Gastrointestinal stromal tumour (GIST): British Sarcoma Group clinical practice guidelines.

BACKGROUND: British Sarcoma Group guidelines for the management of GIST were initially informed by those published by the European Society of Clinical Oncology. This update was written by a group of experts to includes a discussion of the highlight improvements in our knowledge of the disease and recent treatment developments. The guidelines include sections on Incidence, Aetiology, Diagnosis, including risk assessment, Treatment and Follow-up. METHODS: A careful review of the literature was performed to ensure that wherever possible recommendations are supported by the results of clinical trials or substantive retrospective reports. Areas of uncertainty are indicated appropriately. CONCLUSION: Guidelines represent a consensus view of current best clinical practice. Where appropriate, key recommendations are given and the levels of evidence and strength of recommendation gradings are those used by the European Society for Medical Oncology (ESMO).

Anti-oxidant and anti-inflammatory potential of different polymer-based mesalamine delayed-release granules in TNBS-induced ulcerative colitis in wistar rats.

Ulcerative colitis (UC) is an inflammatory condition of colon characterized by severe damage to the innermost colon tissues. A number of studies described the use of medication delivery systems based on natural polymers like polysaccharides for the purpose of reaching the colon. In this research, polymer-based mesalamine delayed-release granules (DRGs) were tested for their antioxidant and anti-inflammatory efficacy against UC. Chitosan (C), pectin (P), and pectin-chitosan (PC) mesalamine (M) DRGs were prepared and characterized. Data revealed satisfactory compatibility, flow, packing properties, drug release pattern, and delayed drug release by DRGs. Wistar rats were treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS) (100 mg/kg) via rectal administration. Mesalamine and mesalamine DRGs (50 mg/kg) were administered orally separately for 14 days. Biomarkers of oxidative stress, inflammation, hematological tests, colon profile, and histopathology were performed. The findings demonstrated the good efficacy of the polysaccharides in delivering mesalamine to colon. Mesalamine and mesalamine DRGs based on various polymers showed significant antioxidant and anti-inflammatory effects in rats with UC. Mesalamine granules significantly attenuated colon lipid peroxidation, nitrites, myeloperoxidase activity, and interleukin-1ß levels, and improved anti-oxidants (GSH, SOD). Data showed upregulation of Nrf2 activity by mesalamine granules with CM-DRGs showing maximum effect. Mesalamine and different polymer-based mesalamine DRGs significantly attenuated TNBS-induced decline in body weight, ulcer severity, and colon damage. CM-DRGs showed the most pronounced ameliorative effect on colon and hematology parameters via anti-oxidant and anti-inflammatory activities. Chitosan can be used as a carrier for oral colon delivery of mesalamine in DRG formulation for enhanced therapeutic efficacy in UC.

Simple biliary cysts of the liver can be lined by mucinous epithelium.

AIMS & METHODS: Simple biliary cysts of the liver are described to be lined by biliary epithelium and may be managed nonsurgically or by deroofing only. By contrast, its important differential diagnosis-mucinous cystic neoplasm (MCN)-is at least focally lined by mucinous epithelium, has malignant potential, and therefore should be resected. Following anecdotal observations in routine diagnostic practice, the following case series was assembled to confirm whether simple biliary cysts of the liver can be lined by mucinous epithelium. Detailed clinicoradiological review, including postoperative follow-up, was also completed to assess whether the presence of mucinous epithelium had any associations, including a risk of hepatobiliary neoplasia. RESULTS: Histological review of 21 simple biliary cysts received as surgical specimens over a 3- year period confirmed an absence of ovarian-like stroma in all cases. The lining epithelium of seven cysts showed focal supranuclear/apical mucin, as confirmed histochemically. Cysts with mucinous epithelium were generally larger and more often showed histological evidence of previous haemorrhage than cysts without this epithelium. There were no other statistically-significant differences in clinicoradiological features between cysts with and without mucinous epithelium, including at postoperative radiological follow-up. CONCLUSIONS: Focal mucinous epithelium can be present in at least one-third of surgically-managed, simple biliary cysts of the liver. Such epithelium may be metaplastic and should not be misinterpreted to indicate a diagnosis of MCN but, apart from this, appears to have no clinical significance. Ovarian-like stroma may therefore be the only histological feature that reliably distinguishes MCN from simple biliary cyst.

The Bowel Cancer Screening Programme Expert Board: an analysis of activity during 2017-2020.

AIMS: The inception of the National Health Service Bowel Cancer Screening Programme in England in 2006 highlighted the fact that the differential diagnosis between the presence of epithelial misplacement and adenocarcinoma occurring in colorectal adenomas is problematic. The pathology Expert Board (EB) was created to facilitate the review of difficult cases by a panel of three experienced gastrointestinal pathologists. This article describes a review of the work of the EB over a 4-year period (2017-2020). METHODS AND RESULTS: Four hundred and thirty polyps were referred to the EB from 193 pathologists and 76 hospitals during this time. The EB diagnosis was benign for 67%, malignant for 28%, and equivocal for 2% (with no consensus in the remainder). The most common diagnosis change made by the EB was from malignant to benign-made in 50% of polyps referred with an initially malignant diagnosis. The level of agreement between the individual EB members was 'good' (kappa score of 0.619) but that between the EB and the referring diagnosis was 'poor' (kappa score of 0.149). Data from one EB member indicated that the presence of lamina propria, features of torsion and cytological similarity between the superficial and deep glands were predictors of a benign diagnosis, whereas the presence of irregular neoplastic glands, a desmoplastic reaction and lymphovascular invasion were commonly observed features in polyps with a malignant diagnosis. CONCLUSION: Diagnostic agreement between EB members is better than that between the EB and referring pathologists. There was a consistent trend for the EB to change diagnoses from malignant to benign.

The diagnostic and clinical significance of granulomas in gastrointestinal biopsies from haematopoietic transplant patients.

AIMS: The diagnostic and clinical significance of granulomas in gastrointestinal (GI) biopsies from haematopoietic transplant patients remains disputed, especially following the proposal of cord colitis syndrome (CCS) as a new entity. The aim of the following study was to explore this controversy by identifying such biopsies with granulomas and detailing their clinicopathological associations. METHODS AND RESULTS: Twelve patients with granuloma-containing biopsies were identified from across three scenarios: prospectively during a GI pathologist's routine practice over a period of 5 years; retrospectively from a cohort of transplant patients with clinically validated GI graft versus host disease (GVHD); and retrospectively from a cohort of patients who had received umbilical cord blood (UCB). Their clinicopathological assessments (which included unique long-term patient follow-up) showed that granulomas are only rarely seen across all GI biopsies from haematopoietic transplant patients, and may uncommonly constitute a histological feature of GI GVHD. Granulomas-and especially well-defined, non-cryptolytic ones-are more commonly present in GI biopsies from UCB recipients, but do not show any accompanying histological features that are different from those seen in granuloma-containing biopsies from other patient groups. Furthermore, the three UCB recipients with granuloma-containing biopsies were clinically diagnosed with GVHD rather than CCS. Finally, polymorphic post-transplant lymphoproliferative disorder (PTLD) can present histologically as GI granulomatous inflammation that mimics Crohn's disease. CONCLUSIONS: Granulomas in GI biopsies of haematopoietic transplant patients may often indicate a treatable aetiology such as GVHD or PTLD. Granulomas are more commonly seen in GI biopsies from UCB recipients, but do not necessarily indicate a diagnosis of CCS.

Calponin and MUC6 complement inhibin as diagnostic immunomarkers of serous cystadenoma in endoscopic ultrasound-guided aspiration/biopsy specimens.

AIMS: Because serous cystadenoma (SCA) does not usually require excision, it is critical to distinguish it from differential diagnoses which do, especially neuroendocrine tumour (NET). The gold standard for diagnosing SCA is assessment of endoscopic ultrasound-guided fine needle aspiration/biopsy (EUS-FNAB) material. Inhibin immunohistochemistry aids this assessment, but such positivity is not absolutely sensitive or specific to SCA. The following is the largest known study of SCA EUS-FNAB specimens and the first to compare four potential SCA immunomarkers between themselves and inhibin, compared against NET. METHODS AND RESULTS: Immunohistochemistry for calponin, mucin 6 (MUC6), glucose transporter 1 (GLUT1) and vascular endothelial growth factor A (VEGFA) was performed on 30 EUS-FNAB and three resection specimens of SCA and 32 EUS-FNAB specimens of NET. GLUT1 and VEGFA were suboptimal as diagnostic immunomarkers of SCA, being expressed by 10 and 44% of NETs, respectively. Further, their expression by cellular constituents of blood which often contaminate EUS-FNAB specimens hampered identification of neoplastic cells, especially in hypocellular samples. While 19% of NETs showed nuclear MUC6 positivity, cytoplasmic expression of the protein showed 100% specificity and sensitivity as an SCA marker. However, assessing MUC6 in EUS-FNAB specimens must also consider the protein's focal expression in physiological pancreatic, gastric or duodenal tissues, which can contaminate these specimens. Calponin was less sensitive (71% versus 100%) but more specific (100% versus 91%) than inhibin, although easier to assess in EUS-FNAB specimens than MUC6. CONCLUSIONS: Of the four potential immunomarkers of SCA suggested by the existing literature, calponin and MUC6 are useful complementary studies to inhibin for application to EUS-FNAB specimens.

Current dilemmas in the pathological staging of colorectal cancer: the results of a national survey.

AIMS: Accurate and consistent pathological staging of colorectal carcinoma (CRC) in resection specimens is especially crucial to guide adjuvant therapy. The aim of this study was to assess whether certain staging scenarios yield discordant opinions in the setting of current international and UK national guidelines. METHODS AND RESULTS: Members of the UK Gastrointestinal Pathology External Quality Assurance Scheme were invited to complete an anonymous, on-line survey that presented 15 scenarios related to pT or pR staging of CRC, and three questions about the respondent. The survey invitation was e-mailed to 405 pathologists, and 184 (45%) responses were received. The respondents had discordant opinions on whether and how CRC pT or pR staging is affected by: acellular mucin lakes and duration after short-course radiotherapy; the nature of the carcinoma at a resection margin or peritoneal surface; and microscopic evidence of perforation. This discordance was rarely related to the respondent's occupation type, and was not related to duration of work as a consultant or the staging guidelines used. CONCLUSIONS: This survey confirms that there remain several clinically critical but unresolved pT and pR staging issues for CRC. These issues therefore deserve attention in future versions of international and national staging guidelines.

Primary peri-anal adenocarcinoma of intestinal type - a new proposed entity.

AIMS: The currently recognised subtypes of anal canal/peri-anal adenocarcinoma are those arising from low rectal mucosa or columnar cuff, fistula-related tumours and anal gland carcinoma. This report presents two examples of a hitherto undescribed subtype of peri-anal adenocarcinoma with an intestinal phenotype. METHODS AND RESULTS: A 74-year-old man had a peri-anal tumour locally excised, whereas a 73-year-old female underwent an abdominoperineal resection for peri-anal Paget's disease with an underlying carcinoma. Neither patient had a history of perineal fistulae, Crohn's disease or previous gastrointestinal neoplasia, and neither showed clinical, radiological or endoscopic evidence of another abdominal or pelvic tumour. Both resection specimens contained adenocarcinoma, which were similar in demonstrating an intestinal morphology and CDX2 immunopositivity. The man has shown a disease-free outcome thus far, but the woman has suffered with nodal and pelvic recurrence within a few months of surgery. CONCLUSIONS: The name 'primary peri-anal adenocarcinoma of intestinal type' is proposed for this previously unrecognised subtype of perineal neoplasia. Awareness of its distinct existence - by recognising its intestinal morphology and immunophenotype while excluding metastasis from the intestinal tract - should help to collate data to determine its specific prognosis and to formulate its best management.

Using a mesocosm approach to evaluate marine benthic assemblage alteration associated with CO2 enrichment in coastal environments.

The effects of acidification related to the CO2 enrichment in the coastal environments on marine macrobenthic abundance, diversity and richness were analyzed in a medium- term (21 days) using mesocosm experiments. Two sampling sites located in the Bay of Cadiz - SW, Spain were selected and tested at pH values ranged from 7.9 to 6.0 (±â€¯0.1). Moreover, variations in the concentrations of metals in the sediment samples were analyzed at the end of each experiment. The results showed low variation in the concentrations of metals in the sediment among the pH treatments. A significant decrease (p < 0.05) in the abundance, diversity and richness of assemblages were measured between the control and the lowest pH level in both sampling sites tested in this study (Rio San Pedro and El Trocadero). The majority of species were found in all samples except in pH 6.0 which only two species were found (Hydrobia ulvae and Scrobicularia plana,) in Rio San Pedro sediment fauna. In general, the results of cluster analysis showed 60% and 40% similarity in all replicated tests in El Trocadero and Rio San Pedro of sediment fauna, respectively. The results of the Principal Component Analysis (PCA) showed that both sediment parameters and pH reduction can interfere in the benthic assemblage indices. Although the assemblages' indices have shown decreases only in the lower pHs, the organisms also could be impacted by chronic effects. Therefore, the extension of this study is important in order to improve the knowledge about the risks associated with CO2 enrichment in on marine organisms.

A33 shows similar sensitivity to but is more specific than CDX2 as an immunomarker of colorectal carcinoma.

AIMS: CDX2 is widely used as a sensitive and specific immunomarker for colorectal carcinoma (CRC), but neither its sensitivity nor its specificity is absolute. The aim of this study was to compare CDX1 and A33 with CDX2 as immunomarkers for CRC. METHODS AND RESULTS: As a pilot study, whole sections of 51 cases of liver metastatic carcinoma with different origins-colorectum (n = 32), breast (n = 3), oesophagogastric tract (n = 4), lung (n = 3), pancreas (n = 8), and prostate (n = 1)-were immunostained with CDX1, CDX2, and A33. A33 showed higher sensitivity as a CRC immunomarker, greater interobserver reproducibility for assessment of expression and less background cross-reactivity than CDX1. Therefore, only A33 was compared with CDX2 for a tissue microarray (TMA)-based study of primary adenocarcinomas with different origins: CRC (n = 55), liver deposits of metastatic CRC (n = 60), breast (n = 101), lung (n = 40), oesophagogastric tract (n = 134), ovary (n = 67), pancreas (n = 77), and prostate (n = 56). When the whole section and TMA cases of CRC were combined, A33 had a sensitivity of 95.9% and CDX2 had a sensitivity of 97.2%. When the whole section and TMA cases of non-colorectal carcinomas were combined, A33 had a specificity of 85.4% as a marker of CRC and CDX2 had a specificity of 64.3%. The higher specificity of A33 than of CDX2 as a CRC immunomarker was particularly seen among pancreatic and ovarian carcinomas. Furthermore, unlike what was seen with CDX2, none of the prostatic and lung carcinomas studied showed A33 positivity. CONCLUSIONS: A33 shows similar sensitivity to but is more specific than CDX2 as an immunomarker of CRC.

Vibrio alginolyticus infections in the USA, 1988-2012.

Vibrio alginolyticus causes soft tissue and bloodstream infection; little systematically collected clinical and epidemiological information is available. In the USA, V. alginolyticus infections are reported to the Cholera and Other Vibrio Illness Surveillance system. Using data from 1988 to 2012, we categorised infections using specimen source and exposure history, analysed case characteristics, and calculated incidence rates using US Census Bureau data. Most (96%) of the 1331 V. alginolyticus infections were from coastal states. Infections of the skin and ear were most frequent (87%); ear infections occurred more commonly in children, lower extremity infections more commonly in older adults. Most (86%) infections involved water activity. Reported incidence of infections increased 12-fold over the study period, although the extent of diagnostic or surveillance bias is unclear. Prevention efforts should target waterborne transmission in coastal areas and provider education to promote more rapid diagnosis and prevent complications.

Using High-Technology Simulators to Prepare Anesthesia Providers Before Implementation of a New Electronic Health Record Module: A Technical Report.

Learning to use a new electronic anesthesia information management system can be challenging. Documenting anesthetic events, medication administration, and airway management in an unfamiliar system while simultaneously caring for a patient with the vigilance required for safe anesthesia can be distracting and risky. This technical report describes a vendor-agnostic approach to training using a high-technology manikin in a simulated clinical scenario. Training was feasible and valued by participants but required a combination of electronic and manual components. Further exploration may reveal simulated patient care training that provides the greatest benefit to participants as well as feedback to inform electronic health record improvements.

Vibriosis, not cholera: toxigenic Vibrio cholerae non-O1, non-O139 infections in the United States, 1984-2014.

Toxigenic strains of Vibrio cholerae serogroups O1 and O139 have caused cholera epidemics, but other serogroups - such as O75 or O141 - can also produce cholera toxin and cause severe watery diarrhoea similar to cholera. We describe 31 years of surveillance for toxigenic non-O1, non-O139 infections in the United States and map these infections to the state where the exposure probably originated. While serogroups O75 and O141 are closely related pathogens, they differ in how and where they infect people. Oysters were the main vehicle for O75 infection. The vehicles for O141 infection include oysters, clams, and freshwater in lakes and rivers. The patients infected with serogroup O75 who had food traceback information available ate raw oysters from Florida. Patients infected with O141 ate oysters from Florida and clams from New Jersey, and those who only reported being exposed to freshwater were exposed in Arizona, Michigan, Missouri, and Texas. Improving the safety of oysters, specifically, should help prevent future illnesses from these toxigenic strains and similar pathogenic Vibrio species. Post-harvest processing of raw oysters, such as individual quick freezing, heat-cool pasteurization, and high hydrostatic pressurization, should be considered.

Gastrointestinal pathology in transplant patients.

The assessment of gastrointestinal (GI) specimens from transplant patients is complicated by the wide range of potentially rare pathologies that may be found in this clinical setting. Acute GI graft-versus-host disease (GvHD) is characterized by epithelial cell apoptosis, although there is increasing recognition that acute and/or chronic inflammation may also be present. By contrast, thus far there are no histological features known to be specific to chronic GI GvHD. Mycophenolate mofetil colitis may mimic both GvHD and inflammatory bowel disease, whereas both cytomegalovirus (CMV) and adenovirus infections can cause gland apoptosis. Post-transplant lymphoproliferative disorder should be considered if a Crohn's-like histological picture is seen, and granulomas in biopsies from umbilical cord blood recipients should raise a suspicion of cord colitis syndrome. Finally, the GI tract may be involved directly or indirectly by the disease that originally required haematopoietic stem cell or liver transplantation.

Abdominal monophasic synovial sarcoma is a morphological and immunohistochemical mimic of gastrointestinal stromal tumour.

AIMS: Synovial sarcomas may arise within retroperitoneal or pelvic tissues or, more rarely, within the luminal gastrointestinal tract. This case series aims to demonstrate how such primary abdominal synovial sarcomas may particularly mimic gastrointestinal stromal tumour (GIST) on both morphological and immunohistochemical grounds. METHODS AND RESULTS: Four cases of primary abdominal synovial sarcoma were reviewed morphologically and with immunohistochemistry, fluorescence in-situ hybridization with an SS18 break-apart probe, and KIT/PDGFRA mutation analysis. The four patients comprised two males and two females, with a median age of 42 years (range: 17-59 years). Two synovial sarcomas arose within the stomach, one within the small-intestine mesentery, and the fourth within the retroperitoneum. All four tumours showed only a monophasic spindle cell component in the tissues available for review. All four tumours showed DOG1 immunopositivity, and three coexpressed CD117. Three tested cases did not show activating KIT or PDGFRA mutations, whereas all four cases showed chromosomal rearrangement of SS18. CONCLUSIONS: A diagnosis of synovial sarcoma should be considered particularly if an abdominal spindle cell neoplasm shows a haemangiopericytomatous pattern and diffuse CD99 and CD56 immunopositivity. A confident distinction between abdominal synovial sarcoma and GIST requires KIT/PDGFRA mutation analyses and specific molecular testing for synovial sarcoma.

An immunohistochemical study of potential diagnostic and therapeutic biomarkers of wild-type gastrointestinal stromal tumours.

AIMS: The aims of this study were to investigate whether succinate dehydrogenase B (SDHB), insulin growth factor 1 receptor (IGF1R), HER2, epidermal growth factor receptor (EGFR) and/or BRAF V600E immunohistochemistry could screen for wild-type gastrointestinal stromal tumours (GISTs), and to determine what proportion of wild-type GISTs expressed these proteins and might therefore represent candidates for targeted therapies. METHODS AND RESULTS: Twenty-seven wild-type GISTs and 91 KIT-mutated or PDGFRA-mutated GISTs were immunostained for SDHB, IGF1R, HER2, and EGFR. A preliminary study of the BRAF VE1 antibody showed non-specific staining, and indicated it was neither a specific nor a sensitive marker of wild-type GISTs. SDHB loss showed 100% specificity but only 37% sensitivity as such a marker. EGFR and IGF1R were expressed by 63% and 33% of the wild-type GISTs but also by 56% and 32% of the KIT/PDGFRA mutant GISTs, respectively. Therefore, adding EGFR and/or IGF1R to SDHB as a panel only decreased the specificity of SDHB loss as a marker for wild-type status. CONCLUSIONS: All five antibodies failed, individually or collectively, to represent highly sensitive and highly specific markers for wild-type GIST. However, whereas HER2 has been excluded as a therapeutic biomarker, both EGFR and IGF1R are expressed by some wild-type GISTs and are therefore potential therapeutic targets.

Cholera in the United States, 2001-2011: a reflection of patterns of global epidemiology and travel.

US cholera surveillance offers insight into global and domestic trends. Between 2001 and 2011, 111 cases were reported to the Centers for Disease Control and Prevention. Cholera was associated with international travel in 90 (81%) patients and was domestically acquired in 20 (18%) patients; for one patient, information was not available. From January 2001 to October 2010, the 42 (47%) travel-associated cases were associated with travel to Asia. In October 2010, a cholera epidemic started in Haiti, soon spreading to the Dominican Republic (Hispaniola). From then to December 2011, 40 (83%) of the 48 travel-associated cases were associated with travel to Hispaniola. Of 20 patients who acquired cholera domestically, 17 (85%) reported seafood consumption; 10 (59%) ate seafood from the US Gulf Coast. In summary, an increase in travel-associated US cholera cases was associated with epidemic cholera in Hispaniola in 2010-2011. Travel to Asia and consumption of Gulf Coast seafood remained important sources of US cholera cases.

Typhoid fever acquired in the United States, 1999-2010: epidemiology, microbiology, and use of a space-time scan statistic for outbreak detection.

Although rare, typhoid fever cases acquired in the United States continue to be reported. Detection and investigation of outbreaks in these domestically acquired cases offer opportunities to identify chronic carriers. We searched surveillance and laboratory databases for domestically acquired typhoid fever cases, used a space-time scan statistic to identify clusters, and classified clusters as outbreaks or non-outbreaks. From 1999 to 2010, domestically acquired cases accounted for 18% of 3373 reported typhoid fever cases; their isolates were less often multidrug-resistant (2% vs. 15%) compared to isolates from travel-associated cases. We identified 28 outbreaks and two possible outbreaks within 45 space-time clusters of ⩾2 domestically acquired cases, including three outbreaks involving ⩾2 molecular subtypes. The approach detected seven of the ten outbreaks published in the literature or reported to CDC. Although this approach did not definitively identify any previously unrecognized outbreaks, it showed the potential to detect outbreaks of typhoid fever that may escape detection by routine analysis of surveillance data. Sixteen outbreaks had been linked to a carrier. Every case of typhoid fever acquired in a non-endemic country warrants thorough investigation. Space-time scan statistics, together with shoe-leather epidemiology and molecular subtyping, may improve outbreak detection.

Expression of human CD46 modulates inflammation associated with GalTKO lung xenograft injury.

Evaluation of lungs from GalTKO.hCD46 pigs, genetically modified to lack the galactose-α(1,3)-galactose epitope (GalTKO) and to express human CD46, a complement regulatory protein, has not previously been described. Physiologic, hematologic and biochemical parameters during perfusion with heparinized fresh human blood were measured for 33 GalTKO.hCD46, GalTKO (n = 16), and WT pig lungs (n = 16), and 12 pig lungs perfused with autologous pig blood. Median GalTKO.hCD46 lung survival was 171 min compared to 120 for GalTKO (p = 0.27) and 10 for WT lungs (p < 0.001). Complement activation, platelet activation and histamine elaboration were significantly reduced during the first 2 h of perfusion in GalTKO.hCD46 lungs compared to GalTKO (ΔC3a at 120' 812 ± 230 vs. 1412 ± 1047, p = 0.02; ΔCD62P at 120' 9.8 ± 7.2 vs. 25.4 ± 18.2, p < 0.01; Δhistamine at 60' 97 ± 62 vs. 189 ± 194, p = 0.03). We conclude that, in addition to significant down-modulation of complement activation, hCD46 expression in GalTKO lungs diminished platelet and coagulation cascade activation, neutrophil sequestration and histamine release. Because GalTKO.hCD46 lung failure kinetics correlated directly with platelet and neutrophil sequestration, coagulation cascade activation and a rise in histamine levels within the first hour of perfusion, further progress will likely depend upon improved control of these pathways, by rationally targeted additional modifications to pigs and pharmacologic interventions.