Local therapy in endometrial cancer: evidence based review

KEY POINTS: (1) Surgery is the standard primary treatment for early stage endometrial cancer, with local adjuvant therapies such as pelvic radiotherapy and vaginal brachytherapy most often used in patients with high risk of recurrence. (2) There are currently very few well designed studies evaluating local therapies in endometrial cancer. (3) To date, the available evidence suggests that adjuvant external beam radiotherapy reduces locoregional recurrence in stage I disease but not the risk of death. Considering the high survival rate and low recurrence risk of patients with early stage disease, postoperative adjuvant radiotherapy should perhaps be limited to patients with high risk of recurrence, particularly since such radiotherapy is associated with increased long-term complications and toxicity. (4) Adjunctive chemotherapy has so far failed to demonstrate any improvement over radiotherapy in terms of overall survival in patients with intermediate and high-risk endometrial cancer. (5) Further well controlled studies are required in order to confidently establish the optimal use of local treatments and other therapies in endometrial cancer.     

Staff smoking and other barriers to nicotine dependence intervention in addiction treatment settings: a review

The aims of this review were to assess smoking prevalence among drug abuse treatment staff and summarize the range of barriers to provision of nicotine dependence intervention to clients receiving addictions treatment. A systematic literature search was conducted to identify publications reporting on workforce smoking prevalence, attitudes toward smoking, and perceived barriers to providing smoking cessation treatment in drug abuse treatment settings. Twenty papers met study inclusion criteria. Staff smoking prevalence estimates in the literature ranged from 14% to 40%. The most frequently reported barriers to providing nicotine dependence intervention in addiction treatment settings were lack of staff knowledge or training in this area, that smoking cessation concurrent with other drug or alcohol treatment may create a risk to sobriety, and staff are themselves smokers. Staff smoking is not uniformly elevated in the drug abuse treatment workforce. Smoking prevalence may be lower where staff are more educated or professionally trained, and may be higher in community-based drug treatment programs. Barriers to treating nicotine dependence may be addressed through staff training, policy development, and by supporting staff to quit smoking. State departments of alcohol and drug programs, and national and professional organizations, can also support treatment of nicotine dependence in drug abuse treatment settings.     

Associations between social media,adolescent mental health,and diet: A systematic review

Social media use is integral to many adolescents' lives. It brings benefits but can also have detrimental effects on both physical and mental health. We conducted a systematic review examining associations between social media use, adolescent mental health (including body image, self-esteem, stress, interpersonal relationships and loneliness, anxiety, and depressive symptoms), and dietary outcomes. Quantitative studies published between 2019 and 2023 investigating both mental health and diet were searched in 11 databases. The risk of bias was appraised using ROBINS-E. Data were narratively synthesized by type of association, PROGRESS-Plus health equity characteristics, and related to social media influencers. Twenty-one studies were included, of which only one focused on influencers. Sex/gender was the only equity characteristic assessed (n = 8), with mixed results. The findings suggest significant positive correlations between social media use and both depressive and disordered eating symptoms, body dissatisfaction, and anxiety. Four studies identified body image, self-esteem, or anxiety as moderators acting between social media exposure and dietary outcomes. Policy interventions mitigating the impact of social media on adolescents—particularly body image and disordered eating—are needed, alongside follow-up studies on causal pathways, the role of influencers, equity impacts, dietary intake, and the best measurement tools to use.     

No evidence of compensatory changes in energy balance,despite reductions in body weight and liver fat,during dapagliflozin treatment in type 2 diabetes mellitus: A randomized,double-blind,placebo-controlled,cross-over trial (ENERGIZE)

Aim

This study assessed the impact of dapagliflozin on food intake, eating behaviour, energy expenditure, magnetic resonance imaging (MRI)-determined brain response to food cues and body composition in patients with type 2 diabetes mellitus (T2D).

Materials and Methods

Patients were given dapagliflozin 10 mg once daily in a randomized, double-blind, placebo-controlled trial with short-term (1 week) and long-term (12 weeks) cross-over periods. The primary outcome was the difference in test meal food intake between long-term dapagliflozin and placebo treatment. Secondary outcomes included short-term differences in test meal food intake, short- and long-term differences in appetite and eating rate, energy expenditure and functional MRI brain activity in relation to food images. We determined differences in glycated haemoglobin, weight, liver fat (by ¹H magnetic resonance spectroscopy) and subcutaneous/visceral adipose tissue volumes (by MRI).

Results

In total, 52 patients (43% were women) were randomized; with the analysis of 49 patients: median age 58 years, weight 99.1 kg, body mass index 35 kg/m², glycated haemoglobin 49 mmol/mol. Dapagliflozin reduced glycated haemoglobin by 9.7 mmol/mol [95% confidence interval (CI) 3.91-16.27, p = .004], and body weight (−2.84 vs. −0.87 kg) versus placebo. There was no short- or long-term difference in test meal food intake between dapagliflozin and placebo [mean difference 5.7 g (95% CI −127.9 to 139.3, p = .933); 15.8 g (95% CI −147.7 to 116.1, p = .813), respectively] nor in the rate of eating, energy expenditure, appetite, or brain responses to food cues. Liver fat (median reduction −4.7 vs. 1.95%), but not subcutaneous/visceral adipose tissue, decreased significantly with 12 weeks of dapagliflozin.

Conclusions

The reduction in body weight and liver fat with dapagliflozin was not associated with compensatory adaptations in food intake or energy expenditure.     

Cysteine-lowering treatment with mesna against obesity: Proof of concept and results from a human phase I,dose-finding study

Aim

To investigate whether mesna—sodium-2-mercaptoethane sulfonate) can reduce diet-induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%.

Methods

C3H/HeH mice were shifted to a high-fat diet ± mesna in drinking water; body composition was measured at weeks 0, 2 and 4. In an open, phase I, single ascending dose study, oral mesna (400, 800, 1200, 1600 mg) was administered to 17 men with overweight or obesity. Mesna and tCys concentrations were measured repeatedly for a duration of 48 hours postdosing in plasma, as well as in 24-hour urine.

Results

Compared with controls, mesna-treated mice had lower tCys and lower estimated mean fat mass gain from baseline (week 2: 4.54 ± 0.40 vs. 6.52 ± 0.36 g; week 4: 6.95 ± 0.35 vs. 8.19 ± 0.34 g; P_overall = .002), but similar lean mass gain. In men with overweight, mesna doses of 400-1600 mg showed dose linearity and were well tolerated. Mesna doses of 800 mg or higher decreased plasma tCys by 30% or more at nadir (4h post-dosing). With increasing mesna dose, tCys AUC_0-12h decreased (P_trend < .001), and urine tCys excretion increased (P_trend = .004).

Conclusions

Mesna reduces diet-induced fat gain in mice. In men with overweight, single oral doses of mesna (800-1600 mg) were well tolerated and lowered plasma tCys efficiently. The effect of sustained tCys-lowering by repeated mesna administration on weight loss in humans deserves investigation.     

miR-21-5p promotes NASH-related hepatocarcinogenesis

Background and Aims

The mechanisms governing the progression of non-alcoholic fatty liver disease (NAFLD) towards steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain elusive. Here, we evaluated the role of hsa-miRNA-21-5p in NASH-related hepatocarcinogenesis.

Methods

Hepatic hsa-miR-21-5p expression was evaluated in two cohorts of patients with biopsy-proven NAFLD (n = 199) or HCC (n = 366 HCC and n = 11 NAFLD-HCC). Serum/liver metabolomic profiles were correlated with hsa-miR-21-5p in NAFLD obese patients. Wild-type (WT) and Mir21 KO mice were fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks to induce NASH and NASH-HCC, respectively.

Results

In obese individuals, hsa-miR-21-5p expression increased with NAFLD severity and associated with a hepatic lipotoxic profile. CDAA-fed WT mice displayed increased hepatic mmu-miR-21-5p levels and progressively developed NASH and fibrosis, with livers presenting macroscopically discernible pre-neoplastic nodules, hyperplastic foci and deregulated cancer-related pathways. Mir21 KO mice exhibited peroxisome-proliferator-activated receptor α (PPARα) activation, augmented mitochondrial activity, reduced liver injury and NAS below the threshold for NASH diagnosis, with the pro-inflammatory/fibrogenic milieu reversing to baseline levels. In parallel, Mir21 KO mice displayed reduced number of pre-neoplastic nodules, hepatocyte proliferation and activation of oncogenic signalling, being protected from NASH-associated carcinogenesis. The hsa-miRNA-21-5p/PPARα pathway was similarly deregulated in patients with HCC- or NASH-related HCC, correlating with HCC markers and worse prognosis.

Conclusions

Hsa-miR-21-5p is a key inducer of whole-spectrum NAFLD progression, from simple steatosis to NASH and NASH-associated carcinogenesis. The inhibition of hsa-miR-21-5p, leading to a pro-metabolic profile, might constitute an appealing therapeutic approach to ameliorate NASH and prevent progression towards HCC.     

Deficient response inhibition as a cognitive endophenotype of ADHD

OBJECTIVE: To investigate whether a deficient response inhibition is a cognitive endophenotype of attention-deficit/hyperactivity disorder (ADHD). The authors hypothesized that nonaffected siblings of ADHD probands would have a response inhibition between that of ADHD probands and normal controls, although they resembled the controls at a behavioral level. METHOD: Participants were 25 ADHD probands with a family history of ADHD, their nonaffected siblings (n = 25), and 48 normal controls matched for age and IQ. All participants were between 6 and 17 years of age. The nonaffected siblings were compared with their ADHD siblings and with controls on measures reflecting different types of response inhibition. RESULTS: The nonaffected siblings had results similar to those of the ADHD probands, who differed from the controls on all inhibition measures (p <.05). CONCLUSIONS: Siblings of ADHD probands, while not behaviorally expressing the disorder, have ADHD-associated deficits in response inhibition. This suggests that subtyping based on measures of response inhibition can help identify genetic susceptibility to ADHD. Children with a genetic vulnerability to ADHD may have hidden cognitive deficits in the absence of manifest behavioral symptoms. Therefore, they should be monitored to detect possible learning problems.