Quality of care evaluation in non-functioning pituitary adenoma with chiasm compression: visual outcomes and timing of intervention clinical recommendations based on a systematic literature review and cohort study

Purpose

Surgery in patients with non-functioning pituitary macroadenomas (NFMA) is effective in ameliorating visual function. The urgency for decompression, and preferred timing of surgery related to the preoperative severity of dysfunction is unknown.

Methods

Systematic review for evidence to provide clinical guidance for timing of surgical decompression of the optic chiasm, and a cohort study of 30 NFMA patients, in whom mean deviation (MD), and severity of visual dysfunction was assessed.

Results

Systematic review 44 studies were included with a total of 4789 patients. Postoperatively, visual field defects improved in 87.0% of patients, stabilized in 12.8% and worsened in 1.0%. Specific protocols regarding timing of surgery were not reported. Only seven studies (16.7%) reported on either the duration of visual symptoms, or diagnostic, or treatment delay.

Cohort study 30 NFMA patients (50% female, 60 eyes, mean age 58.5?±?14.8 years), had a median MD of???5.3 decibel (IQR???3.1 to???10.1). MD was strongly correlated with clinical severity (r?=????0.94, P?<?0.0001), and were used for severity of defects cut-off values: (1) normal?>????2 dB, (2) mild???2 dB to???4 dB, (3) moderate???4 to???8 dB, (4) severe???8 to???17 dB, (5) very severe?<????17 dB.

Conclusion

Surgical decompression is highly effective in improving visual function. Uniform, quantitative grading of visual dysfunction was lacking. MD is a promising quantitative outcome measure. We provide recommendations for the evaluation of timing of surgery, considering severity of visual impairment, which will need further validation based on expert clinical practice.

     

Characterising the Microstructure of an Additively Built Al-Cu-Li Alloy

Al-Cu-Li alloys are famous for their high strength, ductility and weight-saving properties, and have for many years been the aerospace alloy of choice. Depending on the alloy composition, this multi-phase system may give rise to several phases, including the major strengthening T₁ (Al₂CuLi) phase. Microstructure investigations have extensively been reported for conventionally processed alloys with little focus on their Additive Manufacturing (AM) characterised microstructures. In this work, the Laser Powder Bed Fusion (LPBF) built microstructures of an AA2099 Al-Cu-Li alloy are characterised in the as-built (no preheating) and preheat-treated (320 °C, 500 °C) conditions using various analytical techniques, including Synchrotron High-Energy X-ray Diffraction (S-HEXRD). The observed dislocations in the AM as-built condition with no detected T₁ precipitates confirm the conventional view of the difficulty of T₁ to nucleate on dislocations without appropriate heat treatments. Two main phases, T₁ (Al₂CuLi) and T_B (Al_7.5Cu₄Li), were detected using S-HEXRD at both preheat-treated temperatures. Higher volume fraction of T₁ measured in the 500 °C (75.2 HV_0.1) sample resulted in a higher microhardness compared to the 320 °C (58.7 HV_0.1) sample. Higher T_B volume fraction measured in the 320 °C sample had a minimal strength effect.     

Defined morphological criteria allow reliable diagnosis of colorectal serrated polyps and predict polyp genetics

Criteria for the diagnosis of serrated colorectal lesions (hyperplastic polyp, sessile serrated adenoma without or with dysplasia—which we called mixed polyp—and traditional serrated adenoma) for which consensus has been reached should be validated for applicability in daily practice in terms of inter-observer reproducibility and their association with clinical features and (epi)genetic events. A study set was created from a consecutive series of colorectal polyps (n?=?1,926) by selecting all sessile serrated adenomas, traditional serrated adenomas and mixed polyps. We added consecutive series of hyperplastic polyps, classical adenomas and normal mucosa samples for a total of 200 specimens. With this series, we conducted an inter-observer study, encompassing ten pathologists with gastrointestinal pathology experience from five European countries, in three rounds in which all cases were microscopically evaluated. An assessment of single morphological criteria was included, and these were correlated with clinical parameters and the mutation status of KRAS, BRAF and PIK3CA and the methylation status of MLH1. Gender, age and localisation were significantly associated with certain types of lesions. Kappa statistics revealed moderate to good inter-observer agreement for polyp classification (κ = 0.56 to 0.63), but for single criteria, this varied considerably (κ = 0.06 to 0.82). BRAF mutations were frequently found in hyperplastic polyps (86 %, 62/72) and sessile serrated adenomas (80 %, 41/51). KRAS mutations occurred more frequently in traditional serrated adenomas (78 %, 7/9) and less so in classical adenomas (20 %, 10/51). Single morphological criteria for sessile serrated adenomas showed significant correlation with BRAF mutation (all p?≤?0.001), and those for classical adenomas or traditional serrated adenoma correlated significantly with KRAS mutation (all p?<?0.001). Therefore, single well-defined morphological criteria are predictive for genetic alterations in colorectal polyps.     

Controversial association results for INSIG2 on body mass index may be explained by interactions with age and with MC4R

Among the single-nucleotide polymorphisms (SNPs) previously reported to be associated with body mass index (BMI) and obesity, we focus on a common risk variant rs7566605 upstream of the insulin-induced gene 2 (INSIG2) gene and a rare protective variant rs2229616 on the melanocortin-4 receptor (MC4R) gene. INSIG2 is involved in adipogenesis and MC4R effects hormonal appetite control in response to the amount of adipose tissue. The influence of rs2229616 (MC4R) on BMI and obesity has been confirmed repeatedly and insight into the underlying mechanism provided. However, a main effect of rs7566605 (INSIG2) is under debate because of inconsistent replications of association. Interaction of rs7566605 with age may offer an explanation. SNP–age and SNP–SNP interaction models were tested on independent individuals from three population-based longitudinal cohorts, restricting the analysis to an observed age of 25–74 years. KORA S3/F3, KORA S4/F4 (Augsburg, Germany, 1994–2005, 1999–2008), and Framingham-Offspring data (Framingham, USA, 1971–2001) were analysed, with a total sample size of N=6926 in the joint analysis. The effect of interaction between rs7566605 and age on BMI and obesity status is significant and consistent across studies. This new evidence for rs7566605 (INSIG2) complements previous research. In addition, the interaction effect of rs7566605 with the MC4R variant rs2229616 on BMI was observed. This effect size was three times larger than that in a previously reported single-locus main effect of rs2229616. This leads to the conclusion that SNP–age or SNP–SNP interactions can mask genetic effects for complex diseases if left unaccounted for.     

Prevalence and risk factors of cataract after chemotherapy with or without central nervous system irradiation for childhood acute lymphoblastic leukaemia: an LEA study

Corticosteroid and central nervous system (CNS) irradiation can induce cataract in childhood lymphoblastic leukaemia survivors. Few prospective studies with systematic ophthalmological evaluation have been published. Cataract was prospectively assessed by serial slip lamp tests in 517 patients. All had acute lymphoblastic leukaemia, all had been treated by chemotherapy with or without CNS irradiation, and none had received haematopoietic stem cell transplantation. Median ages at last evaluation and follow‐up duration from leukaemia diagnosis were 16·8 and 10·9 years, respectively. Cataract was observed in 21/517 patients (4·1%). Cumulative incidence was 4·5 ± 1·2% at 15 years and reached 26 ± 8·1% at 25 years. CNS irradiation was the only risk factor: prevalence was 11·1% in patients who had received irradiation and 2·8% in those who did not. We did not detect any steroid dose effect: cumulative dose was 5133 and 5190 mg/m² in patients with and without cataract, respectively. Cataract occurrence did not significantly impact quality of life. We conclude that, in the range of steroid dose reported here, the cataract risk proves very low 15 years after treatment without CNS irradiation but an even more prolonged follow‐up is required because of potential very late occurrence.     

From the Cover: Molecular determinants of Hv1 proton channel inhibition by guanidine derivatives

The voltage-gated proton channel Hv1 plays important roles in proton extrusion, pH homeostasis, and production of reactive oxygen species in a variety of cell types. Excessive Hv1 activity increases proliferation and invasiveness in cancer cells and worsens brain damage in ischemic stroke. The channel is composed of two subunits, each containing a proton-permeable voltage-sensing domain (VSD) and lacking the pore domain typical of other voltage-gated ion channels. We have previously shown that the compound 2-guanidinobenzimidazole (2GBI) inhibits Hv1 proton conduction by binding to the VSD from its intracellular side. Here, we examine the binding affinities of a series of 2GBI derivatives on human Hv1 channels mutated at positions located in the core of the VSD and apply mutant cycle analysis to determine how the inhibitor interacts with the channel. We identify four Hv1 residues involved in the binding: aspartate 112, phenylalanine 150, serine 181, and arginine 211. 2GBI appears to be oriented in the binding site with its benzo ring pointing to F150, its imidazole ring inserted between residue D112 and residues S181 and R211, and the guanidine group positioned in the proximity of R211. We also identify a modified version of 2GBI that is able to reach the binding site on Hv1 from the extracellular side of the membrane. Understanding how compounds like 2GBI interact with the Hv1 channel is an important step to the development of pharmacological treatments for diseases caused by Hv1 hyperactivity.The Hv1 voltage-gated proton channel (also known as HVCN1 or voltage-sensor–only protein) regulates the production of superoxide and other reactive oxygen species by NADPH oxidase (NOX) enzymes in a variety of cell types, including microglial cells (1) and leukocytes (2). NOX activity causes membrane depolarization and intracellular accumulation of protons. Hv1 allows sustained NOX activity by repolarizing the membrane and extruding excess protons from the cell (3–5).Hv1 has been shown to enhance brain damage in a mouse model of ischemic stroke through its NOX-modulating activity (1). The channel was also found overexpressed in many B-cell malignancies (6) and breast and colorectal cancer tissues (7, 8). High Hv1 activity was shown to increase invasiveness of breast cancer cells and be associated with shorter overall and recurrence-free survival in breast cancer patients (7). These findings highlight that excessive activity of the Hv1 channel can have serious pathological consequences in ischemic stroke and cancer and that small-molecule inhibitors targeting Hv1 could lead to the development of new neuroprotective or anticancer drugs.The Hv1 protein is made of four membrane-spanning segments (S1–S4) (9, 10), and it is related to the voltage-sensing domains (VSDs) of other voltage-gated ion channels (11) and voltage-sensitive phosphatases (VSPs) (12). The inner end of the S4 segment is connected to a coiled-coil domain responsible for protein dimerization (13, 14). As a result, the channel is made of two VSD subunits, each containing a gated proton pore (15–17).The block of voltage-gated sodium, potassium, and calcium channels by small molecules has been studied for decades. Its mechanism has been elucidated for many drugs, and in the majority of cases, the inhibitors were found to bind to different regions of the pore domain (18, 19). With the exception of peptide toxins (20, 21), not much is known about compounds interacting with VSDs (22), and only recently have there been successful attempts to produce small-molecule drugs that specifically target these domains in voltage-gated ion channels (23, 24).We have recently shown that some guanidine derivatives have the ability to inhibit Hv1 activity and that one of these compounds, 2-guanidinobenzimidazole (2GBI), binds the channel''s VSD only in the open conformation (25). We have also found that the binding site is within the proton permeation pathway and faces the cytoplasm.Here, we explore the chemical space available to guanidine derivatives for Hv1 binding. We then use a mutation cycle analysis approach to identify the residues in the channel that contribute to the binding environment of 2GBI and establish the overall orientation of the blocker within the VSD in the open conformation. Our results suggest that residues D112, F150, S181, and R211 are located close to each other deep within the membrane and in the proximity of the intracellular vestibule of the VSD, where they can interact with the blocker. We discuss our binding model in the context of a recent crystal structure of the channel (26).     

Preoperative and post‐operative psychosocial interventions for bariatric surgery patients: A systematic review

Psychosocial interventions are increasingly being utilized to help patients prepare for, and adjust to changes following, bariatric surgery in order to optimize psychosocial adjustment and weight loss. The current systematic review examined the impact of preoperative and post‐operative psychosocial interventions with a behavioural and/or cognitive focus on weight, dietary behaviours, eating pathology, lifestyle behaviours, and psychological functioning. A PsycINFO and Medline search of publications was conducted in March 2019. Two authors assessed retrieved titles and abstracts to determine topic relevance and rated the quality of included studies using a validated checklist. Forty‐four articles (representing 36 studies) met the study inclusion criteria. The current evidence is strongest for the impact of psychosocial interventions, particularly cognitive behavioural therapy, on eating behaviours (eg, binge eating and emotional eating) and psychological functioning (eg, quality of life, depression, and anxiety). The evidence for the impact of psychosocial interventions on weight loss, dietary behaviours (eg, dietary intake), and lifestyle behaviours (eg, physical activity) is relatively weak and mixed. Psychosocial interventions can improve eating pathology and psychosocial functioning among bariatric patients, and the optimal time to initiate treatment appears to be early in the post‐operative period before significant problematic eating behaviours and weight regain occur.     

Estradiol release kinetics determine tissue response in ovariectomized rats

Estrogen replacement is an effective therapy of postmenopausal symptoms such as hot flushes, bone loss, and vaginal dryness. Undesired estrogen effects are the stimulation of uterine and mammary gland epithelial cell proliferation as well as hepatic estrogenicity. In this study, we examined the influence of different estradiol release kinetics on tissue responsivity in ovariectomized (OVX) rats. Pulsed release kinetics was achieved by ip or sc administration of estradiol dissolved in physiological saline containing 10% ethanol (EtOH/NaCl) whereas continuous release kinetics was achieved by sc injection of estradiol dissolved in benzylbenzoate/ricinus oil (1+4, vol/vol). Initial 3-d experiments in OVX rats showed that pulsed ip estradiol administration had profoundly reduced stimulatory effects on the uterus and the liver compared with continuous release kinetics. On the other hand, both administration forms prevented severe vaginal atrophy. Based on these results, we compared the effects of pulsed (sc in EtOH/NaCl) vs. continuous (sc in benzylbenzoate/ricinus oil) estradiol release kinetics on bone, uterus, mammary gland, and liver in a 4-month study in OVX rats. Ovariectomy-induced bone loss was prevented by both administration regimes. However, pulsed estradiol resulted in lower uterine weight, reduced induction of hepatic gene expression, and reduced mammary epithelial hyperplasia relative to continuous estradiol exposure. We conclude that organ responsivity is influenced by different hormone release kinetics, a fact that might be exploited to reduce undesired estradiol effects in postmenopausal women.     

Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2

With interest waning in the use of cyclooxygenase-2 (COX-2) inhibitors for inflammatory disease, prostaglandin receptors provide alternative targets for the treatment of COX-2-mediated pathological conditions in both the periphery and the central nervous system. Activation of prostaglandin E2 receptor (PGE(2)) subtype EP2 promotes inflammation and is just beginning to be explored as a therapeutic target. To better understand physiological and pathological functions of the prostaglandin EP2 receptor, we developed a suite of small molecules with a 3-aryl-acrylamide scaffold as selective EP2 antagonists. The 12 most potent compounds displayed competitive antagonism of the human EP2 receptor with K(B) 2-20 nM in Schild regression analysis and 268- to 4,730-fold selectivity over the prostaglandin EP4 receptor. A brain-permeant compound completely suppressed the up-regulation of COX-2 mRNA in rat cultured microglia by EP2 activation and significantly reduced neuronal injury in hippocampus when administered in mice beginning 1 h after termination of pilocarpine-induced status epilepticus. The salutary actions of this novel group of antagonists raise the possibility that selective block of EP2 signaling via small molecules can be an innovative therapeutic strategy for inflammation-related brain injury.