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Bile leak is a rare complication after Laparoscopic Cholecystectomy. Subvesical bile duct (SVBD) injury is the second cause of minor bile leak, following the unsuccessful clipping of the cystic duct stump. The aim of this study is to pool available data on this type of biliary tree anatomical variation to summarize incidence of injury, methods used to diagnose and treat SVBD leaks after LC. Articles published between 1985 and 2021 describing SVBD evidence in patients operated on LC for gallstone disease, were included. Data were divided into two groups based on the intra or post-operative evidence of bile leak from SVBD after surgery. This systematic report includes 68 articles for a total of 231 patients. A total of 195 patients with symptomatic postoperative bile leak are included in Group 1, while Group 2 includes 36 patients describing SVBD visualized and managed during LC. Outcomes of interest were diagnosis, clinical presentation, treatment, and outcomes. The management of minor bile leak is controversial. In most of cases diagnosed postoperatevely, Endoscopic Retrograde Cholangio-Pancreatography (ERCP) is the best way to treat this complication. Surgery should be considered when endoscopic or radiological approaches are not resolutive.

The intricate behavior of particle acceleration and transport mechanisms complicates the overall efforts in formulating a comprehensive understanding of solar energetic particle (SEP) events; these efforts include observations of low-energy particles (from tens of keV to hundreds of MeV) by space-borne instruments and measurements by the ground-based neutron monitors of the secondary particles generated in the Earth atmosphere by SEPs in the GeV range. Numerous space-borne missions provided good data on the nature/characteristics of these solar particles in past solar cycles, but more recently—concurrently with the rise toward the maximum of solar cycle 25—the High-Energy Particle Detector (HEPD-01) proved to be well suited for the study of solar physics and space weather. Its nominal 30–300 MeV energy range for protons can enlarge the detection capabilities of solar particles at low Earth orbit, closer to the injection limit of many SEP events. In this work, we characterize three SEP events within the first six months of 2022 through spectral and velocity dispersion analysis, assessing the response of HEPD-01 to >M1 events.

Time-dependent energy spectra of galactic cosmic rays (GCRs) carry crucial information regarding their origin and propagation throughout the interstellar environment. When observed at the Earth, after traversing the interplanetary medium, such spectra are heavily affected by the solar wind and the embedded solar magnetic field permeating the inner sectors of the heliosphere. The activity of the Sun changes significantly over an 11 yr solar cycle—and so does the effect on cosmic particles; this translates into a phenomenon called solar modulation. Moreover, GCR spectra during different epochs of solar activity provide invaluable information for a complete understanding of the plethora of mechanisms taking place in various layers of the Sun’s atmosphere and how they evolve over time. The High-Energy Particle Detector (HEPD-01) has been continuously collecting data since 2018 August, during the quiet phase between solar cycles 24 and 25; the activity of the Sun is slowly but steadily rising and is expected to peak around 2025/2026. In this paper, we present the first spectra for ∼50–250 MeV galactic protons measured by the HEPD-01 instrument—placed on board the CSES-01 satellite—from 2018 August to 2022 March over a one-Carrington-rotation time basis. Such data are compared to the ones from other spaceborne experiments, present (e.g., EPHIN, Parker Solar Probe) and past (PAMELA), and to a state-of-the-art three-dimensional model describing the GCRs propagation through the heliosphere.

High-energy, long gamma-ray bursts (GRBs) can be generated by the core collapse of massive stars at the end of their lives. When they happen in the close-by universe they can be exceptionally bright, as seen from the Earth in the case of the recent, giant, long-lasting GRB221009A. GRB221009A was produced by a collapsing star with a redshift of 0.152: this event was observed by many gamma-ray space experiments, which also detected an extraordinary long gamma-ray afterglow. The exceptionally large fluence of the prompt emission of about 0.013 erg cm ^−2 illuminated a large geographical region centered on India and including Europe and Asia. We report in this paper the observation of sudden electron flux changes correlated with GRB221009A and measured by the HEPP-L charged particle detector on board the China Seismo-Electromagnetic Satellite, which was orbiting over Europe at the time of the GRB event. The time structure of the observed electron flux closely matches the very distinctive time dependence of the photon flux associated with the main part of the emission at around 13:20 UTC on 2022 October 9. To test the origin of these signals, we set up a simplified simulation of one HEPP-L subdetector: the results of this analysis suggest that the signals observed are mostly due to electrons created within the aluminum collimator surrounding the silicon detector, providing real-time monitoring of the very intense photon fluxes. We discuss the implications of this observation for existing and forthcoming particle detectors on low Earth orbits.

Resumen: Introducción y objetivos: La estrategia watch and wait (WW) es una alternativa a la resección anterior (RA) en pacientes con cáncer de recto (CR), con respuesta clínica completa a la neoadyuvancia. Existen pocos reportes que describan la calidad de vida (CV) y los trastornos funcionales anorrectales (TFA) en esta población. Objetivo: Analizar y comparar los TFA y la CV en pacientes con adenocarcinoma de recto localmente avanzados tratados con neoadyuvancia con diferentes estrategias: grupo 1 (G1): WW y grupo 2 (G2): RA. Material y métodos: Se incluyeron 30 pacientes (G1: n = 20 y G2: n = 10) que cumplieron al menos 12 meses de finalizado el tratamiento neoadyuvante, edad mediana de 59.5 años (rango: 41-79), 15 son hombres. Los TFA fueron evaluados con: a) historia clínica, b) diario de continencia anal de 21 días, c) escala de continencia anal de Jorge y Wexner, d) manometría anorrectal (MAR) y la CV con el cuestionario de incontinencia fecal (FIQL). Resultados: Diario de continencia anal: G1: incontinencia fecal (40%) y urgencia defecatoria (45%) vs. G2 incontinencia fecal (60%) y urgencia defecatoria (30%), sin diferencias significativas (p = NS). Escala de continencia anal: la incontinencia fecal de G1 fue significativamente menos severa que la de G2 [mediana 6.5 puntos vs. 13 puntos; (p = 0.0142)]. MAR: sin diferencias entre los grupos. CV: es significativamente diferente entre ambos grupos (FIQL/G1: 3.7 vs. FIQL/G2: 2.8; p < 0.03). Conclusiones: La estrategia de seguimiento WW en pacientes con CR localmente avanzado estaría asociada con una mejor CV y menor incontinencia fecal. Abstract: Introduction: The watch-and-wait (WW) strategy is an alternative to anterior resection in patients with rectal cancer (RC) that have had a complete clinical response to neoadjuvant treatment. Few reports describe the quality of life and functional anorectal disorders (FADs) in that population. Aim: To analyze and compare the FADs and quality of life in patients with locally advanced adenocarcinoma of the rectum treated with neoadjuvant therapy, divided into two different strategy groups: group 1 (G1), WW; and group 2 (G2), anterior resection. Materials and methods: Thirty patients (G1: n = 20 and G2: n = 10) that had finished neoadjuvant therapy at least 12 months prior were included. Mean patient age was 59.5 years (range: 41-79) and 15 of the patients were men. The FADs were evaluated through: a) clinical history, b) 21-day bowel diary, c) Jorge and Wexner fecal incontinence scale, d) anorectal manometry (ARM), and fecal incontinence quality of life scale (FIQL). Results: Bowel diary: fecal incontinence (40%) and urge to defecate (45%) in G1 vs. fecal incontinence (60%) and urge to defecate (30%) in G2, with no significant differences (p = NS). Fecal incontinence scale: fecal incontinence in G1 was significantly less severe than that in G2 (median 6.5 points vs. 13 points [p = 0.0142]). ARM: no differences between the two groups. Quality of life: significantly different between the two groups (FIQL/G1: 3.7 vs. FIQL/G2: 2.8; p < 0.03). Conclusions: The WW follow-up strategy in patients with locally advanced rectal cancer was associated with better quality of life and reduced fecal incontinence.

Introduction: The watch-and-wait (WW) strategy is an alternative to anterior resection in patients with rectal cancer (RC) that have had a complete clinical response to neoadjuvant treatment. Few reports describe the quality of life and functional anorectal disorders (FADs) in that population. Aim: To analyze and compare the FADs and quality of life in patients with locally advanced adenocarcinoma of the rectum treated with neoadjuvant therapy, divided into two different strategy groups: group 1 (G1), WW; and group 2 (G2), anterior resection. Materials and methods: Thirty patients (G1: n = 20 and G2: n = 10) that had finished neoadjuvant therapy at least 12 months prior were included. Mean patient age was 59.5 years (range: 41-79) and 15 of the patients were men. The FADs were evaluated through: a) clinical history, b) 21-day bowel diary, c) Jorge and Wexner fecal incontinence scale, d) anorectal manometry (ARM), and fecal incontinence quality of life scale (FIQL). Results: Bowel diary: fecal incontinence (40%) and urge to defecate (45%) in G1 vs. fecal incontinence (60%) and urge to defecate (30%) in G2, with no significant differences (p = NS). Fecal incontinence scale: fecal incontinence in G1 was significantly less severe than that in G2 (median 6.5 points vs. 13 points [p = 0.0142]). ARM: no differences between the two groups. Quality of life: significantly different between the two groups (FIQL/G1: 3.7 vs. FIQL/G2: 2.8; p

Abstract Background Transanal dissection of the rectum has been recently introduced for ileal pouch-anal anastomosis (IPAA) in UC showing promising results. Thanks to the precise identification of the rectotomy site the risk of long rectal stump is avoided, and a single stapled anastomosis is performed easily. The aim of this study is to analyze our initial experience of transanal proctocolectomy and ileal pouch-anal anastomosis (TaIPAA), considering postoperative complications and medium-term functional outcomes. Methods Our Center has experienced the transanal approach for proctectomy and IPAA since August 2018. All patients underwent Enhanced Recovery After Surgery (ERAS) protocol. Postoperative complications occurring within 30 days after surgery were taken into consideration. Fecal continence, genito-urinary activity and global quality of life at 1 and 6 months after ileostomy reversal have been assessed. Results Until March 2019, 8 patients underwent transanal proctocolectomy and ileal pouch-anal anastomosis (TaIPAA). In all cases the laparoscopic approach was performed during the transabdominal phase; abdominal drainage was never used. At the time of the pouch construction a defunctioning loop ileostomy was created in all patients. Stoma closure was performed in all cases at a median time of 6 months after surgery. Postoperative complications occurred in only one patient, who showed rectal bleeding, not required a re-invertation. There were no cases of anastomotic leakage. Medium-term functional outcomes were determined prospectively using previously validated quality of life questionnaires (Cleveland Global Quality of Life). Fecal incontinence for liquid or solid stool, genitourinary and sexual functions were also investigated, showing comparable results with the literature data. Conclusions In our experience, transanal proctocolectomy and ileal pouch-anal anastomosis provided good short and medium-term functional results in UC.

In this paper we report the detection of five strong gamma-ray bursts (GRBs) by the High-Energy Particle Detector (HEPD-01) mounted on board the China Seismo-Electromagnetic Satellite, operational since 2018 on a Sun-synchronous polar orbit at a ∼507 km altitude and 97° inclination. HEPD-01 was designed to detect high-energy electrons in the energy range 3–100 MeV, protons in the range 30–300 MeV, and light nuclei in the range 30–300 MeV n ^−1 . Nonetheless, Monte Carlo simulations have shown HEPD-01 is sensitive to gamma-ray photons in the energy range 300 keV–50 MeV, even if with a moderate effective area above ∼5 MeV. A dedicated time correlation analysis between GRBs reported in literature and signals from a set of HEPD-01 trigger configuration masks has confirmed the anticipated detector sensitivity to high-energy photons. A comparison between the simultaneous time profiles of HEPD-01 electron fluxes and photons from GRB190114C, GRB190305A, GRB190928A, GRB200826B, and GRB211211A has shown a remarkable similarity, in spite of the different energy ranges. The high-energy response, with peak sensitivity at about 2 MeV, and moderate effective area of the detector in the actual flight configuration explain why these five GRBs, characterized by a fluence above ∼3 × 10 ^−5 erg cm ^−2 in the energy interval 300 keV–50 MeV, have been detected.

The aim of this study was to describe the processes that control humic carbon sequestration in soil. Three experimental sites differing in terms of management system and climate were selected: (i) Abanilla-Spain, soil treated with municipal solid wastes in Mediterranean semiarid climate; (ii) Puch-Germany, soil under intensive tillage and conventional agriculture in continental climate; and (iii) Alberese-Italy, soil under organic and conventional agriculture in Mediterranean subarid climate. The chemical-structural and biochemical soil properties at the initial sampling time and one year later were evaluated. The soils under organic (Alberese, soil cultivated with Triticum durum Desf.) and nonintensive management practices (Puch, soil cultivated with Triticum aestivum L. and Avena sativa L.) showed higher enzymatically active humic carbon, total organic carbon, humification index (B/E3s), and metabolic potential (dehydrogenase activity/water soluble carbon) if compared with conventional agriculture and plough-based tillage, respectively. In Abanilla, the application of municipal solid wastes stimulated the specific β-glucosidase activity (extracellular β-glucosidase activity/extractable humic carbon) and promoted the increase of humic substances with respect to untreated soil. The evolution of the chemical and biochemical status of the soils along a climatic gradient suggested that the adoption of certain management practices could be very promising in increasing SOC sequestration potential.

Fractures of the lateral condyle of the humerus are one of the most common fractures in children, accounting for between 10% and 20% of fractures involving the elbow, with a peak incidence at 6 years of age. Treatment is often surgical for displaced fractures > 2 mm, according to Milch and Jakob classification. There is no consensus in the literature about the appropriate surgical management of these fractures. Objectives : The aim of this study is to describe, propose, and evaluate outcomes and complications of the surgical technique of reduction and osteosynthesis using trans-bone suture with resorbable threads. Methods : Patients with lateral condyle fractures treated with this surgical technique from 2015 to 2019 were included in this retrospective study, with a minimum follow-up of 24 months. For clinical and functional assessment of the elbow, Mayo Elbow Scores were recorded; we assessed the time of fracture healing, carrying angles, and Baumann angle of the affected limb compared to the healthy contralateral elbow for radiographic data. Complications have also been described. Results : We achieved satisfactory results; 36 patients with lateral condyle fractures were included in this study. Radiological healing was achieved in all cases. There was only one complication. No cases required additional surgical procedures. Almost all patients achieved a complete flexion of 110 degrees or more and complete extension. Conclusions : This surgical technique has good functional outcomes and fracture healing, a lower incidence of complications when compared to other surgical techniques, and no mechanical failure with good clinical and radiological results.

Aberrant cyclin-dependent kinase 2 (CDK2) activation has been identified as a main resistance mechanism to CDK4/6 inhibition in hormone-receptor positive (HR+) breast cancer. Additionally, consistent preclinical evidence states its crucial role in MYC and CCNE1 overexpressed cancer survival, such as triple-negative breast cancers (TNBC), thus representing an appealing and relatively unexplored target treatment opportunity. Despite emerging initial results of novel CDK2 inhibitors (CDK2i) activity, a comprehensive outcomes collection is currently absent from the scientific literature. We aim to provide an overview of ongoing clinical trials involving CDK2i in the context of metastatic breast cancer (mBC), either as monotherapy or in combination with other agents. The review extends beyond CDK2i to encompass novel emerging CDK4 inhibitors, combined CDK2/4/6 inhibitors, and the well-known pan-CDK inhibitors including those specifically directed at CDK2. Delving into the results, we critically appraise the observed clinical efficacy and offer valuable insights into their potential impact and future applications., Competing Interests: Declaration of Competing Interest Armando Santoro: Advisory Board: Bristol-Myers Squibb (BMS), Servier, Gilead, Pfizer, Eisai, Bayer, Merck Sharp & Dohme (MSD). Consultancy: Arqule, Sanofi, Incyte. Speaker’s Bureau: Takeda, BMS, Roche, Abb-Vie, Amgen, Celgene, Servier, Gilead, Astrazeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer, MSD (all outside the submitted work); Alberto Zambelli has received personal fees and non-financial support from Novartis, AstraZeneca, Lilly, Pfizer, Daiichi Sankyo, MDS Merck Sharp&Dome, Roche, Seagen, Exact Sciences, Gilaed, Istituto Gentili; Rosalba Torrisi has received funding from Astra Zeneca, Pfizer, Eli Lilly, Exact Sciences and MSD; Rita De Sanctis honoraria for advisory board consultancy from Novartis, Istituto Clinico Gentili, Amgen, EISAI, Lilly and Gilead (all outside the present work). The other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Based on the unprecedented results observed in recent clinical trials, antibody-drug conjugates (ADCs) have revolutionized the treatment algorithm of metastatic breast cancer (mBC). The strategy of sequencing different ADCs in other lines of therapy is highly attractive, but the proportion of patients who have undergone such a strategy in the context of published clinical trials is still limited, especially for modern ADCs. HER2-positive disease is primarily managed with a sequence of different ADCs. Historically, trastuzumab emtansine (T-DM1) has been the most commonly used ADC for both early and metastatic HER2-positive disease. Considering the recent evidence related to trastuzumab deruxtecan (T-DXd), it is expected to assume the role of the main ADC in our clinical practice. Herein, we report a retrospective analysis of the sequence of different ADCs relying on available published data from clinical trials.

We investigated whether we could identify a panel of miRNAs associated with response to treatment in tumor tissues of patients with Hormone Receptor-positive/HER2-negative metastatic breast cancer treated with endocrine therapy (ET) and the CDK4/6 inhibitor (CDK4/6i)i palbociclib. In total, 52 patients were evaluated, with 41 receiving treatment as the first line. The overall median PFS was 20.8 months (range 2.5-66.6). In total, 23% of patients experienced early progression (<6 months). Seven miRNAs ( miR-378e , miR-1233 , miR-99b-5p , miR-1260b , miR-448 , -miR-1252-5p , miR-324-3p , miR-1233-3p ) showed a statistically significant negative association with PFS. When we considered PFS < 6 months, miR-378e , miR-99b-5p , miR-877-5p , miR-1297 , miR-455-5p , and miR-4536-5p were statistically associated with a poor outcome. In the multivariate analysis, the first three miRNAs confirmed a significant and independent impact on PFS. The literature data and bioinformatic tools provide an underlying molecular rationale for most of these miRNAs, mainly involving the PI3K/AKT/mTOR pathway and cell-cycle machinery as cyclin D1, CDKN1B, and protein p27 Kip1 and autophagy. Our findings propose a novel panel of miRNAs associated with a higher likelihood of early progression in patients treated with ET and Palbociclib and may contribute to shed some light on the mechanisms of de novo resistance to CDK4/6i, but this should be considered exploratory and evaluated in larger cohorts.

Supracondylar fractures of the humerus are frequent paediatric injuries. The aims of this study were to evaluate the applicability and reproducibility of the Gartland and Wilkins classification, the Baumann angle (BA) and the Anterior Humeral Line (AHL). This retrospective monocentric observational study was conducted on 217 patients. Four observers assessed the pre-operative radiographs by applying the Gartland and Wilkins classification and the post-operative X-rays by measuring the BA and AHL. The kappa coefficient (K) and the Cohen's kappa were used for the reliability of the Gartland classification; the Intraclass Correlation Coefficient (ICC) for that of the BA. The AHL was evaluated in a double manner by using first the K and the Cohen's kappa and then the ICC. A total of 186 patients were eligible. Inter-observer reliability for the Gartland classification was K = 0.73-0.61 for type III, 0.65-0.61 for type Ia and 0.43-0.26 for type IIb. The Baumann angle mean value in the first data collection was 73.5 ± 6.85 (inter-observer ICC 0.74) and 72.9 ± 6.83 (inter-observer ICC 0.77) for the second data collection; AHL: inter-observer ICC 0.87 for the first evaluation and 0.80 for the second one. Gartland's classification modified by Wilkins has a high degree of reliability. BA and AHL appear reproducible and reliable.

(1) Background: Venous thromboembolism (VTE) is a frequent complication in ambulatory lung cancer patients during chemotherapy and is associated with increased mortality. (2) Methods: We analyzed 568 newly diagnosed metastatic lung cancer patients prospectively enrolled in the HYPERCAN study. Blood samples collected before chemotherapy were tested for thrombin generation (TG) and a panel of hemostatic biomarkers. The Khorana risk score (KRS), new-Vienna CATS, PROTECHT, and CONKO risk assessment models (RAMs) were applied. (3) Results: Within 6 months, the cumulative incidences of VTE and mortality were 12% and 29%, respectively. Patients with VTE showed significantly increased levels of D-dimer, FVIII, prothrombin fragment 1 + 2, and TG. D-dimer and ECOG performance status were identified as independent risk factors for VTE and mortality by multivariable analysis and utilized to generate a risk score that provided a cumulative incidence of VTE of 6% vs. 25%, death of 19% vs. 55%, and in the low- vs. high-risk group, respectively ( p < 0.001). While all published RAMs significantly stratified patients for risk of death, only the CATS and CONKO were able to stratify patients for VTE. (4) Conclusions: A new prediction model was generated to stratify lung cancer patients for VTE and mortality risk, where other published RAMs failed.

Background: Risk assessment models (RAMs) are relevant approaches to identify cancer outpatients at high risk of venous thromboembolism (VTE). Among the proposed RAMs, the Khorana (KRS) and the new-Vienna CATS risk scores have been externally validated in ambulatory patients with cancer., Objectives: To test KRS and new-Vienna CATS scores in 6-month VTE prediction and mortality in a large prospective cohort of metastatic cancer outpatients during chemotherapy., Patients/methods: Newly diagnosed patients with metastatic non-small cell lung, colorectal, gastric, or breast cancers were analyzed (n = 1286). The cumulative incidence of objectively confirmed VTE was estimated with death as a competing risk and multivariate Fine and Gray regression., Results: Within 6 months, 120 VTE events (9.7%) occurred. The KRS and the new-Vienna CATS scores showed comparable c-stat. Stratification by KRS provided VTE cumulative incidences of 6.2%, 11.4%, and 11.5% in the low-, intermediate-, and high-risk categories, respectively (p = ns), and of 8.5% vs. 11.8% (p = ns) in the low- vs. high-risk group by the single 2-point cut-off value stratification. Using a pre-defined 60-point cut-off by the new-Vienna CATS score, 6.6% and 12.2% cumulative incidences were obtained in the low- and high-risk groups, respectively (p < 0.001). Furthermore, having a KRS ≥2 = or a new-Vienna CATS score >60 points was also an independent risk factor for mortality., Conclusion: In our cohort, the 2 RAMs showed a comparable discriminating potential; however, after the application of cut-off values, the new-Vienna CATS score provided statistically significant stratification for VTE. Both RAMs proved to be effective in identifying patients at increased risk of mortality., Competing Interests: Declaration of competing interests All authors declare that they have no potential conflicts of interest related to this research., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Aims: Anthracyclines are the chemotherapeutic agents most frequently associated with cardiotoxicity, while remaining widely used. Different neurohormonal blockers have been tested as a primary prevention strategy to prevent or attenuate the onset of cardiotoxicity, with mixed results. However, prior studies were often limited by a nonblinded design and an assessment of cardiac function based only on echocardiographic imaging. Moreover, on the basis of an improved mechanistic understanding of anthracycline cardiotoxicity mechanisms, new therapeutic strategies have been proposed. Among cardioprotective drugs, nebivolol might be able to prevent the cardiotoxic effects of anthracyclines, through its protective properties towards the myocardium, endothelium, and cardiac mitochondria. This study aims to evaluate the cardioprotective effects of the beta blocker nebivolol in a prospective, placebo-controlled, superiority randomized trial in patients with breast cancer or diffuse large B cell lymphoma (DLBCL) who have a normal cardiac function and will receive anthracyclines as part of their first-line chemotherapy programme., Methods: The CONTROL trial is a randomized, placebo-controlled, double-blinded, superiority trial. Patients with breast cancer or a DLBCL, with a normal cardiac function as assessed by echocardiography, scheduled for treatment with anthracyclines as part of their first-line chemotherapy programme will be randomized 1 : 1 to nebivolol 5 mg once daily (o.d.) or placebo. Patients will be examined with cardiological assessment, echocardiography and cardiac biomarkers at baseline, 1 month, 6 months and 12 months. A cardiac magnetic resonance (CMR) assessment will be performed at baseline and at 12 months. The primary end point is defined as left ventricular ejection fraction reduction assessed by CMR at 12 months of follow-up., Conclusion: The CONTROL trial is designed to provide evidence to assess the cardioprotective role of nebivolol in patients undergoing chemotherapy with anthracyclines., Clinical Trial Registration: The study is registered in the EudraCT registry (number: 2017-004618-24) and in the ClinicalTrials.gov registry (identifier: NCT05728632)., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

This work aims at preparing and characterizing a versatile multifunctional platform enabling the immobilization of macromolecules on a titanium surface by robust covalent grafting. Functionalized titanium is widely used in the biomedical field to improve its properties. Despite its high biocompatibility and osteointegrability, titanium implants are not very stable in the long term due to the onset of inflammation and bacterial infections. The proposed method allows the superficial insertion of three different organic linkers to be used as anchors for the attachment of biopolymers or bioactive molecules. This strategy used green solvents and is a good alternative to the proposed classic methods that employ organic solvents. The uniformly modified surfaces were characterized by micro-Fourier transform infrared spectroscopy (micro-FTIR), X-ray Photoelectron spectroscopy (XPS) and Near-Edge X-ray Absorption Fine Structure (NEXAFS). The latter made it possible to assess the orientation of the linker molecules with respect to the titanium surface. To test the efficiency of the linkers, two polymers (alginate and 2-(dimethylamino)-ethyl methacrylate (PDMAEMA)), with the potential ability to increase biocompatibility, were covalently attached to the titanium surfaces. The obtained results are a good starting point for the realization of stable polymeric coatings permanently bonded to the surface that could be used to extend the life of biomedical implants.

In clinical trials testing abemaciclib in patients with hormone-receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer, diarrhea is a very common adverse event (occurring in approximately 85% of patients, any grade). Nonetheless, this toxicity leads to abemaciclib discontinuation in a small proportion of patients (approximately 2%) thanks to the use of effective loperamide-based supportive therapy. We aimed to determine whether the incidence of abemaciclib-induced diarrhea in real-world trials was higher than the one reported in clinical trials, where patients are highly selected, and to evaluate the success rate of standard supportive care in this setting. We conducted a retrospective, observational, monocentric study including 39 consecutive patients with HR+/HER2- advanced breast cancer treated with abemaciclib and endocrine therapy at our institution from July 2019 to May 2021. Overall, diarrhea of any grade occurred in 36 patients (92%), of whom 6 (17%) had diarrhea of grade ≥3. In 30 patients (77%), diarrhea was associated with other adverse events, including fatigue (33%), neutropenia (33%), emesis (28%), abdominal pain (20%), and hepatotoxicity (13%). Loperamide-based supportive therapy was administered to 26 patients (72%). Abemaciclib dose was reduced in 12 patients (31%) due to diarrhea, and treatment was permanently discontinued in 4 patients (10%). In 58% of patients (15/26), diarrhea was effectively managed with supportive care and did not require abemaciclib dose reduction and/or discontinuation. In our real-world analysis, we observed a higher incidence of diarrhea related to abemaciclib compared to data from clinical trials, and a higher rate of permanent treatment discontinuation due to gastrointestinal toxicity. Better implementation of guideline-based supportive care could help to manage this toxicity.

In this work, we compare nanoaggregation driven by pH-induced micellization (PIM) and by the standard solvent displacement (SD) method on a series of pH-, light-, and thermosensitive amphiphilic block copolymers. Specifically, we investigate poly(HIABMA)- b -poly(OEGMA) and poly(HIABMA)- b -poly(DEGMA- r -OEGMA), where HIABMA = [(hydroxyimino)aldehyde]butyl methacrylate, OEGMA = oligo(ethylene glycol)methyl ether methacrylate, and DEGMA = di(ethylene glycol)methyl ether methacrylate. The weakly acidic HIA group (p K a ≈ 8) imparts stability to micelles at neutral pH, unlike most of the pH-responsive copolymers investigated in the literature. With SD, only some of our copolymers yield polymeric micelles (34-59 nm), and their thermoresponsivity is either poor or altogether absent. In contrast, PIM affords thermoresponsive, smaller micelles (down to 24 nm), regardless of the polymer composition. In some cases, cloud points are remarkably well defined and exhibit limited hysteresis. By combining turbidimetric, dyamic light scattering, and small-angle X-ray scattering measurements, we show that SD yields loose micelles with POEGMA segments partly involved in the formation of the hydrophobic core, whereas PIM yields more compact core-shell micelles with a well-defined PHIABMA core. We conclude that pH-based nanoaggregation provides advantages over block-selective solvation to obtain compact micelles exhibiting well-defined responses to external stimuli.

Background: the tight and reciprocal interaction between cancer and hemostasis has stimulated investigations on the possible role of hemostatic biomarkers in predicting specific cancer outcomes, such as disease progression (DP) and overall survival (OS). In a prospective cohort of newly diagnosed metastatic gastrointestinal (GI) cancer patients from the HYPERCAN study, we aimed to assess whether the hemostatic biomarker levels measured before starting any anticancer therapy may specifically predict for 6-months DP (6m-DP) and for 1-year OS (1y OS). Methods: plasma samples were collected and tested for thrombin generation (TG) as global hemostatic assay, and for D-dimer, fibrinogen, and prothrombin fragment 1 + 2 as hypercoagulation biomarkers. DP and mortality were monitored during follow-up. Results: A prospective cohort of 462 colorectal and 164 gastric cancer patients was available for analysis. After 6 months, DP occurred in 148 patients, providing a cumulative incidence of 24.8% (21.4−28.4). D-dimer and TG endogenous thrombin potential (ETP) were identified as independent risk factors for 6m-DP by multivariate Fine−Gray proportional hazard regression model corrected for age, cancer site, and >1 metastatic site. After 1 year, we observed an OS of 75.7% (71.9−79.0). Multivariate Cox regression analysis corrected for age, site of cancer, and performance status identified D-dimer and ETP as independent risk factors for 1y OS. Patients with one or both hemostatic parameters above the dichotomizing threshold were at higher risk for both 6m-DP and 1-year mortality. Conclusion.: in newly diagnosed metastatic GI cancer patients, pretreatment ETP and D-dimer appear promising candidate biomarkers for predicting 6m-DP and 1y OS. In this setting, for the first time, the role of TG as a prognostic biomarker emerges in a large prospective cohort.

We retrospectively investigated in women treated with fulvestrant for HR+/HER2 negative advanced breast cancer clinical, pathological and molecular features associated with long-term benefit from treatment defined as being progression-free at 18 months. Specifically, we analyzed on formalin-fixed paraffin-embedded tumor samples ESR1 and PI3KCA mutations and miRNAs profiles. 59 patients were evaluable (median age of 67 years, range 32-92). 18-month PFS rate was 27%; the lack of visceral metastases significantly predicted the likelihood of being progression-free at 18 months, while PI3KCA mutations, found in 36% of patients, were not associated with 18-month PFS. As of miRNAs, miR-549a, miR-644a, miR-16-5p were negatively while let-7c-5p was positively associated with 18-month PFS. In addition, miR-520d-3p and miR-548g-3p values were significantly lower while miR-603, miR-181a-5p and miR-199a-miR-199b-3p values were significantly higher in patients achieving 18-month PFS. In silico analysis of targets modulated by these two latter groups of miRNAs show that in patients achieving 18-month PFS the Hippo and Wnt signaling pathways were predicted to be upregulated while endocrine resistance was potentially repressed by miR-603, miR-181a-5p and miR-199a-miR-199b-3p. Our results provide additional clues on the molecular mechanisms involved in fulvestrant activity and resistance. Underlying pathways should be further elucidated and confirmed in larger cohorts., (© 2022. The Author(s).)