Bruno M. Schmied

Primary malignant hepatic epithelioid hemangioendothelioma : A comprehensive review of the literature with emphasis on the surgical therapy

Malignant hepatic epithelioid hemangioendothelioma (HEH) is a rare malignant tumor of vascular origin with unknown etiology and a variable natural course. The authors present a comprehensive review of the literature on HEH with a focus on clinical outcome after different therapeutic strategies. All published series on patients with HEH (n = 434 patients) were analyzed from the first description in 1984 to the current literature. The reviewed parameters included demographic data, clinical manifestations, therapeutic modalities, and clinical outcome. The mean age of patients with HEH was 41.7 years, and the male‐to‐female ratio was 2:3. The most common clinical manifestations were right upper quadrant pain, hepatomegaly, and weight loss. Most patients presented with multifocal tumor that involved both lobes of the liver. Lung, peritoneum, lymph nodes, and bone were the most common sites of extrahepatic involvement at the time of diagnosis. The most common management has been liver transplantation (LTx) (44.8% of patients), followed by no treatment (24.8% of patients), chemotherapy or radiotherapy (21% of patients), and liver resection (LRx) (9.4% of patients). The 1‐year and 5‐year patient survival rates were 96% and 54.5%, respectively, after LTx; 39.3% and 4.5%, respectively, after no treatment, 73.3% and 30%, respectively, after chemotherapy or radiotherapy; and 100% and 75%, respectively, after LRx. LRx has been the treatment of choice in patients with resectable HEH. However, LTx has been proposed as the treatment of choice because of the hepatic multicentricity of HEH. In addition, LTx is an acceptable option for patients who have HEH with extrahepatic manifestation. Highly selected patients may be able to undergo living‐donor LTx, preserving the donor pool. The role of different adjuvant therapies for patients with HEH remains to be determined. Cancer 2006.

Wound complications following kidney and liver transplantation.

Abstract:  Advances in surgical techniques and immunosuppression (IS) have led to an appreciable reduction in postoperative complications following transplantation. However, wound complications as probably the most common type of post‐transplantation surgical complication can still limit these improved outcomes and result in prolonged hospitalization, hospital readmission, and reoperation, consequently increasing overall transplant cost. Our aim was to review the literature to delineate the evidence‐based risk factors for wound complications following kidney and liver transplantation (KTx, LTx), and to present the preventive and therapeutic modalities for this bothersome morbidity. Generally, wound complications are categorized as superficial and deep wound dehiscences, perigraft fluid collections and seroma, superficial and deep wound infections, cellulitis, lymphocele and wound drainage. The results of several studies showed that the most important risk factors for wound complications are IS and obesity. Additionally, there are surgical and/or technical factors, including type of incision, reoperation, and surgeons expertise, as well as comorbidities such as advanced age, diabetes mellitus, malnutrition, and uremia. Preventive management of wound complications necessitates defining their etiological factors so that their detrimental effects on healing processes can be addressed and reduced. IS modalities and agents, especially sirolimus (SRL), and steroids (ST) should be adjusted according to the patients co‐existing risk factors. SRL should be administered three months after transplantation and ST should be tapered as soon as possible. A body mass index (BMI) lower than 30 kg/m2 is advisable for inclusion in a transplantation program, but higher BMIs do not exclude recipients. Surgical risk factors can be prevented by applying precise surgical techniques. Therapeutic modalities must focus on the most efficient and cost‐effective medications and/or interventions to facilitate and improve wound healing.

Safe and early discharge after colorectal surgery due to C-reactive protein: a diagnostic meta-analysis of 1832 patients.

Objective:To assess the predictive value of C-reactive protein (CRP) level for postoperative infectious complications after colorectal surgery. Background:Postoperative infectious complications after colorectal surgery are frequent and associated with relevant short- and long-term sequelae. Therefore, the identification of a diagnostic tool for early recognition of postoperative infectious complications is of cardinal importance. Methods:A meta-analysis was performed for diagnostic studies evaluating CRP as a predictor for postoperative infectious complications on days 1 to 5 after colorectal surgery. Results:Six studies including a total of 1832 patients were identified. The best performance of CRP to predict postoperative infectious complications was on postoperative day 4, on which the mean CRP cutoff value was 135 mg/L (SD: 10 mg/L), the pooled sensitivity 68% (95% CI: 57%–79%), the specificity 83% (95% CI: 77%–90%) and the negative predictive value 89% (95% CI: 87%–92%). The pooled area under the receiver operating characteristic curve was 0.81 (95% CI: 0.73–0.89). Conclusions:This diagnostic meta-analysis of 1832 patients-–the first in the literature–-provides compelling evidence that C-reactive protein on postoperative day 4 has a high negative predictive value for infectious complications of 89%. Therefore, CRP measurement allows safe and early discharge of selected patients after colorectal surgery.

Impaired islet turnover in human donor pancreata with aging

OBJECTIVE The prevalence of type 2 diabetes mellitus escalates with aging although beta-cell mass, a primary parameter of beta-cell function, is subject to compensatory regulation. So far it is unclear whether the proliferative capacity of pancreatic islets is restricted by senescence. MATERIALS AND METHODS Human pancreatic tissue from n=20 non-diabetic organ donors with a mean age of 50.2+/-3.5 years (range 7-66 years) and mean body mass index of 25.7+/-0.9 kg/m(2) (17.2-33.1 kg/m(2)) was morphometrically analyzed to determine beta-cell volume, beta-cell replication, beta-cell apoptosis, islet neogenesis, and pancreatic duodenal homeobox-1 (PDX-1) expression. RESULTS Relative beta-cell volume in human pancreata (mean 2.3+/-0.2%) remains constant with aging (r=0.26, P=ns). Beta-cell replication (r=0.71, P=0.0004) decreases age-dependently, while beta-cell apoptosis does not change significantly (r=0.42, P=0.08). Concomitantly, PDX-1 expression is downregulated with age in human pancreatic tissue (r=0.65, P=0.002). The rate of islet neogenesis is not affected by aging (r=0.13, P=ns). CONCLUSIONS In non-diabetic humans, aging is linked with impaired islet turnover possibly due to reduced PDX-1 expression. As beta-cell replication is considered to be the main mechanism responsible for beta-cell regeneration, these changes restrict the flexibility of the aging human pancreas to adapt to changing demands for insulin secretion and increase the risk for the development of diabetes mellitus in older subjects.

In vivo accuracy assessment of a needle-based navigation system for CT-guided radiofrequency ablation of the liver.

Computed tomography (CT)-guided percutaneous radiofrequency ablation (RFA) has become a commonly used procedure in the treatment of liver tumors. One of the main challenges related to the method is the exact placement of the instrument within the lesion. To address this issue, a system was developed for computer-assisted needle placement which uses a set of fiducial needles to compensate for organ motion in real time. The purpose of this study was to assess the accuracy of the system in vivo. Two medical experts with experience in CT-guided interventions and two nonexperts used the navigation system to perform 32 needle insertions into contrasted agar nodules injected into the livers of two ventilated swine. Skin-to-target path planning and real-time needle guidance were based on preinterventional 1 mm CT data slices. The lesions were hit in 97% of all trials with a mean user error of 2.4 +/- 2.1 mm, a mean target registration error (TRE) of 2.1 +/- 1.1 mm, and a mean overall targeting error of 3.7 +/- 2.3 mm. The nonexperts achieved significantly better results than the experts with an overall error of 2.8 +/- 1.4 mm (n=16) compared to 4.5 +/- 2.7 mm (n=16). The mean time for performing four needle insertions based on one preinterventional planning CT was 57 +/- 19 min with a mean setup time of 27 min, which includes the steps fiducial insertion (24 +/- 15 min), planning CT acquisition (1 +/- 0 min), and registration (2 +/- 1 min). The mean time for path planning and targeting was 5 +/- 4 and 2 +/- 1 min, respectively. Apart from the fiducial insertion step, experts and nonexperts performed comparably fast. It is concluded that the system allows for accurate needle placement into hepatic tumors based on one planning CT and could thus enable considerable improvement to the clinical treatment standard for RFA procedures and other CT-guided interventions in the liver. To support clinical application of the method, optimization of individual system modules to reduce intervention time is proposed.

Transdifferentiation of human islet cells in a long-term culture

It has been established that ductal cells or precursor cells within the ductal tree of the pancreas can differentiate into islet cells. Although islet cells can also form exocrine cells, it is unclear whether they arise from precursor (stem) cells or from mature endocrine cells by transdifferentiation. Using a defined culture medium and technique for islet purification, for the first time we were able to maintain human islets in culture for more than a year. Multilabeling immunohistochemical and immunoelectron microscopic examination of the islets at different days of culture using islet cell markers (antibodies to hormones, neuron-specific enolase, chromogranin A) and ductal cell markers (cytokeratins 7 and 19, carbonic anhydrase II, DU-PAN2, CA 19-9, and MUC1) revealed that endocrine cells gradually transdifferentiate to ductal, acinar, and intermediary cells. Although islet hormone secretion ceased after day 28 in culture, endocrine cells were still detectable at day 60. However, later, all endocrine and exocrine cells were replaced by undifferentiated cells that expressed neuron-specific enolase, chromogranin A, laminin, vimentin, cytokeratin 7 and 19, &agr;-1-antitrypsin, transforming growth factor-&agr;, and epidermal growth factor receptor. Our data thus show that, under proper conditions, human islets can be maintained in vitro over a long period and that, in the culture condition, islet cells seem to transdifferentiate to exocrine cells and undifferentiated cells, which may be considered pancreatic precursor (stem) cells.

Pancreatic Cell Lines: A Review

Pancreatic cancer has an extremely poor prognosis and lacks early diagnostic and therapeutic possibilities, mainly because of its silent course and explosive fatal outcome. The histogenesis of the disease and early biochemical and genetic alterations surrounding carcinogenesis are still controversial. In vitro studies offer a useful tool to study physiologic, pathophysiologic, differentiation, and transformation processes of cells and to understand some of these shortcomings. The extreme difficulties in isolating individual pancreatic cells and their purification by maintaining their native characteristics have limited research in this area. This review is intended to present and discuss the current availability of rodent and pancreatic cell lines, their differences as well as the difficulties, limitations, and characteristics of these cultured cells. Discussed are in vitro models; ductal, islet, and acinar cell culture; cell differentiation; cell transformation, including genetic and chromosomal alterations; as well as tumor cell markers. Also addressed are the advantages and problems associated with the cell culture in humans and rodents. Advancements in tissue culture technique and molecular biology offer steady progress in this important line of research. The improved methods not only promise the establishment of &bgr;-cell cultures for the treatment of diabetes, but also for studying sequential genetic alterations during pancreatic carcinogenesis and in understanding the tumor cell origin.

Diagnostic accuracy of C-reactive protein and white blood cell counts in the early detection of inflammatory complications after open resection of colorectal cancer: a retrospective study of 1,187 patients.

Purpose Although widely used, there is a lack of evidence concerning the diagnostic accuracy of C-reactive protein (CRP) and white blood cell counts (WBCs) in the postoperative period. The aim of this study was to evaluate the diagnostic accuracy of CRP and WBCs in predicting postoperative inflammatory complications after open resection of colorectal cancer.

An integrative approach for the transplantation of high-risk sensitized patients.

Background. Sensitized patients have a lower chance of receiving a crossmatch-negative kidney and, if transplanted, are at risk of antibody-mediated allograft rejection. Methods. For safe and timely transplantation of sensitized patients at our center, we developed an integrative algorithm that includes identification of high-risk patients, good human leukocyte antigen match, inclusion in the Eurotransplant Acceptable Mismatch Program when applicable, apheresis, anti-CD20 therapy, posttransplant antibody monitoring, and protocol biopsies. Thirty-four high-risk recipients of a deceased donor kidney (DDK: n=28) or living donor kidney (LDK: n=6) were transplanted using this algorithm. Results. One-year graft survival, death-censored graft survival, and patient survival rates in DDK recipients were 92.4%, 96.4%, and 95.8%, respectively. No graft loss or patient death was observed in the six LDK patients. Median serum creatinine at 1 year in DDK and LDK recipients was 1.2 and 1.4 mg/dL, respectively. Eleven DDK and three LDK patients experienced at least one biopsy-proven acute rejection episode, mostly showing borderline changes. Antibody-mediated rejection without graft loss was diagnosed in two DDK and one LDK patients. Delayed graft function was observed in 13 DDK and 1 LDK patients. Infectious complications were infrequent. Conclusions. We describe an algorithm for the categorization and treatment of presensitized high-risk patients. This protocol provides effective prevention of antibody-mediated rejection and is associated with a low rate of side effects and good graft outcome.

The link between exocrine pancreatic cancer and the endocrine pancreas

SummaryBackground. The histogenesis of pancreatic cancer is still debatable. Ductal, ductular, and acinar cells all have been declared the tumor progenitor cells. Our long-term human and experimental studies indicate that pancreatic ductal adenocarcinomas arise within ductal cells and islets. Supporting studies are presented in this article. Methods. Several human studies and experimental studies on Syrian hamsters conducted within the last 20 years were used in this article. Hamster and human islets were established, and their growth and morphologic changes were examined electron microscopically, immunohistochemically, cytogenetically, and molecular biologically. Results. Studies using the hamster pancreatic cancer model showed that most pancreatic adenocarcinomas develop within islets, most probably from stem cells, which are also believed to be the progenitor cells for tumors that develop within ducts. Studies in newly established human and hamster islets culture validated the immense potential of islet cells to differentiate and become malignant. The higher susceptibility of islet cells to become malignant could be related to their high drug-metabolizing enzymes and their high proliferation rate. Dietary studies indicate that the promoting effect of a high-fat diet on pancreatic carcinogenesis is unrelated to the energy intake, but rather is related to its effect on islet cell replication.Conclusion. Experimental and human studies during 20 years of research in our laboratories point to the importance of pancreatic islets in the development of ductal-type adenocarcinomas. We believe that pancreatic cancer that develops within ducts, but more frequently within islets, derives from pancreatic stem cells that are distributed within the ductal trees and within the islets