Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment naive advanced TC. They received ramucirumab, carboplatin and paclitaxel for 6 cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was ORR according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were PFS, OS and safety. Centralized radiologic review was performed. RESULTS: From 11/2018 to 06/2023, 52 patients were screened, 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. ECOG PS was 0 in 68.5%, 1 in 31.4% patients. At the present analysis carried out some months later the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95%CI 63.1-91.6]. At the centralized radiological review of 33/35 evaluable patients, ORR was 57.6% [95%CI 39.2-74.5]. After a median follow-up of 31.6 months, median PFS was 18.1 [95%CI 10.8-52.3] and median OS 43.8 [95%CI 31.9-NR] months. Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE≥G3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

A comprehensive review of healthy effects of vegetarian diets.

AIMS: A comprehensive review comparing the effect of vegetarian (V) and non-vegetarian (NV) diets on the major cardiometabolic diseases' outcomes was performed. DATA SYNTHESIS: We performed literature research (up to December 31, 2022) of the evidence separately for vascular disease (VD), obesity (OB), dyslipidemia (Dysl), hypertension (HPT), type 2 diabetes (T2D), metabolic syndrome (MetS), analyzing only cohort studies and randomized controlled studies (RCTs) and comparing the effect of V and NV diets. Cohort studies showed advantages of V diets compared to NV diets on incidence and/or mortality risk for ischemic heart disease, overweight and OB risk. Most cohort studies showed V had lower risk of HPT and lower blood pressure (BP) than NV and V diets had positive effects on T2D risk or plasma parameters. The few cohort studies on the risk of MetS reported mixed results. In RCTs, V diets, mainly low-fat-vegan ones, led to greater weight loss and improved glycemic control than NV diets and in the only one RCT a partial regression of coronary atherosclerosis. In most RCTs, V diets significantly reduced LDL-C levels (but also decreased HDL-C levels) and BP. CONCLUSIONS: In this comprehensive review of the association between V diets and cardiometabolic outcomes, we found that following this type of diet may help to prevent most of these diseases. However, the non-uniformity of the studies, due to ethnic, cultural, and methodological differences, does not allow for generalizing the present results and drawing definitive conclusions. Further, well-designed studies are warranted to confirm the consistency of our conclusions.

Voltage-tunable dual-band Ge/Si photodetector operating in VIS and NIR spectral range.

Extending and controlling the spectral range of light detectors is very appealing for several sensing and imaging applications. Here we report on a normal incidence dual band photodetector operating in the visible and near infrared with a bias tunable spectral response. The device architecture is a germanium on silicon epitaxial structure made of two back-to-back connected photodiodes. The photodetectors show a broad photoresponse extending from 390nm to 1600nm with the capability to electronically select the shorter (400-1100 nm) or the longer (1000-1600 nm) portion with a relatively low applied voltage. Devices exhibit peak VIS and NIR responsivities of 0.33 and 0.63 A/W, respectively, a low optical crosstalk (<-30dB), a wide dynamic range (>120dB) and, thanks to their low voltage operation, maximum specific detectivities of 7·1011cmHz1/2/W and 2·1010cmHz1/2/W in the VIS and NIR, respectively.

Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE).

BACKGROUND: Weight loss is a milestone in the prevention of chronic diseases associated with high morbility and mortality in industrialized countries. Very-low calorie ketogenic diets (VLCKDs) are increasingly used in clinical practice for weight loss and management of obesity-related comorbidities. Despite evidence on the clinical benefits of VLCKDs is rapidly emerging, some concern still exists about their potential risks and their use in the long-term, due to paucity of clinical studies. Notably, there is an important lack of guidelines on this topic, and the use and implementation of VLCKDs occurs vastly in the absence of clear evidence-based indications. PURPOSE: We describe here the biochemistry, benefits and risks of VLCKDs, and provide recommendations on the correct use of this therapeutic approach for weight loss and management of metabolic diseases at different stages of life.

Position paper on vegetarian diets from the working group of the Italian Society of Human Nutrition.

BACKGROUND: Interest in vegetarian diets is growing in Italy and elsewhere, as government agencies and health/nutrition organizations are emphasizing that regular consumption of plant foods may provide health benefits and help prevent certain diseases. METHODS AND RESULTS: We conducted a Pubmed search, up to September, 2015, for studies on key nutrients (proteins, vitamin B12, iron, zinc, calcium, vitamin D, and n-3 fatty acids) in vegetarian diets. From 295 eligible publications the following emerged: Vegetarians should be encouraged to supplement their diets with a reliable source of vitamin B12 (vitamin-fortified foods or supplements). Since the plant protein digestibility is lower than that of animal proteins it may be appropriate for vegetarians to consume more proteins than recommended for the general population. Vegetarians should also be encouraged to habitually consume good sources of calcium, iron and zinc - particularly vegetables that are low in oxalate and phytate (e.g. Brassicaceae), nuts and seeds, and calcium-rich mineral water. Calcium, iron, and zinc bioavailability can be improved by soaking, germination, and sour-dough leavening that lower the phytate content of pulses and cereals. Vegetarians can ensure good n-3 fatty acid status by habitually consuming good sources of a-linolenic acid (walnuts, flaxseeds, chia seeds, and their oils) and limiting linoleic acid intake (corn and sunflower oils). CONCLUSIONS: Well-planned vegetarian diets that include a wide variety of plant foods, and a reliable source of vitamin B12, provide adequate nutrient intake. Government agencies and health/nutrition organizations should provide more educational resources to help Italians consume nutritionally adequate vegetarian diets.

The effect of parathyroid hormone (1-84) treatment on serum bone morphogenetic protein 4 and vascular endothelial growth factor in postmenopausal women with established osteoporosis.

PURPOSE: To investigate the effect of 18 months' parathyroid hormone 1-84 (PTH 1-84) treatment on serum levels of bone morphogenetic protein 4 (BMP4) and vascular endothelial growth factor (VEGF), in postmenopausal women with established osteoporosis. METHODS: Thirty-seven postmenopausal women with osteoporosis (mean age 72.9 ± 8.1 years old) and 23 healthy controls (mean age 68.9 ± 9.9 years old) were enrolled. Patients were treated with daily subcutaneous injections of PTH (1-84) 100 mcg for 18 months, plus calcium 1 gr and vitamin D 800 IU per os daily. Blood samples were taken every 6 months during the study. RESULTS: At baseline, there were no differences considering anthropometric parameters, co-morbidities, current medications used between patients and controls. Mean serum VEGF levels were significantly higher in osteoporotic patients compared to controls (436.7 ± 259.7 vs. 260.3 ± 184.3 pg/ml, p = 0.006), while there were no differences in mean serum values of BMP4 (5.3 ± 1.7 vs. 5.7 ± 1.6 pg/ml, p = 0.40). Serum VEGF levels increased by approximately 20% after 12 months of PTH (1-84) treatment compared to baseline (p = 0.03) and by 22% after 18 months (p = 0.01). A significant increase of 10% in mean serum BMP4 levels was observed after 18 months of PTH (1-84) treatment compared to baseline (p = 0.02). In the control group we found no differences after 18 months compared to baseline in BMP4 (5.7 ± 1.6 vs. 6.0 ± 1.5 pg/ml, p = 0.53) and VEGF (260.3 ± 184.3 vs. 257.4 ± 107.1 pg/ml, p = 0.94). CONCLUSIONS: PTH (1-84) treatment increased serum levels of VEGF and BMP4 in postmenopausal women with severe osteoporosis.

A novel combined glucocorticoid-mineralocorticoid receptor selective modulator markedly prevents weight gain and fat mass expansion in mice fed a high-fat diet.

BACKGROUND: We have previously shown that antagonism of the mineralocorticoid receptor (MR) results in a potent antiadipogenic activity, in vitro and in vivo. Excessive glucocorticoid exposure is associated with obesity and related disorders in humans and mice. METHODS: In this study, responses to a novel combined glucocorticoid receptor (GR)/MR antagonist were investigated in a model of diet-induced obesity. Female 10-week-old C57BL/6J mice were fed with normal chow or a high-fat diet (HFD) for 9 weeks. Mice fed a HFD were concomitantly treated for 9 weeks with the GR antagonist mifepristone (80 mg kg(-1) per day) or the novel combined GR/MR antagonist CORT118335 (80 mg kg(-1) per day). Male, juvenile 6-week-old C57BL/6J mice fed HFD were treated with CORT118335 for 4 weeks. RESULTS: Mice fed a HFD showed a significant increase in total body weight and white fat mass, with impaired glucose tolerance and increased fat infiltration in livers. Interestingly, only CORT118335 completely prevented the HFD-induced weight gain and white fat deposition, whereas mifepristone showed no effect on body weight and modestly increased subcutaneous fat mass. Importantly, food intake was not affected by either treatment, and CORT118335 dramatically increased PGC-1α protein expression in adipose tissue, without any effect on UCP1. Both CORT118335 and mifepristone produced metabolic benefit, improving glucose tolerance, increasing adiponectin plasma levels, decreasing leptin and reducing mean adipocyte size. When tested in vitro, CORT118335 markedly reduced 3T3-L1 differentiation and reversed MR-mediated pro-adipogenic effects of aldosterone; differently, GR-mediated effects of dexamethasone were not antagonized by CORT118335, suggesting that it mostly acts as an antagonist of MR in cultured preadipocytes. CONCLUSIONS: Combined GR/MR pharmacological antagonism markedly reduced HFD-driven weight gain and fat mass expansion in mice through the increase in adipose PGC-1α, suggesting that both receptors represent strategic therapeutic targets to fight obesity. The effects of CORT118335 in adipocytes seem predominantly mediated by MR antagonism.

Costs associated with emergency care and hospitalization for severe hypoglycemia.

BACKGROUND AND AIMS: We aimed to determine the direct economic cost of the management of severe hypoglycemia among people with diabetes in Italy. METHODS AND RESULTS: Data of cases with an acceptance diagnosis of hypoglycemia between January 2011 and June 2012 were collected in 46 Emergency Departments (EDs). Emergency care costs were computed by estimating the average cost per ambulance service, ED visit and short-term (<24 h) observation period. Hospitalization expenditure was estimated using the average cost reimbursed by the Italian healthcare system for hospital admission per patient with diabetes in a specific hospital ward. We retrieved 3516 hypoglycemic episodes occurring in subjects with diabetes. Half the cases (51.8%) required referral to EDs by means of the emergency ambulance services. A total of 1751 cases (49.8%) received an ED visit followed by discharge; 604 cases (17.2%) received a short-term observation period; 1161 (33.1%) were hospitalized. Unit costs for emergency care management were estimated at €205 for an ambulance call, €23 for an ED visit, and €220 for a short-term observation. The mean hospitalization cost was estimated at €5317; the average cost per each severe hypoglycemic event totaled €1911. From a base case assumption, the total direct cost of severe hypoglycemia in patients with diabetes in Italy was estimated to be approximately €23 million per year. CONCLUSION: Severe hypoglycemia in patients with diabetes constitutes a remarkable economic burden for national healthcare systems. Measures for preventing hypoglycemia are mandatory in diabetes management programs considering the impact on patients and on health spending.

Characterization of endocrine features and genotype-phenotypes correlations in blepharophimosis-ptosis-epicanthus inversus syndrome type 1.

OBJECTIVE: Blepharophimosis syndrome (BPES) is an autosomal dominant genetic condition resulting from heterozygous mutations in the FOXL2 gene and clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure. The distinction between the two forms is critical for female patients, as it may allow to predict fertility and to plan an appropriate therapy. Identifying an underlying causative mutation is not always predictive of the clinical type of BPES since genotype-phenotype correlations are not yet fully delineated. Here, we describe the clinical and hormonal phenotypes of three female patients with BPES type 1 from two novel families, correlate their phenotypes with identified mutations, and investigate the effects of hormone replacement therapy (HRT). METHODS: Clinical, biochemical, and genetic evaluation were undertaken in all the patients and genotype-phenotype correlation was analyzed. The effects of substitutive hormonal therapy on secondary sexual characteristics development and induction of menarche were evaluated. RESULTS: All patients presented with primary amenorrhea or other signs of ovarian dysfunction. Two distinct mutations, a missense p.H104R change and an in-frame p.A222_A231dup10 duplication in the FOXL2 gene were identified. Observed phenotypes were not in accordance with the prediction based on the current genotype-phenotype correlations. HRT significantly improved secondary sexual characteristics development, as well as the induction of menarche. CONCLUSIONS: This study highlights the importance of early recognition of BPES and emphasizes the need of personalized therapy and follow-up in female patients carrying distinct FOXL2 mutations.

Quantum Signature of Analog Hawking Radiation in Momentum Space.

We consider a sonic analog of a black hole realized in the one-dimensional flow of a Bose-Einstein condensate. Our theoretical analysis demonstrates that one- and two-body momentum distributions accessible by present-day experimental techniques provide clear direct evidence (i) of the occurrence of a sonic horizon, (ii) of the associated acoustic Hawking radiation, and (iii) of the quantum nature of the Hawking process. The signature of the quantum behavior persists even at temperatures larger than the chemical potential.

The management of severe hypoglycemia by the emergency system: the HYPOTHESIS study.

BACKGROUND AND AIMS: Severe hypoglycemia is not rare in diabetes and markedly impacts on health resource use. We aimed to describe the characteristics of patients attending emergency departments (EDs) following a severe episode of hypoglycemia, the factors associated with the management of events and the final outcome. METHODS AND RESULTS: We carried out a retrospective analysis of cases attending 46 Italian EDs for hypoglycemia from January 2011 to June 2012. A total of 3753 records were retrieved from the databases of the participating centers, part of a network repeatedly involved in collaborative studies; 3516 episodes occurred in subjects with diabetes (median age, 76 years; range, 1-102). Comorbidities were recorded in 2320 (65.9%) diabetes cases; association with trauma or road accidents in 287 (8.2%) and 47 (1.3%), respectively. Patients were treated with insulin (49.8%), oral agents (31.4%), or combination treatment (15.1%). The event required assistance by the out-of-hospital Emergency services in 1821 cases (51.8%). Following the ED visit, admission to hospital departments was deemed necessary in 1161 cases (33.1%). Diabetes treatment (oral agents: OR, 1.63; 95% confidence interval (CI), 1.37-1.94), increasing age (OR, 1.39; 95% CI, 1.31-1.48) and the number of comorbidities (OR, 1.51; 95% CI, 1.38-1.66) were the main drivers of admission. The in-hospital death rate was 10%, associated with the number of comorbidities (OR, 1.28; 95%CI, 1.01-1.63). CONCLUSION: Severe hypoglycemia requiring referral to EDs is associated with a significant work-up of the Emergency services and a remarkable in-hospital death rate in frail individuals with diabetes.

Author Correction: Low testosterone levels and high estradiol to testosterone ratio are associated with hyperinflammatory state and mortality in hospitalized men with COVID-19.

Correction to: Eur Rev Med Pharmacol Sci 2021; 25 (19): 5889-5903. DOI: 10.26355/eurrev_202110_26865. PMID: 34661247-published online on October 12, 2021. In the main text, D-dimer unit of measurement was mistakenly indicated as mg/dL rather than as ng/mL. The sentence "With regard to markers of coagulation, non-survivors showed significantly higher median levels of D-dimer as compared to survivors: 1348 mg/dL 949.5 mg/dL, respectively (p=0.03)." in its correct form is the following: "With regard to markers of coagulation, non-survivors showed significantly higher median levels of D-dimer as compared to survivors: 1348 ng/mL vs. 949.5 ng/mL, respectively (p=0.03).". In the first column of Table III (third row), D-dimer unit of measurement was mistakenly indicated as mg/dL rather than as ng/mL. Correction: "D-dimer (ng/mL)". There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/26865.

A novel biotechnology product for the degradation of biofilm-associated polysaccharides produced by Streptococcus mutans.

In this study we evaluated the activity of ABR preparation, a first-in-class agent obtained through fermentation process by genetically unmodified Bacillus spp., in breaking down polysaccharide produced by Streptococcus mutans, primary coloniser of tooth surface and abundant in dental biofilms. Our results showed that ABR preparation is able in degrading sugars formed by S. mutans, both in broth culture and onto teeth surface. Its activity is not influenced by the presence of saliva, commercial mouthwashes or oral disinfectants. ABR preparation has the potential to remove preformed plaque and counteract its development, thus offering conservative control of gingival and periodontal disease.

The importance of vitamin D and omega-3 PUFA supplementation: a nonpharmacologic immunomodulation strategy to halt autoimmunity.

The large, randomized, double-blind, placebo-controlled trial VITAL (Vitamin D and omega 3 trial) recently confirmed that vitamin D and omega-3 polyunsaturated fatty acid (PUFA) co-supplementation (VIDOM) can reduce the incidence of autoimmune diseases. Based on these relevant results, this commentary summarizes the molecular mechanisms behind the anti-inflammatory and immunomodulatory properties of vitamin D and omega-3 PUFAs. We also describe the potential bidirectional interplay between vitamin D metabolism and omega-3 PUFA metabolism that underlies the rationale for VIDOM co-supplementation and that may contribute to enhance the anti-inflammatory and immunomodulatory actions of vitamin D and omega-3 PUFAs when these compounds are administered in combination.

Impact of previous corticosteroid exposure on outcomes of patients receiving immune checkpoint inhibitors for advanced non-small cell lung cancer: a retrospective observational study.

BACKGROUND: Immunosuppressive dosing of corticosteroids at the start of treatment impairs immune checkpoint inhibitor (ICI) efficacy in advanced non-small cell lung cancer (NSCLC). Previous cumulative dose and intake modality of corticosteroids may result in different levels of immunosuppression. We sought to determine whether these aspects could predict disease control and survival in NSCLC patients receiving ICIs. METHODS: We conducted a retrospective single-center study, including patients treated with ICI as second-line therapy at our institution between July 2015 and February 2021. A prednisone equivalent threshold of 700 mg defined low (LCD) or high (HCD) cumulative dosing during the 90 days before starting ICIs. At least one 5-day course of ≥ 10 mg prednisone equivalent determined whether the intake was pulse (PCD, ≤ 5 days) or continuous (CCD, > 5 days). RESULTS: We included 113 consecutive patients. Durable control benefit and no clinical benefit (NCB) were reported in 53 (47%) and 60 (53%) of the cases, respectively. ECOG PS 1-2, negative PD-L1 expression, HCD, and CCD were significantly related to NCB in multivariate analysis. The median PFS was 4.6 months (95%CI: 3.9-6.3) and median OS was 6.9 months (95% CI: 6.0-8.9) after a median follow-up time of 43.5 months (95% CI: 32.6-54.4). Multivariate analysis of survival confirmed ECOG PS 1-2 (p = 0.005), negative PD-L1 expression (p = 0.002), and CCD (p = 0.001) significantly correlated with an increased risk of mortality. CONCLUSIONS: These findings imply that immunosuppressive corticosteroid dosing before ICIs, even of short duration, might affect survival. The constraints of this study and lack of reliable comparisons suggest a hypothesis-generating value of these results.

Antineoplastic treatment class modulates COVID-19 mRNA-BNT162b2 vaccine immunogenicity in cancer patients: a secondary analysis of the prospective Vax-On study.

BACKGROUND: Preliminary analysis from the Vax-On study did not find a correlation between cancer treatment type and antibody response to COVID-19 vaccination. We carried out a secondary subgroup analysis to verify the effects of comprehensive cancer treatment classification on vaccine immunogenicity. METHODS: The Vax-On study prospectively enrolled patients who started a two-dose messenger RNA-BNT162b2 vaccine schedule from 9 March 2021 to 12 April 2021 (timepoint-1). Those on active treatment within the previous 28 days accounted for the exposed cases. Patients who had discontinued such treatment by at least 28 days or received intravesical therapy represented the control cases. Quantification of immunoglobulin G (IgG) antibodies against the receptor binding domain of the S1 subunit of the SARS-CoV-2 spike protein was carried out before the second dose (timepoint-2) and 8 weeks thereafter (timepoint-3). Seroconversion response was defined at ≥50 arbitrary units/ml IgG titer. Classification of antineoplastic agents was based on their pharmacodynamic properties. RESULTS: Three hundred and sixty-six patients were enrolled (86 and 260 as control and exposed cases, respectively). Univariate analysis revealed a significantly lower IgG titer after both doses of vaccine in subgroups treated with tyrosine kinase inhibitors (TKIs), multiple cytotoxic agents, alkylating agents, and topoisomerase inhibitors. At timepoint-3, seroconversion response was significantly impaired in the topoisomerase inhibitors and mechanistic target of rapamycin (mTOR) inhibitors subgroups. After multivariate testing, treatment with alkylating agents and TKIs was significantly associated with a reduced change in IgG titer at timepoint-2. Treatment with mTOR inhibitors resulted in a similar interaction at each timepoint. Cyclin-dependent kinase 4/6 inhibitor treatment was independently correlated with an incremental variation in IgG titer at timepoint-3. Specific subgroups (TKIs, antimetabolites, alkylating agents, and multiple-agent chemotherapy) predicted lack of seroconversion at timepoint-2, but their effect was not retained at timepoint-3. Eastern Cooperative Oncology Group performance status 2, immunosuppressive corticosteroid dosing, and granulocyte colony-stimulating factor use were independently linked to lower IgG titer after either dose of vaccine. CONCLUSIONS: Drugs interfering with DNA synthesis, multiple-agent cytotoxic chemotherapy, TKIs, mTOR and cyclin-dependent kinase 4/6 inhibitors differentially modulate humoral response to messenger RNA-BNT162b2 vaccine.

Diagnostic role of internal mammary lymph node involvement in tuberculous pleurisy: a multicenter study.

BACKGROUND AND OBJECTIVES: Diagnosis of tuberculous pleurisy (TP) may be challenging and it often requires pleural biopsy. A tool able to increase pre-test probability of TP may be helpful to guide diagnostic work-up and enlargement of internal mammary lymph node (IMLN) has been suggested to play a potential role. The aim of the present investigation was to assess role of IMLN involvement in TP in a multi-centric case-control study, by comparing its prevalence and test performance to those observed in patients with infectious, non-tuberculous pleurisy (NTIP), and in controls free from respiratory diseases (CP). METHODS: A total of 419 patients, from 14 Pulmonology Units across Italy were enrolled (127 patients affected by TP, 163 affected by NTIP and 129 CP). Prevalence, accuracy and predictive values of ipsilateral IMLN involvement between cases and control groups were assessed, as well as concordance between chest computed tomography (CT scan) and thoracic ultrasound (TUS) measurements. RESULTS: The prevalence of ipsilateral IMLN involvement in TP was significantly higher than that observed in NTIP and CP groups (respectively 77.2%, 39.3% and 14.7%). Results on test performance, stratified by age, revealed a high positive predictive value in patients aged ≤50 years, while a high negative predictive value in patients aged >50 years. The comparison between CT scan and ultrasound showed moderate agreement (Kappa=0.502). CONCLUSIONS: Evaluation of IMLN involvement plays a relevant role in assessing the pre-test probability of TP. Considering the increasing global prevalence of mycobacterial infections, a tool able to guide diagnostic work-up of suspected TP is crucial, especially where local sources are limited.