlying mechanism may also account for the persistence of liver infections, such as malaria and viral hepatitis. These phenomena have led to the hypothesis that antigen presentation within the liver is abortive, leading to T cell tolerance or apoptosis. Here we test this hypothesis in an optimized orthotopic liver transplantation model. In direct contradiction to this model, the liver itself induces full CD8+ T cell activation and differentiation. The effects of microchimerism were neutralized by bone marrow transplantation in the liver donor, and the lack of liver-derived antigen-presenting cells was documented by eight-color flow cytometry and by sensitive functional assays. We conclude that local antigen presentation cannot explain liver tolerance. On the contrary, the liver may be an excellent priming site for naive CD8+ T cells.
Activated CD8؉ T cells migrate to the liver at the end of an immune response and go through apopt... more Activated CD8؉ T cells migrate to the liver at the end of an immune response and go through apoptosis there, but this mechanism is impaired in mice lacking Toll-like receptor-4. This allowed us to test the importance of liver trapping in an ongoing immune response. In the absence of Toll-like receptor-4, reduced liver accumulation was associated with an increase in the circulating CD8؉ T cell pool, more long-lived memory T cells and increased CD8؉ T cell memory responses. Using experimental orthotopic liver transplantation, we showed that the effect of Toll-like receptor-4 on the formation of the CD8؉ T cell memory resides in the liver. Conclusion: These studies reveal a new function for the liver, which is to regulate the magnitude of T cell memory responses through a Toll-like receptor-4-dependent mechanism. (HEPATOLOGY 2007;45:178-186.) Materials and Methods Animals. C57BL/10SnJ mice (with normal TLR-4, referred to as WT) and C57BL/10ScN mice (which lack
Kupffer cells form a large intravascular macrophage bed in the liver sinusoids. The differentiati... more Kupffer cells form a large intravascular macrophage bed in the liver sinusoids. The differentiation history and diversity of Kupffer cells is disputed; some studies argue that they are derived from blood monocytes, whereas others support a local origin from intrahepatic precursor cells. In the present study, we used both flow cytometry and immunohistochemistry to distinguish 2 subsets of Kupffer cells that were revealed in the context both of bone marrow transplantation and of orthotopic liver transplantation. One subset was radiosensitive and rapidly replaced from hematogenous precursors, whereas the other was relatively radioresistant and long-lived. Both were phagocytic but only the former population was recruited into inflammatory foci in response to CD8+ T-cell activation. We propose the name “sessile” for the radioresistant Kupffer cells that do not participate in immunoinflammatory reactions. However, we found no evidence that these sessile Kupffer cells arise from immature i...
Background: The management of rectal cancer (RC) has substantially changed over the last decades ... more 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 International consensus criteria (ICC) have redefined borderline resectability for pan... more Background International consensus criteria (ICC) have redefined borderline resectability for pancreatic ductal adenocarcinoma (PDAC) according to three dimensions: anatomical (BR-A), biological (BR-B), and conditional (BR-C). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumour and vessels but that biological and conditional dimensions also are important. Methods Patients’ tumours were retrospectively defined borderline resectable according to ICC. The study cohort was grouped into either BR-A or BR-B and compared with patients considered primarily resectable (R). Differences in postoperative complications, pathological reports, overall (OS), and disease-free survival were assessed. Results A total of 345 patients underwent resection for PDAC. By applying ICC in routine preoperative assessment, 30 patients were classified as stage BR-A and 62 patients as stage BR-B. In total, 253 patients were considered R. The cohort...
Background: Liver resection is the most effective available therapy for patients with hepatocellu... more Background: Liver resection is the most effective available therapy for patients with hepatocellular carcinoma (HCC). The accurate selection of patients for surgery requires determination of technical resectability and the risk of recurrence, as well as assessment of liver function and functional reserve to avoid postoperative liver failure. Previous studies have underlined the effectiveness and reliability of the LiMAx® test to evaluate liver function preoperatively. Nevertheless, data concerning HCC evaluation are lacking. Methods: From 2014 to 2019, 92 patients with HCC underwent additional assessment of liver function using the LiMAx test prior to decision for or against liver resection. Preoperative LiMAx results were compared between cirrhotic and noncirrhotic liver. The clinical decision for surgery was evaluated applying the various liver function parameters available. Results: Forty-six patients underwent liver resection. The LiMAx results were higher in resected patients (...
The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transpla... more The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8 T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis...
Liver Anesthesiology and Critical Care Medicine, 2012
Organ allocation for donor livers in the USA follows an algorithm of medical urgency determined b... more Organ allocation for donor livers in the USA follows an algorithm of medical urgency determined by 3-month mortality risk based on objective laboratory values. However, a framework of local and regional distribution units is superimposed on the prioritization of organ recipients resulting in significant geographical differences with regard to waiting time and severity of disease at the time of transplant. Changes in the current allocation and distribution policies are evaluated but have to balance increased cold ischemia times and cost efficiency with equity. While the number of “standard criteria” deceased organ donors has remained relatively stable over the last decade, there was an increase of primarily older donors, donors with comorbidities, and donations after cardiac death. These so-called expanded criteria donors together with the use of donors with steatotic livers have broadened the donor pool, but bear an increased risk of organ dysfunction to the liver recipient. Currently clinical outcome research focuses on which patient population will benefit the most from which type of expanded criteria organ. In the United States, living donor liver transplantation has not evolved into a significant proportion of the total number of liver transplantations and remains an option predominantly for pediatric recipients and recipients who are not prioritized in the current allocation system.
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Papers by Ingo Klein