Graves' orbitopathy post-SARS-CoV-2 vaccines: report on six patients.

CONTEXT: Autoimmune and inflammatory thyroid diseases (Graves' disease, subacute thyroiditis, chronic autoimmune thyroiditis) have been reported following SARS-CoV-2 vaccines but Graves' orbitopathy (GO) post-COVID-19 vaccination is uncommon. METHODS: We describe six new patients seen in Endocrinology Departments with Outpatient Clinics for GO following SARS-CoV-2 vaccines in France. RESULTS: After COVID-19 vaccination, GO was observed in six patients (three men, three women, mean age 53 ± 6 years) with a personal past history of Graves' disease (5/6) or orbitopathy (4/6). New-onset (n = 2) or recurrence (n = 4) of GO was observed following mRNA vaccines after the first (3/6) or second (3/6) dose, with the mean time from vaccination to GO at 23.8 ± 10.4 days. In one patient, thyrotoxicosis was confirmed by increased free T4 and low TSH concentrations while others had normal TSH levels, during chronic levothyroxine treatment in three patients. Four patients had significant anti-TSH receptor antibodies levels. According to the severity and activity of GO, the patients were treated using selenium (n = 2), intravenous glucocorticoids (n = 2), teprotumumab (n = 1), tocilizumab (n = 2) and orbital decompression (n = 1) with a significant improvement in GO signs and symptoms observed by most patients. CONCLUSION: In this study, we report the main data from six new patients with GO following SARS-CoV-2 vaccines. Clinicians need to be aware of the risk of new-onset or recurrent GO in predisposed patients with autoimmune thyroid diseases after COVID-19 vaccination. This study should not raise any concerns regarding SARS-CoV-2 vaccination since the risk of COVID-19 undoubtedly outweighs the incidence of uncommon GO after SARS-CoV-2 vaccination.

Research and innovation as a catalyst for food system transformation.

BACKGROUND: Food systems are associated with severe and persistent problems worldwide. Governance approaches aiming to foster sustainable transformation of food systems face several challenges due to the complex nature of food systems. SCOPE AND APPROACH: In this commentary we argue that addressing these governance challenges requires the development and adoption of novel research and innovation (R&I) approaches that will provide evidence to inform food system transformation and will serve as catalysts for change. We first elaborate on the complexity of food systems (transformation) and stress the need to move beyond traditional linear R&I approaches to be able to respond to persistent problems that affect food systems. Though integrated transdisciplinary approaches are promising, current R&I systems do not sufficiently support such endeavors. As such, we argue, we need strategies that trigger a double transformation - of food systems and of their R&I systems. KEY FINDINGS AND CONCLUSIONS: Seizing the opportunities to transform R&I systems has implications for how research is done - pointing to the need for competence development among researchers, policy makers and society in general - and requires specific governance interventions that stimulate a systemic approach. Such interventions should foster transdisciplinary and transformative research agendas that stimulate portfolios of projects that will reinforce one another, and stimulate innovative experiments to shape conditions for systemic change. In short, a thorough rethinking of the role of R&I as well as how it is funded is a crucial step towards the development of the integrative policies that are necessary to engender systemic change - in the food system and beyond.

Treatment with somatostatin analogs and chemoembolization of liver metastases for severe hypoglycemia in malignant insulinomas.

BACKGROUND: Preventing hypoglycemia is of vital importance and a major challenge in patients with severe symptomatic hypoglycemia related to malignant unresectable insulinomas, but there is no consensus treatment. PATIENTS: Five patients with malignant unresectable insulinomas were referred to our department for severe hypoglycemia. At referral the five patients were dependent on iv infusion of glucose solution. Patient 1 had a locally invasive 5-cm insulinoma, patients 2, 3 and 4 had multiple liver metastases and patient 5 had a 2.5-cm pancreatic tumor with multiple liver and lung metastases. Before referral to our department, 4/5 patients had been administered systemic chemotherapy and 3/5 therapeutic doses of radiolabeled octreotide without any benefit on blood glucose levels. Octreoscan scintigraphy was positive in 4 patients (patients 1-4). Diazoxide alone or combined with glucocorticoids had failed to control hypoglycemia. Continuous sc administration of octreotide (up to 1500 µg/day) resulted in normalization of blood glucose levels in patient 1. Chemoembolization of liver metastases normalized blood glucose levels in patient 2, minimized hypoglycemia in patients 3 and 4, and normalized blood glucose levels in patient 5 when followed by subcutaneous administration of octreotide (2000 µg/day). Chemoembolization had to be repeated four times in patient 3 to control blood glucose levels. CONCLUSION: Chemoembolization of liver metastases and high-dose octreotide in responsive patients (alone or combined with chemoembolization) can control severe hypoglycemia in patients with symptomatic malignant unresectable insulinomas; the efficacy of octreotide can be improved after chemoembolization of liver metastases.

[Carcinological results of laparoscopic adrenalectomy for adrenal metastasis]. / Résultats de la chirurgie des métastases surrénaliennes par voie laparoscopique.

INTRODUCTION AND OBJECTIVES: Indication of laparoscopic adrenalectomy for adrenal metastasis remains debated. Our aim was to analyze its carcinological results. MATERIAL AND METHODS: In a series of 332 laparoscopic adrenalectomies, 13 were for adrenal metastasis (kidney=5, lung=3, melanoma=3, breast=1, eye=1). The indication was curative (single metastasis) in nine cases (69%), the four other patients (31%) having a polymetastatic disease. All alive patients were interviewed in August 2010. Survival was estimated using the Kaplan-Meyer method, with comparisons using the log rank test. RESULTS: Mean operative time was 174.2 ± 102 minutes. Blood loss was 351 ± 136 mL. Three conversions (23%) were necessary, for gastric perforation, wound of vena cava and inability to dissect the adrenal. Surgical margins were positive in six cases (46%). The risk of positive margin was lower in case of metastasis of renal cell carcinoma (Fischer, p=0.02). The median of overall survival was 14 months (3-45). Survival was significantly higher in metastases of renal cell carcinoma (p=0.035) than in metastases of other tumors, 24 months (11-36) vs six months (3-45), respectively. There was no difference according to the laparoscopic technique used, neither according to the age, nor according to the tumoral size. CONCLUSIONS: Laparoscopic surgery did not offer sufficient guarantee to be considered as the standard treatment in case of adrenal metastasis. However, with a survival rate of 60%, a lower rate of surgical margins, metastases of renal cell carcinoma seem to be the better candidates for laparoscopic adrenalectomy.

A proactive medical necessity review program reduces revenue loss associated with outpatient medical benefit drugs.

PURPOSE: A common denial trend that occurs with "outpatient medical benefit drugs" (ie, medications covered by a medical benefit plan and administered in an outpatient visit) is payers not requiring or permitting prior authorization (PA) proactively, yet denying the drug after administration for medical necessity. In this situation, a preemptive strategy of complying with payer-mandated requirements is critical for revenue protection. To address this need, our institution incorporated a medical necessity review into its existing closed-loop, pharmacy-managed precertification and denials management program. SUMMARY: Referrals for targeted payers and high-cost medical benefit drugs not eligible for PA and deemed high risk for denial were incorporated into the review. Payer medical policies were evaluated and clinical documentation assessed to confirm alignment. This descriptive report outlines the medical necessity workflow as a component of the larger precertification process, details the decision-making process when performing the review, and delineates the roles and responsibilities for involved team members. A total of 526 drug orders were evaluated from September 2018 to August 2019, with 146 interventions completed. Of the 761 individual claims affected by proactive medical necessity review, 99.2% resulted in payment and less than 1% resulted in revenue loss, safeguarding more than $5.3 million in annual institutional drug reimbursement. At the time of analysis, there were only 3 cases of revenue loss. CONCLUSION: Our institution's pharmacy-managed medical necessity review program for high-cost outpatient drugs safeguards reimbursement for therapies not eligible for payer PA. It is a revenue cycle best practice that can be replicated at other institutions.

Engineered humanized dimeric forms of IgG are more effective antibodies.

Humanized IgG1 M195 (HuG1-M195), a complementarity determining region-grafted recombinant monoclonal antibody, is reactive with CD33, an antigen expressed on myelogenous leukemia cells. M195 is in use in trials for the therapy of acute myelogenous leukemia. Since biological activity of IgG may depend, in part, on multimeric Fab and Fc clustering, homodimeric forms of HuG1-M195 were constructed by introducing a mutation in the gamma 1 chain CH3 region gene to change a serine to a cysteine, allowing interchain disulfide bond formation at the COOH terminal of the IgG. Despite similar avidity, the homodimeric IgG showed a dramatic improvement in the ability to internalize and retain radioisotope in target leukemia cells. Moreover, homodimers were 100-fold more potent at complement-mediated leukemia cell killing and antibody-dependent cellular cytotoxicity using human effectors. Therefore, genetically engineered multimeric constructs of IgG may have advantages relative to those forms that are found naturally.

The multidrug resistance phenotype confers immunological resistance.

Multidrug resistance (MDR), which is due, in part, to the overexpression of P-glycoprotein, confers resistance to a variety of natural product chemotherapeutic agents such as daunorubicin, vincristine, and colchicine. RV+ cells are a P-glycoprotein overexpressing variant of the HL60 myeloid leukemia cell line. In addition to classic MDR, RV+ cells displayed relative resistance to complement-mediated cytotoxicity with both immunoglobulin G and M antibodies against different cell surface antigens, but not to antibody-dependent cellular cytotoxicity and lymphokine-activated killing. Complement resistance was reversed both by treatment with verapamil and with specific monoclonal antibodies (mAbs) capable of binding to P-glycoprotein and blocking its function. To further confirm that the resistance of RV+ cells was not a consequence of the selection of the cells on vincristine, a second system involving P-glycoprotein infectants was also investigated. K562 cells infected with the MDR1 gene, which were never selected on chemotherapeutic drugs, also displayed relative resistance to complement-mediated cytotoxicity. This MDR1 infection-induced resistance was also reversed by mAbs that bind to P-glycoprotein. Therefore, the MDR phenotype as mediated by P-glycoprotein provides resistance to complement-mediated cytotoxicity. The increased intracellular pH and the decreased membrane potential due to the MDR phenotype may result in abnormal membrane attack complex function. This observation may have implications for the possible mechanisms of action of P-glycoprotein and for a possible physiologic role for P-glycoprotein in protection against complement-mediated autolysis.

Outcomes of orbital decompression using surgical navigation in thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy can result in proptosis. In such cases, orbital decompression surgery is often warranted to reduce the adverse impact on patient quality of life. Due to the anatomical complexity of the orbit, navigation can be of considerable assistance during orbital decompression. The objective of this study was to evaluate the benefits of using a surgical navigation device in orbital decompression surgery. A retrospective study was performed based on patients who underwent decompression surgery with (N+) or without (N-) a navigation device between 1997 and 2017. Included patients had undergone unilateral or bilateral orbital decompression by resection of the orbital floor and medial wall of the orbit. Criteria assessed were the presence of debilitating postoperative diplopia, postoperative proptosis reduction, symmetry of protrusion of the eyeballs, and the duration of surgery. Three hundred and fifty eyes were analysed (191 patients): 205 in the N+ group and 145 in the N- group. Use of the surgical navigation system resulted in a greater proptosis reduction, and this result was statistically significant for the right eyeball (P=0.03). The surgical navigation system had no effect on symmetry of protrusion of the eyeballs or on postoperative diplopia. Setting up the navigation device increased the duration of surgery by 40 minutes on average.

[Immune-related adverse events after immune checkpoints inhibitors in 2019: An update]. / Toxicités immunologiques induites par les inhibiteurs de checkpoint en 2019 : mise au point.

Use of checkpoint inhibitors to treat cancer was one of the most important revolution these last years and an increasing number of new types of tumors is currently under investigation with these new treatments. However, immune-related adverse events associated with these agents frequently affect various organs, mimicking auto-immune or inflammatory diseases. Some of these effects can be severe, often requiring hospitalization and specialized treatment (immunosuppression). Most known agents are ipilimumab (anti-CTLA-4 antibody) nivolumab and pembrolizumab (anti-PD-1 antibodies). New molecules are now approved or in development as anti-PD-L1 antibodies, anti-LAG-3 or anti-TIM-3 antibodies, increasing the probability and new description of immune-related adverse events. With his experience in auto-immune diseases, the immunologist/internal medicine specialist has an important role in the management of these toxicities. The goal of this review is to focus on the incidence, diagnostic assessment and recommended management of the most relevant immune-related adverse events.

[Prevention of thyroid disorders in pregnant women]. / Prévention des désordres thyroïdiens au cours de la grossesse.

BACKGROUND: Iodine is essential for biosynthesis of thyroid hormones and daily iodine intake needs are increased during pregnancy. Thyroid dysfunctions (hypothyroidism, hyperthyroidism) are due to autoimmune diseases (Hashimoto's disease, Graves' disease) in most women of childbearing age. During pregnancy they are associated with maternal and fetal complications: maternal hypothyroxinemia during the first trimester of gestation can be associated with abnormal cognitive development and intellectual outcomes in the newborn and the children. In patients with Graves' disease, TSH-receptor antibodies cross the placenta and can induce fetal and neonatal dysfunctions. OBJECTIVES: In order to prevent maternal and fetal complications and ameliorate the pronostic of thyroid disorders in pregnant women, the prevention should be: a systematic prophylaxis of iodine deficiency in pregnant women; an adjustment of the preconception levothyroxine treatment in women with hypothyroidism diagnosed before the pregnancy; a targeted screening for maternal hypothyroidism in high-risk women; a rational measurement for TSH-receptor and anti-thyroperoxydase antibodies in some women with autoimmune thyroid diseases.

Multiple endocrine neoplasia type 2a and germ line C634G RET mutation diagnosed in an 80-year-old patient.

An 80-year-old man presented with progressive fatigue. Blood tests showed that serum calcium was increased (2.93 mmol/l, normal range 2.20-2.55 mmol/l) and serum concentration of intact parathyroid hormone (iPTH) inappropriately high (198 pg/ml, normal range 15-85 pg/ml). Neck ultrasonography and Tc-MIBI scintigraphy revealed a right parathyroid adenoma and a multinodular goiter. Serum calcitonin was significantly increased (220 pg/ml, normal range<10 pg/ml). Concomitantly, a chest-abdominal computed tomography was performed and revealed a 22 mm right adrenal incidentaloma. The urinary catecholamines and metabolites were two-fold above the upper limit of normal. After right adrenalectomy which confirmed the diagnosis of pheochromocytoma, the patient underwent total thyroidectomy with dissection of the central lymph node compartment and right parathyroidectomy. On histopathologic examination, both thyroid lobes presented 13 foci of MTC without lymph node metastasis and the parathyroid gland presented a benign adenoma without hyperplasia. The patient underwent screening and genetic testing revealing a germ line C634 G RET mutation. The diagnosis of Men2a at the age of 80 years and the absence of lymph node metastasis of the multiple MTC in a carrier of C634G mutation were unusual and argued for the possible role of genetic modifier(s) in this MEN 2a patient.

Short- and long-term somatostatin analogue treatment in patients with hypoglycaemia related to endogenous hyperinsulinism.

BACKGROUND: The long-term efficacy of somatostatin analogues on insulinomas has not been studied. DESIGN: A prospective study to evaluate the response of octreotide in 21 patients with hypoglycaemia related to endogenous hyperinsulinism who were not treated by surgery. RESULTS: Reasons for not undergoing surgery were: refusal (n = 3), old age with multiple diseases (n = 5), unlocalized insulinomas (n = 2), malignant unresectable insulinomas (n = 5), multiple insulinomas (n = 3) and diffuse beta-cell disease (n = 3). Hypoglycaemia was responsive to octreotide in 14 of the 21 patients. A short 100-microg octreotide test correctly predicted the efficacy of treatment in six patients with benign insulinomas. Octreoscan scintigraphy was positive in 6 of the 16 patients of whom three were responsive and three unresponsive to octreotide. Octreoscan scintigraphy was negative in 10 of the 16 patients, eight of whom were responsive to octreotide. Subcutaneous octreotide treatment was prolonged for > 6 months (7-144 months, 67 +/- 47 months) in 11 responsive patients. No tachyphylaxis was observed. However, the octreotide dose had to be increased in two patients after 3 and 18 months, respectively. Only one patient suffered from symptomatic biliary lithiasis after 3 years of treatment. CONCLUSION: Long-term octreotide treatment can be used to control hypoglycaemia in patients with endogenous hyperinsulinism who are not eligible for surgery; octreotide efficacy on hypoglycaemia could be predicted by a short 100 microg-octreotide test in patients with benign insulinomas, but was not correctly predicted by Octreoscan scintigraphy.

Cross-validation of Levenson's Psychopathy Scale in a sample of federal female inmates.

Levenson, Kiehl, and Fitzpatrick's Self-Report Psychopathy Scale (LSRPS) is evaluated to determine the factor structure and concurrent validity of the instrument among 430 federal female inmates. Confirmatory factor analysis fails to validate the expected 2-factor structure. Subsequent exploratory factor analysis reveals a 3-factor structure (egocentric, antisocial, and callous), where each factor accounts for significant variance in scores on several theoretically relevant measures. Higher scores on the antisocial factor of the LSRPS are associated with a history of varied psychopathological and negative legal outcomes, suggesting evidence of concurrent validity. However, the egocentric and callous factors do not seem to measure precisely the same construct as the primary psychopathy factor from the Levenson et al. study. The 3-factor structure proposed here has been proposed by other researchers and found in other samples of psychopathy in female inmates. Implications for both research and clinical practice using the LSRPS with female inmates are discussed.

[New medical treatments in pituitary adenomas]. / Actualités thérapeutiques dans la prise en charge médicale des adénomes hypophysaires.

Currently, the role of dopaminergic and somatostatinergic agonists in the treatment of pituitary adenomas is quite well established. Nevertheless, a clearer understanding of the expression of dopaminergic and somatostatinergic receptors at the cellular level of pituitary adenomas as well as the development of newer analogues compounds may drastically change current therapeutic modalities. In particular, the emphasis on the co-expression of different receptors types or subtypes in adenomatous cells highlights functional interactions between receptors leading to an increase in their activity. Newer molecules are also in the process of development : new somatostatin analogues with more universal binding properties to different receptors subtypes, as well as chimeric molecules capable of binding to somatostatinergic and dopaminergic receptors. In the midst of GH-secreting pituitary adenomas, a positive correlation exists between the expression of Sst2 mRNA and the inhibition of GH release by somatostatin analogues. The involvement of Sst5 subtype in adenomas resistant to preferential Sst2 agonists has recently been proved. Another recently developed compound has a more universal Sst binding profile. This compound, named SOM-230, has a 25, 5 and 40 times higher binding affinity to Sst1, Sst3 and Sst5 receptors respectively, and 2,5 times lower affinity to Sst2, when compared to octreotide. SOM-230 could therefore allow for much more effective methods in treating patients suffering from acromegaly. Besides, the use of a chimeric molecule presenting a binding affinity to both Sst2 and D2 subtypes (BIM-23A287) inhibits the secretion of GH in ways similar to the Sst2 or D2 agonists used alone or concurrently but however in a concentration 50 times lower than that of the latter. The discovery of Sst5 and D2 subtypes at the level of corticotropic adenomas reveals newer therapeutic perspectives with promising preliminary results with the use of SOM-230 ; these finding lead to a rise in interest in cabergoline. In the midst of non-functioning pituitary adenomas, the expression of Sst2, Sst3 and D2 receptors will perhaps allow the use of combined therapies associating the new somatostatin analogues to the dopaminergic agonists or even use dopastatin (BIM-23A760, chimeric molecule Sst2-Sst5-D2). The preliminary results obtained in vitro with this molecule are actually encouraging since they show a dose dependent inhibition of the cellular replication mechanisms in 60 % of the cases. Finally, concerning prolactinomas the discovery of Sst5 receptors lead to consider the use of somatostatinergic agonists specific to the Sst5 receptor, SOM-230 in particular. Nevertheless, it seems that adenomas resistant to dopaminergic agonist due to a lack of expression of D2 receptor fail to express Sst5 receptors as well. On the other hand, dopastatin appears to be more efficient than cabergoline in the management of this type of adenomas. Therefore, the growing awareness concerning the mechanisms involved in the control of pituitary secretions as well as cellular proliferation will perhaps allow physicians to treat the pathology of pituitary adenomas, macroadenomas in particular, using solely pharmacological means instead of invasive surgical procedures and/or radiotherapy.

[Retroperitoneal laparoscopic adrenalectomy in a pregnant woman presenting MEN2a with a pheochromocytoma: case report and review of the literature]. / Surrénalectomie par coelioscopie rétropéritonéale au cours de la grossesse chez une patiente présentant un phéochromocytome dans le cadre d'une NEM2a: un nouveau cas et revue de la littérature.

The diagnosis of pheochromocytoma during pregnancy is uncommon and is at high risk for both mother and baby. We report the case of a 22-year-old woman with MEN2a (mutation C634Y in exon 11 of RET) who had undergone surgery for medullary carcinoma of the thyroid and hyperparathyroidism when she was 18. She was asymptomatic when she was seen at 22 weeks of gestation because of increased urinary metanephrine levels. A 24-h blood pressure monitoring was normal. Abdominal magnetic resonance imaging (MRI) revealed a right-sided, 34x31x28mm, well-limited, adrenal mass with high signal intensity on T2-weighted images; the contralateral adrenal was normal. At 26 weeks of gestation and after an adequate labetalol preparation, a retroperitoneal laparoscopic right-sided adrenalectomy was performed without maternal or foetal complications. Pathohistological examination confirmed the presence of a 3cm pheochromocytoma in the right adrenal gland, with no sign of malignancy. The levels of urinary methoxylated metabolites were normal two months after surgery. The pregnancy progressed normally and the patient delivered a healthy child without complications. In conclusion, firstly, all MEN2a women should be screened for a pheochromocytoma with a 24-h urinary metanephrine and normetanephrine evaluation before or early during pregnancy, even with normal blood pressure; secondly, pheochromocytoma diagnosed during pregnancy should be operated on during pregnancy because of the risks for both mother and baby; thirdly, after medical therapy, retroperitoneal laparoscopic adrenalectomy can be performed during the second trimester of pregnancy.

[Toxicity of immune checkpoints inhibitors]. / Toxicité des inhibiteurs de points de contrôle immunitaires.

INTRODUCTION: Anti-tumoral immunotherapy is currently the basis of a profound modification of therapeutic concepts in oncology, in particular since the arrival of immune checkpoint inhibitors (ICI). In addition to their efficacy profile, these immune-targeted agents also generate adverse events. With the increasing use of ICI for a growing number of tumor types, awareness of immunotherapy-related adverse events is essential to ensure prompt diagnosis and effective management of these potentially serious adverse events. BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) are two co-inhibitory receptors that are expressed on activated T cells against which therapeutic blocking antibodies have reached routine clinical use. Immune checkpoint blockade can induce inflammatory adverse effects, termed immune-related adverse events (irAEs), which resemble autoimmune disease. Though severe irAEs remain rare, they can be fatal if not diagnosed and treated in an appropriate manner. OUTLOOK AND CONCLUSION: Additional studies are needed to better understand the clinical characteristics and chronology of these adverse effects and to clarify their pathophysiological mechanisms.

The impact of UGT1A8, UGT1A9, and UGT2B7 genetic polymorphisms on the pharmacokinetic profile of mycophenolic acid after a single oral dose in healthy volunteers.

We studied whether polymorphisms in the UGT1A8, UGT1A9, and UGT2B7 genes, the enzymes producing the phenolic (MPAG) and acyl (AcMPAG) glucuronides of mycophenolic acid (MPA), could contribute to the interindividual variation observed in mycophenolate mofetil (MMF) pharmacokinetics (PKs). This study enrolled 17 healthy volunteers with no polymorphisms (controls) and 17 carriers of UGT1A9 -275/-2152 selected among 305 individuals genetically screened for UDP-glucuronosyltransferase (UGT) polymorphisms. Additional investigative groups included carriers of UGT1A8*2 (A173G) (n=9), UGT1A8*3 (C277Y) (n=4), and UGT1A9*3 (M33T) (n=5). Genetic analysis also included UGT2B7 to detect UGT2B7*2 (His268Tyr) and the promoter haplotype -1248A>G, -1241T>C, -1054T>C, -842G>A, -268A>G, -102T>C. Kinetics were measured in plasma and urine after a single 1.5 g oral dose of MMF, by high-performance liquid chromatography coupled with tandem mass spectrometry, over 12 h after drug intake. Compared to controls, MPA exposure was significantly lower for UGT1A9 -275/-2152 carriers, with no significant changes in MPAG. The estimates of enterohepatic (re)cycling (area under the concentration-time curve (AUC6-12 h/AUC0-12 h)) were significantly lower for MPA, MPAG, and AcMPAG in UGT1A9 -275/-2152 subjects. Compared with controls, UGT1A9*3 carriers had higher MPA and AcMPAG exposure, whereas homozygosity for the UGT1A8*2 allele and heterozygosity for UGT1A8*3 allele had no impact on MPA PKs. Compared with UGT2B7*1/*1 individuals (n=10), UGT2B7*2/*2 subjects (n=17) presented significantly higher free MPA C(max) values and elevated free and total MPA. Results indicate that after a single oral dose of MMF in healthy volunteers, specific UGT genotypes significantly alter MPA PKs and this clearly warrants additional studies with complete and detailed genetic profiling of UGT1A8, UGT1A9, and UGT2B7 genes.