Management of chemotherapy hypersensitivity reactions and desensitization: An SGO clinical practice statement.

OBJECTIVE: The goal of this practice statement is to help members and their multidisciplinary teams recognize infusion reactions and hypersensitivity reactions in the clinical setting. It will provide recommendations to help guide response to reactions and desensitization when appropriate, to promote safe use of chemotherapeutic agents among all providers in the delivery process. METHODS: A multi-disciplinary team of healthcare professionals from the Society of Gynecologic Oncology Education Committee collaborated to review peer reviewed literature and guidelines to develop a practice statement on the management of chemotherapy hypersensitivity reactions and desensitization regimens. RESULTS: There is always potential for a patient to have a reaction to any medication, with both infusion reactions and hypersensitivity reactions potentially occurring in the treatment of gynecologic cancers. Premedication to prevent reactions should be given at least prior to infusion for regimens that include the most common agents associated with reactions. At the time when reaction is occurring it might be difficult to distinguish between an infusion reaction versus true hypersensitivity given the similarities in signs and symptoms, therefore it is important that orders to manage reactions be included in every chemotherapy order set so the infusion nurse can provide immediate interventions while waiting for the provider to arrive to assess the patient. Desensitization is a potential option to allow the patient to continue to receive the offending agent. While a variety of desensitization regimens have been presented in the literature, the goal is to minimize steps and variability to decrease opportunity for errors during chemotherapy preparation or administration. CONCLUSION: Incorporating a review of the literature and clinical experience from the SGO Education Committee, this paper provides an overview of current approaches for prevention and management of reactions to commonly used chemotherapy agents for gynecologic cancers.

Patient, treatment and discharge factors associated with hospital readmission within 30days after surgery for vulvar cancer.

OBJECTIVES: The majority of hospital readmissions are unexpected and considered adverse events. The goal of this study was to examine the factors associated with unplanned readmission after surgery for vulvar cancer. METHODS: Patient demographic, treatment, and discharge factors were collected on 363 patients with squamous cell carcinoma in situ or invasive cancer who underwent vulvectomy at our institution between January 2001 and June 2014. Clinical variables were correlated using χ2 test and Student's t-test as appropriate for univariate analysis. Multivariate analysis was then performed. RESULTS: Of 363 eligible patients, 35.6% had in situ disease and 64.5% had invasive disease. Radical vulvectomy was performed in 39.1% and 23.4% underwent lymph node assessment. Seventeen patients (4.7%) were readmitted within 30days, with length of stay ranging 2 to 37days and 35% of these patients required a re-operation. On univariate analyses comorbidities, radical vulvectomy, nodal assessment, initial length of stay, and discharge to a post acute care facility (PACF) were associated with hospital readmission. On multivariate analysis, only discharge to a PACF was significantly associated with readmission (OR 6.30, CI 1.12-35.53, P=0.04). Of those who were readmitted within 30days, 29.4% had been at a PACF whereas only 6.6% of the no readmission group had been discharged to PACF (P=0.003). CONCLUSIONS: Readmission affected 4.7% of our population, and was associated with lengthy hospitalization and reoperation. After controlling for patient comorbidities and surgical radicality, multivariate analysis suggested that discharge to a PACF was significantly associated with risk of readmission.

Autoantibody epitopes to the smaller isoform of glutamate decarboxylase do not differ in Swedish and Japanese type 1 diabetes patients and may be associated with high-risk human leucocyte antigen class II alleles.

Type 1 diabetes (T1D) is an autoimmune disease with a strong human leucocyte antigen (HLA) class II association. Depending on geographic locations, the disease-associated HLA class II alleles vary. We evaluated the beta cell-specific autoimmunity reflected in autoantibodies directed to the smaller isoform of glutamate decarboxylase (GAD65) in Japanese and Swedish T1D patients. GAD65Ab epitope specificities were assessed using GAD65-specific recombinant Fab. GAD65Ab epitope specificities did not differ between Swedish and Japanese patients. Only recognition of the MICA-4-defined middle epitope was significantly stronger in the Japanese T1D patient group compared to the Swedish T1D patients (P = 0.001). Binding to the b96.11-defined middle epitope was substantial in both groups and showed significant associations with high-risk HLA class II haplotypes. In the Japanese T1D group the association was with haplotype DRB1*0802-DQB1*0302 (P = 0.0008), while in the Swedish T1D patients binding to the b96.11-defined epitope as associated with the presence of high-risk HLA genotypes DR3-DQB1*0201 and/or DR4-DQB1*0302 (P = 0.02). A significant association between reduction in binding in the presence of recombinant Fab (rFab) DPD and high-risk allele DQB1*0201 was found (P = 0.008) in the Swedish T1D patients only. We hypothesize that epitope-specific autoantibodies effect the peptide presentation on HLA class II molecules by modulating antigen uptake and processing. Molecular modelling of the high-risk HLA class II molecules will be necessary to test whether these different molecules present similar peptide-binding specificities.

GAD65 autoantibody epitopes in adult patients with latent autoimmune diabetes following GAD65 vaccination.

AIMS: Subcutaneous injection of recombinant human GAD65 (rhGAD65) in patients with latent autoimmune diabetes in adults (LADA) correlates with an increase in C-peptide levels. In this study we analysed the effect of rhGAD65 administration on the GAD65-specific autoimmune response. METHODS: Longitudinal serum samples obtained from LADA patients (n = 47) who received 4, 20, 100 or 500 microg alum-formulated rhGAD65 or placebo by subcutaneous injection twice (4 weeks apart) were analysed for their epitope recognition using GAD65-specific recombinant Fab and GAD65/67 fusion proteins. RESULTS: Overall, minor changes in the epitope pattern were observed using either approach. Only in the 500-microg dosage group was an increase in GAD65Ab level associated with a significant increase in the binding to a conformational epitope located at the middle part of GAD65. CONCLUSIONS: Our data suggest that the apparent beneficial effects of 20 microg alum-formulated recombinant human GAD65 is not explained by changes in the GAD65Ab epitope pattern.

Longitudinal changes in epitope recognition of autoantibodies against glutamate decarboxylase 65 (GAD65Ab) in prediabetic adults developing diabetes.

We analysed the beta cell-specific autoimmunity reflected in autoantibodies to the smaller isoform of glutamate decarboxylase (GAD65Ab) in the prediabetic period of GAD65Ab-positive healthy adults who developed Type 2 diabetes (T2D) during a follow-up period of 10 years. We found that of the adults that tested GAD65Ab-positive at baseline (n=25), six developed T2D and one developed Type 1 diabetes (T1D). Of the subjects that tested GAD65Ab-negative at baseline (n=2209), 81 developed T2D, one developed T1D and four developed unclassified diabetes, indicating that the risk for GAD65Ab-positive healthy adults to develop diabetes is increased sixfold. The GAD65Ab epitopes were characterized in a competition radioligand binding assay using recombinant Fab derived of GAD65-specific monoclonal antibodies. We observed that the GAD65Ab epitope specificities in the prediabetic period changed dynamically. Specifically, the binding to a middle and a C-terminal epitope increased during the follow-up period (P=0 x 03), causing a significant increase in the number of epitopes recognized (P=0 x 03). These findings are similar to previous observations of dynamic changes in the prediabetic period of schoolchildren at high risk for T1D development. However, the character of the epitopes differs between the two populations, suggesting differences in the beta cell-specific autoimmune response in the prediabetic period of patients with latent autoimmune diabetes in adults (LADA) and T1D.

Longitudinal epitope analysis of insulin-binding antibodies in type 1 diabetes.

Autoantibodies to insulin (IAA) are one of the first markers of the autoimmune process leading to type 1 diabetes (T1D). While other autoantibodies in T1D have been studied extensively, relatively little is known about IAA and their binding specificities, especially after insulin treatment is initiated. We hypothesize that insulin antibodies (IA) that develop upon initiation of insulin treatment differ in their epitope specificities from IAA. We analysed insulin antibody binding specificities in longitudinal samples of T1D patients (n = 49). Samples were taken at clinical diagnosis of disease and after insulin treatment was initiated. The epitope specificities were analysed using recombinant Fab (rFab) derived from insulin-specific monoclonal antibodies AE9D6 and CG7C7. Binding of radiolabelled insulin by samples taken at onset of the disease was significantly reduced in the presence of rFab CG7C7 and AE9D6. rFab AE9D6 competed sera binding to insulin significantly better than rFab CG7C7 (P = 0.02). Binding to the AE9D6-defined epitope in the initial sample was correlated inversely with age at onset (P = 0.005). The binding to the AE9D6-defined epitope increased significantly (P < 0.0001) after 3 months of insulin treatment. Binding to the CG7C7-defined epitope did not change during the analysed period of 12 months. We conclude that epitopes recognized by insulin binding antibodies can be identified using monoclonal insulin-specific rFab as competitors. Using this approach we observed that insulin treatment is accompanied by a change in epitope specificities in the emerging IA.

Identification and characterization of a novel isoform of the vesicular gamma-aminobutyric acid transporter with glucose-regulated expression in rat islets.

Pancreatic islets are unique outside the nervous system in that they contain high levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), synthesized by the enzyme glutamic acid decarboxylase (GAD). Since the role that GABA plays in the islet and the mechanisms whereby the two major GAD isoforms (GAD65 and GAD67) function as diabetes-associated autoantigens are unknown, continued characterization of the islet GAD-GABA system is important. We previously demonstrated that the GABA and glycine transporter vesicular inhibitory amino acid transporter (VIAAT also known as VGAT) is present in rat islets. Here we identify a novel 52 kDa variant of VIAAT in rat islets: VIAAT-52 (V52). V52 is an amino-terminally truncated form of VIAAT (V57) that likely results from utilization of a downstream start site of translation. V57 and V52 display different patterns of post-translational modification and cellular expression. Our results have indicated that islet content of V52, but not V57, is responsive to changes in glucose concentration and other extracellular conditions. VIAAT is expressed in the islet alpha cells, but there have been conflicting findings regarding the presence of VIAAT in the beta cells. Here we have also provided additional evidence for the presence of VIAAT in islet beta cells and show that the beta cell line INS-1 expresses V57. V52 may be better adapted than V57 to the unique rat alpha cell GAD-GABA system, which lacks GAD65 and in which VIAAT traffics to secretory granules rather than just to synaptic microvesicles.

Epitope analysis of insulin autoantibodies using recombinant Fab.

Autoantibodies to insulin are often the first autoantibodies detected in young children with type 1 diabetes and can be present before the onset of clinical diabetes. These autoantibodies and their epitopes are, however, not well characterized. We explored the use of monoclonal antibodies and their recombinant Fab as reagents for epitope analysis. In this study we cloned and characterized the recombinant Fab of the insulin-specific monoclonal antibody CG7C7. We found the epitope of this antibody to be located predominantly at the A-chain loop of the insulin molecule. The recombinant Fab was then used to compete for insulin binding against insulin autoantibodies present in sera from patients with type 1 or type 1.5 diabetes. In competition experiments with sera positive for autoantibodies to insulin the recombinant Fab significantly reduced the binding to [125I]-insulin by sera of type 1 (n = 35) and type 1.5 diabetes [latent autoimmune diabetes in adults (LADA)] (n = 14) patients (P < 0.0001). We conclude that competition between insulin-specific monoclonal antibodies or their recombinant Fab and insulin autoantibodies should prove useful in the epitope analysis of autoantibodies to insulin.

Knowledge-based segmentation of pediatric kidneys in CT for measurement of parenchymal volume.

PURPOSE: The purpose of this work was to develop an automated method for segmenting pediatric kidneys in helical CT images and measuring their volume. METHOD: An automated system was developed to segment the kidneys. Parametric features of anatomic structures were used to guide segmentation and labeling of image regions. Kidney volumes were calculated by summing included voxels. For validation, the kidney volumes of four swine were calculated using our approach and compared with the "true" volumes measured after harvesting the kidneys. Automated volume calculations were also performed in a cohort of nine children. RESULTS: The mean difference between the calculated and measured values in the swine kidneys was 1.38 ml. For the pediatric cases, calculated volumes ranged from 41.7 to 252.1 ml/kidney, and the mean ratio of right to left kidney volume was 0.96. CONCLUSION: These results demonstrate the accuracy of a volumetric technique that may in the future provide an objective assessment of renal damage.

Mycotic aneurysm of the thoracic aorta due to Aspergillus terreus: case report and review.

Mycotic aneurysms of the aorta caused by fungi are uncommon. We describe an unusual case of aortic aneurysm infection caused by Aspergillus terreus, which most likely spread from an adjacent pulmonary focus. Successful treatment included partial pneumonectomy, resection of the aneurysm with graft repair, and prolonged sequential administration of amphotericin B and itraconazole. A review of the published experience with aortic aneurysms caused by Aspergillus species is also presented. When invasive aspergillosis is suspected in proximity to areas with major vascular structures in immunocompromised patients, further investigation to rule out vascular invasion may be warranted. If the diagnosis is confirmed, aggressive and prompt treatment with antifungal agents combined with surgical debridement is essential to improve outcome.

Mycotic pseudoaneurysm of the aortic arch: an unusual complication of invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis (IPA) is usually a condition of the immunocompromised patients. The organism has a tendency to invade pulmonary blood vessels. Extension of a pulmonary parenchymal lesion to involve the mediastinal great vessels is very rare. This is the first case where the extension of IPA to the aortic arch and the formation of a pseudoaneurysm were demonstrated on serial CT scans.

Variable morbidity in alagille syndrome: a review of 43 cases.

BACKGROUND: Alagille syndrome is one of the most common inherited disorders that cause chronic liver disease in children. Early reports suggested a benign course in these patients. Subsequent reports showed significant morbidity and mortality. This study was designed to analyze the long-term clinical course in Alagille syndrome. METHODS: The records of children with Alagille syndrome seen during a 20-year period were reviewed. RESULTS: Forty-three patients were identified. Liver disease was diagnosed before 12 months of age in 95%. The frequencies of renal anomalies (50%) and intracranial hemorrhage (12%) were significant. The high incidence of chronic otitis media (35%) has not been reported previously. One patient had a renal transplant. Vascular compromise as a pathologic mechanism for some characteristics of the syndrome is also suggested by the presence of small bowel stenosis and atresia, tracheal and bronchial stenosis, renal artery stenosis, middle aortic syndrome, and avascular necrosis of the humeral and femoral heads. Twenty (47%) patients underwent liver transplantation. Five of six who underwent Kasai procedure required liver transplantation. Twelve died (28%), five after liver transplantation. One patient died of intracranial bleeding. Sixteen (37%) without liver transplantation and 15 (35%) who underwent liver transplantation are alive. CONCLUSIONS: Some patients with early-onset and more severe liver disease can benefit from liver transplantation. Careful and complete assessment should be made of infants with a cholestatic syndrome, to avoid misdiagnosis and unnecessary Kasai procedures. Our observation of vascular compromise in various organ systems suggests that notch signaling pathway defects affect angiogenesis in Alagille syndrome.

Optic nerve hypoplasia secondary to intracranial teratoma.

PURPOSE: To postulate a causal relation between optic nerve hypoplasia and a suprasellar teratoma. METHOD: Case report. RESULTS: A 6-month-old infant with suprasellar teratoma was visually inattentive and had searching nystagmus. He had moderately severe, bilateral optic nerve hypoplasia with the left eye being somewhat worse than the right eye. CONCLUSIONS: Optic nerve hypoplasia is a major cause of impaired vision in children and rarely has been attributed to an intracranial tumor. Our case, involving a patient with a suprasellar teratoma and optic nerve hypoplasia, supports a causal relation between the two.

Cloning and expression of the mammalian cytosolic branched chain aminotransferase isoenzyme.

The cDNA for the rat cytosolic branched chain aminotransferase (BCATc) has been cloned. The BCATc cDNA encodes a polypeptide of 410 amino acids with a calculated molecular mass of 46.0 kDa. By Northern blot analysis, BCATc message of approximately 2.7 kilobases was readily detected in rat brain, but was absent from liver, a rat hepatoma cell line, kidney, and skeletal muscle. When expressed in COS-1 cells, the enzyme is immunologically indistinguishable from the native enzyme found in rat brain cytosol. Comparison of the rat BCATc sequence with available data bases identified the Escherichia coli (and Salmonella typhimurium) branched chain aminotransferase (BCAT) and revealed a Haemophilus influenzae BCAT, a yeast BCAT, which is hypothesized to be a mitochondrial form of the enzyme, and the murine BCATc (protein ECA39). Calculated molecular masses for the complete proteins are 33.9 kDa, 37.9 kDa, 42.9 kDa, and 43.6 kDa, respectively. The rat BCATc sequence was 84% identical with murine BCATc, 45% identical with yeast, 33% identical with H. influenzae, 27% identical with the E. coli and S. typhimurium BCAT, and 22% identical with the evolutionary related D-amino acid aminotransferase (D-AAT) (Tanizawa, K., Asano, S., Masu, Y., Kuramitsu, S., Kagamiyama, H., Tanaka, H., and Soda, K. (1989) J. Biol. Chem. 264, 2450-2454). Amino acid sequence alignment of BCATc with D-AAT suggests that the folding pattern of the overlapping mammalian BCATc sequence is similar to that of D-AAT and indicates that orientation of the pyridoxal phosphate cofactor in the active site of the eukaryotic BCAT is the same as in D-AAT. Thus, BCAT are the only eukaryotic aminotransferases to abstract and replace the proton on the re face of the pyridoxal phosphate cofactor. Finally, requirements for recognition of substrate L-amino acid and alpha-carboxylate binding are discussed.

The value of portal vein pulsatility on duplex sonograms as a sign of portal hypertension in children with liver disease.

OBJECTIVE: The purpose of this study was to determine the significance of portal vein pulsatility on duplex Doppler waveforms in children with end-stage hepatic failure undergoing liver transplantation. SUBJECTS AND METHODS: Thirty-eight children with end-stage hepatic decompensation were examined with color-assisted spectral Doppler waveform analysis of the hepatic artery and the portal vein. Correlation was made with age, duration of illness, clinical and pathologic diagnosis, and presence of portal hypertension. Findings were compared with those for six patients with acute viral hepatitis and 12 healthy control subjects. RESULTS: Portal vein pulsatility was noted in all 36 patients in whom portal vein flow was detected by Doppler imaging. The majority of these (34) had clinical or sonographic evidence of portal hypertension. In two patients, no portal vein flow was identified in the liver hilum; both had a large portosystemic shunt through collaterals or surgical graft. Significantly increased pulsatility of the hepatic artery waveform (resistive index [RI] = 0.89 +/- 0.15, p < .0001) was seen in patients with end-stage liver disease. In contrast, no portal vein pulsatility and normal hepatic artery pulsatility (RI = 0.60 +/- 0.11) was noted in all patients with acute hepatitis and control subjects. CONCLUSION: Portal vein waveform pulsatility is 94% sensitive and 90% specific for portal hypertension in end-stage liver disease.

Imaging of the adrenal gland in children.

Ultrasonography (US), computed tomography (CT), and magnetic resonance (MR) imaging have replaced intravenous urography and angiography in evaluation of children with suspected disease of the adrenal glands. Although the spatial resolution of MR imaging is still somewhat inferior to that of CT, it allows tissue characterization and better evaluation of tumor extension owing to its multiplanar imaging capability. Initial diagnosis of an adrenal mass in a child is made with US, which is also used to document regression of uncomplicated neonatal adrenal hemorrhage. MR imaging is used for evaluation of tumor extension when surgery is to be performed. Imaging findings such as size, shape, and signal intensity are often not specific for a pathologic condition and must be interpreted in conjunction with the patient's age, the clinical history (eg, trauma), results of physical examination (eg, palpable mass or presence of an endocrine syndrome), and hormone levels in blood and urine.

Imaging in pediatric liver transplantation.

Liver transplantation is an accepted and successful mode of treatment for pediatric end-stage liver disease. On the basis of a review of 229 liver transplantations in 185 children, the authors describe the imaging findings of the preoperative evaluation, the uncomplicated transplantation, various postoperative complications, and the suggested percutaneous treatment of some of these complications. The most frequent indications for liver transplantation encountered in this review were biliary atresia (52%), acute fulminant hepatic failure (11%), alpha 1-antitrypsin deficiency (9%), cryptogenic cirrhosis (6%), and chronic active hepatitis (4%). (The remaining 18% were various rare indications, representing < 4% each.) Routine Doppler ultrasound is the modality of choice for the screening of postoperative complications, supplemented with computed tomography, hepatobiliary scintigraphy, and cholangiography or angiography as needed. Familiarity with the normal graft appearance, as influenced by various surgical and technical factors, and knowledge of the underlying condition of the patient and the clinical course of postoperative complications are crucial for a correct interpretation of the findings from imaging studies.

Pediatric intracranial vascular malformations: evaluation of treatment results with color Doppler US. Work in progress.

To determine the value of color Doppler ultrasound (US) in the preoperative assessment and evaluation of treatment results in children with intracranial vascular malformations (VMs), the authors performed 36 color Doppler US studies in nine children who underwent endovascular embolization. Color flow imaging with spectral waveform analysis of feeding arteries, nidus, draining veins, and uninvolved cranial vasculature was performed, and correlation was made with other imaging findings. In most VMs, color Doppler US enabled the authors to map the lesion completely. Hemodynamic changes after embolization included improvement in blood supply to uninvolved portions of the brain and increase in caliber and flow of feeding vessels that were not occluded during embolization. Serial volume flow measurements were performed with Doppler US in major extracranial arteries. Success of embolization was indicated by substantial decrease of total carotid artery flow. Color Doppler US is a noninvasive modality that adds important imaging and hemodynamic data to those provided by angiography.