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.

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.

Insulin therapy and weight change in Native-American NIDDM patients.

OBJECTIVE: To determine whether NIDDM patients exposed to insulin therapy in a clinical setting gain weight. RESEARCH DESIGN AND METHODS: This study, an historical cohort chart review, was conducted at the IHS clinic on the Navajo Reservation in Northern Arizona. We studied 27 Native Americans with NIDDM and 102 Native-American nondiabetic control subjects. RESULTS: Insulin therapy consisting of a mean of 105 U/day was associated with a mean weight gain of 3.0 +/- 2.2 kg/yr. When insulin was discontinued or decreased, a mean weight loss of 5.2 +/- 2.7 kg/yr was observed in the same patients. No significant weight gain was noted in 102 nondiabetic control subjects, nor in 20 of 27 insulin-treated patients given oral hypoglycemic agents before initial insulin therapy. CONCLUSIONS: Insulin therapy appeared to be associated with weight gain in this group of NIDDM patients. This suggests that observations for weight gain be undertaken when treating NIDDM patients with insulin, because it may exacerbate the underlying pathophysiology of the disease.

Daily variations in monoamine turnover in the brain of the ring dove (Streptopelia risoria).

A method for measuring the concentration and turnover of serotonin, dopamine and noradrenaline in small amounts of brain tissue was validated for the ring dove (Streptopelia risoria). Turnover rates of the catecholamines calculated as the rate of depletion after tyrosine hydroxylase inhibition agreed well with turnover rate measured as rate of accumulation after inhibition of monoamine oxidase at 2.5 h, but not 5 h, after drug administration. Using the monoamine oxidase inhibitor, pargyline, turnover of serotonin, dopamine and noradrenaline were estimated in the same tissue. Both the concentration and turnover of the amines in hypothalamus, paleostriatum and hyperstriatum fluctuated over a 24 h period. Serotonin turnover was greatest during the middle of the dark period in all three tissues. In contrast, for both dopamine and noradrenaline the highest turnover was observed during the light period and the lowest during the dark period.

Tracer kinetic modeling approaches for the quantification of hepatic function with technetium-99m DISIDA and scintigraphy.

Serial scintigraphic images following injection of [99mTc]iminodiacetic acid compounds such as [99mTc]diisopropyl-iminodiacetic acid (DISIDA) provide qualitative information about liver function. We have investigated approaches for quantitatively describing liver function in terms of the kinetics of DISIDA extraction and excretion by the liver. Several compartmental model configurations were evaluated. A three-compartment model (blood, hepatic parenchyma, intrahepatic bile) was found to fit the data best and was used in conjunction with dynamic image data to obtain estimates of rate constants for liver extraction and excretion of DISIDA, and mean residence time (MRT) of DISIDA in the liver. A noncompartmental approach based on a parametric deconvolution technique was also used to estimate the noncompartmental mean residence time (MRTnc). To assess limitations of the noncompartmental approach, computer simulations were performed using the three-compartment model to generate time-activity curves followed by analysis of these curves by the noncompartmental method. The effect of plasma total bilirubin level on DISIDA uptake and MRT was also investigated. These techniques are readily adaptable to standard nuclear medicine computing facilities, and could be used in the clinical setting to numerically describe serial DISIDA studies (especially in liver transplant patients) efficiently and noninvasively.

Neurotransmitter effects on release of prolactin and growth hormone in vitro from pituitary glands of the pigeon, Columba livia.

Single pigeon anterior pituitary glands were incubated with or without a hypothalamus in media containing various drugs. Release of prolactin and growth hormone was quantified by an electrophoretic-densitometric method. The hypothalamus stimulated release of both prolactin and growth hormone from the pituitary gland. Dopamine did not affect hormone release from pituitary glands incubated alone, but inhibited hypothalamus-stimulated release of prolactin and augmented hypothalamus-stimulated release of growth hormone in a dose-related manner. The effects of dopamine were reversed by its antagonist, pimozide. Serotonin stimulated release of prolactin and inhibited release of growth hormone from pituitary-hypothalamus co-incubations, and these effects were blocked by its antagonist, methysergide. Thyrotrophin releasing hormone (TRH) stimulated release of both hormones directly from pituitary glands incubated alone. Dopamine now inhibited TRH-stimulated release of prolactin, without affecting TRH-stimulated release of growth hormone. These results indicate that the neurotransmitters, dopamine and serotonin, affect the in-vitro release of factors from the hypothalamus which control the secretion of prolactin and growth hormone. In addition, dopamine may inhibit release of prolactin directly from the pituitary gland, but only when secretion of prolactin is high initially.

Effects of synthetic mammalian thyrotrophin releasing hormone, somatostatin and dopamine on the secretion of prolactin and growth hormone from amphibian and reptilian pituitary glands incubated in vitro.

Pituitary glands of grassfrog (Rana pipiens), bullfrog (Rana catesbeiana), clawed toad (Xenopus laevis) and two species of terrapin (Chrysemys picta and Pseudemys scripta) were incubated in medium containing hypothalamic extract (HE), thyrotrophin releasing hormone (TRH), somatostatin, dopamine, or combinations of these treatments. Prolactin and GH concentrations in the medium were determined by densitometry after polyacrylamide-gel electrophoretic separation. Hypothalamic extract stimulated secretion of both hormones in all species tested. Thyrotrophin releasing hormone stimulated secretion of prolactin and GH, showing a biphasic pattern of response. Dopamine had little effect alone, but inhibited HE- and TRH-stimulated release of prolactin, but not GH, in both amphibia and reptiles. Somatostatin by itself had no apparent effect on release of hormones, but it inhibited HE- and TRH-stimulated release of GH from both amphibian and reptilian pituitary glands. These results indicate that factors affecting mammals and birds also interact in the regulation of secretion of prolactin and GH in lower vertebrate species.

Dopaminergic inhibition of prolactin release from pituitary glands of the domestic fowl incubated in vitro.

Anterior pituitary glands from broiler fowl were incubated by themselves, with hypothalamic tissue or with thyrotrophin releasing hormone (TRH) in medium containing dopamine and its antagonist pimozide. The presence of hypothalamic tissue or TRH resulted in a stimulation of release of prolactin. Neither dopamine nor pimozide affected prolactin release directly from the pituitary gland. Dopamine inhibited the release of prolactin stimulated by hypothalamic tissue or TRH, in a concentration-dependent fashion. Pimozide diminished the response to dopamine. After pituitary glands were preincubated for 20 h in medium containing oestradiol-17 beta, the basal release of prolactin was enhanced as was the response to TRH. Both basal and TRH-stimulated release of prolactin from the oestrogen-primed pituitary glands was inhibited by dopamine, an effect blocked by pimozide. Hypothalami from broiler fowl were incubated for up to 8 h in medium containing dopaminergic drugs and pituitary glands were incubated in this medium, alone or with pimozide. As indicated by the prolactin released by the pituitary glands, the hypothalami appeared to secrete prolactin-releasing activity in a time-related fashion. Dopaminergic activity was also present in the hypothalami, since pimozide enhanced the prolactin-releasing activity of the medium. Dopamine apparently inhibited and pimozide stimulated the secretion of releasing activity from the hypothalamus. These results suggest that dopamine inhibits release of prolactin directly from the pituitary gland only when prolactin secretion is high. The hypothalamus secretes at least two factors regulating prolactin secretion, a prolactin-releasing factor and a dopaminergic prolactin-inhibiting factor. Dopamine may also play an inhibitory role in the regulation of secretion of the prolactin-releasing factor.

Serotoninergic regulation of corticosterone secretion in domestic fowl.

The effects of serotoninergic drugs on adrenocortical function in domestic fowl were examined. Administration of the serotonin receptor agonist 2-(1-piperazinyl)quinoline maleate (quipazine), an inhibitor of serotonin metabolism, N-methyl-N-2-propynylbenzylamine HCl (pargyline), as well as serotonin itself, all increased plasma concentrations of corticosterone. The maximum responses to serotonin and quipazine occurred 1 h after treatment. The quipazine-stimulated response was partly prevented by the serotonin antagonist cyproheptadine. Cockerels pretreated with dexamethasone, a synthetic steroid known to inhibit pituitary ACTH release, showed attenuated responses to subsequent quipazine, pargyline or serotonin injection. Serotonin, quipazine and cyproheptadine did not affect corticosterone release directly from the adrenal gland incubated in vitro, nor did they affect adrenal responsiveness to ACTH stimulation. The neurotoxin 5,6-dihydroxytryptamine injected into day-old chicks decreased plasma concentrations of corticosterone for up to 7 days after treatment, with corresponding decreases in the hypothalamic concentration of serotonin, but not dopamine or noradrenaline concentrations. These results show that adrenal corticosterone secretion is regulated by a central serotoninergic system, probably acting on the hypothalamo-pituitary-adrenal axis.

Somatostatin tonically inhibits growth hormone secretion in domestic fowl.

Passive immunization of immature chickens with sheep somatostatin (SRIF) antiserum promptly increased the basal plasma GH concentration and augmented TRH-induced GH secretion. Although exogenous SRIF had no inhibitory effect on the basal GH concentration in untreated birds or birds pretreated with non-immune sheep serum, it suppressed the stimulatory effect of SRIF immunoneutralization on GH secretion. These results suggest that SRIF is physiologically involved in the control of GH secretion in birds, in which it appears to inhibit GH release tonically.

Serotoninergic inhibition of LH secretion in the domestic fowl.

Immature cockerels were injected with drugs known to affect serotoninergic activity. The receptor agonist quipazine as well as pargyline, an inhibitor of serotonin breakdown, both reduced plasma LH concentrations in a time-dependent fashion. The effect of pargyline was also dose-related. The serotonin precursor, tryptophan, reduced plasma LH levels. Tryptophan and pargyline were as effective in pubertal cockerels as in 3-week-old birds. Responses to quipazine were attenuated by the antagonist, methysergide, although another antagonist, cyproheptadine, also reduced plasma LH levels. Serotonin itself had no effect on plasma LH levels. Parachlorophenylalanine, which blocks serotonin synthesis, had no effect on plasma LH by itself, but attenuated the tryptophan-induced inhibition of LH. These data indicate that serotoninergic mechanisms inhibit secretion of LH in domestic fowl. This mechanism probably operates through the central nervous system.

Mechanisms of release of prolactin from fowl anterior pituitary glands incubated in vitro: effects of calcium and cyclic adenosine monophosphate.

Fowl anterior pituitary glands were bisected and each half was pretreated in either Medium 199 or medium containing EGTA to deplete endogenous calcium (Ca2+) stores, after which they were incubated in Medium 199, or Ca2+-free medium, containing prolactin release-stimulating agents and verapamil, a Ca2+ channel blocker. High K+ concentrations, hypothalamic extract, synthetic thyrotrophin-releasing hormone (TRH) and dibutyryl cyclic AMP (dbcAMP) all stimulated release of prolactin from control (non EGTA-treated) hemianterior pituitary glands. The effects of TRH and dbcAMP were not additive, but the response to submaximal concentrations of TRH was augmented by theophylline, a phosphodiesterase inhibitor. Reduction of Ca2+ availability with EGTA or verapamil reduced basal release of prolactin, prevented the prolactin-stimulating effects of high K+ concentrations and TRH, and markedly attenuated responses to hypothalamic extract and dbcAMP, EGTA being more effective than verapamil. Increasing the Ca2+ concentration of the medium did not augment basal or stimulated release of prolactin. These results suggest that both Ca2+ and cyclic AMP may act as intracellular mediators in the release of prolactin. Both basal and stimulated release of prolactin depend upon the presence of Ca2+. Although influx from the medium may be the major source of Ca2+, endogenous stores of Ca2+, perhaps mobilized by dbcAMP, may be able to maintain some release of prolactin. The prolactin-stimulating effects of TRH may be mediated by cyclic AMP.

Inhibition by testosterone of prolactin and growth hormone release from chicken anterior pituitary glands in vitro.

Pituitary glands and hypothalami from broiler fowl were incubated in medium containing testosterone, and prolactin and GH release were determined. Pituitary glands were also preincubated for 20 h in medium containing testosterone, and then in medium containing various secretagogues. Testosterone inhibited the release of prolactin directly from the pituitary gland in a concentration-related manner. The hypothalamus stimulated the release of prolactin, but by a lesser amount in the presence of testosterone. When pituitary glands were preincubated with testosterone, subsequent release of prolactin was inhibited, except with the highest concentration which stimulated prolactin release. Hypothalamic extract (HE) markedly stimulated prolactin release from control pituitary glands although testosterone-primed glands were less responsive. The stimulation of prolactin release by thyrotrophin releasing hormone (TRH) and prostaglandin E2 (PGE2) was also reduced by preincubation of the pituitary glands with testosterone. Priming with testosterone did not affect the release of GH from pituitary glands alone, but reduced the TRH-, HE- and PGE2-stimulated release of GH. These results demonstrate that testosterone directly inhibits prolactin secretion and reduces the sensitivity of pituitary lactotrophs and somatotrophs to provocative stimuli.

Somatostatin immunoneutralization stimulates thyroid function in fowl.

The influence of somatostatin on thyroid function has been examined in immature domestic fowl passively immunized with somatostatin antiserum. Plasma thyroxine (T4) and tri-iodothyronine (T3) concentrations were markedly increased within 10 min of antisomatostatin administration and remained raised for at least 5 h. The increases in the T3 and T4 concentrations following somatostatin immunoneutralization were directly related to the volume of antisera administered. The increase in the T3 concentration exceeded the increase in the T4 concentration, resulting in a T3 : T4 ratio greater than unity. While the raised T4 concentration began to decline 30 min after antisomatostatin administration, raised T3 concentrations were sustained for at least 2 h, and further increased the plasma T3 : T4 ratio. These results demonstrate that somatostatin immunoneutralization stimulates thyroid function in fowl. The magnitude and rapidity of the thyroidal responses to somatostatin immunoneutralization suggests that they occur independently of the hypothalamic-pituitary-thyroid axis. Somatostatin appears to exert a tonic inhibitory control on avian thyroid function, possibly by effects mediated at the thyroid gland to inhibit T4 release and by peripheral effects to suppress the conversion of T4 and T3.

Effects of passive immunization with antisomatostatin serum on plasma corticosterone concentrations in young domestic cockerels.

Young cockerels (6-8 weeks old) were injected with serum from sheep immunized against somatostatin-14 (anti-SRIF) or normal sheep serum (NSS). Blood samples were withdrawn periodically for the determination of plasma corticosterone concentration by radioimmunoassay. With frequent (every 10 min) sampling, NSS-treated control animals exhibited increased plasma corticosterone levels, presumably as a stress response to the experimental manipulation. Anti-SRIF stimulated a much greater increase in plasma corticosterone concentrations and a peak response was observed within 10 to 20 min, when the plasma corticosterone level reached more than twice that of the corresponding control value. With less frequent sampling, plasma corticosterone increased with anti-SRIF administration to as much as nine times the corresponding control value, and the peak response occurred much later. Under pentobarbitone anaesthesia, which itself increased basal corticosterone concentrations, anti-SRIF treatment promoted further increases in plasma corticosterone levels although to a smaller magnitude compared with conscious birds. The results suggest that endogenous somatostatin may play a role in the regulation of adrenocortical function in the domestic fowl. The mechanism of response may involve a central component.

Effect of dehydration, haemorrhage and oviposition on serum concentrations of vasotocin, mesotocin and prolactin in the chicken.

Serum concentrations of arginine vasotocin (AVT), mesotocin and prolactin were determined by radioimmunoassay in Rhode Island Red chickens during and after dehydration, haemorrhage and oviposition. During dehydration increased circulating levels of AVT, mesotocin and prolactin were found. As water deprivation proceeded, marked differences were observed. After an initial rise in serum AVT, mesotocin and prolactin levels during mild and moderate dehydration, concentrations of both AVT and prolactin tended to normalize during continued water deprivation, while those of mesotocin remained high throughout the whole dehydration experiment with the highest at the end of the water-deprivation period. Removal of 5 ml blood at intervals of 10 min during six consecutive time-periods did not affect serum osmolality and circulating levels of AVT and prolactin, but slightly increased mesotocin. These results suggest an osmoregulatory role for AVT and prolactin, whereas mesotocin may be involved in volume control. Finally, 1 min after oviposition, control values of 19.5 +/- 3.4 pmol AVT/1 (n = 9) were raised more than sevenfold to 142.9 +/- 12.5 pmol/l (n = 11). Thereafter, a decline occurred with a half-life for AVT of 13 min with raised serum levels up to 31 min after oviposition. In contrast, the serum concentrations of mesotocin and prolactin remained unaffected by oviposition.

Direct stimulation of growth hormone secretion by galanin in the domestic fowl*.

Abstract Galanin, a novel peptide originally isolated from porcine intestine, has a wide distribution in the nervous system and is known to enhance the release of growth hormone in mammals, though the mechanism of its actions is still subject to debate. In the current study, the effects of galanin on growth hormone secretion in the domestic fowl were investigated. Intravenous injections of galanin into both 8-week old and 18-week old female Hubbard broilers produced marked increases in plasma growth hormone, similar in magnitude to that evoked by human growth hormone-releasing factor. Galanin produced dose-related increases in growth hormone release, with a peak response occurring within 10 min of administration. Growth hormone release in response to a maximal challenge of growth hormone-releasing factor was further augmented when galanin was given at the same time. Galanin stimulated growth hormone release from chick hemipituitary glands in vitro, a response which was not dependent upon hypothalamic input. In addition, galanin potentiated the actions of growth hormone-releasing factor on growth hormone release in vitro and these responses were reversed by somatostatin. These results show that galanin is able to stimulate growth hormone release in the domestic fowl by acting directly on the pituitary gland.