Epidemiological and Clinical Characteristics of Alveolar Echinococcosis: An Emerging Infectious Disease in Alberta, Canada.

Human alveolar echinococcosis (AE) is a zoonotic cestode infection which is usually fatal in the absence of treatment. Treatment involves major surgery or indefinite antiparasitic therapy. The incidence is rising in Europe and Asia, with an increased risk observed in immunocompromised individuals. Previously, AE acquisition in North America was extremely rare, except for one remote Alaskan Island. Recent studies have demonstrated a new European-like strain of Echinococcus multilocularis (Em) in wildlife and in human AE in western Canada. We report the experience of all AE patients diagnosed in Alberta. Each was diagnosed by histopathology, serology, and PCR-confirmed by a reference laboratory. Seventeen cases of human AE, aged 19-78 years, nine females, were diagnosed between 2013 and 2020: all definitely or probably acquired in Alberta. Six lived in urban areas, and 14 had kept dogs. In eight, the lesions were found incidentally on abdominal imaging performed for other indications. Six were immunocompromised to varying degrees. Six were first diagnosed at surgery. All have been recommended benzimidazole therapy. One died of surgical complications. Clinicians should be aware of this diagnostic possibility in patients presenting with focal nonmalignant hepatic mass lesions. Greater urbanization of coyotes, the predominant definitive host of Em in Alberta, and growing numbers of immune suppressed individuals in the human population may lead to increasing recognition of AE in North America.

Impact of Safe Distance on Long-Term Outcome After Surgical Therapy of Alveolar Echinococcosis.

INTRODUCTION: In humans, alveolar echinococcosis (AE) is a serious helminthic disease. Additionally to a long-term medical treatment, in all suitable cases a complete surgical resection with a 20-mm safe distance (minimal distance of larval tissue to resection margin) is recommended. We analyzed the influence of the safe distance and the effect of the postoperative anthelmintic prophylaxis on the long-term outcome of patients who underwent surgery with curative intent. OBJECTIVE: Ninety-two operated patients were evaluated regarding the safe distance, the duration of medical therapy with benzimidazole derivates, and the further course of AE. RESULTS: Median follow-up after surgical procedure was 8.3 years. Twelve patients had a safe distance of 20 mm or more, 16 patients between 10 and 19 mm, 21 patients between 1 and 10 mm, and 10 patients 1 mm. In a further 33 patients, the affected liver was resected without any safe distance. Recurrence of AE was seen in 15 patients between 4 months and 24 years after initial operation. Safe distances of patients with recurrent disease were: 13 ×  no safe distance, one patient with 1-mm and one patient with 13-mm safe distance. In all patients except one with recurrent AE, postoperative therapy with benzimidazole derivates was stopped. CONCLUSION: A safe distance of at least 1 mm in combination with medical anthelmintic treatment continuing for two years might offer a good chance of being disease-free long term, but the exact period of medical treatment needed is not defined. The therapy regime should be determined through an interdisciplinary approach in specialized centers.

Sensitive and specific immunohistochemical diagnosis of human alveolar echinococcosis with the monoclonal antibody Em2G11.

BACKGROUND: Alveolar echinococcosis (AE) is caused by the metacestode stage of Echinococcus multilocularis. Differential diagnosis with cystic echinococcosis (CE) caused by E. granulosus and AE is challenging. We aimed at improving diagnosis of AE on paraffin sections of infected human tissue by immunohistochemical testing of a specific antibody. METHODOLOGY/PRINCIPAL FINDINGS: We have analysed 96 paraffin archived specimens, including 6 cutting needle biopsies and 3 fine needle aspirates, from patients with suspected AE or CE with the monoclonal antibody (mAb) Em2G11 specific for the Em2 antigen of E. multilocularis metacestodes. In human tissue, staining with mAb Em2G11 is highly specific for E. multilocularis metacestodes while no staining is detected in CE lesions. In addition, the antibody detects small particles of E. multilocularis (spems) of less than 1 µm outside the main lesion in necrotic tissue, liver sinusoids and lymphatic tissue most probably caused by shedding of parasitic material. The conventional histological diagnosis based on haematoxylin and eosin and PAS stainings were in accordance with the immunohistological diagnosis using mAb Em2G11 in 90 of 96 samples. In 6 samples conventional subtype diagnosis of echinococcosis had to be adjusted when revised by immunohistology with mAb Em2G11. CONCLUSIONS/SIGNIFICANCE: Immunohistochemistry with the mAb Em2G11 is a new, highly specific and sensitive diagnostic tool for AE. The staining of small particles of E. multilocularis (spems) outside the main lesion including immunocompetent tissue, such as lymph nodes, suggests a systemic effect on the host.

Endotoxin elimination in sepsis: physiology and therapeutic application.

PURPOSE: The present review summarizes key papers on the elimination of endotoxin in human. RESULTS: Lipopolysaccharides (LPS) are extremely strong stimulators of inflammatory reactions, act at very low concentrations, and are involved in the pathogenesis of sepsis and septic shock. Elimination of LPS is vital; therefore, therapeutic detoxification of LPS may offer new perspectives. Multiple mechanisms eliminate LPS in human comprising molecules that bind LPS and prevent it from signaling, enzymes that degrade and detoxify LPS, processes that inactivate LPS following uptake into the reticulo-endothelial system, and mechanisms of adaptation that modify target cells responding to LPS. These mechanisms are powerful and detoxification capacity adapts as required. Results of therapeutic interventions aiming at the removal of LPS by medication (immunoglobulins) or extracorporeal means are controversial. At least in part, animal experiments revealed increased survival. Human trials confirmed the positive effects on parameters of secondary importance, but not on morbidity or survival which was attributed to the heterogeneity of patients suffering from consequences of severe infectious diseases and sepsis. CONCLUSION: The hypothesis of LPS-driven inflammatory processes remains very attractive. However, few therapeutic yet immature options have been developed to date.

Effect of major abdominal surgery on the host immune response to infection.

PURPOSE OF REVIEW: The present review summarizes key studies on the effects of major abdominal surgery on the host response to infection published during the last 18 months. RECENT FINDINGS: Surgical trauma causes stereotyped systemic proinflammatory and compensatory anti-inflammatory reactions. It is leukocyte reprogramming rather than general immune suppression. The list of recent findings is long. Preoperative infectious challenge was found to increase survival. Obesity is associated with increased production of interleukin-17A in peritonitis. Abdominal surgery alters expression of toll-like receptors (TLRs). The acute phase reaction down-regulates the transcription factor carbohydrate response element binding protein. Myosin light chain kinase activation is a final pathway of acute tight junction regulation of gut barrier and zonula occludens 1 protein is an essential effector. The brain is involved in regulating the immune and gut system. Elimination of lipopolysaccharide is challenging. Th1/Th2 ratio is lowered in patients with postoperative complications. Cholinergic anti-inflammatory pathways can inhibit tissue damage. The new substance PXL01 prevents adhesions. Postoperative infection causes incisional hernias. Hypothermia reduced human leukocyte antigen DR surface expression and delayed tumor necrosis factor clearance. Systems biology identified interferon regulatory factor 3 as the negative regulator of TLR signaling. Protective immunity could contribute defeating surgical infections. SUMMARY: Systemic inflammation is the usual response to trauma. All organs seem to be involved and linked up in cybernetic systems aiming at reconstitution of homeostasis. Although knowledge is still fragmentary, it is already difficult to integrate known facts and new technologies are required for information processing. Defining criteria to develop therapeutic strategies requires much more insight into molecular mechanisms and cybernetics of organ systems.

Hepatic infestation of Echinococcus multilocularis with extension to regional lymph nodes.

OBJECTIVE: The objective of this paper is to prove lymph node infestation by Echinococcus multilocularis and provide evidence for systematic lymph node dissection in curative resections for alveolar echinococcosis (AE). BACKGROUND: Human AE is a life threatening parasitic condition, usually caused by an intrahepatic infiltrative and destructive growth of the larvae E. multilocularis. WHO guidelines provide radical hepatic resection for curative treatment. However, the current norms do not consider dissection of regional lymph nodes. No report to date has visualized concurrent lymph node infestation. METHODS: Radical excision of infested liver including regional lymph nodes with subsequent histological examination was carried out in a patient suffering from AE. The literature was reviewed and a revised state-of-the-art treatment of AE deduced. RESULTS: Upon inspection the liver displayed macroscopic features of AE, in contrast to the regional lymph nodes which appeared unsuspicious. Further histological analysis confirmed regional lymph node infestation of E. multilocularis. CONCLUSIONS: This is the first publication on histological evidence of E. multilocularis in regional hepatic lymph nodes, and thus, demonstrating dissemination from the liver. Since AE can spread through lymphatic drainage, even without causing macroscopic conspicuity, resection should not be resumed to the liver tissue only, but rather to consider the routine removal of regional lymph nodes as well. Omission of lymph node dissection can leave behind parasitic tissue and surgical procedures erroneously judged as curative.

After 3 years of starvation: duodenum swallowed remaining stomach.

A 42-year-old morbidly obese patient (BMI 44.1 kg/m(2)) was admitted to our emergency room with upper abdominal pain, nausea, and cholestasis. Nine years ago, a vertical banded gastroplasty had been performed (former BMI 53.5 kg/m(2)) with a subsequent weight loss to BMI 33.0 kg/m(2). After regaining weight up to a BMI of 47.6 kg/m(2), 5 years ago a conversion to a gastric bypass was realized. A computed tomography of the abdomen showed an invagination of the remaining stomach into the duodenum causing obstruction of the orifice of common bile duct. The patient underwent an open desinvagination of the intussusception and resection of the remaining stomach. Gastroduodenal intussusception is rare and mostly secondary to gastric lipoma. To prevent this rare but serious complication, the remaining stomach could be fixed at the crura of the diaphragm, tagged to the anterior abdominal wall by temporary gastrostomy tube, or resected.

Palliative operation for the treatment of alveolar echinococcosis.

BACKGROUND: The World Health Organization guidelines recommend radical hepatic resection for definite treatment of alveolar echinococcosis (AE), because it can cure the patient. However, parasitic masses are not entirely removable in about 70% of patients. Even so, palliative resections are carried out, although cure cannot be achieved. As conservative treatment has improved, the role of palliative surgical procedures has to be redefined. METHODS: Critical appraisal of published reports on palliative resections for AE and estimation of the level of evidence and grade of recommendation. RESULTS: Prospective randomized trials comparing palliative resections, radical resections, and conservative treatment are lacking. Most papers analyzed case series retrospectively. The number of palliative operations is significant. In the past, palliative resections were recommended in order to enhance anthelminthic drug efficacy but advances in conservative and interventional treatment improved the prognosis of AE. Prolonged survival by systematic palliative resections is not evident. However, palliative surgery is an option to treat persistent bacterial infection, fistulas, and obstructing or compressing masses. The indication is based on individual considerations and decisions. CONCLUSION: Curative surgery for AE is feasible if parasitic tissue is entirely removable. The benefit of palliative resections is uncertain because long-term results of conservative treatment are favorable. Palliative surgery is an option for complications not being manageable otherwise.

Effect of major abdominal surgery on endotoxin release and expression of Toll-like receptors 2/4.

BACKGROUND: Surgery can cause endotoxemia, and endotoxin aggregates to Toll-like receptors and acts proinflammatory; repetitive endotoxin application can cause tolerance. The objective of the study is to characterize early inflammatory response and expression of TLR2/4 during major abdominal surgery. MATERIALS AND METHODS: A prospective controlled study of 20 patients with elective major abdominal surgery was performed. Blood samples were collected before and at a defined time after surgery. Endotoxemia, capability of plasma to inactivate endotoxin, cytokine release of LPS-stimulated mononuclear cells, quantitative TLR mRNA expression, and plasma concentrations of TNFalpha, IL-6, C-reactive protein (CRP), alpha(1)-acid glycoprotein, transferrin, and albumin were measured. RESULTS: Surgery caused endotoxemia (p = 0.053), and the capability of plasma to inactivate endotoxin was reduced (p = 0.0002). Two hours postoperatively, the plasma concentrations of TNFalpha and IL-6 peaked significantly, but the liberation capacity of mononuclear cells for cytokines (TNFalpha, IL-1beta, IL-6) was significantly reduced. The concentration of CRP and alpha(1)-acid glycoprotein peaked 48 h postoperatively, but those of transferrin and albumin were significantly decreased (p < 0.001, respectively). Median mRNA expression of TLR2 and TLR4 of mononuclear cells was not altered, and there was no obvious trend over time. CONCLUSION: Major abdominal surgery is associated with endotoxemia, reduced capability of plasma to inactivate endotoxin, cytokine kinetics resembling those of healthy man after experimentally given LPS, and substantial acute-phase reaction. The cytokine liberation of mononuclear cells suggests a state of postoperative endotoxin tolerance. Despite these substantial changes, trends in TLR2/4 expression are not obvious.

Long-term experience on surgical treatment of alveolar echinococcosis.

INTRODUCTION: Alveolar echinococcosis (AE) is life-threatening and reports on surgical procedures and results are rare, but essential. MATERIALS AND METHODS: Longitudinal surveillance and long-term follow-up of patients surgically treated for AE during the periods 1982-1999 (group A) and 2000-2006 (group B). SETTING: University hospital within an endemic area. RESULTS: The median (min-max) follow-up period was 141 (5-417) months. Forty-eight surgical procedures were performed in 36 patients with AE: 63% were partial resections of the liver (additional extrahepatic resection in ten of them), 17% just extrahepatic resections, 10% biliodigestive anastomosis, and 10% exploratory laparotomies. Seventy-five percent of the operations were first-time procedures, 25% done due to a relapse. Forty-two percent of the operations were estimated to be curative (R0), whereas 58% were palliative (R1, R2). All patients had additional medical treatment and periodical follow-up. Two out of 18 (11%) patients, estimated to have had curative surgery, developed a relapse 42 and 54 months later. R0-resection rates depended on the primary, neighboring, metastasis stage of AE (S1, 100%; S2, 100%; S3a, 33%; S3b, 27%; S4, 11%). During the period 2000-2006 elective radical surgery for AE was done only if a safe distance of at least 2 cm was attainable. This concept was associated with an increased R0-resection rate of 87% for group B compared to 24% for group A. Operative procedures done to control complicated courses of AE (jaundice, cholangitis, vascular compression, bacterial superinfection) have not been curative (R2) in 82% because the disease had spread into irresectable structures. Morbidity was 19%. All patients with curative resections are alive. Fifty-six percent of the patients with palliative treatment are alive as long as 14-237 months, 28% died from AE 164-338 months after diagnosis (late lethality), and 17% died due to others diseases 96-417 months after diagnosis of AE. One out of seven (14%) patients suffering from suppurative parasitic necrosis died because it was impossible to control systemic sepsis (3% hospital lethality). CONCLUSION: Curative surgery for AE is feasible if the parasitic mass is removable entirely. The earlier the stage, the more frequent is R0 resectability. The observance of a minimal safe distance increases the rate of R0 resections. The benefit of palliative surgery is uncertain due to favorable long-term results of medical treatment alone. However, necrotic tissue is at risk of bacterial superinfection, which can cause life-threatening sepsis. Palliative surgery is an option to treat complications, which could not be managed otherwise.

Endotoxemia and endotoxin tolerance in patients with ARDS.

BACKGROUND: The significance of endotoxemia in man is controversial, induces cytokine release and stimulates the immune system. Exaggerated cytokine release of mononuclear cells was observed in acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, repetitive administration of endotoxin can cause tolerance. OBJECTIVE: To investigate endotoxemia, plasma TNFalpha, IL-1beta, IL-6, the liberation capacity of those cytokines from mononuclear cells after LPS challenge (Delta values), and plasma antibodies to endotoxins and alpha-hemolysin of Staphylococcus aureus in ALI/ARDS. DESIGN: A prospective clinical study was conducted. SETTING: The study was carried out at the University Hospital Ulm, Ulm, Germany. SUBJECTS: The respondents were 23 patients with ALI/ARDS. INTERVENTIONS: ALI/ARDS was defined according to the American-European Consensus Conference on ARDS. Blood was collected periodically. Parameters were measured by LAL or ELISA. RESULTS: ARDS (P(a)O(2)/F(i)O(2) < 200) revealed higher endotoxemia (0.22-0.46 [0.06-1.15] EU/mL vs 0.05-0.14 [0.02-0.63] EU/mL) than ALI (P(a)O(2)/F(i)O(2) > 200) but lower DeltaIL-6 (124-209 [10-1214] pg/mL vs 298-746 [5-1797] pg/mL), DeltaTNFalpha (50-100 [6-660] pg/mL vs 143-243 [12-2795] pg/mL), and DeltaIL-1 (2-3 [0-26] pg/mL vs 2-14 [0-99] pg/mL). Endotoxemia correlated negative with P(a)O(2)/F(i)O(2) (r, -0.44 to -0.50). All patients presented antibodies to lipopolysaccharides and alpha-hemolysin, but the level did not correlate with P(a)O(2)/F(i)O(2). CONCLUSIONS: ALI/ARDS is associated with endotoxemia. The more severe the disease, the more intense is endotoxemia but the lower is the capacity of mononuclear cells to release cytokines (tolerance). Antibodies against Gram-positive and Gram-negative bacteria are detectable in the plasma but without relation to P(a)O(2)/F(i)O(2).

Choledochal cyst as a diagnostic pitfall: a case report.

INTRODUCTION: Choledochal cysts are rare congenital anomalies. Their diagnosis is difficult, particulary in adults. CASE PRESENTATION: This case report demonstrates the diagnostic and therapeutic pitfalls. CONCLUSION: To prevent cost-intensive and potentially life-threating complications, a choledochal cyst must be considered in the differential diagnosis whenever the rather common diagnosis of a hepatic cyst is considered.

Laparoscopic cholecystectomy associated lethal hemorrhage.

BACKGROUND AND OBJECTIVES: Blood oozing after cholecystectomy is a rare but potentially life-threatening complication. Recently, 2 patients died from this cause. The deaths resulted in criminal proceedings and medical experts were called in. The objective of this report is to describe their findings and to elucidate preoperatively unknown risk factors of bleeding. METHODS: Medical records, autopsy, and histological examination of the liver, heart, pancreas, spleen, and kidney pertaining to 2 recent cases of laparoscopic cholecystectomy were examined. Current literature on this topic was reviewed. RESULTS: Preoperative risks included renal insufficiency, diabetes mellitus, and cardiopathy. The histological examination, in particular of the gallbladder bed of the liver, disclosed siderosis, inflammation, and fatty degeneration. These factors supported and perpetuated blood oozing. Postoperative ultrasonography and a hemogram might have detected and prevented death. CONCLUSION: Inflammatory alterations, siderosis, and fatty degeneration of the liver are risk factors of postoperative hemorrhage. Autopsy and histological examination can detect those factors. Adequate postsurgical observation is mandatory, especially for patients at risk.

Pre-clinical evaluation of the activity of irinotecan as a basis for regional chemotherapy.

BACKGROUND: Irinotecan alone and in combination with 5-fluorouracil (5-FU) displays potent activity in advanced colorectal cancer. The aim of this study was to estimate the potential efficacy of irinotecan for hepatic arterial infusion (HAI) chemotherapy. MATERIALS AND METHODS: We investigated the anti-proliferative effects of irinotecan alone and in combination with 5-FU in HT29 and NMG64/84 colon and COLO-357, MIA PaCa-2 and PANC-1 pancreatic cancer cell lines and in fresh tumors from patients with primary colon cancer (n=2) and colorectal liver metastases (n=11) in vitro, using the MTT growth assay and the human tumor colony-forming assay (HTCA), mimicking conditions which are achievable during HAI. RESULTS: Irinotecan displayed concentration- and time-dependent cytotoxic effects in all tested cell lines. Treatment of cell lines with irinotecan followed by 5-FU did not result in synergistic anti-proliferative effects. In the HTCA, the sensitivity of each cell line varied depending on the incubation times (30, 90, 180 and 1440 min). Independent of the individual sensitivity, the IC50 concentration and time products were lowest when incubating with irinotecan for 30 min for all cell lines. The IC50 of irinotecan in HT29, NMG64/84, COLO-357, MIA PaCa-2 and PANC-1 cells at 30 min were 200, 160, 100, 400 and 150 microg/ml, respectively, in the HTCA. All isolated tumor samples displayed concentration-dependent inhibition of colony formation after exposure to irinotecan for 30 min. The IC50 of irinotecan of 5 of the 11 liver metastases was <100 microg/ml. CONCLUSION: Irinotecan seems to be suitable for HAI therapy phase II studies. Due to the observation that several liver metastases had IC50 values that may be clinically achievable by HAI, patients with such tumors may benefit in the future from HAI using irinotecan.