Postsurgical Recurrent Cushing Disease: Clinical Benefit of Early Intervention in Patients with Normal Urinary Free Cortisol

Objective: To assess the performance of biochemical markers in the detection of recurrent Cushing disease (CD), as well as the potential benefit of early intervention in recurrent CD patients with elevated late-night salivary cortisol (LNSC) and normal urinary free cortisol (UFC).Methods: The design was a single-center, retrospective chart review. Patients treated by the authors from 2008–2013 were included. Recurrence was defined by postsurgical remission of CD with subsequent abnormal LNSC, UFC, or dexamethasone suppression test (DST).Results: We identified 15 patients with postsurgical recurrent CD after initial remission; all but one underwent testing with LNSC, DST, and UFC. Although 12 of 15 patients had normal UFC at time of recurrence, DST was abnormal in 11 of 15, and all 14 patients with LNSC results had ≥1 elevated measurement. Nine patients (7 with normal UFC) showed radiologic evidence of a pituitary tumor at time of recurrence. Among the 14 patients with available follow-up data, 12 have demonstrated significant improvement since receiving treatment. Five patients underwent repeat pituitary surgery and 4 achieved clinical and biochemical remission. Eight patients received mifepristone or cabergoline, and 6 showed clinical and/or biochemical improvement. Three patients (2 with prior mifepristone) underwent bilateral adrenalectomy and 2 demonstrated significant clinical improvements.Conclusion: LNSC is more sensitive than UFC or DST for detection of CD recurrence. Prompt intervention when LNSC is elevated, despite normal UFC, may yield significant clinical benefit for many patients with CD. Early treatment for patients with recurrent CD should be prospectively evaluated, utilizing LNSC elevation as an early biochemical marker.Abbreviations:ACTH = adrenocorticotropic hormoneCD = Cushing diseaseCS = Cushing syndromeCV = coefficient of variationDST = dexamethasone suppression testIPSS = inferior petrosal sinus samplingLNSC = late-night salivary cortisolQoL = quality of lifeTSS = transsphenoidal adenoma resectionUFC = urinary free cortisol     

Mifepristone Treatment for Mild Autonomous Cortisol Secretion Due to Adrenal Adenomas: A Pilot Study

Objective: Adrenal incidentalomas are increasingly detected with the widespread use of thoracic and abdominal imaging. The most common secretory syndrome in adrenal nodules is autonomous cortisol secretion (ACS). Recent data show that even mild cortisol excess is associated with adverse outcomes. The glucocorticoid receptor antagonist mifepristone has been used in patients with overt Cushing syndrome and hyperglycemia. The purpose of our study was to determine the effect of mifepristone on metabolic parameters in patients with ACS and concomitant prediabetes or diabetes.Methods: Eight patients with either unilateral or bilateral adrenal nodules with ACS were included in the study. Fasting laboratory tests including glucose and insulin levels to calculate homeostatic model assessment for insulin resistance (HOMA-IR) were performed at baseline and again after either 3 months (3 patients) or 6 months (5 patients) on mifepristone 300 mg daily treatment. Patients also completed several validated surveys on mood and quality of life at baseline and follow-up.Results: There were significant reductions in fasting glucose measurements and insulin resistance as measured by HOMA-IR in the 6 of 8 study patients in whom these measurements were available (P = .03).Conclusion: This pilot study demonstrates that mifepristone treatment of ACS is associated with a significant decrease in fasting glucose and insulin resistance as measured by HOMA-IR scores. Mifepristone treatment of ACS may be considered as a medical option for patients with ACS due to adrenal adenomas with concomitant abnormal glucose parameters in whom surgical removal is not being considered.Abbreviations: ACS = autonomous cortisol secretion; ACTH = adrenocorticotropic hormone; AI = adrenal incidentaloma; DHEAS = dehydroepiandrosterone sulfate; GR = glucocorticoid receptor; HbA1c = hemoglobin A1c; HOMA-IR = homeostatic model assessment for insulin resistance; ODT = overnight dexamethasone suppression test; QoL = quality of life; STAI = state trait anxiety inventory; TSH = thyroid stimulating hormone; UFC = urinary free cortisol     

Patients' Perception On Clinical Outcome And Quality Of Life After A Diagnosis Of Cushing Syndrome

Objective: Excess cortisol production (Cushing syndrome, CS) is a chronic disease affecting many organ systems and impacting quality of life (QoL). This study analyzed factors associated with self-reported QoL, including aspects related to the diagnosis and treatment modalities of CS.Methods: In collaboration with the Cushing's Support and Research Foundation (CSRF), surveys using a validated QoL instrument were sent to CSRF members. Data were analyzed for associations between QoL and demographic, treatment, and disease factors.Results: A total of 269 patients completed the survey. Respondents were 89.9% female, and the mean age was 48 years (SD 12, range 16–76). Respondents visited a median of 4 physicians (range 1–40) prior to the diagnosis of CS, with a median of 5 years (mean 7, SD 5, range 1–30) to obtain a diagnosis, showing a statistically significant negative correlation (P<.001). In one-quarter of cases, someone other than a physician suggested the diagnosis. Multiple regression analysis demonstrated that remission status, time to diagnosis, radiation therapy, and hypopituitarism were significant predictors of QoL. There was no association between QoL and patient's sex, age, replacement steroid use, having follow-up with an endocrinologist, or surgical approach.Conclusion: This is one of the largest QoL studies of CS patients and provides information for treatment and education goals. It is notable that early diagnosis and treatment was the major predictor of better QoL after achieving remission from disease, highlighting the need for awareness about the disorder. Patients in remission had better QoL, emphasizing the importance of disease control.Abbreviations:CD = Cushing diseaseCS = Cushing syndromeCSRF = Cushing's Support and Research FoundationQoL = quality of life     

Efficacy,safety and immunogenicity of hexavalent rotavirus vaccine in Chinese infants

A randomized, double-blind, placebo-controlled multicenter trial was conducted in healthy Chinese infants to assess the efficacy and safety of a hexavalent live human-bovine reassortant rotavirus vaccine (HRV) against rotavirus gastroenteritis (RVGE). A total of 6400 participants aged 6–12 weeks were enrolled and randomly assigned to either HRV (n = 3200) or placebo (n = 3200) group. All the subjects received three oral doses of vaccine four weeks apart. The vaccine efficacy (VE) against RVGE caused by rotavirus serotypes contained in HRV was evaluated from 14 days after three doses of administration up until the end of the second rotavirus season. VE against severe RVGE, VE against RVGE hospitalization caused by serotypes contained in HRV, and VE against RVGE, severe RVGE, and RVGE hospitalization caused by natural infection of any serotype of rotavirus were also investigated. All adverse events (AEs) were collected for 30 days after each dose. Serious AEs (SAEs) and intussusception cases were collected during the entire study. Our data showed that VE against RVGE caused by serotypes contained in HRV was 69.21% (95%CI: 53.31–79.69). VE against severe RVGE and RVGE hospitalization caused by serotypes contained in HRV were 91.36% (95%CI: 78.45–96.53) and 89.21% (95%CI: 64.51–96.72) respectively. VE against RVGE, severe RVGE, and RVGE hospitalization caused by natural infection of any serotype of rotavirus were 62.88% (95%CI: 49.11–72.92), 85.51% (95%CI: 72.74–92.30) and 83.68% (95%CI: 61.34–93.11). Incidences of AEs from the first dose to one month post the third dose in HRV and placebo groups were comparable. There was no significant difference in incidences of SAEs in HRV and placebo groups. This study shows that this hexavalent reassortant rotavirus vaccine is an effective, well-tolerated, and safe vaccine for Chinese infants.     

Identification of Potential Markers for Cushing Disease

Objective: Cushing disease (CD) causes a wide variety of nonspecific symptoms, which may result in delayed diagnosis. It may be possible to uncover unusual combinations of otherwise common symptoms using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Our aim was to identify and evaluate dyads of clinical symptoms or conditions associated with CD.Methods: We conducted a matched case-control study using a commercial healthcare insurance claims database designed to compare the relative risk (RR) of individual conditions and dyad combinations of conditions among patients with CD versus matched non-CD controls.Results: With expert endocrinologist input, we isolated 10 key conditions (localized adiposity, hirsutism, facial plethora, polycystic ovary syndrome, abnormal weight gain, hypokalemia, deep venous thrombosis, muscle weakness, female balding, osteoporosis) with RRs varying from 5.3 for osteoporosis to 61.0 for hirsutism (and infinite RR for localized adiposity). The RRs of dyads of these conditions ranged from 4.1 for psychiatric disorders/serious infections to 128.0 for hirsutism/fatigue in patients with versus without CD. Construction of uncommon dyads resulted in further increases in RRs beyond single condition analyses; for example, osteoporosis alone had an RR of 5.3, which increased to 8.3 with serious infections and to 52.0 with obesity.Conclusion: This study demonstrated that RR of any one of 10 key conditions selected by expert opinion was ≥5 times greater in CD compared to non-CD, and nearly all dyads had RR≥5. An uncommon dyad of osteoporosis and obesity had an RR of 52.0. If clinicians consider the diagnosis of CD when the highest-risk conditions are seen, identification of this rare disease may improve.Abbreviations:CD = Cushing diseaseCPT = Current Procedural TerminologyCS = Cushing syndromeEMR = electronic medical recordICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical ModificationID = identificationRR = relative risk     

Successful Long-Term Treatment of Cushing Disease with Mifepristone (RU486)

ObjectiveWe describe a girl with Cushing disease for whom surgery and radiation treatments failed and the sub- sequent clinical course with mifepristone therapy.MethodsWe present the patient’s clinical, biochemi- cal, and imaging findings.ResultsA 16-year-old girl presented with classic Cushing disease. After transsphenoidal surgery, Cyberknife radiosurgery, ketoconazole, and metyrapone did not control her disease, and she was prescribed mifepristone, which was titrated to a maximal dosage of 1200 mg daily with subsequent symptom improvement. Mifepristone (RU486) is a high-affinity, nonselective antagonist of the glucocor- ticoid receptor. There is limited literature on its use as an off-label medication to treat refractory Cushing disease. Over her 8-year treatment with mifepristone, her therapy was complicated by hypertension and hypokalemia requir- ing spironolactone and potassium chloride. She received a 2-month drug holiday every 4 to 6 months to allow for withdrawal menstrual bleeding with medroxyprogester- one acetate. Urinary cortisol, serum cortisol, and cortico- tropin levels remained elevated during mifepristone drug holidays. While on mifepristone, her signs and symptoms of Cushing disease resolved. Repeated magnetic resonance imaging demonstrated stable appearance of the residual pituitary mass. Bilateral adrenalectomy was performed, and mifepristone was discontinued after 95 months of medical therapy.ConclusionsWe describe the longest duration of mifepristone therapy thus reported for the treatment of refractory Cushing disease. Mifepristone effectively controlled all signs and symptoms of hypercortisolism. Menstruating women who take the drug on a long-term basis should receive periodic drug holidays to allow for menses. The lack of reliable serum biomarkers to monitor the success of mifepristone therapy requires careful clini- cal judgment and may make its use difficult in Cushing disease. (Endocr Pract. 2012;18:e114-e120)     

A New Therapeutic Approach in the Medical Treatment of Cushing’S SYNDROME: GLUCOCORTICOID RECEPTOR BLOCKADE WITH MIFEPRISTONE

ObjectiveCushing’s syndrome (CS) is a serious endocrine disorder caused by prolonged exposure to high cortisol levels. Initial treatment of this condition is dependent upon the cause, but is generally surgical. For patients whose hypercortisolism is not cured by surgery, medical therapy is often required. Drugs that have typically been used for CS medical therapy act by decreasing cortisol levels. Mifepristone is a glucocorticoid receptor antagonist now available for use in patients with CS. Unlike other agents, mifepristone does not decrease cortisol levels, but directly antagonizes its effects. Our objective is to review the pharmacology and clinical use of this novel agent and to discuss detailed guidance on the management of CS patients treated with mifepristone.MethodsWe review the literature regarding mifepris-tone use in CS and recently published clinical trial data. Detailed information related to clinical assessment of mifepristone use, potential drug interactions, drug initiation and dose titration, and monitoring of drug tolerability are provided.ResultsClinical trial data have shown that mifepris-tone improves glycemic control and blood pressure, causes weight loss and a decrease in waist circumference, lessens depression, and improves overall wellbeing. However, adverse effects include adrenal insufficiency, hypokalemia, and endometrial thickening with vaginal bleeding. These findings are supported by the earlier literature case reports.ConclusionThis article provides a review of the pharmacology and clinical use of mifepristone in Cushing’s syndrome, as well as detailed guidance on the management of patients treated with this novel agent. (Endocr Pract. 2013;19:313-326)     

Safety evaluation of the single-dose Ad26.COV2.S vaccine among healthcare workers in the Sisonke study in South Africa: A phase 3b implementation trial

BackgroundReal-world evaluation of the safety profile of vaccines after licensure is crucial to accurately characterise safety beyond clinical trials, support continued use, and thereby improve public confidence. The Sisonke study aimed to assess the safety and effectiveness of the Janssen Ad26.COV2.S vaccine among healthcare workers (HCWs) in South Africa. Here, we present the safety data.Methods and findingsIn this open-label phase 3b implementation study among all eligible HCWs in South Africa registered in the national Electronic Vaccination Data System (EVDS), we monitored adverse events (AEs) at vaccination sites through self-reporting triggered by text messages after vaccination, healthcare provider reports, and active case finding. The frequency and incidence rate of non-serious and serious AEs were evaluated from the day of first vaccination (17 February 2021) until 28 days after the final vaccination in the study (15 June 2021). COVID-19 breakthrough infections, hospitalisations, and deaths were ascertained via linkage of the electronic vaccination register with existing national databases. Among 477,234 participants, 10,279 AEs were reported, of which 138 (1.3%) were serious AEs (SAEs) or AEs of special interest. Women reported more AEs than men (2.3% versus 1.6%). AE reports decreased with increasing age (3.2% for age 18–30 years, 2.1% for age 31–45 years, 1.8% for age 46–55 years, and 1.5% for age > 55 years). Participants with previous COVID-19 infection reported slightly more AEs (2.6% versus 2.1%). The most common reactogenicity events were headache (n = 4,923) and body aches (n = 4,483), followed by injection site pain (n = 2,767) and fever (n = 2,731), and most occurred within 48 hours of vaccination. Two cases of thrombosis with thrombocytopenia syndrome and 4 cases of Guillain-Barré Syndrome were reported post-vaccination. Most SAEs and AEs of special interest (n = 138) occurred at lower than the expected population rates. Vascular (n = 37; 39.1/100,000 person-years) and nervous system disorders (n = 31; 31.7/100,000 person-years), immune system disorders (n = 24; 24.3/100,000 person-years), and infections and infestations (n = 19; 20.1/100,000 person-years) were the most common reported SAE categories. A limitation of the study was the single-arm design, with limited routinely collected morbidity comparator data in the study setting.ConclusionsWe observed similar patterns of AEs as in phase 3 trials. AEs were mostly expected reactogenicity signs and symptoms. Furthermore, most SAEs occurred below expected rates. The single-dose Ad26.COV2.S vaccine demonstrated an acceptable safety profile, supporting the continued use of this vaccine in this setting.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT04838795","term_id":"NCT04838795"}}NCT04838795; Pan African Clinical Trials Registry PACTR202102855526180.

Saimbarashe Takuva, Azwi Takalani, and colleagues investigate the frequency and incidence of adverse events reported after receipt of a single dose of the Ad26.COV2.S COVID-19 vaccine among health care workers in South Africa.     

Prevention and Management of Insulin-Associated Hypoglycemia in Hospitalized Patients

Objective: To determine whether appropriate therapeutic changes in insulin doses are made to prevent and manage insulin-associated hypoglycemic events in non–critically ill hospitalized patients.Methods: This retrospective study was conducted in hospitalized adults on medical or surgical floors with insulin-associated hypoglycemia, excluding treatment with insulin infusions, insulin pumps, and parenteral nutrition. The first hypoglycemic event after 48 hours of admission was the index event. Over the 1-year study period, a total of 457 insulin-associated hypoglycemic events were included as index events.Results: An indication for an insulin dose adjustment was identified in 32 and 42% of patients on day -2 and day -1, respectively, before the index hypoglycemic event, of which 35 and 55%, respectively, had an insulin dose reduction ≥10%. Following the hypoglycemic event, 44% of patients had an insulin dose reduction of ≥20%. Therapeutic reduction of the total daily insulin dose by ≥20% was associated with increased odds of normoglycemia and lower odds of hyperglycemia but was not associated with lower odds of recurrent hypoglycemia on the day following the index hypoglycemic event. There was a high prevalence of hypoglycemic risk factors in this population, with kidney disease and nil per os status being the most prevalent contributing factors.Conclusion: Adherence to the current practice recommendation to reduce insulin doses in patients with borderline hypoglycemia and following overt hypoglycemia was modest. Further studies are needed to understand the associated risks and to define appropriate therapeutic changes for insulin treated patients with borderline and overt hypoglycemia.Abbreviations:AKI = acute kidney injuryBG = blood glucoseCKD = chronic kidney diseaseESRD = end-stage renal diseaseICU = intensive care unitNPH = Neutral Protamine HagedornNPO = nil per osOR = odds ratioTDD = total daily dose     

Pituitary Mri Findings in Patients With Pituitary and Ectopic Acth-Dependent Cushing Syndrome: Does A 6-Mm Pituitary Tumor Size Cut-Off Value Exclude Ectopic Acth Syndrome?

Objective: Expert opinion and a consensus statement on Cushing syndrome (CS) indicate that in a patient with a clinical presentation and biochemical studies consistent with a pituitary etiology, the presence of a pituitary tumor ≥6 mm is highly suggestive of Cushing disease (CD). The purpose of the present study was to determine the optimal pituitary tumor size that can differentiate between patients with CD and ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS) and obviate the need for inferior petrosal sinus sampling (IPSS).Methods: We performed a retrospective study of 130 patients seen between 2000 and 2012 including 104 patients with CD and 26 patients with EAS.Results: A pituitary lesion was reported in 6/26 (23%) patients with EAS and 71/104 (68.3%) patients with CD, with median (range) sizes of 5 mm (3–14) and 8 mm (2–31), respectively. All tumors in the EAS group measured ≤6 mm except for 1 that measured 14 mm. The presence of a pituitary tumor >6 mm in size had 40% sensitivity and 96% specificity for the diagnosis of CD. ACTH levels >209 pg/mL and serum potassium <2.7 mmol/L were found in patients with EAS. All patients with EAS had a 24-hour urine free cortisol (UFC) >3.4 times the upper limit of normal (×ULN)Conclusion: Pituitary incidentalomas as large as 14 mm in size can be seen in patients with EAS. However, the 6-mm tumor size cut-off value provided 96% specificity and may be a reasonable threshold to proceed with surgery without the need for IPSS when the biochemical data support a pituitary etiology.Abbreviations: ACTH = adrenocorticotropic hormone CD = Cushing disease CRH = corticotropin-releasing hormone CS = Cushing syndrome EAS = ectopic ACTH secretion IPSS = inferior petrosal sinus sampling HDDST = high-dose dexamethasone suppression test LDDST = low-dose dexamethasone suppression test MRI = magnetic resonance imaging UFC = urine free cortisol ULN = upper limit of normal     

Pathogenesis of Cushing Disease: An Update on the Genetics of Corticotropinomas

Objective: Cushing disease is a rare severe condition caused by pituitary tumors that secrete adrenocorticotropic hormone (ACTH), leading to excessive endogenous glucocorticoid production. Tumors causing Cushing disease, also called corticotropinomas, are typically monoclonal neoplasms that mainly occur sporadically.Methods: Literature review.Results: Cushing disease is very rarely encountered in genetic familial syndromes. Oncogenes and tumor suppressor genes commonly associated with other tumor types are only rarely mutated in this tumor type. The advent of next-generation sequencing led to the identification of a single mutational hotspot in the ubiquitin-specific protease 8 (USP8) gene in almost half of Cushing disease tumors.Conclusion: The new discoveries showcase a novel mechanism responsible for corticotroph tumorigenesis and ACTH hypersecretion and highlight USP8 and its downstream signaling pathways as potential promising pharmacologic targets for the management of Cushing disease.Abbreviations: ACTH = adrenocorticotropic hormone; BRG1 = Brahma-related gene 1; CABLES1 = CDK5 and ABL1 enzyme substrate 1; CD = Cushing disease; CNC = Carney complex; DICER1 = cytoplasmic endoribonuclease III; EGFR = epidermal growth factor receptor; GR = glucocorticoid receptor; IL = interleukin; MEN = multiple endocrine neoplasia; miRNA = microRNA; POMC = proopiomelanocortin; SSTR = somatostatin receptor; USP8 = ubiquitin-specific protease 8     

Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week,randomized, double-blind,placebo-controlled study

Background

The long-acting muscarinic antagonist (LAMA) umeclidinium (UMEC) and the combination of UMEC with the long-acting β₂-agonist (LABA) vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease (COPD) in the US and EU. They are not indicated for the treatment of asthma.

Methods

In this 52-week, double-blind, placebo-controlled, parallel-group safety study (GSK study DB2113359; {"type":"clinical-trial","attrs":{"text":"NCT01316887","term_id":"NCT01316887"}}NCT01316887), patients were randomized 2:2:1 to UMEC/VI 125/25 mcg, UMEC 125 mcg, or placebo. Study endpoints included adverse events (AEs), clinical chemistry and hematology parameters, vital signs, 12-lead, and 24-hour Holter electrocardiograms. COPD exacerbations and rescue medication use were assessed as safety parameters; lung function was also evaluated.

Results

The incidence of on-treatment AEs, serious AEs (SAEs), and drug-related AEs was similar between treatment groups (AEs: 52–58%; SAEs: 6–7%; drug-related AEs: 12–13%). Headache was the most common AE in each treatment group (8–11%). AEs associated with the LAMA and LABA pharmacologic classes occurred at a low incidence across treatment groups. No clinically meaningful effects on vital signs or laboratory assessments were reported for active treatments versus placebo. The incidences of atrial arrhythmias with UMEC/VI 125/25 mcg were similar to placebo; for UMEC 125 mcg, the incidences of ectopic supraventricular beats, sustained supraventricular tachycardia, and ectopic supraventricular rhythm were ≥2% greater than placebo. With active treatments, COPD exacerbations were fewer (13–15% of patients reporting ≥1 exacerbation) and on average less rescue medication was required (1.6–2.2 puffs/day) versus placebo (24% reporting ≥1 exacerbation, 2.6 puffs/day). Both active treatments improved lung function versus placebo.

Conclusion

UMEC/VI 125/25 mcg and UMEC 125 mcg were well tolerated over 12 months in patients with COPD.     

An Open-Label Extension Study of Parathyroid Hormone Rhpth(1-84) in Adults with Hypoparathyroidism

Objective: Hypoparathyroidism is characterized by inadequate parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, and bone abnormalities. Adults with hypoparathyroidism treated with recombinant human PTH, rhPTH(1-84), in the 24-week, phase III REPLACE study maintained serum calcium despite reductions in oral calcium and active vitamin D. This study assessed the long-term efficacy and safety of rhPTH(1-84) for hypoparathyroidism.Methods: This was a 24-week, open-label, flexible-dose extension study of REPLACE (REPEAT) conducted in 3 outpatient centers in Hungary. Patients who previously completed or enrolled in REPLACE received 50 μg/day rhPTH(1-84), escalated to 75 and then to 100 μg/day, if needed, to reduce active vitamin D and oral calcium. The primary endpoint was ≥50% reduction in oral calcium (or ≤500 mg/day) and active vitamin D (or calcitriol ≤0.25 μg/day or alfacalcidol ≤0.50 μg/day) with normocalcemia.Results: Twenty-four patients (n = 16 previously treated with rhPTH[1-84]; n = 8 rhPTH[1-84]-naïve) were enrolled and completed the study. At Week 24, 75% of patients (95% confidence interval [CI], 53.3–90.2%) achieved the study endpoint; 58% eliminated oral calcium and active vitamin D. Urinary calcium, serum phosphate, and calcium × phosphate (Ca × P) product decreased by Week 24. Mean serum bone turnover markers increased with rhPTH(1-84). Treatment-emergent adverse events (TEAEs) were reported by 92% of patients. No serious adverse events (AEs) occurred.Conclusion: This study used a simplified treatment algorithm intended to better mimic typical clinical practice and demonstrated the extended efficacy and safety of rhPTH(1-84) in patients with hypoparathyroidism and confirmed the REPLACE findings. Sustained rhPTH(1-84) efficacy up to 48 weeks was observed despite treatment interruption between studies.Abbreviations:AE = adverse eventBMD = bone mineral densityBSAP = bone-specific alkaline phosphataseBTM = bone turnover markerCa × P product = calcium × phosphate productCTX = cross-linked C-telopeptide of type 1 collagenOCN = osteocalcin25(OH)D = 25-hydroxyvitamin DP1NP = aminoterminal propeptide of type 1 collagenPTH = parathyroid hormonerhPTH(1-84) = recombinant human parathyroid hormoneTEAE = treatment-emergent adverse eventULN = upper limit of normal     

Retrospective Analysis of Patients With Graves Orbitopathy Treated By Pulses Of Methylprednisolone,With a Focus on Adverse Events

Objective: Graves orbitopathy (GO) is an extrathyroidal manifestation of autoimmune thyroid disease. Early treatment with glucocorticoids in appropriately selected patients is recommended for active, moderate to severe, and sight-threatening disease. The recently published European Group on Graves Orbitopathy guidelines re-evaluated the recommended doses of intravenous methylprednisolone (ivMP) in response to the potential for adverse effects. We retrospectively reviewed our patient cohort treated with our ivMP protocol and analyzed the side effects of this treatment when given during hospitalization in our tertiary referral center.Methods: Between May 2007 and May 2017, a total of 171 consecutive patients with active, moderate to severe, or sight-threatening GO were treated with ivMP in a cumulative dose of 7.5 grams, given monthly in three hospital sessions. Adverse events were reported using Version 4 of Common Terminology Criteria for Adverse Events.Results: Ninety-two percent of patients who started the treatment were able to finish it; 5% did not finish the study due to adverse events, and 3% did not finish the treatment protocol because of noncompliance. The most common adverse events were asymptomatic changes in laboratory values (liver enzymes), psychiatric disorders, and infectious complications. None of the patients in the study died during the ivMP treatment, including those patients who experienced adverse effects or discontinued the protocol because of noncompliance.Conclusion: High-dose ivMP for active, moderate to severe, and sight-threatening GO, when applied cautiously in carefully selected and monitored patients, is generally safe during the treatment period.Abbreviations: AE = adverse effect; CAS = clinical activity score; CTCAE = Common Terminology Criteria for Adverse Events; DM = diabetes mellitus; EUGOGO = European Group on Graves Orbitopathy; GC = glucocorticoid; GO = Graves orbitopathy; ivMP = intravenous methylprednisolone     

Two Doses of Candidate TB Vaccine MVA85A in Antiretroviral Therapy (ART) Na?ve Subjects Gives Comparable Immunogenicity to One Dose in ART+ Subjects

Tuberculosis (TB) is a global public health problem exacerbated by the HIV epidemic. Here we evaluate a candidate TB vaccine, MVA85A, in a Phase I study in HIV-infected adults in Senegal. 24 patients were enrolled: Group 1∶12, antiretroviral therapy (ART) naïve, adults, with CD4 counts >300 and HIV RNA load <100 000 copies/ml. Group 2∶12 adults, stable on ART, with CD4 counts >300, and an undetectable HIV RNA load. Safety was evaluated by occurrence of local and systemic adverse events (AEs) and by monitoring of CD4 count, HIV RNA load, haematology and biochemistry. Immunogenicity was evaluated by ex-vivo interferon-gamma ELISpot assay. 87.7% of AEs were mild; 11.6% were moderate; and 0.7% were severe. 29.2% of AEs were systemic; 70.8% were expected local AEs. There were no vaccine-related Serious Adverse Events (SAEs) or clinically significant effects on HIV RNA load or CD4 count. In ART naive subjects, the first MVA85A immunisation induced a significant immune response at 1 and 4 weeks post-immunisation, which contracted to baseline by 12 weeks. Durability of immunogenicity in subjects on ART persisted out to 24 weeks post-vaccination. A second dose of MVA85A at 12 months enhanced immunogenicity in ART naïve subjects. Subjects on ART had higher responses after the first vaccination compared with ART naïve subjects; responses were comparable after 2 immunisations. In conclusion, MVA85A is well-tolerated and immunogenic in HIV-infected subjects in Senegal. A two dose regimen in ART naïve subjects is comparable in immunogenicity to a single dose in subjects on ART.Clinicaltrials.gov trial identifier {"type":"clinical-trial","attrs":{"text":"NCT00731471","term_id":"NCT00731471"}}NCT00731471.     

Clinical Implication of UGT1A1 Promoter Polymorphism for Irinotecan Dose Escalation in Metastatic Colorectal Cancer Patients Treated with Bevacizumab Combined with FOLFIRI in the First-line Setting

PURPOSE: This study aimed to identify the efficacy and toxicity of the FOLFIRI regimen (fluorouracil, leucovorin, and irinotecan) with irinotecan dose escalation plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC) via UGT1A1 genotyping. METHODS: We administered bevacizumab plus FOLFIRI with irinotecan dose escalation to treat 70 mCRC patients. The UGT1A1 *1/*1 and *1/*28 genotypes started with a 180-mg/m² dose of irinotecan, and UGT1A1 *28/*28 genotype started with a dose of 120 mg/m². The dose of irinotecan was escalated at increasing intervals of 20 to 30 mg/m² until grade 3/4 adverse events (AEs) occurred. The clinical response rate, toxicity, and survival were analyzed. RESULTS: The clinical response and disease control rates of mCRC patients treated with FOLFIRI plus bevacizumab were significantly better in patients with UGT1A1 *1/*1 and *1/*28 genotypes than in patients with UGT1A1 *28/*28 (P = .006 and P < .001, respectively). Grade 3/4 AEs were significantly more common in mCRC patients with the UGT1A1 *28/*28 genotype (P < .001). Progression-free survival was significantly higher in UGT1A1 *1/*1 and *1/*28 patients (P = .002). mCRC patients who underwent metastasectomy achieved better overall survival than those who did not undergo metastasectomy (P = .015). CONCLUSIONS: Our study showed that mCRC patients with UGT1A1 *1/*1 and *1/*28 genotypes could receive escalated doses of irinotecan to obtain a more favorable clinical outcome without significant AEs.     

Lanreotide Therapy in Carcinoid Syndrome: Prospective Analysis of Patient-Reported Symptoms in Patients Responsive To Prior Octreotide Therapy And Patients Naïve To Somatostatin Analogue Therapy in The Elect Phase 3 Study

Objective: This ELECT prospective analysis examined lanreotide depot/autogel for carcinoid syndrome (CS) symptom control in patients with neuroendocrine tumors (NETs) who were responsive to prior octreotide (prior octreotide group) compared with patients who were naïve to prior somatostatin analogue treatment (de novo group).Methods: Adults with histopathologically confirmed NET and stable CS (diarrhea and/or flushing) were randomized to subcutaneous (SC) lanreotide 120 mg or placebo every 4 weeks for 16 weeks. Patients reported diarrhea and/or flushing symptom severity and frequency and short-acting SC octreotide rescue therapy daily using an Interactive Voice/Web Response System. To evaluate the efficacy of lanreotide compared with placebo, the novel primary endpoint of patient-determined use of SC octreotide rescue therapy for breakthrough symptoms was used as a surrogate for symptom control. Clinically meaningful patient-reported treatment benefit was examined using daily patient-reported symptoms of diarrhea and flushing.Results: Of the 115 randomized patients, 51 (n = 26 lanreotide, n = 25 placebo) were octreotide-naïve (de novo) and 64 (n = 33 lanreotide; n = 31 placebo) received prior octreotide. Lanreotide versus placebo patients had a lower mean percentage of days of SC octreotide rescue therapy in de novo and prior octreotide groups (least squares &lsqb;LS] mean difference -19.1, P = .0477 and -6.9, P = .4332, respectively). The mean percentage of days with moderate/severe diarrhea and/or flushing was lower in lanreotide versus placebo patients in de novo and prior octreotide groups (LS mean difference -14.6, P = .0140 and -10.9, P = .0746, respectively). The transition from octreotide to lanreotide was generally well-tolerated.Conclusion: Improvement in CS symptoms occurred with lanreotide treatment, regardless of prior octreotide use.Abbreviations:CI = confidence intervalCS = carcinoid syndromeDB = double blindELECT = Evaluation of Lanreotide depot/autogel Efficacy and safety as a Carcinoid-syndrome TreatmentIOL = initial open-labelIVRS/IWRS = interactive voice/web response systemLS = least squareNET = neuroendocrine tumorOR = odds ratioSC = subcutaneousSSA = somatostatin analogueSSTR = somatostatin receptorTEAE = treatment-emergent adverse event     

Efficacy and Safety of Dulaglutide in Hispanic/Latino Patients with Type 2 Diabetes in the Award Clinical Program

Objective: The aim of this post hoc analysis was to assess the efficacy and safety of once-weekly dulaglutide in Hispanic/Latino patients with type 2 diabetes (T2D) in phase 3 AWARD trials 1 to 6.Methods: Hispanic/Latino data at Week 26 were pooled across studies for each dulaglutide dose to analyze the change from baseline in glycosylated hemoglobin (HbA1c), percent to HbA1c goal, and adverse events (AEs). Change from baseline in HbA1c, change from baseline in weight and hypoglycemia were analyzed by Hispanic/Latino and non-Hispanic/Latino subgroups for each study.Results: Of the 3,136 patients randomized to dulaglutide 1.5 or 0.75 mg, 949 were reported as having Hispanic/Latino ethnicity. Baseline characteristics were similar for Hispanic/Latino and overall populations, except there were slightly more Hispanic/Latino females and weight was slightly lower for Hispanic/Latino patients. Hispanic/Latino patients receiving dulaglutide 1.5 mg had a reduction in HbA1c of 1.25% (95% confidence interval [CI]: -1.35, -1.15); dulaglutide 0.75 mg had a reduction of 1.07% (95% CI: -1.18, -0.96). Reductions in HbA1c and percent to goal HbA1c <7% and ≤6.5% were similar between Hispanic/Latino patients and the overall population. Weight change and hypoglycemia were similar between Hispanic/Latino and non-Hispanic/Latino subgroups for all studies. Treatment-emergent AEs were consistent with the overall population.Conclusion: Dulaglutide improved glycemic control with the potential for weight loss in Hispanic/Latino patients with T2D. Dulaglutide was well tolerated and had a low risk of hypoglycemia when used without insulin secretagogues or insulin. In the Hispanic/Latino population, dulaglutide efficacy and safety was consistent with that of the overall population.Abbreviations:AE = adverse eventAWARD = Assessment of Weekly AdministRation of dulaglutide in DiabetesBID = twice dailyCARMELA = The Cardiovascular Risk Factor Multiple Evaluation of Latin AmericaCI = confidence intervalGLP-1 RA = glucagon-like peptide-1 receptor agonistHbA1c = glycosylated hemoglobinT2D = type 2 diabetes     

The Evaluation of Incidentally Discovered Adrenal Masses

Objective: The objective of this Disease State Clinical Review is to provide clinicians with a practical approach to the evaluation of incidentally discovered adrenal masses.Methods: A case-based clinical approach to the evaluation of adrenal masses is presented. Recommendations were developed using available prospective and randomized studies, cohort studies, cross-sectional studies, anecdotal observations, and expert opinions.Results: Incidentally discovered adrenal masses are common. The approach to the patient with an adrenal mass should involve assessment of malignant potential via imaging characteristics and adrenal hormone excess via clinical and biochemical features. The roles of biopsy, surgical or medical therapy, and longitudinal surveillance are also important to consider and are influenced by case-specific factors. Inappropriate or inadequate evaluations may put patients at increased risk for developing preventable adverse cardiometabolic outcomes or cancer.Conclusion: Incidentally discovered adrenal masses require a multimodal assessment that involves interpretation of multiple imaging characteristics, dynamic and static hormonal measurements, and a nuanced approach to considering interventional diagnostics, treatments, and longitudinal surveillance. Herein, we review these evaluations and provide a practical approach for clinicians.Abbreviations: ACTH = adrenocorticotropic hormone; CS = Cushing syndrome; CT = computed tomography; DHEAS = dehydroepiandrosterone sulfate; HU = Hounsfield units; MRI = magnetic resonance imaging; UFC = urinary free cortisol     

Differential Regulation of 11β-Hydroxysteroid Dehydrogenase Type 1 Activity in Patients with Differing Etiologies of Hypopituitarism

Objective: Pituitary patients with different etiologies of hypopituitarism exhibit differing phenotypes, despite similar replacement therapy strategies. We hypothesized that differential regulation of the isoenzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), which mediates the net autocrine conversion of cortisone to cortisol in adipose tissues and liver, may play a role.Methods: We studied 11β-HSD1 activity (using urine cortisol/cortisone metabolites ratio) in 36 hypopituitary patients with treated craniopharyngiomas, treated remitted Cushing disease, and treated nonfunctioning pituitary adenomas + prolactinomas on and off growth hormone (GH) replacement.Results: 11β-HSD1 activity was higher in subjects with craniopharyngioma both on and off GH, as evidenced by increased tetrahydrocortisol to tetrahydrocortisone metabolite ratios compared to other diagnostic groups, but there was no difference in body mass index, insulin levels, serum hormone measurements, or hydrocortisone dose between groups.Conclusion: Craniopharyngiomas are associated with enhanced 11β-HSD1 activity compared to other diagnostic hypopituitary groups, and this may contribute to the adverse phenotypic and metabolic features seen in this condition.Abbreviations: BMI = body mass index; Em = cortisone metabolites; Fm = cortisol metabolites; GH = growth hormone; 11β-HSD1 = 11β-hydroxysteroid dehydrogenase type 1; IGF-1 = insulin-like growth factor 1; NFPA = nonfunctioning pituitary adenoma; THE = tetrahydrocortisone; THF = tetrahydrocortisol