Impact of Diabetes and Metformin Use on Enteropancreatic Neuroendocrine Tumors: Post Hoc Analysis of the CLARINET Study

The prognostic role of diabetes mellitus (DM) in advanced enteropancreatic neuroendocrine tumors (NETs) is unclear. Progression free survival (PFS) was assessed in post-hoc analyses of the 96-week, phase III, double-blind, placebo-controlled CLARINET study of lanreotide 120 mg in patients with advanced non-functional enteropancreatic NETs with DM (with/without metformin) and without DM. Of 204 patients, there were 79 with DM (lanreotide, n = 42 {metformin, n = 14}; placebo, n = 37 {metformin, n = 10}) and 125 without DM (lanreotide, n = 59; placebo, n = 66). Median PFS was 96.0 and 98.0 weeks with and without DM, respectively (hazard ratio 1.20 {95% confidence interval 0.79 to 1.82}; p = 0.380). No difference in PFS was observed in lanreotide-treated patients with/without DM (p = 0.8476). In the placebo group, median PFS was numerically shorter with versus without DM (p = 0.052) and was significantly longer in patients with DM and metformin (85.7 weeks) versus without metformin (38.7 weeks; p = 0.009). Multivariable Cox analyses showed that DM at baseline was not associated with PFS (p = 0.079); lanreotide was significantly associated with lower disease progression risk (p = 0.017). Lanreotide efficacy was confirmed in patients with advanced enteropancreatic NETs, regardless of diabetic status; DM was not a negative prognostic factor. A potential antitumor effect of metformin was observed in patients receiving placebo.

A multicenter Spanish study of atropine 0.01% in childhood myopia progression

To evaluate the efficacy and safety of atropine 0.01% eye drops for myopia control in a multicentric pediatric Spanish cohort. An interventional, prospective, multicenter study was designed. Children aged between 6 and 14 years, with myopia between − 2.00 D to − 6.00 D, astigmatism < 1.50 D and documented previous annual progression greater than − 0.5 D (cycloplegic spherical equivalent, SE) were included. Once nightly atropine 0.01% eye drops in each eye were prescribed to all participants for 12 months. Age, gender, ethnicity and iris color were registered. All patients underwent the same follow-up protocol in every center: baseline visit, telephone consultation 2 weeks later and office controls at 4, 8 and 12 months. At each visit, best-corrected visual acuity, and cycloplegic autorefraction were assessed. Axial length (AL), anterior chamber depth and pupil diameter were measured on an IOL Master (Carl Zeiss Meditec, Inc, Dublin, CA). Adverse effects were registered in a specific questionnaire. Mean changes in cycloplegic SE and AL in the 12 months follow-up were analyzed. SE progression during treatment was compared with the SE progression in the year before enrollment for each patient. Correlation between SE and AL, and annual progression distribution were evaluated. Progression risk factors were analyzed by multivariate logistic regression analyses. Of the 105 recruited children, 92 completed the treatment. Mean SE and AL changes were − 0.44 ± 0.41 D and 0.27 ± 0.20 mm respectively. Mean SE progression was lower than the year before treatment (− 0.44 ± 0.41 D versus − 1.01 ± 0.38 D; p < 0.0001). An inverse correlation between SE progression and AL progression (r: − 0.42; p < 0.0001) was found. Fifty-seven patients (62%) had a SE progression less than − 0.50 D. No risk factors associated with progression could be identified in multivariate analyses. Mean pupil diameter increment at 12-months visit was 0.74 ± 1.76 mm. The adverse effects were mild and infrequent, and decreased over the time. Atropine 0.01% is effective and safe for myopia progression control in a multicentric Spanish children cohort. We believe this efficacy might be extensible to the myopic pediatric population from Western countries with similar social and demographic features. More studies about myopia progression risk factors among atropine treated patients are needed.

Assessing the prognostic utility of smoldering multiple myeloma risk stratification scores applied serially post diagnosis

The Mayo-2018 smoldering multiple myeloma (SMM) risk score is used routinely in the clinical setting but has only been validated at diagnosis. In SMM patients, the progression risk decreases over time. However, the utility of applying risk stratification models after diagnosis is unknown. We retrospectively studied 704 SMM patients and applied the Mayo 2018 and IMWG-2020 risk stratification models at annual landmark timepoints up to 5 years post diagnosis. The Mayo-2018 and IMWG-2020 models reliably stratified patients based on progression risk when applied post diagnosis. The respective 2-year progression risk in Mayo-2018 high risk patients versus IMWG-2020 intermediate-high risk patients was 51% versus 62% at the 1-year landmark and 47% versus 45% at the 4-year landmark. We showed that patients categorized at Mayo-2018 high-risk at follow-up had a similar risk of progression if the baseline risk assessment was low-intermediate versus high-risk (HR 1.04, 95% CI 0.46–2.36, p = 0.931 at 5-year landmark). Patients migrating to a higher risk category during follow up had a higher progression risk compared to patients with stable/decreased risk categorization. Our findings support the use of these risk scores post-diagnosis and suggest that patients evolving to a high-risk category may benefit from early intervention therapeutic approaches.

MicroRNAs in Molecular Classification and Pathogenesis of Breast Tumors

The current clinical practice of breast tumor classification relies on the routine immunohistochemistry-based expression analysis of hormone receptors, which is inadequate in addressing breast tumor heterogeneity and drug resistance. MicroRNA expression profiling in tumor tissue and in the circulation is an efficient alternative to intrinsic molecular subtyping that enables precise molecular classification of breast tumor variants, the prediction of tumor progression, risk stratification and also identifies critical regulators of the tumor microenvironment. This review integrates data from protein, gene and miRNA expression studies to elaborate on a unique miRNA-based 10-subtype taxonomy, which we propose as the current gold standard to allow appropriate classification and separation of breast cancer into a targetable strategy for therapy.

AGO2 expression levels and related genetic polymorphisms: influence in renal cell progression and aggressive phenotypes

Aim: Renal cell carcinoma (RCC) is the most lethal urological cancer and up to 40% of patients submitted to surgery will relapse. Thus, the study aim was to analyze the associations of AGO2 SNPs with RCC patients’ prognosis, and evaluate their effect on AGO2 mRNA levels. Materials & methods: The AGO2 rs4961280, rs3928672 and rs11996715 polymorphisms and the relative quantification of AGO2 mRNA levels were analyzed by real-time PCR. Results: We observed that AGO2 rs4961280 AC + AA genotypes carriers presented a higher cancer progression risk (OR= 3.13, p < 0.001), a reduced progression-free survival (log rank test, p = 0.003) and an increased risk of an early relapse (HR= 2.26, p = 0.008). In fact, these patients also presented higher circulating levels of AGO2 mRNA (p = 0.043), with the high levels being associated with more aggressive tumors. Conclusion: The AGO2 rs4961280 AA/AC genotypes are unfavorable RCC prognostic biomarkers, with the AGO2 levels being a useful RCC aggressive phenotype biomarker.

Baseline Alpha-Fetoprotein, Alpha-Fetoprotein-L3, and Des-Gamma-Carboxy Prothrombin Biomarker Status in Bridge to Liver Transplant Outcomes for Hepatocellular Carcinoma

The biomarkers α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP fraction (AFP-L3), and des-γ-carboxy prothrombin (DCP) have emerging implications in hepatocellular carcinoma (HCC) surveillance, overall prognosis, and post-surgical recurrence risk. This retrospective study investigated treatment and bridge to liver transplant (LT) prognosis associated with AFP, AFP-L3%, and DCP biomarker profiles prior to liver-directed therapy (LDT). In a 140-patient cohort, each biomarker was associated with HCC progression risk using the established thresholds of AFP > 20 ng/mL, AFP-L3 > 15%, and DCP > 7.5 ng/mL. Over 60% of the cohort expressed at least one biomarker at baseline. Although most biomarker-positive patients expressed the clinical standard AFP (57/87), only 32% were positive for AFP alone. Biomarker accumulation increased HCC progression risk but was not associated with demographic factors or preserved liver function. Biomarker triple negative patients had smaller index HCC (p = 0.003), decreased multifocal burden (p = 0.010), and a higher objective response rate (ORR, 62% compared to 46%, p = 0.011). Expressing all three biomarkers at baseline was associated with dismal first-line ORR (12%) with a median time to progression (TTP) of only 181 days post-LDT. Patients with triple negative status for the HCC biomarkers AFP, AFP-L3%, and DCP have the highest first-line ORR with < 5% HCC progression 1-year post-LDT. Biomarker profiling can establish baseline prognosis for identifying optimal bridge to LT and downstaging to LT candidates with triple negative biomarker status and providing an ideal post-LDT target as a compliment to radiographic response.

May be Urinary Excretion of α2-macroglobulin (MW 720 kDa) a Proteinuric Marker of Podocytopathy? Insight from Analysis of 204 Patients with Glomerulonephritis (GN) and Nephrotic Syndrome, 177 with Functional Outcome

Background: In IgAN with cellular crescents (CIgAN) urinary excretion of α2-macroglobulin (α2m/C, MW 720 kDa) may be a marker of podocytes damage induced by crescents. The purpose of the study was the evaluation of the clinical significance of α2m/C excretion in 177 patients with glomerulonephritis (GN), nephrotic syndrome (NS) and functional outcome. Methods: In all 177 patients α2m/C excretion was measured; the patients were divided in 2 groups: α2mC=0 (n. 72) and α2m/C >0 (n. 105); for each group were assessed the outcomes considered in combination: Remission & persistent nephrotic syndrome (PNS) with long lasting NRF designed “Remission & NRF”; ESRD & eGFR < 50% & PNS with CRF designed “Progression and progression risk”. Results: In 72 patients with α2m/C=0 “Remission & NRF” was 78% and “Progression & progression risk” was 22%; in 105 patients with α2m/C>0 “remission & NRF” was 52% and “Progression & progression risk” was 48%. “Remission & NRF” in each GN type with α2m/C=0 was: 100% in MCD and LN; 82%, 79%, 67% in FSGS, IMN, MPGN; in α2m/C>0 “Progression and progression risk” was 0%, 38%, 46%, 54%, 56%, 85% in MCD, LN, IMN, MPGN, FSGS, CIgAN with cellular crescents, respectively. Conclusion: Urinary excretion of α2m is a very simple marker available in all clinical practice laboratories, marker of damage of podocytes at least in CIgAN and LN with crescents and marker of GFB damage in different GN types and useful to predict outcome and treatment responsiveness.