Search

Background: The Triglyceride-Glucose Index (TYG) has been proposed as a prognostic index for mortality in the general population, in T2DM, and in patients with cardiovascular diseases. However, data on the respective predictive roles of TYG, glucose tolerance (GT), and metabolic syndrome (MS) for mortality in obesity are lacking., Methods: We analyzed 1359 obese patients (371 men and 988 women), aged 44.1 ± 12.64 years, followed for 14.3 ± 4.44 years. They were subdivided according to glucose tolerance, in normal glucose tolerance (NGT), impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM). We analyzed the risk of death associated with blood glucose (BG) quartiles, TYG quartiles and MS quartiles. Cox proportional-hazard models were used to evaluate the risk of death associated with independent variables that were highly statistically significant at univariate analysis., Results: Different degrees of glucose tolerance were associated with a progressive deterioration of clinical outcomes, and increased all-cause mortality (6.3 %, 10.1 %, and 20.4 %, respectively). In all groups, age and male sex were associated with increased mortality. Higher TYG or TYG quartiles, BG or BG quartiles, and MS or MS quartiles were all associated with increased all-cause mortality in the whole cohort., Conclusion: TYG, blood glucose and MS are risk factors for mortality in obesity, with a progressively stronger value in IFG and T2DM as compared to NGT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Research Trust of DiabetesIndia (DiabetesIndia) and National Diabetes Obesity and Cholesterol Foundation (N-DOC). Published by Elsevier Ltd. All rights reserved.)

Heart failure (HF) often coexists with non-cardiac comorbidities (NCC), but their association with long-term HF re-hospitalizations is not defined. Using the Lombardy Regional Health Database, that includes >10 million residents, we assessed the risk of re-hospitalization for HF after first HF discharge as a function of NCC, employing age- and sex-adjusted Cox proportional-hazard models. Kaplan Meier curves for HF re-hospitalizations were stratified for number of NCC. End of follow-up was June 30th 2021. Between January 1st 2015 to December 31st 2019, 88,528 consecutive patients were discharged from hospital with a primary diagnosis of HF; over 42.8 ± 18.3 months follow-up, 79,533 HF re-hospitalizations occurred (32.94/100 patient/year). Number of NCC, age, and male sex were significantly associated with re-hospitalization risk. Compared to those without NCC, females and males with >4 NCC had a 3.08 (CI 2.73-3.47) and a 2.62 (CI 2.39-2.87) fold higher risk, respectively. Risk of all-cause death increased with number of NCC (hazard ratio (HR): 1.42 (1.38-1.46) for HF patients with 1-2 NCC, HR: 1.90 (1.82-1.98) for patients with 3-4 NCC, HR: 2.20 (2.01-2.40) for those with HF and >4 NCC), as it did the number of days spent in hospital because of HF (from 19.91±19.25 for patients without NCC to 45.35±33.00 days for those with >4 NCC, p < 0.0001). In conclusion, this study shows that in patients hospitalized with HF, HF re-hospitalizations, all-cause mortality, and time spent in hospital increased with number of NCC. NCC associates with a worse clinical trajectory in patients with HF., Competing Interests: Declarations of competing interest The authors have no conflict of interests relative to the content of this study., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Molecular characterization is pivotal for managing non-small cell lung cancer (NSCLC), although this process is often time-consuming and patients' conditions might worsen while molecular analyses are processed. Our primary aim was to evaluate the performance of "up-front" next-generation sequencing (NGS) through liquid biopsy (LB) of hospitalized patients with newly detected lung neoplasm in parallel with conventional diagnosis. The secondary aim included longitudinal monitoring through LB of patients with oncogenic alterations at baseline., Methods: We enrolled 47 consecutive patients immediately after hospitalization and radiological detection of symptomatic lung neoplasm. LB from peripheral blood was performed at baseline, in parallel with conventional biopsy (CB), when feasible. Additionally, LBs were repeated during treatment in patients with actionable gene alterations at baseline. Oncomine™ Lung cfTNA Research Assay panel was employed for processing plasma samples in NGS., Results: 47 hospitalized patients were enrolled. LB identified 28 patients with gene alterations, including mutations of EGFR (n = 7), KRAS (n = 12), ERBB2 (n = 1), TP53 (n = 2), BRAF (n = 1), one ALK rearrangement, and 4 patients with combined mutations involving EGFR, KRAS and PIK3CA. LB and CB were consistent, except for two patients. Three patients with positive LB for oncogenic drivers did not undergo CB due to contraindications. Median time to molecular results after LB was significantly lower compared to time to molecular report after CB (11 versus 22 days, p < 0.001)., Conclusions: Despite limited numbers, our study supports the role of front-line LB for improving management of symptomatic patients with lung cancer, potentially leading to early targeted therapy initiation., Competing Interests: Declaration of competing interest Chiara Dellepiane has received honoraria for consulting activities of Astra Zeneca, Merck Sharp and Dohme, Bristol-Myers-Squibb, Roche. Francesco Spagnolo has been an advisory boards member for MSD, Novartis, Pierre Fabre, Sun Pharma, Philogen and has received lecture fees/honoraria for consulting activities of BMS, MSD, Novartis, Pierre Fabre, Merck, Sanofi, Sun Pharma, IGEA. Matteo Lambertini reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD and Exact Sciences and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Knight and Takeda, Travel Grants from Gilead and Daiichi Sankyo, and research support (to the Institution) from Gilead outside the submitted work. Lucia Del Mastro has received honoraria for consulting activities, speaker bureau or advisory boards from Roche, Novartis, Pfizer, Eli Lilly, Astra Zeneca, Merck-Sharp-Dohme, Seagen, Gilead, Pierre Fabre, Eisai, Exact sciences, Ipsen, GSK, Agendia, Stemline Menarini, Daiichi Sakyo. Carlo Genova has received honoraria for consulting activities, speaker bureau or advisory boards from Astra Zeneca, Bristol-Myers-Squibb, Eli Lilly, Janssen, Merck Sharp and Dohme, Novartis, Roche, Sanofi, Takeda. The other authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Rapid On-Site Evaluation (ROSE) during bronchoscopy allows us to assess sample adequacy for diagnosis and molecular analyses in the context of precision oncology. While extemporaneous smears are typically evaluated by pathologists, their presence during bronchoscopy is not always possible. Our aim is to assess the concordance between ROSE performed by interventional pulmonologists and cytopathologists., Methods: We performed ROSE on 133 samples collected from 108 patients who underwent bronchoscopy for the diagnosis of suspect thoracic findings or for mediastinal lymph node staging (May 2023-October 2023). Randomly selected smears (one for each collection site) were independently evaluated for adequacy by a pulmonologist and a pathologist to assess the concordance of their evaluation., Results: Among 133 selected smears evaluated by a pulmonologist and pathologist, 100 were adequate for both, 10 were inadequate for both and 23 were discordant; hence, global concordance was 82.7%; Cohen's Kappa was 0.385, defining fair agreement. Concordance was similar irrespective of sample collection site (lymph nodes vs. pulmonary lesions; p = 0.999) and among samples which were considered adequate or inadequate by the pulmonologist ( p = 0.608)., Conclusions: Trained pulmonologists can evaluate the appropriateness of sampling with good concordance with cytopathologists. Our work supports autonomous ROSE by pulmonologists where pathologists are not immediately available.

The pandemic of coronavirus disease 19 (COVID-19), caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2), had severe repercussions for breast cancer patients. Increasing evidence indicates that SARS-CoV-2 infection may directly impact breast cancer biology, but the effects of SARS-CoV-2 on breast tumor cells are still unknown. Here, we analyzed the molecular events occurring in the MCF7, MDA-MB-231 and HCC1937 breast cancer cell lines, representative of the luminal A, basal B/claudin-low and basal A subtypes, respectively, upon SARS-CoV-2 infection. Viral replication was monitored over time, and gene expression profiling was conducted. We found that MCF7 cells were the most permissive to viral replication. Treatment of MCF7 cells with Tamoxifen reduced the SARS-CoV-2 replication rate, suggesting an involvement of the estrogen receptor in sustaining virus replication in malignant cells. Interestingly, a metagene signature based on genes upregulated by SARS-CoV-2 infection in all three cell lines distinguished a subgroup of premenopausal luminal A breast cancer patients with a poor prognosis. As SARS-CoV-2 still spreads among the population, it is essential to understand the impact of SARS-CoV-2 infection on breast cancer, particularly in premenopausal patients diagnosed with the luminal A subtype, and to assess the long-term impact of COVID-19 on breast cancer outcomes., (© 2024. The Author(s).)

Purpose: This work presents a novel platform for stereo reconstruction in anterior segment ophthalmic surgery to enable enhanced scene understanding, especially depth perception, for advanced computer-assisted eye surgery by effectively addressing the lack of texture and corneal distortions artifacts in the surgical scene., Methods: The proposed platform for stereo reconstruction uses a two-step approach: generating a sparse 3D point cloud from microscopic images, deriving a dense 3D representation by fitting surfaces onto the point cloud, and considering geometrical priors of the eye anatomy. We incorporate a pre-processing step to rectify distortion artifacts induced by the cornea's high refractive power, achieved by aligning a 3D phenotypical cornea geometry model to the images and computing a distortion map using ray tracing., Results: The accuracy of 3D reconstruction is evaluated on stereo microscopic images of ex vivo porcine eyes, rigid phantom eyes, and synthetic photo-realistic images. The results demonstrate the potential of the proposed platform to enhance scene understanding via an accurate 3D representation of the eye and enable the estimation of instrument to layer distances in porcine eyes with a mean average error of 190  μ m , comparable to the scale of surgeons' hand tremor., Conclusion: This work marks a significant advancement in stereo reconstruction for ophthalmic surgery by addressing corneal distortions, a previously often overlooked aspect in such surgical scenarios. This could improve surgical outcomes by allowing for intra-operative computer assistance, e.g., in the form of virtual distance sensors., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent: This articles does not contain patient data., (© 2024. The Author(s).)

Background: It is amply demonstrated that cigarette smoke (CS) has a high impact on lung tumor progression worsening lung cancer patient prognosis and response to therapies. Alteration of immune cell types and functions in smokers' lungs have been strictly related with smoke detrimental effects. However, the role of CS in dictating an inflammatory or immunosuppressive lung microenvironment still needs to be elucidated. Here, we investigated the effect of in vitro exposure to cigarette smoke extract (CSE) focusing on macrophages., Methods: Immortalized murine macrophages RAW 264.7 cells were cultured in the presence of CS extract and their polarization has been assessed by Real-time PCR and cytofluorimetric analysis, viability has been assessed by SRB assay and 3D-cultures and activation by exposure to Poly(I:C). Moreover, interaction with Lewis lung carcinoma (LLC1) murine cell models in the presence of CS extract were analyzed by confocal microscopy., Results: Obtained results indicate that CS induces macrophages polarization towards the M2 phenotype and M2-phenotype macrophages are resistant to the CS toxic activity. Moreover, CS impairs TLR3-mediated M2-M1 phenotype shift thus contributing to the M2 enrichment in lung smokers., Conclusions: These findings indicate that, in lung cancer microenvironment of smokers, CS can contribute to the M2-phenotype macrophages prevalence by different mechanisms, ultimately, driving an anti-inflammatory, likely immunosuppressive, microenvironment in lung cancer smokers., Competing Interests: the authors have declared that no competing interests exist., (Copyright: © 2024 Bianchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Triple negative breast cancers (TNBC) are characterized by a poor prognosis and a lack of targeted treatments. Their progression depends on tumor cell intrinsic factors, the tumor microenvironment and host characteristics. Although adipocytes, the primary stromal cells of the breast, have been determined to be plastic in physiology and cancer, the tumor-derived molecular mediators of tumor-adipocyte crosstalk have not been identified yet. In this study, we report that the crosstalk between TNBC cells and adipocytes in vitro beyond adipocyte dedifferentiation, induces a unique transcriptional profile that is characterized by inflammation and pathways that are related to interaction with the tumor microenvironment. Accordingly, increased cancer stem-like features and recruitment of pro-tumorigenic immune cells are induced by this crosstalk through CXCL5 and IL-8 production. We identified serum amyloid A1 (SAA1) as a regulator of the adipocyte reprogramming through CD36 and P2XR7 signaling. In human TNBC, SAA1 expression was associated with cancer-associated adipocyte infiltration, inflammation, stimulated lipolysis, stem-like properties, and a distinct tumor immune microenvironment. Our findings constitute evidence that the interaction between tumor cells and adipocytes through the release of SAA1 is relevant to the aggressiveness of TNBC., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Aims: The role of liver steatosis and increased liver enzymes (ALT) in increasing incident type 2 diabetes mellitus (T2DM) is debated, because of their differential effects on different ethnicities and populations. The aim of this study was to evaluate the role of elevated ALT in the development of T2DM in non-diabetic obese subjects receiving routine medical treatment., Methods: A total of 1005 subjects [296 men and 709 women, aged 45.7 ± 13.12 years, body mass index (BMI) 39.5 ± 4.86 kg/m 2 ] were followed for a mean period of 14.3 ± 4.44 years. Subjects were evaluated for several metabolic variables, including the triglyceride-glucose index and the presence of metabolic syndrome (IDF 2005 definition), and were subdivided into ALT quartiles., Results: T2DM developed in 136 subjects, and the difference was significant between the first and the fourth ALT quartile (p = 0.048). Both at univariate analysis and at stepwise regression, ALT quartiles were associated with incident T2DM. Traditional risk factors for T2DM coexisted, with a somehow greater predictive value, such as triglyceride-glucose index, age, arterial hypertension, LDL-cholesterol, and metabolic syndrome., Conclusions: These data suggest an association between elevated ALT levels and the risk of incident T2DM in obesity., (© 2023. The Author(s).)

Background: Ultrasound (US) has demonstrated to be an effective guidance technique for lumbar spine injections, enabling precise needle placement without exposing the surgeon or the patient to ionizing radiation. However, noise and acoustic shadowing artifacts make US data interpretation challenging. To mitigate these problems, many authors suggested using computed tomography (CT)-to-US registration to align the spine in pre-operative CT to intra-operative US data, thus providing localization of spinal landmarks., Purpose: In this paper, we propose a deep learning (DL) pipeline for CT-to-US registration and address the problem of a need for annotated medical data for network training. Firstly, we design a data generation method to generate paired CT-US data where the spine is deformed in a physically consistent manner. Secondly, we train a point cloud (PC) registration network using anatomy-aware losses to enforce anatomically consistent predictions., Methods: Our proposed pipeline relies on training the network on realistic generated data. In our data generation method, we model the properties of the joints and disks between vertebrae based on biomechanical measurements in previous studies. We simulate the supine and prone position deformation by applying forces on the spine models. We choose the spine models from 35 patients in VerSe dataset. Each spine is deformed 10 times to create a noise-free data with ground-truth segmentation at hand. In our experiments, we use one-leave-out cross-validation strategy to measure the performance and the stability of the proposed method. For each experiment, we choose generated PCs from three spines as the test set. From the remaining, data from 3 spines act as the validation set and we use the rest of the data for training the algorithm. To train our network, we introduce anatomy-aware losses and constraints on the movement to match the physics of the spine, namely, rigidity loss and bio-mechanical loss. We define rigidity loss based on the fact that each vertebra can only transform rigidly while the disks and the surrounding tissue are deformable. Second, by using bio-mechanical loss we stop the network from inferring extreme movements by penalizing the force needed to get to a certain pose., Results: To validate the effectiveness of our fully automated data generation pipeline, we qualitatively assess the fidelity of the generated data. This assessment involves verifying the realism of the spinal deformation and subsequently confirming the plausibility of the simulated ultrasound images. Next, we demonstrate that the introduction of the anatomy-aware losses brings us closer to state-of-the-art (SOTA) and yields a reduction of 0.25 mm in terms of target registration error (TRE) compared to using only mean squared error (MSE) loss on the generated dataset. Furthermore, by using the proposed losses, the rigidity loss in inference decreases which shows that the inferred deformation respects the rigidity of the vertebrae and only introduces deformations in the soft tissue area to compensate the difference to the target PC. We also show that our results are close to the SOTA for the simulated US dataset with TRE of 3.89 mm and 3.63 mm for the proposed method and SOTA respectively. In addition, we show that our method is more robust against errors in the initialization in comparison to SOTA and significantly achieves better results (TRE of 4.88 mm compared to 5.66 mm) in this experiment., Conclusions: In conclusion, we present a pipeline for spine CT-to-US registration and explore the potential benefits of utilizing anatomy-aware losses to enhance registration results. Additionally, we propose a fully automatic method to synthesize paired CT-US data with physically consistent deformations, which offers the opportunity to generate extensive datasets for network training. The generated dataset and the source code for data generation and registration pipeline can be accessed via https://github.com/mfazampour/medphys&#95;ct&#95;us&#95;registration., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: While cutaneous melanomas are well-documented, primary melanoma of the lung (PMML), particularly with endobronchial origin, remains rare and poorly characterized. This case report addresses gaps in understanding by presenting a comprehensive case of a 71-year-old male with primary endobronchial melanoma and conducting a systematic review of PMML cases., Case Presentation: The patient, a former smoker, presented with dyspnea, cough, and hemoptysis. Imaging revealed left lung atelectasis and a suspicious nodule. Bronchoscopy identified an endobronchial mass, subsequently treated with argon plasma coagulation and resection. Biopsy confirmed melanoma. Extensive examinations ruled out a primary skin lesion. Despite initial treatment, recurrence led to pneumonectomy. Histopathology confirmed melanoma. The patient received treatment with pembrolizumab and ipilimumab, but with poor clinical benefit., Conclusions: Primary endobronchial melanoma is a rare entity, comprising 0.01% of lung tumors. This case underscores diagnostic challenges and emphasizes histological criteria to distinguish primary from metastatic lesions. The pathogenesis remains unclear, with theories proposing foetal melanocyte migration or squamous metaplasia. Prognosis varies, necessitating radical surgical extirpation. A systematic review revealed diverse outcomes, supporting the need for further research. In conclusion, endobronchial melanoma involves an endoscopic and surgical management, but evolving therapies, such as immunotherapy, may reshape treatment paradigms. This case contributes to our understanding of PMML, guiding future research and clinical management. As therapeutic options evolve, continued research is crucial to refine our understanding and improve outcomes for this rare malignancy., (© 2024. The Author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and has brought a huge burden in terms of human lives. Strict social distance and influenza vaccination have been recommended to avoid co-infections between influenza viruses and SARS-CoV-2. Scattered reports suggested a protective effect of influenza vaccine on COVID-19 development and severity. We analyzed 51 studies on the capacity of influenza vaccination to affect infection with SARS-CoV-2, hospitalization, admission to Intensive Care Units (ICU), and mortality. All subjects taken into consideration did not receive any anti-SARS-CoV-2 vaccine, although their status with respect to previous infections with SARS-CoV-2 is not known. Comparison between vaccinated and not-vaccinated subjects for each of the four endpoints was expressed as odds ratio (OR), with 95% confidence intervals (CIs); all analyses were performed by DerSimonian and Laird model, and Hartung-Knapp model when studies were less than 10. In a total of 61 029 936 subjects from 33 studies, influenza vaccination reduced frequency of SARS-CoV-2 infection [OR plus 95% CI = 0.70 (0.65-0.77)]. The effect was significant in all studies together, in health care workers and in the general population; distance from influenza vaccination and the type of vaccine were also of importance. In 98 174 subjects from 11 studies, frequency of ICU admission was reduced with influenza vaccination [OR (95% CI) = 0.71 (0.54-0.94)]; the effect was significant in all studies together, in pregnant women and in hospitalized subjects. In contrast, in 4 737 328 subjects from 14 studies hospitalization was not modified [OR (95% CI) = 1.05 (0.82-1.35)], and in 4 139 660 subjects from 19 studies, mortality was not modified [OR (95% CI) = 0.76 (0.26-2.20)]. Our study emphasizes the importance of influenza vaccination in the protection against SARS-CoV-2 infection., (© 2023 Wiley Periodicals LLC.)

Emerging evidence suggests a profound association between the microbiota composition in the gastrointestinal tract and breast cancer progression. The gut microbiota plays a crucial role in modulating the immune response, releasing metabolites, and modulating estrogen levels, all of which have implications for breast cancer growth. However, recent research has unveiled a novel aspect of the relationship between the microbiota and breast cancer, focusing on microbes residing within the mammary tissue, which was once considered sterile. These localized microbial communities have been found to change in the presence of a tumor as compared to healthy mammary tissue, unraveling their potential contribution to tumor progression. Studies have identified specific bacterial species that are enriched within breast tumors and have highlighted the mechanisms by which even these microbes influence cancer progression through immune modulation, direct carcinogenic activity, and effects on cellular pathways involved in cell proliferation or apoptosis. This review aims to provide an overview of the current knowledge on the mechanisms of crosstalk between the gut/mammary microbiota and breast cancer. Understanding this intricate interplay holds promise for developing innovative therapeutic approaches.

Background: Few studies have assessed the differences of patterns of Long COVID (L-COVID) with regards to the pathogenetic SARS-CoV-2 strains., Objectives: To investigate the relationship between demographic and clinical characteristics of acute phase of infection and the persistence of L-COVID symptoms and clinical presentation across different SARS-CoV-2 strains., Methods: In this observational-multicenter study we recorded all demographic and clinical characteristics, severity of infection, presence/persistence of symptoms of fatigue, dyspnoea and altered quality of life (QoL) at baseline and after 6 months, in a sample of Italian patients from Liguria between March 2020 and March 2022., Results: 308 patients (mean age 63.2 years; 55.5% men) with previous COVID were enrolled. Obese patients were 21.2% with a significant difference in obesity prevalence across the second and third wave ( p = 0.012). Treatment strategies differed between waves ( p < 0.001): more patients required invasive mechanical ventilation in the first wave, more patients were treated with high-flow nasal cannula/non-invasive ventilation in the in the second and more patients were treated with oxygen-therapy in the fourth wave. At baseline, a high proportion of patients were symptomatic (dyspnoea and fatigue), with impairment in some QoL indicators. A higher prevalence of patients with pain, were seen in the first wave compared to later infections ( p = 0.01). At follow-up, we observed improvement of dyspnoea, fatigue and some dimensions of QoL scale evaluation such as mobility, usual activities, pain evaluations; instead there was no improvement in remaining QoL scale indicators (usual care and anxiety-depression)., Conclusions: There were no significant differences in the prevalence of the most frequent L-COVID symptoms, except for QoL pain domain that was especially associated with classical variant. Our results show substantial impact on social and professional life and usual care activities. These findings highlight the importance of multidisciplinary post COVID follow-up care including mental health support and rehabilitation program.

Purpose: A computer-assisted surgical system must provide up-to-date and accurate information of the patient's anatomy during the procedure to improve clinical outcome. It is therefore essential to consider the tissue deformations, and a patient-specific biomechanical model (PBM) is usually adopted. The predictive capability of the PBM is highly influenced by proper definition of attachments to the surrounding anatomy, which are difficult to estimate preoperatively., Methods: We propose to predict the location of attachments using a deep neural network fed with multiple partial views of the intraoperative deformed organ surface directly encoded as point clouds. Compared to previous works, providing a sequence of deformed views as input allows the network to consider the temporal evolution of deformations and to handle the intrinsic ambiguity of estimating attachments from a single view., Results: The method is applied to computer-assisted hepatic surgery and tested on both a synthetic and in vivo human open-surgery scenario. The network is trained on a patient-specific synthetic dataset in less than 5 h and produces a more accurate intraoperative estimation of attachments than applying the ones generally used in liver surgery (i.e., fixing vena cava or falciform ligament). The obtained results show 26% more accurate predictions than other solution previously proposed., Conclusions: Trained with patient-specific simulated data, the proposed network estimates the attachments in a fast and accurate manner also considering the temporal evolution of the deformations, improving patient-specific intraoperative guidance in computer-assisted surgical systems., (© 2023. The Author(s).)

Purpose: Trastuzumab is an HER2-specific agent approved as the gold-standard therapy for advanced HER2-positive (HER2+) gastric cancer (GC), but the high rate and rapid appearance of resistance limit its clinical efficacy, resulting in the need to identify new vulnerabilities. Defining the drivers influencing HER2+ cancer stem cell (CSC) maintenance/survival could represent a clinically useful strategy to counteract tumor growth and therapy resistance. Accumulating evidence show that targeting crucial metabolic hubs, as the fatty acid synthase (FASN), may be clinically relevant., Methods: FASN protein and transcript expression were examined by WB and FACS and by qRT-PCR and GEP analyses, respectively, in trastuzumab-sensitive and trastuzumab-resistant HER2+ GC cell lines cultured in adherent (2D) or gastrosphere promoting (3D) conditions. Molecular data were analyzed in silico in public HER2+ GC datasets. The effectiveness of the FASN inhibitor TVB3166 to overcome anti-HER2 therapy resistance was tested in vitro in gastrospheres forming efficiency bioassays and in vivo in mice bearing trastuzumab-resistant GC cells., Results: We compared the transcriptome profiles of HER2+ GC cells cultured in 2D versus 3D conditions finding a significant enrichment of FASN in 3D cultures. FASN upregulation significantly correlated with high stemness score and poor prognosis in HER2+ GC cases. TVB3166 treatment significantly decreased GCSCs in all cell targets. HER2 and FASN cotargeting significantly decreased the capability to form gastrospheres versus monotherapy and reduced the in vivo growth of trastuzumab-resistant GC cells., Conclusion: Our findings indicate that cotargeting HER2 and FASN increase the benefit of anti-HER2 therapy representing a new opportunity for metabolically combating trastuzumab-resistant HER2+ GC., (© 2023. The Author(s).)

This study reports on the safety and efficacy of Xen 45 in patients with glaucoma and high myopia. It was a retrospective study including patients with high myopia (>6D) who underwent Xen implant with 2 years of follow-up. The primary outcome was to report the incidence of hypotony (IOP ≤ 5 mmHg) and hypotony-related complications. Patients with high myopia treated with mitomycin-C-augmented trabeculectomy were included as a control group. We included 14 consecutive patients who underwent Xen implant (seven eyes) and trabeculectomy (seven eyes). The mean myopia was -14.71 ± 5.36 and -15.07 ± 6.11 in the trabeculectomy and Xen groups, respectively ( p > 0.05). The success rate and the mean IOP at 1 and 2 years from the intervention were statistically comparable between the two groups. The group undergoing trabeculectomy showed a higher incidence of hypotony (six eyes (85.71%) vs. two eyes (28.57%)) and hypotony maculopathy (three eyes (42.86%) vs. zero eyes (0%)) and required more postoperative procedures. Patients with high myopia were at higher risk of hypotony-related complications after trabeculectomy. The Xen implant can achieve an IOP control comparable to trabeculectomy with a significantly better safety profile and can be considered as an option for the management of patients with high myopia and glaucoma.

The mammary gland hosts a microbiota, which differs between malignant versus normal tissue. We found that aerosolized antibiotics decrease murine mammary tumor growth and strongly limit lung metastasis. Oral absorbable antibiotics also reduced mammary tumors. In ampicillin-treated nodules, the immune microenvironment consisted of an M1 profile and improved T cell/macrophage infiltration. In these tumors, we noted an under-representation of microbial recognition and complement pathways, supported by TLR2/TLR7 protein and C3-fragment deposition reduction. By 16S rRNA gene profiling, we observed increased Staphylococcus levels in untreated tumors, among which we isolated Staphylococcus epidermidis, which had potent inflammatory activity and increased Tregs. Conversely, oral ampicillin lowered Staphylococcus epidermidis in mammary tumors and expanded bacteria promoting an M1 phenotype and reducing MDSCs and tumor growth. Ampicillin/paclitaxel combination improved the chemotherapeutic efficacy. Notably, an Amp-like signature, based on genes differentially expressed in murine tumors, identified breast cancer patients with better prognosis and high immune infiltration that correlated with a bacteria response signature. This study highlights the significant influence of mammary tumor microbiota on local immune status and the relevance of its treatment with antibiotics, in combination with breast cancer therapies., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background . Overweight and obesity are associated with atrial fibrillation (AF), and bariatric surgery (BS), able to induce sustained and prolonged weight loss, might represent the ideal treatment in the prevention of AF. Previous studies could not definitely establish a role for weight loss and BS in preventing incident AF so far. During the last few years, several studies on the effect of bariatric surgery on cardiovascular diseases have been published, and we performed a systematic review and meta-analysis to evaluate the role of weight loss through BS in the prevention of incident AF in obesity. Methods . This meta-analysis followed the PRISMA guideline. Eligible studies were controlled trials evaluating the appearance of atrial fibrillation in patients undergoing weight loss through BS as compared with patients receiving medical treatment. Quality of studies was assessed according to the Newcastle-Ottawa Quality Assessment Scale, and risk-of-bias was evaluated employing the Egger's test. All analyses were run by a random-effects model according to Hartung and Knapp and sensitivity analyses were performed. Heterogeneity was assessed through Q and I 2 statistics for each comparison, and potential publication bias was formally investigated. Results . Ten studies were included in the meta-analysis, and the overall result was statistically significant [OR = 0.665 (0.475-0.929), p = 0.017], with significant heterogeneity (Q = 48.98, p < 0.001; I 2 = 81.6%), but with no publication bias. In sensitivity analyses, the amount of weight loss, percentage of patients with diabetes and value of the Newcastle-Ottawa Quality Assessment Scale, were all associated with significance of effect. Since age was different in one study, a sensitivity analysis was performed by excluding this study; OR was similar [OR = 0.608 (0.454-0.814), p < 0.001]; heterogeneity was reduced but still significant (Q = 35.74, p < 0.001, I 2 = 77.6%) and again no publication bias was detected. Conclusions . Bariatric surgery as compared to medical treatment is associated with reduced appearance of incident AF.

Cancer is a systemic disease able to reprogram the bone marrow (BM) niche towards a protumorigenic state. The impact of cancer on specific BM subpopulations can qualitatively differ according to the signals released by the tumor, which can vary on the basis of the tissue of origin. Using a spontaneous model of mammary carcinoma, we identified BM mesenchymal stem cells (MSC) as the first sensors of distal cancer cells and key mediators of BM reprogramming. Through the release of IL1B, BM MSCs induced transcriptional upregulation and nuclear translocation of the activating transcription factor 3 (ATF3) in hematopoietic stem cells. ATF3 in turn promoted the formation of myeloid progenitor clusters and sustained myeloid cell differentiation. Deletion of Atf3 specifically in the myeloid compartment reduced circulating monocytes and blocked their differentiation into tumor-associated macrophages. In the peripheral blood, the association of ATF3 expression in CD14+ mononuclear cells with the expansion CD11b+ population was able to discriminate between women with malignant or benign conditions at early diagnosis. Overall, this study identifies the IL1B/ATF3 signaling pathway in the BM as a functional step toward the establishment of a tumor-promoting emergency myelopoiesis, suggesting that ATF3 could be tested in a clinical setting as a circulating marker of early transformation and offering the rationale for testing the therapeutic benefits of IL1B inhibition in patients with breast cancer. Significance: Bone marrow mesenchymal stem cells respond to early breast tumorigenesis by upregulating IL1B to promote ATF3 expression in hematopoietic stem cells and to induce myeloid cell differentiation that supports tumor development., (©2022 The Authors; Published by the American Association for Cancer Research.)

Glucagon (traditional kits for intramuscular administration, Glucagon and Glucagen), although recommended as a remedy for severe hypoglycemia (SH), has been reported to be under-utilized, likely because of technical problems. The aims of this study were to evaluate the use of glucagon in persons with type 1 diabetes in several countries, and to investigate if the availability of new ready-to-use glucagons (Baqsimi, Gvoke, Zegalogue, years 2019 to 2021) has expanded the overall use of glucagon. The source of data was IQVIA-MIDAS (units of glucagon sold), while data on persons with type 1 diabetes in countries were derived from IDF Diabetes Atlas. The use of glucagon has been steady from 2014 to 2019, with a small but significant increase from 2019 to 2021, paradoxically only in countries where new ready-to-use glucagons were not available. The use of glucagon has always been ten fold greater in countries where new ready-to-use glucagons became available than in the other countries (population 108,000,000 vs 28,100,000, 480,291 vs 182,018 persons with type 1 diabetes). A significant correlation was observed in all years between units of glucagon and persons with type 1 diabetes. Availability of new ready-to-use glucagons was associated with a small increase of sales, due only to new ready-to-use glucagons themselves. The use of glucagon (any type) remains low, approximately 1/10 of persons with type 1 diabetes. We conclude that use of glucagon is scarce in most countries, and so far has not been expanded by new ready-to-use glucagons such as the ones considered in this study., (© 2022. The Author(s).)

Hyperprogressive disease (HPD), an aggressive acceleration of tumor growth, was observed in a group of cancer patients treated with anti-PD1/PDL1 antibodies. The presence of a peculiar macrophage subset in the tumor microenvironment is reported to be a sort of "immunological prerequisite" for HPD development. These macrophages possess a unique phenotype that it is not clear how they acquire. We hypothesized that certain malignant cells may promote the induction of an "HPD-related" phenotype in macrophages. Bone-marrow-derived macrophages were exposed to the conditioned medium of five non-small cell lung cancer cell lines. Macrophage phenotype was analyzed by microarray gene expression profile and real-time PCR. We found that human NSCLC cell lines, reported as undergoing HPD-like tumor growth in immunodeficient mice, polarized macrophages towards a peculiar pro-inflammatory phenotype sharing both M1 and M2 features. Lipid-based factors contained in cancer cell-conditioned medium induced the over-expression of several pro-inflammatory cytokines and the activation of innate immune receptor signaling pathways. We also determined that tumor-derived Extracellular Vesicles represent the main components involved in the observed macrophage re-education program. The present study might represent the starting point for the future development of diagnostic tools to identify potential hyperprogressors.

Background: Despite huge efforts to identify biomarkers associated with long-term clinical outcomes in patients with early-stage HER2-positive breast cancer (HER2+ BC) treated with (neo)adjuvant anti-HER2 therapy, no reliable predictors have been identified so far. Fatty acid uptake, a process mediated by the transmembrane transporter CD36, has recently emerged as a potential determinant of resistance to anti-HER2 treatments in preclinical HER2+ BC models., Methods: Here, we investigated the association between baseline intratumor CD36 gene expression and event-free survival in 180 patients enrolled in the phase III trial Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO), which randomly assigned stage II-III HER2+ BC patients to receive neoadjuvant lapatinib, trastuzumab, or lapatinib-trastuzumab in combination with chemotherapy. To this aim, we selected NeoALTTO trial patients for whom pretreatment whole transcriptomic data were available. The main study results were validated in an independent cohort of patients enrolled in the neoadjuvant phase II trial NeoSphere., Results: In 180 NeoALTTO patients, high intratumor CD36 expression was independently associated with worse event-free survival in patients treated with trastuzumab-based therapy (hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.20 to 2.46), but not with lapatinib-based (HR = 1.02, 95% CI = 0.68 to 1.53) or trastuzumab-lapatinib-based (HR = 1.08, 95% CI = 0.60 to 1.94) therapy. Among 331 NeoSphere patients evaluated, high CD36 expression was independently associated with worse patient disease-free survival in both the whole study cohort (HR = 1.197, 95% CI = 1.002 to 1.428) and patients receiving trastuzumab-based neoadjuvant therapy (HR = 1.282, 95% CI = 1.049 to 1.568)., Conclusions: High CD36 expression predicts worse clinical outcomes in early-stage HER2+ BC treated with trastuzumab-based neoadjuvant therapy., (© The Author(s) 2022. Published by Oxford University Press.)

While the results thus far demonstrate the clinical benefit of trastuzumab in breast cancer (BC), some patients do not respond to this drug. HER2 mRNA, alone or combined with other genes/biomarkers, has been proven to be a powerful predictive marker in several studies. Here, we provide evidence of the association between HER2 mRNA levels and the response to anti-HER2 treatment in HER2-positive BC patients treated with adjuvant trastuzumab and show that this association is independent of estrogen receptor (ER) tumor positivity. While HER2 mRNA expression was significantly correlated with HER2 protein levels in ER-negative tumors, no correlation was found in ER-positive tumors, and HER2 protein expression was not associated with relapse risk. Correlation analyses in the ER-positive subset identified ER activity as the pathway inversely associated with HER2 mRNA. Associations between HER2 levels and oncogene addiction, as well as between HER2 activation and trastuzumab sensitivity, were also observed in vitro in HER2-positive BC cell lines. In ER-positive but not ER-negative BC cells, HER2 transcription was increased by reducing ligand-dependent ER activity or inducing ER degradation. Accordingly, HER2 mRNA levels in patients were found to be inversely correlated with blood levels of estradiol, the natural ligand of ER that induces ER activation. Moreover, low estradiol levels were associated with a lower risk of relapse in HER2-positive BC patients treated with adjuvant trastuzumab. Overall, we found that HER2 mRNA levels, but not protein levels, indicate the HER2 dependency of tumor cells and low estrogen-dependent ER activity in HER2-positive tumors.

About 5% of patients with heart failure (HF) reach the end-stage of disease, becoming refractory to therapy. The clinical course of end-stage HF is characterized by repeated hospitalizations, severe symptoms, and poor quality of life. Peritoneal ultrafiltration (PUF), removing water and sodium (Na+), can benefit patients with end-stage HF. However, effects on fluid and electrolyte removal have not been fully characterized. In this pilot study in patients with chronic HF and moderate chronic renal failure, we evaluated the effects of water and sodium removal through PUF on ventricular remodeling, re-hospitalization, and quality of life. Patients with end-stage HF (NYHA class IV, ≥3 HF hospitalization/year despite optimal therapy), not eligible for heart transplantation underwent peritoneal catheter positioning and began a single-day exchange with icodextrin at night (n=6), or 1-2 daily exchanges with hypertonic solution (3.86%) for 2 hours with 1.5-2 L fill volume (n=3). At baseline, average ultrafiltration was 500±200 ml with icodextrin, and 700±100 ml with hypertonic solution. Peritoneal excretion of Na+ was greater with icodextrin (68±4 mEq/exchange) compared to hypertonic solution (45±19 mEq/exchange). After a median 12-month follow-up, rehospitalizations decreased, while NYHA class and quality of life (by Minnesota Living with HF questionnaire), improved. In end-stage HF patients, PUF reduced re-hospitalization and improved quality of life. It can be an additional treatment to control volume and sodium balance., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Breast cancer that highly expresses human epidermal growth factor receptor 2 (HER2+) represents one of the major breast cancer subtypes, and was associated with a poor prognosis until the introduction of HER2-targeted therapies such as trastuzumab. Unfortunately, up to 30% of patients with HER2+ localized breast cancer continue to relapse, despite treatment. MicroRNAs (miRNAs) are small (approximately 20 nucleotides long) non-coding regulatory oligonucleotides. They function as post-transcriptional regulators of gene expression, binding complementarily to a target mRNA and leading to the arrest of translation or mRNA degradation. In the last two decades, translational research has focused on these small molecules because of their highly differentiated expression patterns in blood and tumor tissue, as well as their potential biological function. In cancer research, they have become pivotal for the thorough understanding of oncogenic biological processes. They might also provide an efficient approach to early monitoring of tumor progression or response to therapy. Indeed, changes in their expression patterns can represent a flag for deeper biological changes. In this review, we sum up the recent literature regarding miRNAs in HER2+ breast cancer, taking into account their potential as powerful prognostic and predictive biomarkers, as well as therapeutic tools.

An immunosuppressive microenvironment in lung concurs to pre-malignant lesions progression to cancer. Here, we explore if perturbing lung microbiota, which contribute to immunosuppression, by antibiotics or probiotic aerosol interferes with lung cancer development in a mouse carcinogen-induced tumor model. Urethane-injected mice were vancomycin/neomycin (V/N)-aerosolized or live or dead L. rhamnosus GG ( L.RGG )-aerosolized, and tumor development was evaluated. Transcriptional profiling of lungs and IHC were performed. Tumor nodules number, diameter and area were reduced by live or heat-killed L.RGG , while only a decrease in nodule diameter was observed in V/N-treated lungs. Both L.RGG and V/N reduced Tregs in the lung. In L.RGG -treated groups, the gene encoding the joining chain (J chain) of immunoglobulins was increased, and higher J chain protein and IgA levels were observed. An increased infiltration of B, NK and myeloid-derived cells was predicted by TIMER 2.0. The Kaplan-Meier plotter revealed an association between high levels of J chain mRNA and good prognosis in lung adenocarcinoma patients that correlated with increased B and CD4 T cells and reduced Tregs and M2 macrophages. This study highlights L.RGG aerosol efficacy in impairing lung cancer growth by promoting local immunity and points to this non-invasive strategy to treat individuals at risk of lung cancer.

The microbiota is emerging as a key player in cancer due to its involvement in several host physiological functions, including digestion, development of the immune system, and modulation of endocrine function. Moreover, its participation in the efficacy of anticancer treatments has been well described. For instance, the involvement of the breast microbiota in breast cancer (BC) development and progression has gained ground in the past several years. In this review, we report and discuss new findings on the impact of the gut and breast microbiota on BC, focusing on the HER2+ BC subtype, and the possibility of defining microbial signatures that are associated with disease aggressiveness, treatment response, and therapy toxicity. We also discuss novel insights into the mechanisms through which microorganism-host interactions occur and the possibility of microbiota editing in the prevention and treatment optimization of BC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Di Modica, Arlotta, Sfondrini, Tagliabue and Triulzi.)

The aim of this retrospective study was to evaluate risk factors for 3-years mortality after hospital discharge in all inpatients admitted to a general hospital in Milano, Italy. A total of 2580 consecutive patients admitted to Ospedale San Paolo, July 1 to December 31, 2012, for several classes of diseases (internal medicine, cancer, infectious diseases, trauma and surgery, pneumonia, and heart diseases) were studied. Age, total disease, type of admission, length of admission, age-adjusted Charlson index, prognostic nutritional index (PNI), and full blood count were evaluated. Univariate Cox models were used to evaluate the association between variables and death. Of the 2580 consecutive patients (age 66.8 ± 19.36 years, mean ± SD), 920 died within 3 years after discharge. At univariate analysis, all investigated variables, except sex and lymphocytes, were associated with patient death. Stepwise regression analyses revealed that the age-adjusted Charlson index or age plus total diseases, type of admission, number of admissions, and PNI were significant risk factors in the whole sample and in some classes of disease. Results were superimposable when considering death from date of admission instead of date of discharge, meaning that in-hospital death was not relevant to the total death count (115 out of 902). Seriousness of baseline conditions represents the major risk factor for mortality in most classes of disease, and possibly influences other predictors, such as type of admission and length of stay. This suggests that the current model of hospital admission might be improved, for instance, through comprehensive care at home, instead of hospital admission, or before admission., (© 2022. The Author(s).)

As most erb-b2 receptor tyrosine kinase 2 (HER2)-positive breast cancer (BC) patients currently receive dual HER2-targeting added to neoadjuvant chemotherapy, improved methods for identifying individual response, and assisting postsurgical salvage therapy, are needed. Herein, we evaluated the 41-gene classifier trastuzumab advantage risk model (TRAR) as a predictive marker for patients enrolled in the NeoSphere trial. TRAR scores were computed from RNA of 350 pre- and 166 post-treatment tumor specimens. Overall, TRAR score was significantly associated with pathological complete response (pCR) rate independently of other predictive clinico-pathological variables. Separate analyses according to estrogen receptor (ER) status showed a significant association between TRAR score and pCR in ER-positive specimens but not in ER-negative counterparts. Among ER-positive BC patients not achieving a pCR, those with TRAR-low scores in surgical specimens showed a trend for lower distant event-free survival. In conclusion, in HER2-positive/ER-positive BC, TRAR is an independent predictor of pCR and represents a promising tool to select patients responsive to anti-HER2-based neoadjuvant therapy and to assist treatment escalation and de-escalation strategies in this setting., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: Bariatric surgery (BS) is considered the most efficient treatment for severe obesity. International guidelines recommend multidisciplinary approach to BS (general practitioners, endocrinologists, surgeons, psychologists, or psychiatrists), and access to BS should be the final part of a protocol of treatment of obesity. However, there are indications that general practitioners (GPs) are not fully aware of the possible benefits of BS, that specialty physicians are reluctant to refer their patients to surgeons, and that patients with obesity choose self-management of their own obesity, including internet-based choices. There are no data on the pathways chosen by physicians and patients to undergo BS in the real world in Italy., Methods: An exploratory exam was performed for 6 months in three pilot regions (Lombardy, Lazio, Campania) in twenty-three tertiary centers for the treatment of morbid obesity, to describe the real pathways to BS in Italy., Results: Charts of 2686 patients (788 men and 1895 women, 75.5% in the age range 30-59 years) were evaluated by physicians and surgeons of the participating centers. A chronic condition of obesity was evident for the majority of patients, as indicated by duration of obesity, by presence of several associated medical problems, and by frequency of previous dietary attempts to weight loss. The vast majority (75.8%) patients were self-presenting or referred by bariatric surgeons, 24.2% patients referred by GPs and other specialists. Self-presenting patients were younger, more educated, more professional, and more mobile than patients referred by other physicians. Patients above the age of 40 years or with a duration of obesity greater than 10 years had a higher prevalence of all associated medical problems., Conclusions: The majority of patients referred to a tertiary center for the treatment of morbid obesity have a valid indication for BS. Most patients self-refer to the centers, with a minority referred by a GP or by specialists. Self-presenting patients are younger, more educated, more professional, and more mobile than patients referred by other physicians. Older patients and with a longer duration of obesity are probably representative of the conservative approach to BS, often regarded as the last resort in an endless story., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)