Use of levothyroxine for euthyroid, thyroid antibody positive women with infertility: Analyses of aggregate data from a survey of European thyroid specialists (Treatment of Hypothyroidism in Europe by Specialists: An International Survey).

OBJECTIVES: The use of levothyroxine (LT4) treatment aiming to improve fertility in euthyroid women with positive thyroid peroxidase antibodies (TPOAb) is not supported by the available evidence. The aim of the study was to document the use of LT4 by European thyroid specialists in such patients. DESIGN: The data presented derive from Treatment of Hypothyroidism in Europe by Specialists, an International Survey (THESIS), a questionnaire conducted between 2019 and 2021 to document the management of hypothyroidism by European thyroid specialists. Here, we report the aggregate results on the use of LT4 in infertile, euthyroid women with positive TPOAb. RESULTS: A total of 2316/5406 (42.8%) respondents stated that LT4 may be indicated in TPOAb positive euthyroid women with infertility. The proportion of those replying positively to this question varied widely across different countries (median 39.4, range 22.9%-83.7%). In multivariate analyses males (OR: 0.8; CI: 0.7-0.9) and respondents >60 years (OR: 0.7; 0.6-0.8) were the least inclined to consider LT4 for this indication. Conversely, respondents managing many thyroid patients ("weekly" [OR: 1.4; CI: 1.0-1.9], "daily" [OR: 1.8; CI: 1.3-2.4]) and practicing in Eastern Europe (OR: 1.5; CI: 1.3-1.9) were most likely to consider LT4. CONCLUSIONS: A remarkably high number of respondents surveyed between 2019 and 2021, would consider LT4 treatment in TPOAb positive euthyroid women with infertility. This view varied widely across countries and correlated with sex, age and workload, potentially influencing patient management. These results raise concerns about potential risks of overtreatment.

Control of Thyroid Dysfunction in Spanish Population Registered in the Primary Care Clinical Database: An Analysis of the Proportion of Patients with Thyrotropin Values Outside the Reference Range.

Inadequate control of thyroid dysfunction is common and has deleterious health consequences. Our objective was to determine the prevalence of TSH values outside the reference range, as an indicator of inadequate control of hypothyroidism and hyperthyroidism in patients undergoing treatment for thyroid dysfunction in Spain. An observational, retrospective, non-interventional study was conducted using the Primary Care Clinical Database (BDCAP). Patients treated with thyroid hormone for hypothyroidism and with antithyroid drugs for hyperthyroidism were identified. We assessed serum TSH concentration, considering values from 0.4 to 4.0 mU/l as the reference interval. We found 360 313 people with hypothyroidism on thyroid hormone replacement and 9239 with hyperthyroidism on antithyroid drugs therapy. TSH values outside the reference range in hypothyroid subject were detected in 126 866 (35.20%) people, of whom 107 205 (29.75%) had TSH>4.0 mU/l, suggesting inappropriately low doses of levothyroxine, and 19 661 (5.46%) had TSH<0.4 mU/l, suggesting inappropriate over replacement. In the hyperthyroid group, TSH values outside the reference range were observed in 4252 (46.02%) patients. There were 2833 (30.66%) patients with TSH<0.4 mU/l, suggesting undertreatment, and 1419 (15.36%) with TSH>4.0 mU/l, suggesting overtreatment with antithyroid medication. People over 65 years of age had a lower frequency of undertreatment of hypothyroidism and a lower frequency of overtreatment and undertreatment of hyperthyroidism. In conclusion, our results suggest that inadequate control of thyroid dysfunction, due to its high frequency and its consequences for health, is a public health problem that should be addressed by clinicians and health authorities.

Serum Calcium, Magnesium, and Phosphorus Levels in Patients with COVID-19: Relationships with Poor Outcome and Mortality.

In this retrospective study to assess the impact of serum corrected calcium (CorrCa), magnesium (Mg) and phosphorus (P) levels, all adult patients with laboratory-confirmed COVID-19 hospitalized during 2020 were included. Poor outcome was considered in patients who presented need for mechanical ventilation, intensive care unit (ICU) admission, or in-hospital mortality. We analyzed 2473 patients (956 females) aged (mean±SD) 63.4±15.9 years. During admission, 169 patients (6.8%) required mechanical ventilation, 205 (8.3%) were admitted to the ICU, and 270 (10.9%) died. Composite variable of poor outcome, defined as need for mechanical ventilation, ICU admission or death, was present in 434 (17.5%) patients. In univariate analysis, the need for mechanical ventilation was positively related to Mg levels (OR 8.37, 95% CI 3.62-19.33; p<0.001); ICU admission was related to CorrCa (OR 0.49, 95% CI 0.25-0.99; p=0.049) and Mg levels (OR 5.81, 95% CI 2.74-12.35; p<0.001); and in-hospital mortality was related to CorrCa (OR 1.73, 95% CI 1.14-2.64; p=0.011). The composite variable of poor outcome was only related to Mg (OR 2.68, 95% CI 1.54-4.68; p=0.001). However, in multivariate analysis only CorrCa was significantly related to the need for mechanical ventilation (OR 0.19, 95% CI 0.05-0.72; p=0.014) and ICU admission (OR 0.25; 95% CI 0.09-0.66; p=0.005), but not with in-hospital mortality or the composite variable. In conclusion, CorrCa can be used as a simple and reliable marker of poor outcome in patients with COVID-19, although not to predict the risk of in-hospital mortality.

The effect of vitrification on blastocyst mitochondrial DNA dynamics and gene expression profiles.

PURPOSE: Does vitrification/warming affect the mitochondrial DNA (mtDNA) content and the gene expression profile of blastocysts? METHODS: Prospective cohort study in which 89 blastocysts were obtained from 50 patients between July 2017 and August 2018. mtDNA was measured in a total of 71 aneuploid blastocysts by means of real-time polymerase chain reaction (RT-PCR). Transcriptomic analysis was performed by RNA sequencing (RNA-seq) in an additional 8 aneuploid blastocysts cultured for 0 h after warming, and 10 aneuploid blastocysts cultured for 4-5 h after warming. RESULTS: A significant decrease in mtDNA content just during the first hour after the warming process in blastocysts was found (P < 0.05). However, mtDNA content experimented a significantly increased along the later culture hours achieving the original mtDNA levels before vitrification after 4-5 h of culture (P < 0.05). Gene expression analysis and functional enrichment analysis revealed that such recovery was accompanied by upregulation of pathways associated with embryo developmental capacity and uterine embryo development. Interestingly, the significant increase in mtDNA content observed in blastocysts just after warming also coincided with the differential expression of several cellular stress response-related pathways, such as apoptosis, DNA damage, humoral immune responses, and cancer. CONCLUSION: To our knowledge, this is the first study demonstrating in humans, a modulation in blastocysts mtDNA content in response to vitrification and warming. These results will be useful in understanding which pathways and mechanisms may be activated in human blastocysts following vitrification and warming before a transfer.

Effect of cabergoline on tumor remnant after surgery in nonfunctioning pituitary adenoma.

BACKGROUND: In recent years, dopamine agonists (DAs) have become an attractive therapeutic option to prevent both tumor growth and post-surgical tumor remnant growth in clinically non-functioning pituitary adenoma (NFPA). AIM: To analyze our experience on the effect of cabergoline (CAB) on tumor remnant after initial surgery in NFPA patients. PATIENTS AND METHODS: A retrospective and multicenter study of NFPA patients with tumor remnant after surgery treated with CAB was performed. RESULTS: From a total of 142 NFPA patients (79 men, 55.2%; mean age 57.2 ± 14.2 year) who underwent surgery, we selected 62/142 (43.7%) patients (32 men, 51.6%; mean age 59.3 ± 13.9 year) with tumor persistence (TP) after surgery. In 22/62 (35.5%) TP patients CAB was used (CAB group), while the rest of the patients (40/62, 64.5%) underwent active surveillance [observation (OBS) group)]. The maximum diameter of the tumor remnant did not change significantly in either the CAB group [11.5 (6.0-16.9) mm vs. 12.0 (7.0-15.0) mm, p = 0.85) or the OBS group [8.5 (6.0-13.7) mm vs. 9.0 (6.2-14.0) mm, p = 0.064) at the end of the follow-up [13 (10.5-17) vs. 77.5 (50.2-107.2) months, CAB vs. OBS group; p < 0.001]. At the end of the treatment period with CAB most of the patients (n = 20/22, 90.9%) showed no progression of the tumor remnant [stable disease, SD (n = 17/22, 77.2%) and partial response, PR (n = 3/22, 13.6%)], while 2/22 patients (9.1%) exhibited progression. Similar response rates were observed in the OBS group [SD (n = 32/40, 80%), PR (n = 2/40, 5%), and progression (n = 6/40, 15%)]. Although no statistically significant differences (p = 0.42) were found in these responses, the percentage of progression was 1.65 times higher in the OBS group compared to the CAB group. On the contrary, the percentage of PR was 2.72 times higher in the CAB group compared to the OBS group, despite a significantly shorter follow-up period in the CAB group. CONCLUSION: Although the present study showed no significant differences in the type of tumor response between the CAB and OBS groups of patients, the percentage of PR was higher and that of progression lower in the CAB group compared to the OBS group. This finding does not rule out a potential therapeutic benefit of CAB in the management of tumor remnant in patients with NFPA undergoing surgery.

De Novo Drug Design Using Reinforcement Learning with Graph-Based Deep Generative Models.

Machine learning provides effective computational tools for exploring the chemical space via deep generative models. Here, we propose a new reinforcement learning scheme to fine-tune graph-based deep generative models for de novo molecular design tasks. We show how our computational framework can successfully guide a pretrained generative model toward the generation of molecules with a specific property profile, even when such molecules are not present in the training set and unlikely to be generated by the pretrained model. We explored the following tasks: generating molecules of decreasing/increasing size, increasing drug-likeness, and increasing bioactivity. Using the proposed approach, we achieve a model which generates diverse compounds with predicted DRD2 activity for 95% of sampled molecules, outperforming previously reported methods on this metric.

Novel proteinase inhibitor from the hemolymph of soybean pest Anticarsia gemmatalis (lepidóptera: Noctuidae): Structural modeling and enzymatic kinetic.

New approaches are needed to reduce risks to the environment and natural enemies and to avoid or delay the onset of insecticide resistance. The use of insecticides based on proteinase inhibitors of hemolymph is an alternative for the control of Lepidoptera pests primarily by having low toxicity and short persistence in the environment. Thus, in this study, we describe the purification process and identification of protease inhibitors from hemolymph Anticarsia gemmatalis and their activities against trypsin enzymes. Furthermore, the three-dimensional (3D) structure of the inhibitor and binding mode to trypsin enzymes was determined, and the stability of the inhibitory activity in several pHs and temperature values was evaluated. The inhibitor was characterized as a serpin family inhibitor and named A. gemmatalis hemolymph serpin inhibitor (AHSI), with an approximate mass of 38 ± 2 kDa, highly stable to temperature and pH variations, and with inhibitory capacity on bovine trypsin and gut trypsin of A. gemmatalis demonstrated by calculated Ki values and affinity energy through molecular docking, being a reversible competitive inhibitor that binds to the active site of trypsin-like enzymes. We conclude that the AHSI inhibitor identified from the hemolymph of the soybean pest A. gemmatalis preserves the original structure of the serpin family with a good overall stereochemical quality confirmed from molecular modeling. The docking analysis showed that the reactive site of the inhibitor is in contact with the catalytic cavity of the trypsin with high-affinity energy.

Environmental conditions and plant physiology modulate Cu phytotoxicity in field-contaminated soils.

Foliar Cu concentration has been widely used as a biomarker of plant growth in phytotoxicity bioassays. This relation has helped find plant processes altered by Cu in dose-response experiments (a bivariate approach). However, when plants are grown in field conditions, their responses can vary in function of multiple variables, such as the environment, plant physiology, and other elements in plant (plant ionome). These sources of variability are commonly unreported, which could limit bioassays' utility. Thus, the present study aimed to assess and integrate the mentioned sources of variability on Cu phytotoxicity. Lettuce was used as plant model. Lettuces were grown in growth chambers with contrasting light and air humidity conditions and on two different field-contaminated soils (sandy and loamy soils). Results showed that environmental conditions significantly affected foliar Cu and plant growth, but this effect differed in the two studied soils. Foliar Cu was not a good biomarker of plant growth. In contrast, integrating the potential phytotoxicity effect with the plant's nutritional status allowed a better understanding of plant growth. We remarked on using a structural equation modeling approach (SEM) to integrate plant physiology and plant ionome as moderators of plant growth. Results showed that plant growth was primarily related to plant nutritional status rather than Cu phytotoxicity. Also, the foliar Cu concentration would affect plant nutritional status due to photosynthesis-related plant processes and cation balance. Finally, this research invites to state and include sources of variability when assessing phytotoxicity. This way, it is possible to advance toward understanding complex linked processes occurring in field conditions.

Sunitinib and Evofosfamide (TH-302) in Systemic Treatment-Naïve Patients with Grade 1/2 Metastatic Pancreatic Neuroendocrine Tumors: The GETNE-1408 Trial.

BACKGROUND: Sunitinib (SUN)-induced hypoxia within the tumor could promote the activation of the prodrug evofosfamide (EVO), locally releasing the cytotoxic DNA alkylator bromo-isophosphoramide mustard. SUNEVO, a phase II, open-label, single-arm trial, investigated the potential synergy of SUN plus EVO in advanced progressive pancreatic neuroendocrine tumors (panNETs). METHODS: Systemic treatment-naïve patients with advanced or metastatic, unresectable, grade 1/2 panNETs with a Ki67 ≤20%, received EVO 340 mg/m2 on days 8, 15, and 22 every 4 weeks and sunitinib 37.5 mg/day continuously. The primary endpoint was objective response rate, measured every 8 weeks by RECIST version 1.1. RESULTS: From 2015 to 2018, 17 patients were enrolled. The median age was 62.4 years, 47% had a Ki67 >10%, and 70.6% had liver metastasis. Patients received a median of five and four cycles of SUN and EVO, respectively. After a median follow-up of 15.7 months, 17.6% of patients achieved a complete (n = 1) or partial response (n = 2), and 11 patients had stable disease (64.7%). The median progression-free survival was 10.4 months (95% confidence interval, 2.6-18.0). Treatment-related adverse events (grade ≥3) were observed in 64.7% of the patients, the most frequent being neutropenia (35.3%), fatigue (17.6%), and thrombopenia (11.8%). Treatment discontinuation due to toxicity was reported in 88.2% of the patients. No correlation was found between treatment response and DAXX, ATRX, MEN1, SETD2, and PTEN gene mutations. CONCLUSION: SUN plus EVO had a negative toxicity profile that should be taken into account for further clinical research in advanced panNETs. The combination showed moderate activity in terms of treatment response that did not correlate with somatic mutations. (Clinical trial identification number: NCT02402062) IMPLICATIONS FOR PRACTICE: Addition of hypoxia-activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in pancreatic neuroendocrine tumors (panNETs), reaching a median objective response rate of 17.6% and median progression-free survival of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs' resistance to antiangiogenic agents with other therapies with a safer profile.

Development and Pilot Screen of Novel High Content Assay for Down Regulators of Expression of Heterogenous Nuclear Ribonuclear Protein H2.

BACKGROUND/AIMS: Despite recent advances in melanoma drug discovery, the average overall survival of patients with late-stage metastatic melanoma is approximately 3 years, suggesting a need for new approaches and melanoma therapeutic targets. Previously we identified heterogeneous nuclear ribonucleoprotein H2 as a potential target of anti-melanoma compound 2155-14 (Palrasu et al., Cell Physiol Biochem 2019;53:656-686). In the present study, we endeavored to develop an assay to enable a high throughput screening campaign to identify drug-like molecules acting via down regulation of heterogeneous nuclear ribonucleoprotein H2 that can be used for melanoma therapy and research. METHODS: We established a cell-based platform using metastatic melanoma cell line WM266-4 expressing hnRNPH2 conjugated with green fluorescent protein to enable assay development and screening. High Content Screening assay was developed and validated in 384 well plate format, followed by miniaturization to 1,536 well plate format. RESULTS: All plate-based QC parameters were acceptable: %CV = 6.7±0.3, S/B = 21±2.1, Z' = 0.75±0.04. Pilot screen of FDA-approved drug library (n=1,400 compounds) demonstrated hit rate of 0.5%. Two compounds demonstrated pharmacological response and were authenticated by western blot analysis. CONCLUSION: We developed a highly robust HTS-amenable high content screening assay capable of monitoring down regulation of hnRNPH2. This assay is thus capable of identifying authentic down regulators of hnRNPH1 and 2 in a large compound collection and, therefore, is amenable to a large-scale screening effort.

The biogeography of Dromiciops in southern South America: Middle Miocene transgressions, speciation and associations with Nothofagus.

The current distribution of the flora and fauna of southern South America is the result of drastic geological events that occurred during the last 20 million years, including marine transgressions, glaciations and active vulcanism. All these have been associated with fragmentation, isolation and subsequent expansion of the biota, south of 35°S, such as the temperate rainforest. This forest is mostly dominated by Nothofagus trees and is the habitat of the relict marsupial monito del monte, genus Dromiciops, sole survivor of the order Microbiotheria. Preliminary analyses using mtDNA proposed the existence of three main Dromiciops lineages, distributed latitudinally, whose divergence was initially attributed to recent Pleistocene glaciations. Using fossil-calibrated dating on nuclear and mitochondrial genes, here we reevaluate this hypothesis and report an older (Miocene) biogeographic history for the genus. We performed phylogenetic reconstructions using sequences from two mitochondrial DNA and four nuclear DNA genes in 159 specimens from 31 sites across Chile and Argentina. Our phylogenetic analysis resolved three main clades with discrete geographic distributions. The oldest and most differentiated clade corresponds to that of the northern distribution (35.2°S to 39.3°S), which should be considered a distinct species (D. bozinovici, sensu D'Elía et al. 2016). According to our estimations, this species shared a common ancestor with D. gliroides (southern clades) about ~13 million years ago. Divergence time estimates for the southern clades (39.6°S to 42.0°S) ranged from 9.57 to 6.5 Mya. A strong genetic structure was also detected within and between clades. Demographic analyses suggest population size stability for the northern clade (D. bozinovici), and recent demographic expansions for the central and southern clades. All together, our results suggest that the diversification of Dromiciops were initiated by the Middle Miocene transgression (MMT), the massive marine flooding that covered several lowlands of the western face of Los Andes between 37 and 48°S. The MMT resulted from an increase in global sea levels at the Miocene climatic optimum, which shaped the biogeographic origin of several species, including Nothofagus forests, the habitat of Dromiciops.

Craniopharyngioma in the Elderly: A Multicenter and Nationwide Study in Spain.

BACKGROUND: Craniopharyngioma (CP) is a rare tumor in the elderly whose clinical features and prognosis are not well known in this population. AIM: To evaluate the clinicopathological features and therapeutic outcomes of CP diagnosed in the elderly. PATIENTS AND METHODS: This was a retrospective, multicenter, national study of CP patients diagnosed over the age of 65 years and surgically treated. RESULTS: From a total of 384 adult CP patients, we selected 53 (13.8%) patients (27 women [50.9%], mean age 72.3 ± 5.1 years [range 65-83 years]) diagnosed after the age of 65 years. The most common clinical symptoms were visual field defects (71.2%) followed by headache (45.3%). The maximum tumor diameter was 2.9 ± 1.1 cm. In most patients, the tumor was suprasellar (96.2%) and mixed (solid-cystic) (58.5%). The surgical approach most commonly used was transcranial surgery (52.8%), and more than half of the patients (54.7%) underwent subtotal resection (STR). Adamantinomatous CP and papillary CP were present in 51 and 45.1%, respectively, with mixed forms in the remaining. Surgery was accompanied by an improvement in visual field defects and in headaches; however, pituitary hormonal hypofunction increased, mainly at the expense of an increase in the prevalence of diabetes insipidus (DI) (from 3.9 to 69.2%). Near-total resection (NTR) was associated with a higher prevalence of DI compared with subtotal resection (87.5 vs. 53.6%, p = 0.008). Patients were followed for 46.7 ± 40.8 months. The mortality rate was 39.6% with a median survival time of 88 (95% CI: 57-118) months. DI at last visit was associated with a lower survival. CONCLUSION: CP diagnosed in the elderly shows a similar distribution by sex and histologic forms than that diagnosed at younger ages. At presentation, visual field alterations and headaches are the main clinical symptoms which improve substantially with surgery. However, surgery, mainly NTR, is accompanied by worsening of pituitary function, especially DI, which seems to be a predictor of mortality in this population.

Late Recovery of Parathyroid Function After Total Thyroidectomy: A Case-Control Study.

The clinical characteristics of patients with postoperative hypoparathyroidism who recover parathyroid function more than 12 months after surgery have not been studied. We aimed to evaluate whether the intensity of replacement therapy with calcium and calcitriol is related to the late recovery of parathyroid function. We compared the demographic, surgical, pathological, and analytical features of two groups of patients: cases, i. e., late recovery patients (those who recover parathyroid function>1 year after thyroidectomy, n=40), and controls, i. e., patients with permanent hypoparathyroidism (n=260). Replacement therapy with calcium and calcitriol was evaluated at discharge of surgery, 3-6 months, 12 months, and last visit. No significant differences were found in clinical, surgical, pathological, or analytical characteristics between cases and controls. The proportion of cases who required treatment with calcium plus calcitriol at 12 months was significantly lower than that found in controls (p<0.001). Furthermore, daily calcium and calcitriol doses in controls were significantly higher than those in cases at 3-6 months (p=0.014 and p=0.004, respectively) and at 12 months (p<0.001 and p=0.043, respectively). In several models of logistic regression analysis therapy with calcium and calcitriol at 12 months was negatively related to late recovery of parathyroid function. Although delayed recuperation of parathyroid function after total thyroidectomy is uncommon (13%), follow-up beyond 12 months is necessary in patients with postoperative hypoparathyroidism, especially in those whose needs of treatment with Ca and calcitriol are reducing over time.

A larval aggregation pheromone as foraging cue for insectivorous birds.

Although birds have traditionally been considered anosmic, increasing evidence indicates that olfaction plays an important role in the foraging behaviours of insectivorous birds. Recent studies have shown that birds can exploit herbivore-induced plant volatiles and sexual pheromones of adult insects to locate their prey. Many insectivorous birds prey on immature insects, providing relevant ecosystem services as pest regulators in natural and agricultural ecosystems. We asked whether birds could rely on chemical cues emitted by the immature stages of insects to prey on them. To address this question, we performed field experiments to evaluate if insectivorous birds can detect the aggregation pheromone produced by the larvae of the carpenter worm, Chilecomadia valdiviana. Groups of five artificial larvae were placed in branches of 72 adult trees in a remnant fragment of a sclerophyllous forest in central Chile. Each grouping of larvae contained a rubber septum loaded with either larval pheromone as treatment or solvent alone as control. We found that the number of larvae damaged by bird pecks was significantly higher in groups with dispensers containing the larval extract than in control groups. Our results show that birds can rely on immature insect-derived chemical cues used for larvae aggregation to prey on them.

Isolated ACTH deficiency induced by cancer immunotherapy: a systematic review.

Immunotherapy with immune checkpoint inhibitor (ICI) monoclonal antibodies has shown to be an effective therapeutic alternative in several malignant tumors. However, adverse effects related to an activation of the immune system may accompany ICI therapy. Among the immune-related adverse events (irAEs) are autoimmune endocrine adverse effects, such as thyroiditis, and hypophysitis. Secondary adrenal insufficiency due to isolated ACTH deficiency (IAD) has also been recently reported to be associated with ICI antibodies. We carried out a systematic review of IAD cases induced by cancer immunotherapy published to date using PubMed's database. We selected 35 articles that reported 60 cancer patients diagnosed with IAD induced by ICI therapy. The prevalence was higher in men (ratio 1.6/1). Mean age at diagnosis was 63.2 ± 11.6 (range,30-87). Melanoma was the tumor most commonly reported (35%) followed by lung (28.3%) and kidney cancer (18.3%). The ICI monoclonal antibody most frequently associated was nivolumab in monotherapy (60%), followed by pembrolizumab (18.3%). Median (IQR) time to develop IAD after starting ICI therapy was 6 (4-8) months. The main symptoms at IAD diagnosis were fatigue (82.8%) and anorexia (67.2%). Hyponatremia (68%) and eosinophilia (31.8%) were the laboratory abnormalities most frequently associated with IAD. Pituitary magnetic resonance imaging (MRI) was normal in most patients (93%). Thyroiditis was the most prevalent (35%) endocrine irAE associated with IAD. In conclusion, ICI-induced IAD is a rare and potentially life-threatening condition that must be taken into account whenever treatment with immunotherapy in cancer patients is started due to their potential serious prognostic implications.

Thyroid cancer patients satisfaction at the management outcome: an analysis of the results of a nationwide survey in 485 subjects.

BACKGROUND: We aimed to measure satisfaction of patients with thyroid cancer concerning different aspects of healthcare. METHODS: We developed a web-based survey. Questions focused on patient satisfaction with specialists, the health centers and departments, and the information received about their disease. Level of satisfaction was quantified using a scale of 1 to 5. Values ≥4 were considered a high degree of satisfaction. RESULTS: Four hundred eighty-five patients (aged 43.4 ± 9.9 yrs., 88% females) completed the survey. A high overall satisfaction with the specialists was reported by 52.5% of patients. The most highly valued specialists were surgeons, oncologists, and endocrinologists. 56.5% of respondents reported a high overall satisfaction with the health centers and departments. Lastly, the proportion of patients who were highly satisfied with the information received was only 42.5%. The presence of complications was indirectly related with satisfaction with specialists and information. Satisfaction with health centers and services was directly related with the level of education and inversely related to the time of evolution of the disease. CONCLUSION: Our results show a high degree of overall satisfaction of thyroid cancer patients. However, satisfaction can be improved in some areas, such with regards to the information provided to patients.

The PALBONET Trial: A Phase II Study of Palbociclib in Metastatic Grade 1 and 2 Pancreatic Neuroendocrine Tumors (GETNE-1407).

LESSONS LEARNED: Palbociclib demonstrated no detectable activity in molecularly unselected and heavily pretreated patients with advanced grade 1/2 pancreatic neuroendocrine tumors. Predictive biomarkers that improve patient selection should be investigated in future studies of palbociclib. BACKGROUND: Palbociclib, a CDK4/6 inhibitor, has shown in vitro activity in pancreatic neuroendocrine tumor (pNET) cell lines. Here we prospectively assessed the activity and safety of palbociclib in monotherapy in metastatic refractory pNETs. METHODS: This was a nonrandomized, open-label, phase II study of patients with metastatic grade (G)1/2 pNETs recruited from 10 centers in Spain. Palbociclib 125 mg was orally administered once daily for 21 of 28 days until disease progression or unacceptable toxicity. RESULTS: Twenty-one patients were included; 52.4% were men, and median age was 57.4 years (range, 37.4-73.4). Patients had previously received a median of three prior lines of systemic therapy (range, 1-10) for advanced disease (somatostatin analogues, 71.4%; sunitinib, 81.0%; everolimus, 47.6%; chemotherapy, 47.6%). Nineteen patients were evaluated for objective response rate (ORR), with a median follow-up of 12.4 months (range, 7.53-19.33). No objective and confirmed responses were observed (0%); 11 (57.9%) patients had stable disease, and 6 of them lasted more than 6 months; 8 (42.1%) patients had disease progression as best response. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 0-14.4) and median overall survival (OS) was 18.7 months (95% CI, 7.4-29.9; Fig. 1). Most frequent toxicities of any grade were asthenia (76.2%), neutropenia (42.9%), diarrhea (33.3%), and nausea (33.3%). Five (23.8%) patients developed G3-4 neutropenia and two (9.5%) patients developed G3-4 thrombocytopenia. CONCLUSION: Lack of activity was observed with palbociclib as a single agent in molecularly unselected and heavily pretreated patients with advanced G1/2 pNETs.

Diagnosis, treatment and follow-up of patients with acromegaly in a clinical practice setting in Spain: the ACROPRAXIS program Delphi survey.

AIM: The ACROPRAXIS program aims to describe the management of acromegaly in Spain and provide guidance. METHODS: Ninety-three endocrinologists were organized into 13 panels to discuss the practical issues in managing acromegaly. Based on the key learnings, an online Delphi survey with 62 statements was performed, so those statements achieving consensus could be used as guidance. Statements were rated on a 9-point scale (9, full agreement; consensus > 66.6% of response in the same tertile). RESULTS: Ninety-two endocrinologists (98.8%) answered two rounds of the survey (mean age 47.6 years; 59.8% women; median 18.5 years of experience). Consensus was achieved for 49 (79%) statements. DIAGNOSIS: The levels of insulin-like growth factor I (IGFI) is the preferred screening test. If IGFI levels 1-1.3 ULN, the test is repeated and growth hormone (GH) after oral glucose tolerance test (OGTT) is assessed. A pituitary magnetic resonance is performed after biochemical diagnosis. TREATMENT: Surgery is the first treatment choice for patients with microadenoma or macroadenoma with/without optical pathway compression. Pre-surgical somatostatin analogues (SSA) are indicated when surgery is delayed and/or to reduce anaesthesia-associated risks. After unsuccessful surgery, reintervention is performed if the residual tumor is resectable, while if non-resectable, SSA are administered. Follow-up First biochemical and clinical controls are performed 1-3 months after surgery. Disease remission is considered if random GH levels are < 1 µg/L or OGTT is < 1 or ≤ 0.4 µg/L, depending on the assay's sensitivity. CONCLUSION: Current clinical management for acromegaly is homogeneous across Spain and generally follows clinical guidelines.

A Novel Probe for Spliceosomal Proteins that Induces Autophagy and Death of Melanoma Cells Reveals New Targets for Melanoma Drug Discovery.

BACKGROUND/AIMS: Despite recent advances in melanoma drug discovery, the average overall survival of patients with late stage metastatic melanoma is approximately 3 years, suggesting a need for approaches that identify new melanoma targets. We have previously reported a discovery of novel anti-melanoma compound 2155-14 (Onwuha-Ekpete et al., J Med Chem. 2014 Feb 27; 57(4):1599-608). In the report presented herein we aim to identify its target(s) and mechanism of action. METHODS: We utilized biotinylated analog of 2155-14 to pull down its targets from melanoma cells. Proteomics in combination with western blot were used to identify the targets. Mechanism of action of 2155-14 was determined using flow cytometry, RT-PCR, microscopy, western blot, and enzymatic activity assays. Where applicable, one-way analysis of variance (ANOVA) was used followed by Dunnett post hoc test. RESULTS: In the present study, we identified ATP-dependent RNA helicase DDX1 and heterogeneous nuclear ribonucleoproteins (hnRNPs) H1, H2 and A2/B1 as targets of anti-melanoma compound 215514. To the best of our knowledge, this is a first report suggesting that these proteins could be targeted for melanoma therapy. Mechanistic investigations showed that 2155-14 induces ER stress leading to potentiation of basal autophagy resulting in melanoma cell death in BRAF and NRAS mutated melanoma cells. CONCLUSION: Identification of mode of action of 2155-14 may provide insight into novel therapies against a broad range of melanoma subtypes. These studies were enabled by the novel probe derived from a mixture-based library, an important class of chemical biology tools for discovering novel targets.

Genetic Diversity, Population Structure, and Migration Scenarios of the Marsupial "Monito del Monte" in South-Central Chile.

In this study, we quantified the 3 pivotal genetic processes (i.e., genetic diversity, spatial genetic structuring, and migration) necessary for a better biological understanding and management of the singular "living-fossil" and near-threatened mouse opossum marsupial Dromiciops gliroides, the "Monito del Monte," in south-central Chile. We used 11 microsatellite loci to genotype 47 individuals distributed on the mainland and northern Chiloé Island. Allelic richness, observed and expected heterozygosity, inbreeding coefficient, and levels of genetic differentiation were estimated. The genetic structure was assessed based on Bayesian clustering methods. In addition, potential migration scenarios were evaluated based on a coalescent theory framework and Bayesian approach to parameter estimations. Microsatellites revealed moderate to high levels of genetic diversity across sampled localities. Moreover, such molecular markers suggested that at least 2 consistent genetic clusters could be identified along the D. gliroides distribution ("Northern" and "Southern" cluster). However, general levels of genetic differentiation observed among localities and between the 2 genetic clusters were relatively low. Migration analyses showed that the most likely routes of migration of D. gliroides occurred 1) from the Southern cluster to the Northern cluster and 2) from the Mainland to Chiloé Island. Our results could represent critical information for future conservation programs and for a recent proposal about the taxonomic status of this unique mouse opossum marsupial.