Abstract For decades the vitamin D biological system has been considered almost exclusively as the master integrator of calcium-phosphate homeostasis and bone metabolism. More recently, the discovery ...that many human tissues and cells, which do not directly participate in mineral ion homeostasis, express the vitamin D receptor (VDR) and are able to convert the circulating pro-hormone 25-hydroxyvitamin D in its active form, 1,25-dihydroxyvitamin D, has provided new insights into the biological function of this peculiar endocrine system. Several reports have highlighted a variety of human diseases possibly related to vitamin D insufficiency or deficiency (respectively defined as 25-hydroxyvitamin D serum levels lower than 30 or lower than 20 ng/ml). In particular, experimental and observational studies, including those published in this journal issue, support the concept that vitamin D deficiency is involved in the pathogenesis of congestive heart failure, a disabling condition affecting over 15 million of patients worldwide. Considering that circulating levels of 25-hydroxyvitamin D represent the accepted clinical indicator of individual vitamin D status, the measurement of this pro-hormone can be regarded as an appropriate and cost-effective screening tool in patients with chronic heart failure.
Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene ...(EML4)–ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients.
In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase ALK inhibitor ALKI/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal.
In total, 36 patients were treated (a 450-mg cohort n=14 and a 300-mg cohort n=22). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval CI: 35.9–99.6) in the 450-mg cohort and 60% (95% CI: 26.2–87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7–84.3) in the 450-mg cohort and 25% (95% CI: 5.5–57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients 95% CI: 35.1–87.2 had confirmed responses as compared with those with negative PD-L1 staining (31% 95% CI: 11.0–58.7). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported.
Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.
To investigate the potential of circulating-miRNAs (ct-miRNA) as noninvasive biomarkers to predict the efficacy of single/dual HER2-targeted therapy in the NeoALTTO study.
Patients with plasma ...samples at baseline (T0) and/or after 2 weeks (T1) of treatment were randomized into training (
= 183) and testing (
= 246) sets. RT-PCR-based high-throughput miRNA profiling was employed in the training set. After normalization, ct-miRNAs associated with pathologic complete response (pCR) were identified by univariate analysis. Multivariate logistic regression models were implemented to generate treatment-specific signatures at T0 and T1, which were evaluated by RT-PCR in the testing set. Event-free survival (EFS) according to ct-miRNA signatures was estimated by Kaplan-Meier method and Cox regression model.
In the training set, starting from 51 ct-miRNAs associated with pCR, six signatures with statistically significant predictive capability in terms of area under the ROC curve (AUC) were identified. Four signatures were confirmed in the testing set: lapatinib at T0 and T1 AUC 0.86; 95% confidence interval (CI), 0.73-0.98 and 0.71 (0.55-0.86), respectively; trastuzumab at T1 (0.81; 0.70-0.92); lapatinib + trastuzumab at T1 (0.67; 0.51-0.83). These signatures were confirmed predictive after adjusting for known variables, including estrogen receptor status. ct-miRNA signatures failed to correlate with EFS. However, the levels of ct-miR-140-5p, included in the trastuzumab signature, were associated with EFS (HR 0.43; 95% CI, 0.22-0.84).
ct-miRNAs discriminate patients with and without pCR after neoadjuvant lapatinib- and/or trastuzumab-based therapy. ct-miRNAs at week two could be valuable to identify patients responsive to trastuzumab, to avoid unnecessary combination with other anti-HER2 agents, and finally to assist deescalating treatment strategies.
Background:
Obesity and insulin resistance predispose individuals to the development of both metabolic syndrome and non-toxic nodular thyroid diseases.
Aim:
The aim of this observational, ...cross-sectional study is to evaluate the relationship between metabolic syndrome and multinodular non-toxic goiter in an inpatient population from a geographic area with moderate iodine deficiency. Subjects and methods: We examined 1422 Caucasian euthyroid inpatients. Thyroid volume was determined by ultrasound of the neck. A fine-needle aspiration biopsy was performed to evaluate single thyroid nodules and dominant nodules ≥15 mm in euthyroid multinodular goiter. The diagnosis of metabolic syndrome was made according to the criteria of the American Heart Associaion/National Heart, Lung, and Blood Institute.
Results:
Of the sample, 277 patients had clinical evidence of multinodular non-toxic goiter, 461 met the criteria for the diagnosis of metabolic syndrome, and 132 were found to have both conditions. After adjusting for age, gender, body mass index, nicotinism, parity, alcohol intake, thyroid function, and metabolic syndrome-related pharmacological treatment, metabolic syndrome was found to be an independent risk factor for the occurrence of multinodular non-toxic goiter. The relationship between metabolic syndrome and multinodular non-toxic goiter was apparent in both men and women.
Conclusions:
In this study of euthyroid inpatients, we demonstrate that metabolic syndrome is an independent risk factor for the occurrence of multinodular non-toxic goiter in a geographic area with moderate iodine deficiency. We propose that patients meeting the criteria for metabolic syndrome should be screened for the presence of multinodular non-toxic goiter.
La sindrome metabolica è un fattore di rischio per nefrolitiasi. Questo studio è stato effettuato per valutare il profilo clinico e biochimico di pazienti con nefrolitiasi recidivante da ossalato di ...calcio e sindrome metabolica. Sono stati arruolati un totale di 526 calcolotici, 184 dei quali con sindrome metabolica, e 214 controlli.
I calcolotici con sindrome metabolica hanno mostrato un'escrezione di sodio superiore media (95% intervallo di confidenza), 196 (176-218) vs 160 (150-168) mmol/24h; p
Il Fibroblast Growth Factor-23 (FGF-23) Rendina, D.; De Filippo, G.; Muscariello, R. ...
Giornale di clinica nefrologica e dialisi,
01/2018, Volume:
23, Issue:
4
Journal Article
Peer reviewed
Open access
Negli ultimi due decenni, l'identificazione delle proprietà biologiche del Fibroblast Growth Factor 23 (FGF23) ha notevolmente ampliato le conoscenze sulla regolazione endocrina e paracrina ...dell'omeostasi dei fosfati e sulle relazioni intercorrenti tra asse rene-intestino-tessuto osseo e sistema biologico vitamina D-FTH-calcio-fosfati. Lo studio delle proprietà biologiche di FGF23 ha inoltre aperto interessanti campi di ricerca in ambito clinico e farmacologico.
Cancer Testis Antigens are immunogenic tumor-specific proteins. We investigated NY-ESO-1, MAGE-A3 and PRAME, in addition to WT1 expression in different Breast Cancer (BC) subtypes. We then evaluated ...the expression rate of NY-ESO-1 in early Triple Negative breast cancer (TNBC), and investigated whether its expression would be maintained or lost in the metastatic setting to explore possible immunotherapy indication.
Three subgroups of BC patients were selected by the expression of ER, PgR and Her2. Tissue microarray was performed on a total of 92 Invasive BC. Sections were stained for NY-ESO-1, MAGE-A3, PRAME and WT1. The second cohort was composed by 26 metastatic TNBC patients from whom both the primary and secondary lesion tissues were available. Sections were stained for NY-ESO-1.
NY-ESO-1 was the only differentially expressed antigen and was absent in ER+ and ER-PgR + tumors, as for an exclusive expression of either NY-ESO-1 or at least one hormonal receptor (HR+). NY-ESO-1 was particularly represented in TNBC. No correlation has been found between MAGE-A3 and PRAME expression and subtype WT1 had low expression, except in the Her2+ group. In the second cohort, NY-ESO-1 was expressed in 12 and 24% of primary and metastatic lesions respectively.
This study defines a distinction between HR+ and HR-tumors through NY-ESO-1 expression.
TNBC subgroup has the highest frequency of NY-ESO-1+ cases, and it could be the candidate population for the development of anti-NY-ESO-1 vaccine, both in the adjuvant or metastatic setting, and for the selection of cases suitable for immunotherapy.
•The role of cancer testis antigen expression in breast cancer is controversial.•NY-ESO-1 is the only differentially expressed antigen between breast cancer subgroups.•NYESO-1 is more frequent in metastatic than in the corresponding primary sites.
Precis: NY-ESO-1 is the only differentially expressed antigen between breast cancer subgroups, among those we evaluated, and is restricted to hormonal receptors negative cases with the highest frequency in Triple Negative breast cancer, thus indicating its possible role as anticancer vaccine target in a poor prognosis subgroup still lacking of specific therapies.
Bone-targeted agents (BTA), such as denosumab (DN) and zoledronic acid (ZA), have historically reduced the risk of skeletal related events in cancer patients with bone metastases (BM), with no ...improvement in survival outcomes. In the immunotherapy era, BM have been associated with poor prognosis upon immune-checkpoint inhibitors (ICI). Currently, the impact of bone tumor burden on survival upon BTAs in advanced non-small cell lung cancer (aNSCLC) patients treated with ICI remains unknown.
Data from ICI-treated aNSCLC patients with BM (4/2013-5/2022) in one institution were retrospectively collected. BTA-ICI concurrent treatment was defined as BTA administration at any time before or within 90 days from ICI start. High bone tumor burden (HBTB) was defined as ≥ 3 sites of BM. Median OS (mOS) was estimated with Kaplan-Meier. Aikaike's information criterion (AIC) was used to select the best model for data analysis adjusted for clinical variables.
Of 134 patients included, 51 (38 %) received BTA. At a mFU of 39.6 months (m), BTA-ICIs concurrent treatment did not significantly impact on mOS 8.3 m (95% CI 3.9-12.8) versus (vs) 6.8 m (95% CI 4.0-9.6) p = 0.36; these results were confirmed after adjustment for clinical variables selected by AIC. A multivariate model showed a significant interaction between BTA use and HBTB or radiation therapy to BM. In subgroup analyses, only HBTB confirmed to be associated with significantly longer mOS 8.3 m (95% CI 2.4-14.2) vs 3.5 m (95% CI 2.9-4.1), p = 0.003 and mPFS 3.0 m (95% CI 1.6-4.4) vs 1.8 m (95% CI 1.6-2.0) p = 0.001 upon BTA-ICI concurrent treatment, with the most pronounced OS benefit observed for DN-ICI concurrent regimen 15.2 m (95% CI 0.1-30.7) vs 3.5 m (95% CI 2.9-4.1) p = 0.002.
In the immunotherapy era, HBTB can identify patients experiencing survival benefit with BTA, especially with DN-ICI combination. HBTB should be included as a stratification factor in the upcoming trials assessing BTA and ICI combinations in patients with aNSCLC and BM.
Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer, with 5-10% of cases progressing into invasive disease. Herein, we investigated the association between HER2-low ...and clinico-pathological characteristics in DCIS and subsequent ipsilateral loco-regional relapse (LRR).
We accessed our prospectively maintained institutional database. HER2 status was determined by immunohistochemistry and classified as null (score 0), over-expressed (3+), and low (1+ or 2+); in situ hybridization was not considered since it is not used for routine DCIS diagnostics.
Among 375 patients with DCIS, median age was 54 (27-88) years, with a primary tumor size < 2.5 cm in 63%, grade III in 33%, and positive hormone receptor status (HR) in 81% of cases; 71% underwent breast-conserving surgery, 34% received adjuvant endocrine and 39% radiotherapy. A total of 197 (52%) had tumors with low HER2 expression, which resulted significantly associated with grade I/II (P < .001), Ki67< 20% (P < .001), and HR-positive status (P < .001). HER2-low distribution varied from 19.61% and 50% in ER negative and ER-low (<10%) to 60% and 69% in ER high (50%-95%) and very high tumors (> 95%) (P < .001). After a median 39-month follow-up (IQR 16-65), cumulative incidences of LRR was 0.054. Among 17 patients with paired primary tumor and LRR, 5 had discordant HER2 status, with an even distribution of increased and decreased HER2 expression.
Low HER2 expression in DCIS is associated with features of reduced aggressiveness. Importantly, changes in HER2 expression may occur prompting retesting in recurrent cases, in line with observations in invasive breast cancer.
Among 375 patients with DCIS, those with low HER2 expression (52%) also exhibited less aggressive clinico-pathological features. Importantly, HER2 expression changed in up to one-third of patients experiencing ipsilateral loco-regional relapse, prompting retesting in recurrent cases. Findings align with observations in invasive breast cancer, emphasizing the potential clinical relevance of HER2 status in DCIS.
Contexte Le test GnRH/LHRH est largement utilisé dans l’exploration des HHC. Pourtant, son intérêt, qui n’a pas été évalué, est incertain. Objectif Évaluer les réponses des gonadotrophines à cette ...stimulation chez des HHC/SK, RPS et des hommes normaux (C) de façon à préciser ses performances diagnostiques. Patients et méthodes Étude chez 127 HHC dont 54 % SK (25,5 ± 9,9 ans) ; 90 RPS (14,9 ± 1,0 ans) non traités et 31 C (25,9 ± 5,2 ans). Volume testiculaire (VT) mesuré par orchidomètre. Test GnRH (100 μg) avec dosages de LH et FSH (méthode sandwich) ; sensibilité 0,05 UI/L pour les deux. Dosage Elisa d’inhibine B (IB), sensibilité : 5 pg/mL. Résultats Les bases et les pics de LH (UI/L) étaient : C, base : 4,2 ± 0,9 2,9–6,1, pic : 17,9 ± 3,7 11,1–26,0 ; HHC, base : 0,8 ± 1,0 0,0–7,0, pic : 6,8 ± 7,6 0,1–41,5 ; RPS, base : 1,2 ± 0,8 0,0–3,7, pic : 13,1 ± 6,5 0,4–33,4. Parmi les 127 HHC, 36 avaient des pics de LH dans l’intervalle des pics des contrôles et 69/127 HHC avait des pics de LH dans l’intervalle des pics des RPS. Chez les HHC, il existait une corrélation entre le pic de LH et le VT ( r = 0,39 ; p < 0,0001) et une corrélation encore plus forte entre le pic de LH et l’IB ( r = 0,46 ; p < 0,0001). Chez les RPS, des corrélations similaires existaient. Discussion Le pic de LH chez les HHC/SK est très variable. Il dépend de la profondeur du déficit gonadotrope. Il existe un chevauchement important entre les trois populations. Le pic de LH n’apporte aucune plus-value diagnostique/à la LH de base pour distinguer les HHC/SK des C et des RPS.
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