Aykut B, Lim HK, Ngeve SM, Hoover A, Medina CK, et al.
Annals of thoracic surgery short reports •
Alpha-gal syndrome from tick bites, due to sensitivity to alpha-gal, can cause severe allergies. Heart valve implants contain alpha-gal, yet alpha-gal syndrome screening is not standard before valve replacement. This study examines perioperative outcomes in patients with alpha-gal antibodies. This is a single-institution prospective cohort study of patients undergoing bioprosthetic aortic valve replacement between January 2022 and January 2023. Anti-alpha-gal immunoglobulin E levels were measured, with primary outcomes being severe allergic reactions and in-hospital mortality, and secondary outcomes including intensive care unit and hospital stay. Of 155 patients, 32.7% (n = 19) of surgical aortic valve replacement and 29.9% (n = 29) of transcatheter aortic valve replacement patients had detectable immunoglobulin E levels without subsequent serious allergic reactions or in-hospital mortality. Postoperative hospital stay and valve function were similar across groups. In this study, sensitization to alpha-gal was not associated with serious allergic reactions and did not affect immediate aortic valve function after surgical aortic valve replacement or transcatheter aortic valve replacement.
The Journal of thoracic and cardiovascular surgery •
Galactose-α-1,3-galactose (alpha-gal) is a carbohydrate that is ubiquitously expressed in all mammals except for primates and humans. Patients can become sensitized to this antigen and develop alpha-gal syndrome (AGS), or a red meat allergy. Symptoms range from generalized gastroenteritis and malaise to anaphylaxis, and in endemic areas, the prevalence can be as high as 20%. Although AGS patients commonly avoid alpha-gal by avoiding meat, patients have also developed symptoms due to animal-derived medical products and devices. With the rise in transcatheter aortic valve replacement, we investigate the immunogenicity of common cardiac materials and valves. To assess the in vitro immunoglobulin E response toward common medical products, including cardiac patch materials and bioprosthetic valves in patients with AGS. Immunoblot and immunohistochemistry techniques were applied to assess immunoglobulin E reactivity to various mammalian derived tissues and medical products for patients with AGS. AGS serum showed strong reactivity to all of the commercially available, nonhuman products tested, including various decellularized cardiac patch materials and bioprosthetic aortic valves. AGS serum did not react to tissues prepared using alpha-gal knockout pigs. Despite commercial decellularization processes, alpha-gal continues to be present in animal-derived medical products, including bioprosthetic valves. Serum from patients with AGS demonstrates a strong affinity for these products in vitro. This may have serious potential implications for sensitized patients undergoing cardiac surgery, including early valve failure and accelerated coronary artery disease.
Over the past decade, there has been a growing awareness of a new allergic syndrome known as alpha-gal allergy or alpha-gal syndrome, commonly recognized as a red meat allergy. We performed a review of the literature to identify articles that provide both background on this syndrome in general and any reports of reactions to medications or medical devices related to alpha-gal syndrome. Alpha-gal syndrome results from IgE to the oligosaccharide galactose-α-1,3-galactose, expressed in the meat and tissues of noncatarrhine mammals. It is triggered by the bite of the lone star tick and has been implicated in immediate-onset hypersensitivity to the monoclonal antibody cetuximab and delayed-onset hypersensitivity reactions after the consumption of red meat. There is growing recognition of allergic reactions in these patients to other drugs and medical devices that contain alpha-gal. Many of these reactions result from inactive substances that are part of the manufacturing or preparation process such as gelatin or stearic acid. This allergy may be documented in a variety of ways or informally reported by the patient, requiring vigilance on the part of the anesthesiologist to detect this syndrome, given its serious implications. This allergy presents a number of unique challenges to the anesthesiologist, including proper identification of a patient with alpha-gal syndrome and selection of anesthetic and adjunctive medications that will not trigger this allergy.
Ali M, Kaltenbrun E, Anderson GR, Stephens SJ, Arena S, et al.
Nature communications •
KRAS mutations drive resistance to targeted therapies, including EGFR inhibitors in colorectal cancer (CRC). Through genetic screens, we unexpectedly find that mutant HRAS, which is rarely found in CRC, is a stronger driver of resistance than mutant KRAS. This difference is ascribed to common codon bias in HRAS, which leads to much higher protein expression, and implies that the inherent poor expression of KRAS due to rare codons must be surmounted during drug resistance. In agreement, we demonstrate that primary resistance to cetuximab is dependent upon both KRAS mutational status and protein expression level, and acquired resistance is often associated with KRAS mutations that function even when protein expression is low. Finally, cancer cells upregulate translation to facilitate KRAS-driven acquired resistance, resulting in hypersensitivity to translational inhibitors. These findings demonstrate that codon bias plays a critical role in KRAS-driven resistance and provide a rationale for targeting translation to overcome resistance.
Commins SP, James HR, Stevens W, Pochan SL, Land MH, et al.
The Journal of allergy and clinical immunology •
In 2009, we reported a novel form of delayed anaphylaxis to red meat related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Although patients were remarkably consistent in their description of a 3- to 6-hour delay between eating mammalian meat and the appearance of symptoms, this delay has not been demonstrated under observed studies. We sought to formally document the time course of clinical symptoms after the ingestion of mammalian meat in subjects with IgE to alpha-gal and to monitor ex vivo for the appearance of markers of an allergic reaction. Open food challenges were performed with mammalian meat in 12 subjects with a history of severe urticarial reactions 3 to 6 hours after eating beef, pork, or lamb, as well as in 13 control subjects. Blood samples were taken hourly during each challenge. Ten of 12 subjects with IgE to alpha-gal had clinical evidence of a reaction during the food challenge (vs none of the control subjects, P < .001). The reactions occurred 3 to 7 hours after the initial ingestion of mammalian meat and ranged from urticaria to anaphylaxis. Tryptase levels were positive in 3 challenges. Basophil activation, as measured by increased expression of CD63, correlated with the appearance of clinical symptoms. The results presented provide clear evidence of an IgE-mediated food allergy that occurs several hours after ingestion of the inciting allergen. Moreover, here we report that in vivo basophil activation during a food challenge occurs in the same time frame as clinical symptoms and likely reflects the appearance of the antigen in the bloodstream.
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners •
Previous research has indicated a high incidence of cetuximab hypersensitivity reactions in the southern US. This study documents the incidence of hypersensitivity reactions in North Carolina, and explores whether factors such as patient demographics, allergy history, premedications, and cancer type are potential predictors for cetuximab reactions. This retrospective chart review consisted of 72 consecutively treated patients from Duke University's Morris Oncology treatment center between September 2005 and August 2007. Data regarding stage of malignancy, premedications, and hypersensitivity reactions were collected from electronic databases. The number and type of reactions were characterized. Patients with and without hypersensitivity reactions were compared using bivariate statistics and multivariate logistic regression. Of the 72 patients, 21 (29%) experienced hypersensitivity reactions. The majority of reactions (62%) were grades III or IV. Of the 21 patients having a reaction, 9 (43%) were sent to the emergency room and 5 (24%) had an overnight hospitalization. Three hospitalized patients were admitted to the intensive care unit. Both male gender (p = 0.039) and head/neck cancer (p = 0.014) were related to an increased likelihood of hypersensitivity reaction in bivariate analyses. In multivariate analyses, controlling for demographics, allergy history, premedications, and cancer type/stage, only type of cancer was predictive of hypersensitivity reaction (colon vs head/neck OR = 0.177; 95% CI 0.036-0.858). This study confirms a high rate of cetuximab hypersensitivity reactions in a southern region of the US. Patients with head/neck cancers were significantly more likely to have hypersensitivity reactions than patients with colon cancers.
This phase II trial assessed the activity and tolerability of cetuximab (C225, Erbitux) in combination with carboplatin in patients with relapsed platinum-sensitive ovarian or primary peritoneal carcinoma. Patients were to receive combination therapy with cetuximab (initial dose of 400 mg/m2 intravenously on cycle 1, day 1, followed by weekly infusions of 250 mg/m2) and carboplatin (AUC of 6 on day 1 and every 3 weeks). The primary objectives of this trial were to estimate the anti-tumor activity and adverse events of this combination therapy. Immunohistochemical expression of EGFR was evaluated in tumor specimens from patients enrolled in this trial. Of the 29 patients, 28 (97%) were eligible and evaluable for analysis of the efficacy and toxicity of cetuximab administered in combination with carboplatin. Of the evaluable entries, 26 had EGFR-positive tumors and the response rate in this group of patients was as follows: 9 demonstrated an objective response (3 CR; 6 PR) and 8 had stable disease. The response rate did not meet criteria for opening a second stage of accrual. The median time to progression was 9.4+ months (range: .9-22.2+). The most commonly observed adverse events were dermatologic toxicity (grade 3 in 32%), thrombocytopenia (grade 3 in 14%), and hypersensitivity reactions (grade 3 and 4 in 18%). Cetuximab administered in combination with carboplatin had modest activity in screened patients with EGFR-positive, relapsed platinum-sensitive ovarian or primary peritoneal carcinoma. Cetuximab was associated with an acneiform rash in a majority of patients and occasional serious hypersensitivity reactions.
Gal alpha 1,3 Gal is thought to be the major antigenic epitope present on pig tissues to which XNAs bind. Removal of antibodies directed against that structure may be critical to the success of pig to human xeno-transplantation. As a first step toward the development of ligands capable of removing XNAs, we have used a phage-displayed peptide library to identify a six-amino-acid peptide that binds to the lectin GS-1-B4 (which binds the carbohydrate Gal alpha 1,3 Gal). This peptide blocks the binding of GS-1-B4 to pig aortic endothelial cells. The carbohydrate Gal alpha 1,3 Gal competes with the binding of GS-1-B4 to the peptide, suggesting that they may bind the same site. Using a RBC agglutination assay, we show that this peptide inhibits the agglutination of pig RBCs by heat-inactivated human serum at concentrations similar to that of Gal alpha 1,3 Gal.
Rejection of an organ transplanted into a phylogenetically disparate recipient may be initiated by the binding of xenoreactive natural Abs of the recipient to Ags expressed on donor endothelium leading to the activation of the C system. Having previously shown that human xenoreactive Abs bind predominantly to N-linked oligosaccharides on porcine endothelial cell glycoproteins, we sought to identify those glycoproteins to gain insight into the pathogenesis of the rejection reaction and to develop improved methods for depleting those Abs. Based on amino-terminal and internal sequencing of the glycoproteins, reactivity with monospecific rabbit Abs, and functional properties, the porcine endothelial cell targets of human natural Abs were shown to be the von Willebrand factor, integrin alpha 1, alpha v, alpha 3/alpha 5, beta 1, and beta 3 chains and a 95-kDa glycoprotein homologous with chick DM-GRASP. Human and baboon Abs directed against those glycoproteins were shown to be absorbed during perfusion of porcine organs and the binding of human IgM to the isolated glycoproteins to initiate the activation of C leading to formation of iC3b neoantigen. The determinants recognized by human xenoreactive Abs had immunodominant alpha-galactosyl residues based on affinity chromatography, reactivity with anti-Gal alpha(1-3)Gal Abs and sensitivity to alpha-galactosidase. The findings show that members of the integrin family and the von Willebrand factor are major targets of xenoreactive Abs and suggest potential mechanisms by which the binding of Abs to endothelial cells might perturb the physiology of those cells and thus cause aberrant functioning of a tissue or organ.
