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In the present study we evaluated spontaneous and stimulated adherence of human monwytes to regenerated cellulose and polyacrylonitrile (AN69) membranes. Spontaneous adherence at 60 min was significantly higher for regenerated cellulose (28±2%, <0.001) than for AN69 (11±2) membranes. Stimuli such as bacterial lipopolysaccharide, TNFα, interleukin-1 and -6 as well as platelet-activating factor, but not IL4, significantly enhanced adherence at 60 min to AN69 (28 to 30%). In contrast, adherence was not further inducible in the presence of regenerated cellulose. Both spontaneous and cytokine/bacterial lipopolysaccharide-stimulated adherence were significantly reduced by SDZ-63072, a specific plateletactivating factor receptor antagonist. This difference in sensitivity of monocyte adherence reflects probably the intrinsic ability of regenerated cellulose to provide maximal spontaneous monocyte adhesion. These data suggest that PAF may act as an adherence mediator. This is in line with the ability of regenerated cellulose to directly stimulate monocytes to synthesize plateletactivating factor and with the ability of cytokines and bacterial lipopolysaccharide to stimulate its synthesis. Although AN69 has a low adherence potential, bacterial lipopolysaccharide or cytokines may blunt the biocompatibility of this membrane. [ABSTRACT FROM PUBLISHER]

Background: The addition of pertuzumab (P) to trastuzumab (H) and standard chemotherapy (CT) as neoadjuvant treatment (NaT) for patients with HER2 + breast cancer (BC), has shown to increase the pathological complete response (pCR) rate, without main safety concerns. The aim of NeoPowER trial is to evaluate safety and efficacy of P + H + CT in a real-world population., Methods: We retrospectively reviewed the medical records of stage II-III, HER2 + BC patients treated with NaT: who received P + H + CT (neopower group) in 5 Emilia Romagna institutions were compared with an historical group who received H + CT (control group). The primary endpoint was the safety, secondary endpoints were pCR rate, DRFS and OS and their correlation to NaT and other potential variables., Results: 260 patients were included, 48% received P + H + CT, of whom 44% was given anthraciclynes as part of CT, compared to 83% in the control group. The toxicity profile was similar, excluding diarrhea more frequent in the neopower group (20% vs. 9%). Three patients experienced significant reductions in left ventricular ejection fraction (LVEF), all receiving anthracyclines. The pCR rate was 46% (P + H + CT) and 40% (H + CT) (p = 0.39). The addition of P had statistically correlation with pCR only in the patients receiving anthra-free regimens (OR = 3.05,p = 0.047). Preoperative use of anthracyclines (OR = 1.81,p = 0.03) and duration of NaT (OR = 1.18,p = 0.02) were statistically related to pCR. 12/21 distant-relapse events and 14/17 deaths occurred in the control group. Patients who achieve pCR had a significant increase in DRFS (HR = 0.23,p = 0.009)., Conclusions: Adding neoadjuvant P to H and CT is safe. With the exception of diarrhea, rate of adverse events of grade > 2 did not differ between the two groups. P did not increase the cardiotoxicity when added to H + CT, nevertheless in our population all cardiac events occurred in patients who received anthracycline-containing regimens. Not statistically significant, higher pCR rate is achievable in patients receiving neoadjuvant P + H + CT. The study did not show a statistically significant correlation between the addition of P and long-term outcomes., (© 2024. The Author(s).)

In this study, a UHPLC-PDA method for the simultaneous identification of polyphenols and bitter acids (alpha, beta, and isoalpha) in beer was developed. The resulting chemical profiles were leveraged to distinguish the characteristics of four (IPA, Lager, Blanche, ALE) bergamot-flavored beers, produced on a pilot-scale plant. In a streamlined 29 min analysis, thirty polyphenols and fourteen bitter acids were successfully identified under optimized separation conditions. Validation, encompassing parameters such as LOD (from 0.028 ppm for isorhamnetin to 0.106 for narirutin), LOQ (from 0.077 ppm for naringenin to 0.355 for narirutin), R 2 (always more than 0.9992), repeatability (from 0.67% for tangeretin to 6.38% for myricetin), and reproducibility (from 0.99% for sinensetin to 6% for naringin), was conducted for polyphenol quantification using constructed calibration curves with seven levels. Exploring polyphenolic components as potential discriminators among different beer styles, a total of thirty-two polyphenolic compounds were identified and quantified, including characteristic bergamot peel polyphenols like neoeriocitrin (from 7.85 ppm for CBS2 to 11.95 ppm in CBS1); naringin (from 4.56 ppm for CBS4 to 10.96 in CBS1), and neohesperidin (from 5.93 in CBS3 to 15.95 for CBS2). The multivariate analysis provided additional insights into variations among specific beer styles, revealing discrepancies in the presence or relative concentrations of specific compounds linked to brewing ingredients and processes. This research enhances the fingerprinting of the chemistry governing beer quality through a straightforward and cost-effective analytical approach.

Over the last two decades, the use of Next-Generation Sequencing (NGS) in medical oncology has increased the likelihood of identifying druggable mutations that may be potentially susceptible to targeted treatments. The European Society for Medical Oncology (ESMO) currently does not recommend the use of the NGS test to determine the therapeutic course of patients with metastatic breast cancer (mBC) in daily clinical practice. However, the aim of this work is to evaluate the potential contribution of the NGS test in selecting targeted therapies for patients with mBC. Data were retrospectively collected from 101 patients diagnosed with metastatic breast cancer and treated at the Modena Cancer Center between January 2015 and April 2022. A NGS test was performed on the tumor tissue of each patient at the Laboratory of Molecular Pathology of the University Hospital of Modena. This study analyzed the clinical-pathological characteristics and mutational profile of the population using NGS tests, with a focus on actionable mutations that could be targeted in advanced stages of clinical development. The indicator of this study was to quantify the actionable mutations that resulted in a change of cancer treatment. In total, 101 patients with metastatic breast cancer were analyzed, including 86 with luminal phenotype, 10 who were HER2-positive and 5 who were triple-negative. Median age was 52 years. NGS analysis was conducted on 47 samples of primary breast cancer, 52 on metastatic sites of disease and 2 on liquid biopsies. A total of 85 gene mutations were found. The most common mutations were identified in the PIK3CA (47%), FGFR (19%) and ERBB2 genes (12%), and to a lesser extent in other genes. Of the 61 patients with pathogenic mutations, 46 (75%) had at least one actionable mutation. Of these, nine received treatment with a molecular target drug: eight patients with a mutation of the PIK3CA gene were treated with alpelisib and fulvestrant; one patient with FGFR1/2 amplifications received TAS120. Median PFS for these patients was 3.8 months. The study results show that using the NGS test on cancer tissue of metastatic breast cancer could influence the therapeutic choices, considering the small sample size and limited follow-up. About 9% of the study population had their therapy modified based on the results of NGS. The growing number of detectable mutations and increased accessibility of the test may lead to a greater number of potential therapeutic implications for the NGS assay. Perspectives suggest that NGS analysis can be implemented in daily clinical practice, particularly in contexts where a Molecular Tumor Board (MTB) is active.

The adjuvant endocrine therapy (AET) of HR+ EBC has been changing in recent years. Aromatase inhibitors (AIs) as an upfront strategy (or as part of a switch strategy) have been added to the choice of Tamoxifen (T) alone. Increased TE risk is well known in T-treated patients, while AIs have shown a reduced TE rate. By adding the cyclin dependent kinase 4/6 inhibitors (CDK4/6) to AIs, an increase in TE rate has been shown. We conducted this meta-analysis to evaluate the impact of the AETs on TE incidence. Twelve randomized phase III trials were included. Four trials evaluated the upfront strategy, 6 assessed the switch and 2 the combination with a CDK4/6 inhibitor. The new AETs did not significantly modify or affect the rate of TE events (OR 0.847, 95% CI, 0.528-1.366, P = .489). The OR for CDK4/6 inhibitor plus ET vs. ET was 3.635 (P = .002). Excluding the CDK4/6 inhibitors, the overall OR for AIs vs. T was 0.628 (P < .001), while it was 0.781 (P = .151) for switching T vs. continuing T for 5 years, and 0.52 (P < .0001) for the upfront strategies with AIs. The AIs alone or plus CDK4/6 inhibitors did not affect the rate of TE events. AIs as an upfront strategy is the safest AET, associated with the lowest TE incidence. The switch strategy increases TE rate, whereas the addition of CDK4/6 to the standard AET was shown to significantly increase TE events. The results of the currently ongoing trials with CDK4/6 inhibitors will help obtain additional data to evaluate any differences among the different CDK4/6 inhibitors and clarify the weight of TE adverse events in the benefit/risk balance of this new adjuvant strategy., Competing Interests: Disclosure LM, AT have served as a member of an advisory board and received personal fees and travel grants from Pfizer and Eli Lilly. LC has served as consultant, member of an advisory board and received personal fees and travel grants from Pfizer CM and FP received personal fees and travel grants from Pfizer and Eli Lilly. EB and MB received travel grants from Eli Lilly. IS, RD, FC and MD did not declare competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Breast cancer (BC) is the most common women cancer and cause of cancer death. Despite decades of scientific progress in BC treatments, the clinical benefit of new drugs is modest in several cases. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway mutations are frequent in BC (20-40%) and are significant causes of aggressive tumor behavior, as well as treatment resistance. Improving knowledge of the PI3K/AKT/mTOR pathway is an urgent need. This review aims to highlight the central role of PI3K-mTORC1/C2 mutations in the different BC subtypes, in terms of clinical outcomes and treatment efficacy. The broad base of knowledge in tumor biology is a key point for personalized BC therapy in the precision medicine era.

Background: The generation of data capturing the risk-benefit ratio of incorporating carboplatin (Cb) to neoadjuvant chemotherapy (NACT) for triple-negative breast cancer (TNBC) in a clinical practice setting is urgently needed. Tumour-infiltrating lymphocytes (TILs) have an established role in TNBC receiving NACT, however, the role of TIL dynamics under NACT exposure in patients receiving the current standard of care is largely uncharted., Methods: Consecutive TNBC patients receiving anthracycline-taxane [A-T] +/- Cb NACT at three Institutions were enrolled. Stromal-TILs were evaluated on pre-NACT and residual disease (RD) specimens. In the clinical cohort, propensity-score-matching was used to control selection bias., Results: In total, 247 patients were included (A-T = 40.5%, A-TCb = 59.5%). After propensity-score-matching, pCR was significantly higher for A-TCb vs A-T (51.9% vs 34.2%, multivariate: OR = 2.40, P = 0.01). No differences in grade ≥3 haematological toxicities were observed. TILs increased from baseline to RD in the overall population and across A-T/A-TCb subgroups. TIL increase from baseline to RD was positively and independently associated with distant disease-free survival (multivariate: HR = 0.43, P = 0.05)., Conclusions: We confirmed in a clinical practice setting of TNBC patients receiving A-T NACT that the incorporation of weekly Cb significantly improved pCR. In addition, A-T +/- Cb enhanced immune infiltration from baseline to RD. Finally, we reported a positive independent prognostic role of TIL increase after NACT exposure., (© 2022. The Author(s).)

Pomegranate use is increasing worldwide, as it is considered a tasteful healthy food. It is mainly used as fruit, juice, and jam. The pomegranate peel represents about 40-50% of the total fruit weight and contains numerous and diverse bioactive substances. The aim of this research was to analyze the pomegranate peel chemical composition of Wonderful cultivated in Southern Italy and treated with an innovative physic dry concentration procedure in comparison with the peel composition of freeze-dried Wonderful cultivated in Southern Italy, freeze-dried Wonderful cultivated in South Africa, and freeze-dried pomegranate cultivated in India. The specific aim was to verify how much the growth area, cultivar type, and dry procedure influenced the chemical composition of the peels in terms of valuable bioactive compounds. Spectrophotometric and HPLC identification methods were used to detect antioxidants, antioxidant activities, and phenolic and flavonoid components. Results evidenced that in pomegranate peels of Wonderful cultivated in Calabria and dried with the innovative process, total phenolic substances, total flavonoids, vitamin C, vitamin E, and antioxidant activities were the highest. Great amounts of single phenolic acids and flavonoids were found in Calabrian Wonderful peels dried with the innovative process. Overall, it emerged that a great amount of bioactive and diverse compounds found in Calabrian Wonderful pomegranate peel comes from the niche pedoclimatic conditions, and the physic drying innovative methodology turned out to be an advantageous procedure to concentrate and conserve biocompounds.

Endocrine therapy (ET), associated with CDK 4/6 inhibitors, represents the first choice of treatment for HR+/HER2- metastatic breast cancer (mBC). Primary or secondary endocrine resistance could develop; however validated biomarkers capable of predicting such a conditions are not available. Several studies have shown that HR+/HER2- mBC comprises five intrinsic subtypes. The purpose of this systematic review was to analyze the potential correlations between intrinsic subtype, efficacy of treatment, and patient outcome. Five papers that analyzed the intrinsic subtype with PAM50 assay in patients (pts) with HR+/HER2- mBC treated with ET (alone or in combination) within seven phase III clinical trials (EGF30008, BOLERO-2, PALOMA-2,3, MONALEESA-2,3,7) were identified. Non-luminal subtypes are more frequent in endocrine-resistant pts and in metastatic sites (vs. primary tumors), have less benefit from ET, and worse prognosis. Among these, HER2-enriched subtypes are similar to HER2+ tumors and benefit from the addition of anti-HER2 agents (lapatinib) and, for less clear reasons, of ribociclib (unconfirmed data for palbociclib and everolimus). Basal-like subtypes are similar to triple-negative tumors, making them more sensitive to chemotherapy. The intrinsic subtype is also not static but can vary over time with the evolution of the disease. Currently, the intrinsic subtype does not play a decisive role in the choice of treatment in clinical practice, but has potential prognostic and predictive value that should be further investigated.

Background: Current guidelines consider T-DM1 the standard 2 nd line therapy for HER2 positive metastatic breast cancer (MBC) patients following trastuzumab (T) + pertuzumab (P) and taxane 1 st line treatment. Despite this, there are no prospective studies supporting this sequence., Methods: We performed a meta-analysis using real world data to determine the efficacy of T-DM1 after 1 st line TP in HER2 positive MBC patients. We used a random-effect model to find differences in the rate of 1-year progression free survival (PFS) between TP pre-treated population and the EMILIA phase III pivotal trial., Results: Seven studies were eligible. The meta-analysis showed a combined 1-year PFS risk difference for T-DM1 efficacy after TP in 2 nd or more lines of -0.122, with lower and upper limits of -0.253 and 0.010, respectively (p = 0.07), with low heterogeneity among studies (I 2 0.01%, p = 0.836). Considering the four studies on T-DM1 in 2 nd line setting, 1-year PFS risk was -0.034 (95% CI -0.207 - 0,139; p = 0.701) (I 2 0.01%, p = 0.91)., Conclusion: Overall, the efficacy of T-DM1 after TP seems to be similar to that previously reported in the EMILIA trial. In the second line setting, data are not mature enough to confirm T-DM1 efficacy in TP pre-treated population., (© 2022. The Author(s).)

Ocular adverse events are common to many antineoplastic agents, although often misunderstood. In most cases, they are easily manageable, but sometimes they require instrumental diagnostics and specific treatments. There are currently no international guidelines for the management of these toxicities. In this review we summarized the main ocular adverse events related to the antineoplastic agents used in the treatment of breast cancer, analyzing their clinical presentation and management, trying to provide a useful tool to be used in clinical practice., Competing Interests: Disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject discussed in the manuscript., (Copyright © 2022. Published by Elsevier Inc.)

Immune-related myasthenia gravis is a rare, disabling, and potentially fatal adverse event of immune checkpoint inhibitor treatment. It is important to identify and manage it promptly. We present two cases of immune-related de novo myasthenia gravis observed at the Modena Cancer Center in two elderly patients treated with two anti-PD-1 monoclonal antibodies: cemiplimab and nivolumab.

Background: Few data about the link between nutritional status and survival are available in the metastatic gastric cancer (GC) setting. The aim of this work was to evaluate the prognostic role of tissue modifications during treatment and the benefit of a scheduled nutritional assessment in this setting., Methods: Clinical and laboratory variables of 40 metastatic GC patients treated at Modena Cancer Center were retrieved: 20 received a nutritional assessment on the oncology's discretion, the other 20 received a scheduled nutritional assessment at baseline and every 2-4 weeks. Anthropometric parameters were calculated on Computed Tomography (CT) images at the baseline and after 3 months of chemotherapy., Results: A correlation between baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS), Lymphocyte to Monocyte Ratio (LMR), C-reactive protein (PCR), Prognostic Nutritional Index (PNI) and Overall survival (OS) was highlighted. Among the anthropometric parameters, early skeletal muscle mass depletion (ESMMD) >10% in the first months of treatment significantly impacted on mOS ( p = 0.0023). A link between ESMMD and baseline LDH > 460 U/L, baseline CRP > 2.2 mg/dL and weight decrease during treatment emerged. Patients evaluated with a nutritional scheduled support experienced a mean gain in subcutaneous and visceral fat of 11.4% and 10.21%, respectively., Conclusion: We confirm the prognostic impact of ESMMD > 10% during chemotherapy in metastatic GC. The prognostic role of a scheduled nutritional assessment deserves further confirmation in large prospective trials.

Lipopolysaccharide (LPS) from gram negative bacteria has been shown to prime human polymorphonuclear neutrophil (PMN) production of platelet activating factor (PAF). PAF is a lipid mediator of inflammation and endotoxic shock and is also involved in leukocyte activation occurring during hemodialysis; PAF induces leukopenia, degranulation of lysosomal granules, and adherence to hemodialysis membranes. Transmembrane passage of LPS has also been shown to occur. To evaluate the relevance of transmembrane passage of LPS on the priming of PMN derived production of PAF, we designed in vitro studies using an experimental circuit equipped with different membranes (Cuprophan, polysulfone, polymethylmethacrylate, polyamide) and recirculation of purified human PMNs. At different time intervals, PMNs were stimulated with FMLP (10 microM) after back-filtration of sterile and LPS contaminated dialysate. The results of these studies suggest that priming of PMN derived production of PAF was related to the percent of backfiltered LPS, and they emphasize the need for careful assessment of microbiologic quality to improve biocompatibility.

A complex array of inflammatory mediators are generated as a consequence of blood contact with hemodialysis (HD) membranes. Beside complement activation, other mediators are involved in cell activation, and are thought possibly to be responsible for early and long-term multiple changes in immunity infection, hypercatabolism, beta 2-microglobulin generation and hemostatic mechanisms. Previous studies from our laboratories have established platelet activating factor (PAF) as one of the mediators generated by complement-dependent or independent mechanisms of cell interaction with hemodialysis membranes. Recent studies on the production of PAF from endotoxin-primed polymorphonuclear neutrophils in a closed miniaturized circuit, and on the effect of PAF in mediating endotoxin- and cytokine-induced leukocyte adherence to HD membranes, highlight so far undescribed new roles of this mediator in biocompatibility.

BK-PMMA 2.1 m2 surface dialysers were used in vivo and in vitro for evaluation of their capacity for beta 2-M removal by both adsorption and elimination through the membrane. As expected, in vivo, beta 2-M plasma concentrations were more effectively reduced when the dialyser was used in haemofiltration, rather than in haemodialysis. However, the mass recovered in the ultrafiltrate could not account for the observed difference in beta 2-M removal. In vitro tests demonstrated that membrane adsorption of beta 2-M is greater when the dialyser is used in convection than in diffusion. Therefore, the greater beta 2-M removal during haemofiltration depends on both increased adsorption and membrane elimination by convection. Thanks to adsorption, beta 2-M removal by haemodialysis was greater than for other synthetic membranes, but was insufficient to obtain beta 2-M removal corresponding to the estimated generation.