E-cadherin expression and gene expression profiles in corticotroph pituitary neuroendocrine tumor subtypes.

Corticotroph adenomas/pituitary neuroendocrine tumors (PitNETs) are associated with significant morbidity and mortality. Predictors of tumor behavior have not shown high prognostic accuracy. For somatotroph adenomas/PitNETs, E-cadherin expression correlates strongly with prognosis. E-cadherin expression has not been investigated in other PitNETs. A retrospective chart review of adults with corticotroph adenomas/PitNETs was conducted to assess correlation between E-cadherin expression and tumor characteristics. In addition, gene expression microarray was performed in subset of tumors (n = 16). Seventy-seven patients were identified; 71% were female, with median age of cohort 45.2 years. Seventy-five percent had macroadenomas, of which 22% were hormonally active. Ninety-five percent of microadenomas were hormonally active. Adrenocorticotropic hormone granulation pattern by IHC identified 63% as densely granulated (DG) and 34% as sparsely granulated (SG). All microadenomas were DG (p < .001); 50% of macroadenomas were DG associated with increased tumor invasion compared to SG. E-cadherin IHC was positive in 80%, diminished in 17%, and absent in 20% and did not correlate with corticotroph PitNETs subtype, size, or prognosis. In contrast to the distinct transcriptomes of corticotroph PitNETs and normal pituitaries, a comparison of clinically active and silent corticotroph PitNETs demonstrated similar molecular signatures indicating their common origin, but with unique differences related to their secretory status.

Pseudopheochromocytoma: an Uncommon Cause of Severe Hypertension.

PURPOSE OF REVIEW: Pseudopheochromocytoma or paroxysmal hypertension is an underrecognized condition that requires a thorough investigation of secondary causes of hypertension. In this review, we aim to provide an overview of pathogenesis, clinical manifestations, biochemical evaluation, and potential therapeutic options to manage patients with pseudopheochromocytoma. RECENT FINDINGS: The pathogenesis of this condition has not been completely elucidated but certain patients show overactivity of the sympathetic nervous system and present with elevated epinephrine and dopamine levels. Workup should include a proper evaluation of blood pressure in distinct clinical scenarios, including ambulatory blood pressure monitoring. Management should be focused on treatment of acute hypertensive episodes and prevention of paroxysms. Treatment of patients with pseudopheochromocytoma should be individualized. Psychopharmacotherapy and psychotherapeutic interventions play an important role in controlling patients' symptoms.

Evaluation of Adherence to Guideline-Based Bone Mineral Density Screening in Veterans with HIV.

People with HIV (PWH) have a higher prevalence of bone mineral density (BMD) loss compared to people without HIV. The Infectious Diseases Society of America (IDSA) recommends BMD screening through dual energy X-ray absorptiometry (DXA) in PWH starting at age 50. We aimed to evaluate adherence to this recommendation in a population of Veterans with HIV (VWH). Retrospective cross-sectional analysis of VWH followed from 2014 to 2018 at the Michael E. DeBakey VA Medical Center Infectious Diseases Clinic, Houston, Texas. We collected data through registry extraction and chart review. We calculated the percentage of VWH with timely BMD loss screening by DXA within 5 years of turning 50. Secondary outcomes included prevalence of osteopenia, osteoporosis, and vitamin D deficiency. We included data from 1,243 VWH. Their average age was 52 years (range 18-86). Most were male (95%), and 59% were black. Of the 346 VWH who turned 50 years old during the study period, 78 (22.5%) underwent DXA within 5 years. Of these, 42 (53.8%) had normal BMD, 28 (35.9%) had osteopenia, and 8 (10.3%) had osteoporosis. Nine hundred ninety-three (79.9%) VWH had available 25-hydroxyvitamin D levels; of these, 453 (45%) had normal levels, 304 (30.6%) had vitamin D insufficiency, 184 (18.5%) had vitamin D deficiency, and 52 (5.2%) had severe vitamin D deficiency. Fewer than 25% of eligible VWH underwent timely BMD loss screening by DXA per IDSA guidelines. Almost half of screened VWH showed evidence of BMD loss. Although limited by lack of follow-up and fracture data, this study emphasizes the importance of improving BMD loss screening in this vulnerable population.

Pheochromocytoma and paraganglioma: germline genetics and hereditary syndromes.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors arising from the adrenal medulla and extra-adrenal ganglia, respectively. Approximately 15-25% of PCC/PGL can become metastatic. Up to 30-40% of patients with PCC/PGL have a germline pathogenic variant in a known susceptibility gene for PCC/PGL; therefore, all patients with PCC/PGL should undergo clinical genetic testing. Most of the susceptibility genes are associated with variable penetrance for PCC/PGL and are associated with different syndromes, which include susceptibility for other tumors and conditions. The objective of this review is to provide an overview of the germline susceptibility genes for PCC/PGL, the associated clinical syndromes, and recommended surveillance.

Heterozygous variant in WNT1 gene in two brothers with early onset osteoporosis.

Osteoporosis is a multifactorial disorder characterized by low bone mass and strength, leading to increased risk of fracture. The WNT pathway plays a critical role in bone remodeling by enhancing osteoblastic differentiation, which promotes bone formation, and inhibiting osteoclastic differentiation, decreasing bone resorption. Therefore, genetic alterations of this pathway will lead to impaired bone homeostasis and could contribute to varying response to treatment. We present the case of two brothers with early osteoporosis who were found to have a heterozygous variant of unknown significance in the WNT1 gene, c.1060_1061delCAinsG (p.H354Afs*39). This finding demonstrates that frameshift variants in WNT1 may also act in a dominant fashion leading to decreased bone mass.

A Case of Tumor-Induced Osteomalacia: Finding the Culprit Acetabular Tumor and Successful Resection with a Novel Hip Joint-Preserving Surgery.

INTRODUCTION: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disorder caused by tumors that produce fibroblast growth factor 23 (FGF23) resulting in phosphate wasting and inadequate bone mineralization. Complete resection of the tumor can be curative. However, these tumors are typically difficult to find anatomically due to small size and location. CASE REPORT: We present the case of a patient who presented for evaluation of recurrent fractures and hypophosphatemia in the setting of elevated FGF23 suggestive of TIO. 68Gallium-DOTATATE revealed multiple somatostatin avid lesions in several ribs, left acetabulum, sacrum, right tibia, and feet, some of which appeared with fracture on computed tomography scan, initially concerning for metastatic disease. However, the lesion in acetabulum was considered the culprit tumor given its remarkably higher maximum standard uptake values. Complete surgical removal of the FGF23-secreting tumor led to cure of this disease. CONCLUSION: This case report highlights the challenges with functional imaging differentiating fractures from the culprit lesion and reports on a novel surgical technique that allowed for surgical cure while preserving the hip joint.

Central nervous system intravascular lymphoma leading to rapidly progressive dementia.

Intravascular lymphoma is an uncommon subtype of B-cell lymphoma with neoplastic cells limited to the lumen of small blood vessels. We report a case of a 52-year-old man who presented with constitutional symptoms and rapidly progressive dementia. He was found to have diffuse leptomeningeal and faint parenchymal enhancement on magnetic resonance imaging and was subsequently diagnosed with intravascular lymphoma following a brain biopsy. He responded remarkably well to systemic and intrathecal chemotherapy. The diagnosis and treatment of intravascular lymphoma have been guided by a few case reports and are largely based on expert opinion.

A CASE OF ACQUIRED GENERALIZED LIPODYSTROPHY ASSOCIATED WITH PEMBROLIZUMAB IN A PATIENT WITH METASTATIC MALIGNANT MELANOMA.

OBJECTIVE: To describe an unusual immune-related adverse event (irAE), acquired generalized lipodystrophy (AGL), from checkpoint inhibitor therapy in a patient treated with pembrolizumab. METHODS: This is a case report of a 67-year-old male with metastatic melanoma who was treated with pembrolizumab. Prior to pembrolizumab, the patient was treated with another immune-checkpoint inhibitor and developed autoimmune hemolytic anemia. After starting pembrolizumab, he developed a scrotal mass consistent with panniculitis and after several subsequent cycles, he developed AGL. RESULTS: Loss of subcutaneous fat, unexplained weight loss in combination with worsening insulin resistance and worsening hypertriglyceridemia after initiation of pembrolizumab were consistent with AGL. Autoimmune disorders and other etiologies were ruled out. Despite this irAE, the patient continued to receive pembrolizumab given stabilization of melanoma with treatment. CONCLUSION: We report the second case of a patient who developed AGL secondary to pembrolizumab, and the fourth case to report such complication secondary to antiprogrammed cell death receptor-1 inhibitors. As use of checkpoint inhibitors becomes more common to treat several types of cancer, it is vital for clinicians to recognize these rare irreversible complications that are not frequently reported in clinical trials.

Aromatase Inhibitors Plus Weight Loss Improves the Hormonal Profile of Obese Hypogonadal Men Without Causing Major Side Effects.

Objective: In obese men, the increased expression of the aromatase enzyme in adipose tissue leads to high conversion of androgens to estrogens contributing to hypogonadotropic hypogonadism (HHG). Our objective is to evaluate efficacy and safety of weight loss (WL) plus aromatase inhibitor (AI) therapy in severely obese men with HHG. We hypothesize that AI+WL will be more effective as compared to WL alone in improving the hormonal profile, thus muscle strength and symptoms of HHG (primary outcomes), with no significant adverse effects on lean mass, metabolic profile, and bone mineral density (secondary outcomes). Design: Randomized double-blind placebo-controlled pilot trial. Methods: Twenty-three obese men (BMI≥35 kg/m2), 35-65 years old, were randomized to weight loss (diet and exercise) plus either anastrozole (AI+WL, n = 12) at 1 mg daily or placebo (PBO+WL, n = 11) for 6 months. Inclusion criteria: total testosterone <300 ng/mL (average of 2 measurements), estradiol≥10.9 pg/ml, LH <9 IU/l. Symptoms of hypogonadism by questionnaires; muscle strength by Biodex dynamometer; body composition and bone mineral density by dual-energy X-ray absorptiometry; bone microarchitecture and finite element analysis by high resolution peripheral quantitative-computed tomography. Results: After 6 months of therapy, AI+WL group had higher testosterone (p = 0.003) and lower estradiol (p = 0.001) compared to PBO+WL. Changes in symptoms and muscle strength did not differ between groups. AI+WL resulted in higher fat mass loss than PBO+WL (p = 0.04) without differences in changes in lean mass. Total and LDL cholesterol reduced more in the PBO+WL group compared to AI+WL (p = 0.03 for both), who experienced a minimal increase with unlikely meaningful clinical impact. Tibial trabecular bone area decreased more in PBO+WL than AI+WL group for which it remained stable (p = 0.03). Conclusions:Although AI+WL is effective in reversing the hormonal profile of HHG in severely obese men without causing major side effects, it does not lead to greater improvements in muscle strength and symptoms of hypogonadism compared to WL alone. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02959853.

Randomized Controlled Trial of Bovine Lactoferrin for Prevention of Sepsis and Neurodevelopment Impairment in Infants Weighing Less Than 2000 Grams.

OBJECTIVES: To determine the effect of bovine lactoferrin on prevention of late-onset sepsis (LOS) and neurodevelopment delay. STUDY DESIGN: Randomized, double-blind, controlled trial in neonates with a birth weight of 500-2000 g in 3 neonatal units in Lima, Peru, comparing bovine lactoferrin 200 mg/kg/day with placebo administered for 8 weeks. The primary outcome was the first episode of culture-proven LOS or sepsis-associated death. Neurodevelopment delay was assessed by the Mullen Scales at 24 months corrected age. RESULTS: Of the 414 infants enrolled, 209 received bovine lactoferrin and 205 received placebo. LOS or sepsis-associated death occurred in 22 infants (10.5%) in the bovine lactoferrin group vs 30 (14.6%) in the placebo group; there was no difference after adjusting for hospital and birth weight; hazard ratio 0.73 (95% CI, 0.42-1.26). For infants with birth weights of <1500 g the hazard ratio was 0.69 (95% CI, 0.39-1.25). The mean age-adjusted normalized Mullen composite score at 24 months was 83.3 ± 13.6 in the bovine lactoferrin group vs 82.6 ± 13.1 in the placebo group. Growth outcomes and rehospitalization rates during the 2-year follow-up were similar in both groups, except for significantly less bronchiolitis in the bovine lactoferrin group (rate ratio, 0.34; 95% CI, 0.14-0.86). CONCLUSIONS: Supplementation with bovine lactoferrin did not decrease the incidence of sepsis in infants with birth weights of <2000 g. Growth and neurodevelopment outcomes at 24 months of age were similar. Neonatal bovine lactoferrin supplementation had no adverse effects. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01525316.

Antibiotic Overuse in Premature Low Birth Weight Infants in a Developing Country.

BACKGROUND: Neonatal sepsis is a leading cause of child morbidity and mortality, especially in premature and low birth weight infants. Prompt antibiotic therapy is warranted, but its inappropriate use leads to bacterial resistance and adverse outcomes. Our objective is to describe the antibiotic use for late-onset sepsis in Peruvian premature infants. METHODS: This study is a prospective study as a secondary analysis of a clinical trial in 3 neonatal care units in Peru. We included infants in the first 72 hours of life, with birth weight (BW) <2000 g. We described the antibiotic use as length of therapy (LOT) per 1000 patient days (PD) and antibiotic courses. RESULTS: We included 408 neonates, with 12,204 PD of follow-up; 253 infants (62%) had a BW ≤1500 g. Total antibiotic use for late-onset sepsis was 2395 LOT (196 LOT/1000 PD). Two-hundred and seventy-one patients (66.4%) did not receive antibiotics for late-onset sepsis during their hospitalization. In total, 204 antibiotic courses were administered; 92 infants (22.5%) received 1 course, and 45 (11.0%) received 2-5 antibiotic courses. Mean duration of antibiotic course was 10.8 days (standard deviation: ±7.3). We found a significant association between a lower BW and increased antibiotic use per day (P < 0.001). The most commonly used antibiotics were vancomycin (143 LOT/1000 PD), carbapenems (115 LOT/1000 PD), aminoglycosides (72 LOT/1000 PD) and ampicillin (41 LOT/1000 PD). CONCLUSIONS: Premature infants receive antibiotics for longer than recommended periods of time. Antibiotic overuse is greater in neonates with lower BW. Vancomycin is the most used antibiotic. There is an urgent need to develop antimicrobial stewardship programs in our setting.

Maternal and pregnancy-related factors affecting human milk cytokines among Peruvian mothers bearing low-birth-weight neonates.

Several cytokines have been detected in human milk but their relative concentrations differ among women and vary over time in the same person. The drivers of such differences have been only partially identified, while the effect of luminal cytokines in the fine-regulation of the intestinal immune system is increasingly appreciated. The aim of this study was to investigate the associations between obstetrical complications and human milk cytokine profiles in a cohort of Peruvian women giving birth to Low Birth Weight (LBW) infants. Colostrum and mature human milk samples were collected from 301 Peruvian women bearing LBW infants. The concentration of twenty-three cytokines was measured using the Luminex platform. Ninety-nine percent of women had at least one identified obstetrical complication leading to intra-uterine growth restriction and/or preterm birth. Median weight at birth was 1,420g; median gestational age 31 weeks. A core of 12 cytokines, mainly involved in innate immunity and epithelial cell integrity, was detectable in most samples. Maternal age, maternal infection, hypertensive disorders, preterm labor, and premature rupture of membranes were associated with specific cytokine profiles both in colostrum and mature human milk. Mothers of Very LBW (VLBW) neonates had significantly higher concentrations of chemokines and growth factor cytokines both in their colostrum and mature milk compared with mothers of larger neonates. Thus, maternal conditions affecting pregnancy duration and in utero growth are also associated with specific human milk cytokine signatures.

Factors affecting lactoferrin concentration in human milk: how much do we know?

Lactoferrin (LF) is a breast milk glycoprotein with antimicrobial and anti-inflammatory effects. Its beneficial properties in infants, especially in those born preterm, are currently being studied in clinical trials. However, the maternal and nursing infant factors that may affect LF concentration in breast milk are still not clear. We conducted a systematic review to investigate the factors that may affect the concentration of LF in breast milk. We used a 2-step approach to identify the eligible studies according to inclusion/exclusion criteria, and to determine which studies would be considered. We included 70 qualified articles from 29 countries with publication dates ranging from 1976 to 2015. We described the correlation between LF concentration in breast milk and lactation stage; 10 maternal factors, such as race, parity, among others; and 2 infant factors: infections and prematurity. Colostrum has the highest LF levels, but they decrease with days postpartum. No other factor has been consistently associated with LF concentration. A major limitation of the majority of the published studies is the small sample size and the different methods used to measure LF concentration. Therefore, there is a need for large, multicenter studies with standardized study design, sample collection, and LF measurement methods to identify clinically significant factors associated with LF expression in breast milk, which will help promote exclusive breastfeeding in preterm infants.

Insulin resistance by homeostasis model assessment in HIV-infected patients on highly active antiretroviral therapy: cross-sectional study.

BACKGROUND: The highly active antiretroviral therapy (HAART) has altered the course of HIV infection, transforming it from a fatal illness to a chronic condition, reducing morbidity and mortality. However, this therapy has led to an increased incidence of metabolic problems such as insulin resistance, dyslipidemia, lipodystrophy and impaired glucose metabolism. The objectives of this study are to determine the prevalence of insulin resistance (IR) in a cohort of human immunodeficiency virus (HIV)-infected patients on highly active antiretroviral therapy (HAART) and to investigate the potentially associated factors. METHODS: We conducted a cross-sectional study including 219 adult patients with HIV on HAART. IR was determined through the homeostasis model assessment (HOMA-IR) mathematical model, using fasting plasma glucose (FPG) and insulin. Bivariate and multivariate analyses were performed to assess the association between demographic information, clinical characteristics and laboratory results, and IR. RESULTS: 75 (34.2 %) [95 % confidence interval (CI) 28.9-40.9] HIV-patients on HAART showed IR. 61 (81 %) of these patients were on HAART for more than one year, which was mainly composed by non-protease inhibitors drugs (88 %). Metabolic syndrome (MS) was found in 59 (26.9 %) subjects. In the multivariate analysis, the factors associated with IR were age ≥ 46 years (Prevalence ratio = 2.767, 95 % CI 1.325 to 5.780) and greater body mass index (BMI) (Prevalence ratio = 1.148, 95 % CI 1.054 to 1.250). CONCLUSIONS: The prevalence of IR was 34.2 %. Factors associated with IR were age and BMI. We did not find any significant association between IR and protease inhibitors (PI), which may be explained by the small number of patients using PI as part of their HAART regimen included in our study.

[Unifying criteria for late neonatal sepsis: proposal for an algorithm of diagnostic surveillance]. / Unificar los criterios de sepsis neonatal tardía: propuesta de un algoritmo de vigilancia diagnóstica.

Infections are a major cause of death in neonates. Diagnosis of neonatal sepsis is a major challenge because newborns have very nonspecific clinical signs and auxiliary tests have low sensitivity. In order to improve the correct diagnosis of this condition, we propose an algorithm of diagnostic surveillance for late neonatal sepsis in Peru and countries of the region. The algorithm classifies the episodes as confirmed, probable or possible sepsis, and especially seeks to identify those episodes that do not correspond to sepsis, preventing other diseases to be qualified as "sepsis". Better diagnostics will enable more realistic rates of neonatal sepsis, improve the use of antibiotics and avoid their negative effects on newborns, as well as provide a more accurate view of their impact on public health.

The Role of Maternal Breast Milk in Preventing Infantile Diarrhea in the Developing World.

Multiple interventions have been designed to decrease mortality and disability in children. Among these, breastfeeding is the most cost effective intervention for protecting children against diarrhea and all causes of mortality. Human milk is uniquely suited to the human infant, both in its nutritional composition and in the nonnutritive bioactive factors that promote survival and healthy development. Suboptimal breastfeeding has been linked with numerous adverse child health outcomes including increased incidence of diarrhea and pneumonia. This review provides an update regarding recent studies on the effect of breastfeeding on diarrhea morbidity and mortality in children in developing countries, describes major human milk components responsible for this protective effect (oligosaccharides, secretory immunoglobulins, lactoferrin, bacterial microbiota, etc.), and highlights areas for future research in this topic. Breastfeeding promotion remains an intervention of enormous public health potential to decrease global mortality and promote better growth and neurodevelopment in children.

Lactoferrin for prevention of neonatal sepsis.

Preterm neonates are at risk to acquire infections. In addition to the high mortality associated with sepsis, these patients are at risk for long-term disabilities, particularly neurodevelopment impairment. Several interventions have been evaluated to reduce rates of infections in neonates but have not proven efficacy. Lactoferrin (LF), a milk glycoprotein with anti-inflammatory, immunomodulatory and anti-microbial properties, has the potential to prevent infections in young children. We performed a review of current and ongoing clinical trials of LF for prevention of neonatal sepsis, and found eleven registered clinical trials that include more than 6,000 subjects. Few of these trials have finished; despite their small sample size, the preliminary results show a trend towards a positive protective effect of LF on neonatal infections. Larger trials are underway to confirm the findings of these initial studies. This information will help to define LF's role in clinical settings and, if proven effective, would profoundly affect the treatment of low birth weight neonates as a cost-effective intervention worldwide.

Unificar los criterios de sepsis neonatal tardía: propuesta de un algoritmo de vigilancia diagnóstica / Unifying criteria for late neonatal sepsis: proposal for an algorithm of diagnostic surveillance

Las infecciones constituyen una de las principales causas de muerte en el periodo neonatal. El diagnóstico de sepsis neonatal representa un gran desafío ya que los recién nacidos presentan signos clínicos muy inespecíficos y los exámenes auxiliares tienen una baja sensibilidad. Con el objetivo de mejorar el diagnóstico correcto de esta patología proponemos un algoritmo de vigilancia diagnóstica para sepsis neonatal tardía en el Perú y países de la región. El algoritmo permite clasificar a los episodios como sepsis confirmada, probable o posible, y sobre todo busca identificar aquellos episodios que no corresponden a sepsis, evitando calificar otras patologías como “sepsis”. Un mejor diagnóstico permitiría tener tasas más reales de sepsis neonatal, mejorar el uso de antibióticos y evitar sus efectos negativos en el recién nacido, así como una visión más exacta de su impacto en la salud pública.

Infections are a major cause of death in neonates. Diagnosis of neonatal sepsis is a major challenge because newborns have very nonspecific clinical signs and auxiliary tests have low sensitivity. In order to improve the correct diagnosis of this condition, we propose an algorithm of diagnostic surveillance for late neonatal sepsis in Peru and countries of the region. The algorithm classifies the episodes as confirmed, probable or possible sepsis, and especially seeks to identify those episodes that do not correspond to sepsis, preventing other diseases to be qualified as “sepsis”. Better diagnostics will enable more realistic rates of neonatal sepsis, improve the use of antibiotics and avoid their negative effects on newborns, as well as provide a more accurate view of their impact on public health.