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Background: Genetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib., Methods: This first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50-350 mg once daily [QD] or 300-600 mg twice daily [BID]) with rineterkib (100-300 mg QD) in patients with KRAS-/BRAF-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with KRAS-/BRAF-mutant NSCLC and NRAS-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics., Results: Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAF non-V600 -mutant NSCLC) treated with naporafenib plus rineterkib and two patients (both with KRAS-mutant NSCLC) treated with naporafenib plus trametinib. On-treatment median reductions in DUSP6 mRNA levels from baseline were 45.5% and 76.1% with naporafenib plus rineterkib or trametinib, respectively., Conclusions: Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect., Clinicaltrials: gov identifier: NCT02974725., Competing Interests: Declaration of competing interest David Planchard reports consulting, advisory role or lectures for AstraZeneca, Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Janssen, Pfizer, Roche, Pierre-fabre, Takeda, ArriVent, Mirati and Seagen; clinical trials research as principal investigator or co-investigator (institutional financial interests) for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Abbvie, Janssen, Pierre-fabre, Takeda, ArriVent, Mirati and Seagen; and travel, accommodation and expenses from AstraZeneca, Roche, Novartis and Pfizer. Jürgen Wolf reports grants from BMS, Janssen, Pharmaceutica, Novartis and Pfizer (payment to institution); and consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, support for attending meetings and/or travel, and participation on a data safety monitoring board or advisory board from Amgen,  AstraZeneca, Bayer, BluePrint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Pierre-Fabre, Roche, Seattle Genetics, Takeda and Turning Point. Benjamin Solomon reports fees for advisory boards from Pfizer, AstraZeneca, Janssen, Takeda, Bristol Myers Squibb, Meck, Roche-Genentech, Beigene and Amgen; payment or honoraria for lectures and presentations from AstraZeneca, Pfizer, Glaxo Smith Klein, Merck and Roche; and is a board director of Thoracic Oncology Group of Australasia, Cancer Council Victoria and International Association for the Study of Lung Cancer. Martin Sebastian reports grants or contracts to institution from AstraZeneca; consulting fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Lilly, Roche, Boehringer lngelheim, Amgen, Takeda, Merck-Serono, Pfizer, Pierre-Fabre and DaiIchi- Sankyo; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Lilly, Roche, Boehringer lngelheim, Amgen, Takeda, Merck, GSK, Daiichi and Pfizer; and support for attending meetings and/or travel from Pfizer, Merck and BMS. Martin Wermke reports research funding for institution from Roche; consulting fees from Bristol Myers Squibb, Novartis, Lilly, Boehringer Ingelheim, Immatics, Bayer and ImCheck Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Lilly, Boehringer Ingelheim, SNYLAB, Merck Serono, GWT, Amgen and Novartis; support for attending meetings and/or travel from Pfizer, Bristol Myers Squibb, AstraZeneca, Amgen, GEMoaB, Sanofi/Aventis, Immatics and Merck Serono; and participation on a data safety monitoring board or advisory board for ISA Pharmaceuticals. Rebecca S. Heist reports grants to institution from Abbvie, Agios, Daichii Sankyo, Lilly, Novartis, Mythic, Mirati, Symphogen, Turning Point and Erasca; consulting fees from Novartis, EMD Serono, Daichii Sankyo, Abbvie, Regeneron, Sanofi, Lilly, Claim Therapeutics, AstraZeneca, Amgen and Gilead; and receiving medical writing services from Daichii Sankyo, Novartis, Lilly and Mirati. Jong-Mu Sun has no conflicts of interest to declare. Tae Min Kim reports consulting fees from AstraZeneca, Janssen, Regeneron, Samsung Bioepis, Takeda and Yuhan; participation on Advisory Board for AstraZeneca/Medimmune, Janssen and Regeneron; and other financial or non-financial interests received by the institution from ABBVIE, AstraZeneca, Bayer, Black Diamond Therapeutics, Blueprint Medicines, Boryung, Bristol Myers Squibb, Celgene, F. Hoffmann-La Roche Ltd/Genentech, Inc, Hanmi, Janssen, Novartis, Regeneron, Sanofi, Takeda and Yuhan. Noemi Reguart has received speaker’s honoraria or sponsorship to attend international scientific meetings from Bayer, MSD, BMS, Roche, Boehringer Ingelheim, Janssen, Pfizer, AbbVie, Novartis, Astrazeneca, Lilly, Takeda, Amgen and Merck; and research grants from Novartis, MSD and Pfizer (all for Institution). Miguel F. Sanmamed received research grants from Roche; consulting fees from Numab; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD; support for attending meetings and/or travel from Roche; and participation on advisory board for Numab. Enriqueta Felip reports consulting fees from Abbvie, Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point and Daiichi Sankyo; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda and Touch Oncology; and support for attending meetings and/or travel from AstraZeneca, Janssen and Roche. Pilar Garrido received personal fees for lectures, presentations, speakers bureaus or educational events from Janssen, MSD, Novartis, Medscape, Takeda, TouchTime and Medscape; support for attending meetings and/or travel from Astra Zeneca, Roche and Janssen; personal fees for advisory role from Abbvie, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and Takeda, and personal fees for steering committee from Novartis and IO Biotech IO102-Janssen. Armando Santoro received consultancy fees from Sanofi and Incyte; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Takeda, BMS, Roche, Abbvie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, ArQule, Lilly, Sandoz, Eisai, Novartis, Bayer, MSD and BeiGene; and participation on a data safety monitoring board or advisory board for BMS, Servier, Gilead, Pfizer, Eisai, Bayer and MSD. Douglas Bootle is a Novartis employee. Xuân-Mai Couillebault is a Novartis employee. Anil Gaur is a Novartis employee. Christina Mueller is a Novartis employee and Novartis stockholder. Teresa Poggio is a Novartis employee. Jie Yang is a Novartis employee and Novartis stockholder. Michele Moschetta is a previous Novartis employee, Novartis stockholder and has one patent issued relating to naporafenib. Christophe Dooms has no conflicts of interest to declare. All authors received medical writing support funded by Novartis Pharmaceuticals Corporation., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Neoadjuvant chemotherapy (NAC) is currently used for treating breast cancer in selected cases. Our study aims to evaluate the role of automated breast ultrasound (ABUS) in the assessment of response to NAC and compare the ABUS results with MRI. Methods: A total of 52 consecutive patients were included in this study. ABUS and MRI sensitivity (SE), specificity (SP), diagnostic accuracy (DA), positive predictive value (PPV), and negative predictive value (NPV) were calculated and represented using Area Under ROC Curve (ROC) analysis, searching for any significant difference ( p < 0.05). The McNemar test was used searching for any significant difference in terms of sensitivity by comparing the ABUS and MRI results. The inter-observer agreement between the readers in evaluating the response to NAC for both MRI and ABUS was calculated using Cohen's kappa k coefficient. Results: A total of 35 cases of complete response and 17 cases of persistent disease were found. MRI showed SE, SP, DA, PPV, and NPV values of 100%, 88%, 92%, 81%, and 100%, respectively, with an AUC value of 0.943 ( p < 0.0001). ABUS showed SE, SP, DA, PPV, and NPV values of 88%, 94%, 92%, 89%, and 94%, respectively, with an AUC of 0.913 ( p < 0.0001). The McNemar test revealed no significant difference ( p = 0.1250). The inter-observer agreement between the two readers in evaluating the response to NAC for MRI and ABUS was, respectively, 0.88 and 0.89. Conclusions: Automatic breast ultrasound represents a new accurate, tri-dimensional and operator-independent tool for evaluating patients referred to NAC.

Epilepsy affects 1% of the general population and 30% of patients are resistant to antiepileptic drugs. Although optogenetics is an efficient antiepileptic strategy, the difficulty of illuminating deep brain areas poses translational challenges. Thus, the search of alternative light sources is strongly needed. Here, we develop pH-sensitive inhibitory luminopsin (pHIL), a closed-loop chemo-optogenetic nanomachine composed of a luciferase-based light generator, a fluorescent sensor of intracellular pH (E 2 GFP), and an optogenetic actuator (halorhodopsin) for silencing neuronal activity. Stimulated by coelenterazine, pHIL experiences bioluminescence resonance energy transfer between luciferase and E 2 GFP which, under conditions of acidic pH, activates halorhodopsin. In primary neurons, pHIL senses the intracellular pH drop associated with hyperactivity and optogenetically aborts paroxysmal activity elicited by the administration of convulsants. The expression of pHIL in hippocampal pyramidal neurons is effective in decreasing duration and increasing latency of pilocarpine-induced tonic-clonic seizures upon in vivo coelenterazine administration, without affecting higher brain functions. The same treatment is effective in markedly decreasing seizure manifestations in a murine model of genetic epilepsy. The results indicate that pHIL represents a potentially promising closed-loop chemo-optogenetic strategy to treat drug-refractory epilepsy., (© 2024. The Author(s).)

Introduction: Body image concerns related to breast cancer surgery may challenge patients' quality of life and their treatment outcomes, thus representing a key aspect to be assessed in the psycho-oncological settings. The present longitudinal study is aimed to (1) investigate the association between preoperative body image and postoperative psychological symptoms in breast cancer patients; (2) explore the impact of pre-/post-surgery variation in body image on psychological symptomatology., Methods: N = 72 women undergoing breast cancer surgery were preoperatively screened (T1) using the Body Uneasiness Test (BUT) and were assessed postoperatively (T2) using the Symptom Checklist-90 Revised (SCL-90-R) and re-administered the BUT. Spearman's correlation was used to investigate the relationship between age, preoperative body image and postoperative psychological symptoms, and variation in body image. To predict post-surgical psychological symptomatology, two separated multiple regression models were used to evaluate preoperative body image and its variation after surgery controlling for covariates (i.e., education; intervention type). P significance was set as 0.05 for all analyses and adjusted for multiple comparisons., Results: At T1, anxiety in relation to body image scores emerged as the most frequently experienced psychological symptomatology after surgery (all adjusted p < 0.05). Significant correlations were observed between all SCL-90-R scores at T2 and avoidance behaviors and depersonalization scores at T1. The associations were most significantly strong for somatization, depression, anxiety, and hostility (all adjusted p < 0.05). However, change in body image between pre- and post-intervention was not associated with psychological symptomatology at T2 (all adjusted p > 0.05). Pre-surgery body avoidance was significantly associated with post-intervention psychological symptoms (SOMβ = 0.453, p = 0.0001; DEPβ = 0.507, p = 0.0001; AXβ = 0.459, p = 0.0001; HOSβ = 0.410, p =. 0001). However, increased weight phobia between pre- and post-surgery was statistically associated with increased somatization, anxiety, depression and hostility at T2 (βSOM = 0.439, p = 0.0001; βDEP = 0.454, p = 0.0001; βANX = 0.471, p = 0.0001)., Discussion: Overall, pre-/post-intervention body concerns were significantly associated with primary psychological symptoms in breast cancer patients undergoing surgery. Higher levels of body avoidance and weight phobia were significantly associated with the primary psychological dimensions assessed. As body concerns might act as quality-of-life predictors, their evaluation is crucial in fostering patients' well-being and treatment adherence., 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 © 2024 Verri, Pepe, Abbatantuono, Bottalico, Semeraro, Moschetta, De Caro, Taurisano, Antonucci and Taurino.)

Recent years have ushered in a transformative era in in vitro modeling with the advent of organoids, three-dimensional structures derived from stem cells or patient tumor cells. Still, fully harnessing the potential of organoids requires advanced imaging technologies and analytical tools to quantitatively monitor organoid growth. Optical coherence tomography (OCT) is a promising imaging modality for organoid analysis due to its high-resolution, label-free, non-destructive, and real-time 3D imaging capabilities, but accurately identifying and quantifying organoids in OCT images remain challenging due to various factors. Here, we propose an automatic deep learning-based pipeline with convolutional neural networks that synergistically includes optimized preprocessing steps, the implementation of a state-of-the-art deep learning model, and ad-hoc postprocessing methods, showcasing good generalizability and tracking capabilities over an extended period of 13 days. The proposed tracking algorithm thoroughly documents organoid evolution, utilizing reference volumes, a dual branch analysis, key attribute evaluation, and probability scoring for match identification. The proposed comprehensive approach enables the accurate tracking of organoid growth and morphological changes over time, advancing organoid analysis and serving as a solid foundation for future studies for drug screening and tumor drug sensitivity detection based on organoids.

Light-driven modulation of neuronal activity at high spatial-temporal resolution is becoming of high interest in neuroscience. In addition to optogenetics, nongenetic membrane-targeted nanomachines that alter the electrical state of the neuronal membranes are in demand. Here, we engineered and characterized a photoswitchable conjugated compound (BV-1) that spontaneously partitions into the neuronal membrane and undergoes a charge transfer upon light stimulation. The activity of primary neurons is not affected in the dark, whereas millisecond light pulses of cyan light induce a progressive decrease in membrane resistance and an increase in inward current matched to a progressive depolarization and action potential firing. We found that illumination of BV-1 induces oxidation of membrane phospholipids, which is necessary for the electrophysiological effects and is associated with decreased membrane tension and increased membrane fluidity. Time-resolved atomic force microscopy and molecular dynamics simulations performed on planar lipid bilayers revealed that the underlying mechanism is a light-driven formation of pore-like structures across the plasma membrane. Such a phenomenon decreases membrane resistance and increases permeability to monovalent cations, namely, Na + , mimicking the effects of antifungal polyenes. The same effect on membrane resistance was also observed in nonexcitable cells. When sustained light stimulations are applied, neuronal swelling and death occur. The light-controlled pore-forming properties of BV-1 allow performing "on-demand" light-induced membrane poration to rapidly shift from cell-attached to perforated whole-cell patch-clamp configuration. Administration of BV-1 to ex vivo retinal explants or in vivo primary visual cortex elicited neuronal firing in response to short trains of light stimuli, followed by activity silencing upon prolonged light stimulations. BV-1 represents a versatile molecular nanomachine whose properties can be exploited to induce either photostimulation or space-specific cell death, depending on the pattern and duration of light stimulation.

Background: Contrast-enhanced mammography (CEM) is a promising technique. We evaluated the diagnostic potential of CEM performed immediately after contrast-enhanced computed tomography (CE-CT)., Methods: Fifty patients with breast cancer underwent first CE-CT and then CEM without additional contrast material injection. Two independent radiologists evaluated CEM images. The sensitivity of CEM for detecting index and additional malignant lesions was compared with that of mammography/ultrasonography by the McNemar test, using histopathology as a reference standard. Interobserver agreement for detection of malignant lesions, for classifying index tumors, and for evaluating index tumor size and extent was assessed using Cohen κ. Pearson correlation was used for correlating index tumor size/extent at CEM or mammography/ultrasonography with histopathology., Results: Of the 50 patients, 30 (60%) had unifocal disease while 20 (40%) had multicentric or multifocal disease; 5 of 20 patients with multicentric disease (25%) had bilateral involvement, for a total of 78 malignant lesions, including 72 (92%) invasive ductal and 6 (8%) invasive lobular carcinomas. Sensitivity was 63/78 (81%, 95% confidence interval 70.27-88.82) for unenhanced breast imaging and 78/78 (100%, 95.38-100) for CEM (p < 0.001). The interobserver agreement for overall detection of malignant lesions, for classifying index tumor, and for evaluating index tumor size/extent were 0.94, 0.95, and 0.86 κ, respectively. For index tumor size/extent, correlation coefficients as compared with histological specimens were 0.50 for mammography/ultrasonography and 0.75 for CEM (p ≤ 0.010)., Conclusions: CEM acquired immediately after CE-CT without injection of additional contrast material showed a good performance for local staging of breast cancer., Relevance Statement: When the CEM suite is near to the CE-CT acquisition room, CEM acquired immediately after, without injection of additional contrast material, could represent a way for local staging of breast cancer to be explored in larger prospective studies., Key Points: • CEM represents a new accurate tool in the field of breast imaging. • An intravenous injection of iodine-based contrast material is required for breast gland evaluation. • CEM after CE-CT could provide a one-stop tool for breast cancer staging., (© 2024. The Author(s).)

Head and neck squamous cell carcinoma (HNSCC) is a deadly disease with a poor prognosis due to late diagnosis and limited treatment options. Immunotherapy (IT) is emerging as a promising approach, especially after the failure of standard of care therapies (STs). The objective of this systematic review and meta-analysis was to evaluate whether the addition of IT to STs improves outcomes for patients with HNSCC, including overall survival (OS), progression-free survival (PFS), and quality of life (QoL). This review employed the Population Intervention Comparison and Outcome (PICO) framework to identify relevant search terms in electronic databases, and also included supplementary hand searches. Six primary research articles were selected using the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) flow chart, and were critically appraised. Data extraction from these studies was conducted, and a meta-analysis was performed to aid in the generation of forest plots. The addition of IT to standard anticancer therapies was found to enhance patient outcomes, such as OS, PFS, and QoL. The toxicity profile of IT was acceptable, with minimal treatment-related deaths. The most frequently observed adverse events (AE) were related to the skin, followed by hematological toxicities. Based on our analysis, the addition of IT to STs is a suitable treatment option and is supported by current research. However, further studies are needed to investigate factors that influence treatment effectiveness and to develop optimal therapies. To achieve this, we recommend a comprehensive treatment approach that involves the multidisciplinary team (MDT) and patient assessment tools., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Ovarian cancer (OC) is the most lethal gynaecologic malignancy, attributed to its insidious growth, non-specific symptoms and late presentation. Unfortunately, current screening modalities are inadequate at detecting OC and many lack the appropriate specificity and sensitivity that is desired from a screening test. Nearly 70% of cases are diagnosed at stage III or IV with poor 5-year overall survival. Therefore, the development of a sensitive and specific biomarker for early diagnosis and screening for OC is of utmost importance. Currently, diagnosis is guided by CA125, the patient's menopausal status and imaging features on ultrasound scan. However, emerging evidence suggests that a combination of CA125 and HE4 (another serum biomarker) and patient characteristics in a multivariate index assay may provide a higher specificity and sensitivity than either CA125 and HE4 alone in the early detection of OC. Other attempts at combining various serum biomarkers into one multivariate index assay such as OVA1, ROMA and Overa have all shown promise. However, significant barriers exist before these biomarkers can be implemented in clinical practice. This article aims to provide an up-to-date review of potential biomarkers for screening and early diagnosis of OC which may have the potential to transform its diagnostic landscape., Competing Interests: MM declares no conflict of interests related to this work. MM is a Novartis employee and shareholder., (© The Author(s), 2024.)

Background: We investigated naporafenib (LXH254), a pan-RAF kinase inhibitor, with or without spartalizumab, in patients with advanced solid tumors harboring MAPK pathway alterations., Methods: This first-in-human phase 1 study had two dose-escalation arms: single-agent naporafenib (starting at 100 mg once-daily [QD]) and naporafenib (starting at the recommended dose/regimen)/spartalizumab (400 mg every 4 weeks). The naporafenib/spartalizumab dose-expansion part enrolled patients with KRAS-mutated non-small cell lung cancer (NSCLC) and NRAS-mutated melanoma. The primary objectives were to establish the maximum tolerated doses (MTD)/recommended doses for expansion (RDE) and evaluate tolerability and safety., Results: A total of 142 patients were included in the naporafenib dose-escalation (n = 87), naporafenib/spartalizumab dose-escalation (n = 12) and naporafenib/spartalizumab dose-expansion (n = 43) arms. The MTD/RDE of naporafenib was 600 mg twice-daily (BID). In naporafenib escalation, five patients experienced 7 dose-limiting toxicities: decreased platelet count (1200 mg QD); neuralgia, maculopapular rash, pruritus (600 mg BID); increased blood bilirubin, hyponatremia, peripheral sensory neuropathy (800 mg BID). No DLTs occurred in the naporafenib/spartalizumab arm: the RDE was established at 400 mg BID. The most common treatment-related adverse events were rash and dermatitis acneiform (each 24.1%; naporafenib), nausea and pruritus (each 33.3%; naporafenib/spartalizumab; escalation) and rash (39.5%; naporafenib/spartalizumab; expansion). Naporafenib reduced DUSP6 expression in tumors. Two partial responses (PRs) occurred in naporafenib escalation, and 1 complete response and 3 PRs in the naporafenib/spartalizumab NRAS-mutated melanoma and KRAS-mutated NSCLC arms, respectively., Conclusions: Naporafenib, with or without spartalizumab, showed an acceptable safety profile, pharmacodynamic activity and limited antitumor activity. Additional naporafenib combination therapies are currently under investigation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Filip Janku received research support from Astex, Novartis, BioMed Valley Discoveries, Fore Bio, Deciphera, Bristol-Myers Squibb, Asana, Ideaya Biosciences, Sanofi, Merck, F-star, JSI Innopharm, Bioxcel, Lilly, Bicara, PureTech Health, FujiFilm Pharmaceuticals, Piqur, Sotio, Synlogic, NextCure and Hutchinson Medipharma; served on the Scientific Advisory Boards of Ideaya Biosciences, Synlogic, Sotio, Puretech Health, Deciphera, Crown Bioscience, Asana, Fore Bio, Novartis, Bicara and PegaOne; served as a paid consultant for Mersana Therapeutics, Flame Bio, Cardiff Oncology, MedinCell and Immunomet; has ownership interests in Cardiff Oncology and Monte Rosa Therapeutics; and has the leadership position in Monte Rosa Therapeutics. Tae Min Kim received consulting fees or honoraria for lectures from AstraZeneca, IMBDx, Inc., Janssen, Regeneron, Samsung Bioepis, Takeda and Yuhan; had advisory role for AstraZeneca, Janssen, Regeneron and Takeda; and received a research grant from AstraZeneca-KHIDI outside this work. Gopakumar Iyer reports consulting or advisory role for Bayer, Janssen, Mirati Therapeutics, Basilea Pharmaceutica, Flare Therapeutics and Aadi Bioscience; speakers' bureau for Gilead Sciences and Lynx Group; and research funding (to institution) from Mirati Therapeutics, Novartis, Janssen, Seattle Genetics, LOXO at Lilly and Aadi Bioscience. Anna Spreafico has received consulting fees from Merck, Bristol-Myers Squibb, Oncorus, Janssen, and Medison & Immunocore; and funding support for clinical trials paid to the Institution from Novartis, Bristol-Myers Squibb, Symphogen, AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma/Pfizer, GSK, NuBiyota, Oncorus, Treadwell and Amgen. Elena Elez has received personal speaker honoraria from Organon and Novartis; and personal advisory board honoraria from Amgen, Bayer, Hoffman-La Roche, Merck Serono, Sanofi, Pierre Fabre, MSD and Servier. Noboru Yamamoto reports research grants from Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, ONO, Janssen Pharma, MSD, Merck, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, AstraZeneca, Cmic, InventisBio and Rakuten Medical; advisory roles for Eisai, Takeda, Boehringer Ingelheim, Cmic, Chugai, Merck and Healios; and honoraria as a Speaker from ONO, Chugai, Daiichi-Sankyo and Eisai. Anthonie J. van der Wekken reports grants and other support from AstraZeneca, Pfizer, Roche and Takeda; grants from Boehringer Ingelheim; and other support from Agena and Janssen, outside the submitted work. All payments were made to the University Medical Centre Groningen. Paolo Antonio Ascierto has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer and Erasca; received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer and Sanofi; and travel support from Pfizer, Bio-Al Health and Replimmune. Frederik Marmé reports personal fees from GSK, Roche, Novartis, AstraZeneca, MSD, Vaccibody, Gilead Sciences, Eisai, Pfizer, Myriad, Genomic Health, Seagen, Daiichi Sankyo, Pierre Fabre, Agendia, Lilly and Clovis outside the submitted work. Jean-Jacques Kiladjian reports consulting fees from GSK and Abbvie; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Novartis and AOP Health; participation on a data safety monitoring board or advisory board for Incyte and BMS. Sumit Basu, Fabienne Baffert, Amparo Buigues, Vesselina Cooke and Jaeyeon Kim are employees and stockholders of Novartis. Chi Chen and Elisa Giorgetti are employees of Novartis. Fiona McCarthy is a previous employee and a stockholder of Novartis. Michele Moschetta is a previous employee and a stockholder of Novartis and has submitted a patent application related to LXH254. Reinhard Dummer reports intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer and touchIME outside the submitted work. Maja de Jonge and Michela Maur report no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Statistical analysis of the properties of single microparticles, such as cells, bacteria or plastic slivers, has attracted increasing interest in recent years. In this regard, field flow cytometry is considered the gold standard technique, but commercially available instruments are bulky, expensive, and not suitable for use in point-of-care (PoC) testing. Microfluidic flow cytometers, on the other hand, are small, cheap and can be used for on-site analyses. However, in order to detect small particles, they require complex geometries and the aid of external optical components. To overcome these limitations, here, we present an opto-fluidic flow cytometer with an integrated 3D in-plane spherical mirror for enhanced optical signal collection. As a result, the signal-to-noise ratio is increased by a factor of six, enabling the detection of particle sizes down to 1.5 µm. The proposed optofluidic detection scheme enables the simultaneous collection of particle fluorescence and scattering using a single optical fiber, which is crucial to easily distinguishing particle populations with different optical properties. The devices have been fully characterized using fluorescent polystyrene beads of different sizes. As a proof of concept for potential real-world applications, signals from fluorescent HEK cells and Escherichia coli bacteria were analyzed.

Optical stimulation and control of muscle cell contraction opens up a number of interesting applications in hybrid robotic and medicine. Here we show that recently designed molecular phototransducer can be used to stimulate C2C12 skeletal muscle cells, properly grown to exhibit collective behaviour. C2C12 is a skeletal muscle cell line that does not require animal sacrifice Furthermore, it is an ideal cell model for evaluating the phototransducer pacing ability due to its negligible spontaneous activity. We study the stimulation process and analyse the distribution of responses in multinuclear cells, in particular looking at the consistency between stimulus and contraction. Contractions are detected by using an imaging software for object recognition. We find a deterministic response to light stimuli, yet with a certain distribution of erratic behaviour that is quantified and correlated to light intensity or stimulation frequency. Finally, we compare our optical stimulation with electrical stimulation showing advantages of the optical approach, like the reduced cell stress., (© 2023. The Author(s).)

The incidence of melanoma is increasing and prolonged exposure to ultraviolet (UV) radiation remains the main risk factor. Public health measures have been vital in tackling the increased incidence and prevalence of melanoma. The management of melanoma has been revolutionised with the approval of new immunotherapy treatments (anti PD-1, CTLA-4 and LAG-3 antibodies) and targeted therapies (BRAF and MEK inhibitors). With some of these therapies becoming the standard of care in the management of advanced disease, it is likely we will see their use increase in the adjuvant and neoadjuvant setting. Recently, literature has demonstrated the benefits patients could derive from the combination of immune checkpoint inhibitors (ICIs) due to the promising results on its efficacy when compared to monotherapy. However, greater clarity on its use is needed in more unique presentations such as BRAF-wild type melanoma, where the lack of driver mutations makes disease management more challenging. Surgical resection remains an integral part of the management of earlier stages of the disease with a consequent decrease in reliance on other forms of therapy such as chemotherapy and radiotherapy. Finally, we evaluated the novel emerging experimental approaches to treatment such as adoptive T cell therapy, novel oncolytic treatments and cancer vaccines. We discussed how their use could improve patients' prognosis, enhance treatment efficacy, and potentially achieve cure.

Combination platinum-based chemotherapy has been the standard of care for several decades in first-line treatment of advanced urothelial carcinoma (UC) patients. UC is often chemosensitive, though durable responses are quite rare and the development of chemoresistance still leads to poor clinical outcomes. Up until a few years ago, UC patients could not benefit from any valuable alternatives to cytotoxic chemotherapy, but the scenario has been recently transformed by the advent of immunotherapy. Molecular biology of UC is characterised by a relatively high prevalence of alterations in DNA damage response pathway, genomic instability, high tumour burden, and elevated programmed cell death ligand 1 (PD-L1) protein expression, which are established factors predicting favourable response to immune checkpoint inhibitors (ICIs) in several tumour types. To date, various ICIs have been approved as systemic anti-cancer therapy for advanced UC in multiple settings, including first-line, maintenance, and second-line therapy. ICIs are also in development either as monotherapy or in combination with chemotherapy or other targeted agents. Moreover, a number of alternative ICIs, interleukins, and novel immune molecules have been identified as promising agents in advanced UC. Herein, we review rational and current literature evidence supporting the clinical development and current indications of immunotherapy, particularly focusing on ICIs.

Mechanosensitive ion channels are present in the plasma membranes of all cells. They play a fundamental role in converting mechanical stimuli into biochemical signals and are involved in several physiological processes such as touch sensation, hearing, and blood pressure regulation. This protein family includes TWIK-related arachidonic acid-stimulated K + channel (TRAAK), which is specifically implicated in the maintenance of the resting membrane potential and in the regulation of a variety of important neurobiological functions. Dysregulation of these channels has been linked to various diseases, including blindness, epilepsy, cardiac arrhythmia, and chronic pain. For these reasons, mechanosensitive channels are targets for the treatment of several diseases. Here, we propose a new approach to investigate TRAAK ion channel modulation that is based on nongenetic photostimulation. We employed an amphiphilic azobenzene, named Ziapin2. In the dark, Ziapin2 preferentially dwells in the plasma membrane, causing a thinning of the membrane. Upon light irradiation, an isomerization occurs, breaking the dimers and inducing membrane relaxation. To study the effect of Ziapin2 on the mechanosensitive channels, we expressed human TRAAK (hTRAAK) channels in HEK293T cells. We observed that Ziapin2 insertion in the membrane is able per se to recruit hTRAAK, permitting the exit of K + ions outside the cells with a consequent hyperpolarization of the cell membrane. During light stimulation, membrane relaxation induces hTRAAK closure, generating a consistent and compensatory depolarization. These results add information to the Ziapin2 mechanism and suggest that membrane deformation can be a tool for the nonselective modulation of mechanosensitive channels.

The assembly of supramolecular structures within living systems is an innovative approach for introducing artificial constructs and developing biomaterials capable of influencing and/or regulating the biological responses of living organisms. By integrating chemical, photophysical, morphological, and structural characterizations, it is shown that the cell-driven assembly of 2,6-diphenyl-3,5-dimethyl-dithieno[3,2-b:2',3'-d]thiophene-4,4-dioxide (DTTO) molecules into fibers results in the formation of a "biologically assisted" polymorphic form, hence the term bio-polymorph. Indeed, X-ray diffraction reveals that cell-grown DTTO fibers present a unique molecular packing leading to specific morphological, optical, and electrical properties. Monitoring the process of fiber formation in cells with time-resolved photoluminescence, it is established that cellular machinery is necessary for fiber production and a non-classical nucleation mechanism for their growth is postulated. These biomaterials may have disruptive applications in the stimulation and sense of living cells, but more crucially, the study of their genesis and properties broadens the understanding of life beyond the native components of cells., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Purpose: Metastatic spinal cord compression (MSCC) is a severe complication of cancer that can lead to irreversible neurological impairment, necessitating prompt recognition and intervention. This retrospective, single-centre study aimed to determine the prognostic factors and survival rates among patients presenting with MSCC secondary to lung cancer., Methods and Materials: We identified 74 patients with epidural metastases-related spinal cord compression and a history of lung cancer through the electronic database of Medway Maritime Hospital in the United Kingdom (UK), spanning the period from April 2016 to September 2021. Among them, 39 were below 55 years old, while 35 were aged 55 years or older; 24 patients were diagnosed with small cell lung cancer (SCLC), and 50 patients had non-small cell lung cancer (NSCLC)., Results: The median overall survival (OS) was 5.5 months, with 52 out of 74 patients dying within 6 months of diagnosis with MSCC. For the entire cohort, the statistically significant variables on multi-variate analysis were cancer type (NSCLC had improved OS), the number of involved vertebrae (one to two vertebrae involvement had improved OS), and the time taken to develop motor deficits (≤10 days to develop motor deficits had worsened OS). For the NSCLC cohort, the statistically significant variables on multivariate analysis were molecular alterations (patients with epidermal growth factor receptor ( EGFR ) mutation), pre-treatment ambulatory status, Eastern Cooperative Oncology Group (ECOG) performance status, and the time taken to develop motor deficits., Conclusions: Within the entire cohort, patients diagnosed with NSCLC and spinal metastases affecting one to two vertebrae exhibited enhanced OS. Within the NSCLC subgroup, those with EGFR mutations who were ambulatory and possessed an ECOG performance status of 1-2 demonstrated improved OS. In both the entire cohort and the NSCLC subgroup, the development of motor deficits within a period of ≤10 days was associated with poor OS.

CAR T-cell product quality and stemness (Tstem) are major determinants of in vivo expansion, efficacy, and clinical response. Prolonged ex vivo culturing is known to deplete Tstem, affecting clinical outcome. YTB323, a novel autologous CD19-directed CAR T-cell therapy expressing the same validated CAR as tisagenlecleucel, is manufactured using a next-generation platform in <2 days. Here, we report the preclinical development and preliminary clinical data of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL; NCT03960840). In preclinical mouse models, YTB323 exhibited enhanced in vivo expansion and antitumor activity at lower doses than traditionally manufactured CAR T cells. Clinically, at doses 25-fold lower than tisagenlecleucel, YTB323 showed (i) promising overall safety [cytokine release syndrome (any grade, 35%; grade ≥3, 6%), neurotoxicity (any grade, 25%; grade ≥3, 6%)]; (ii) overall response rates of 75% and 80% for DL1 and DL2, respectively; (iii) comparable CAR T-cell expansion; and (iv) preservation of T-cell phenotype. Current data support the continued development of YTB323 for r/r DLBCL., Significance: Traditional CAR T-cell manufacturing requires extended ex vivo cell culture, reducing naive and stem cell memory T-cell populations and diminishing antitumor activity. YTB323, which expresses the same validated CAR as tisagenlecleucel, can be manufactured in <2 days while retaining T-cell stemness and enhancing clinical activity at a 25-fold lower dose. See related commentary by Wang, p. 1961. This article is featured in Selected Articles from This Issue, p. 1949., (©2023 The Authors; Published by the American Association for Cancer Research.)

Objectives: To develop an intuitive and generally applicable system for the reporting, assessment, and documentation of ADC to complement standard BI-RADS criteria., Methods: This was a multicentric, retrospective analysis of 11 independently conducted institutional review board-approved studies from seven institutions performed between 2007 and 2019. Breast Apparent Diffusion coefficient (ADC-B) categories comprised ADC-B0 (ADC non-diagnostic), ADC-B1 (no enhancing lesion), and ADC-B2-5. The latter was defined by plotting ADC versus cumulative malignancy rates. Statistics comprised ANOVA with post hoc testing and ROC analysis. p values ≤ 0.05 were considered statistically significant., Results: A total of 1625 patients (age: 55.9 years (± 13.8)) with 1736 pathologically verified breast lesions were included. The mean ADC (× 10 -3 mm 2 /s) differed significantly between benign (1.45, SD .40) and malignant lesions (.95, SD .39), and between invasive (.92, SD .22) and in situ carcinomas (1.18, SD .30) (p < .001). The following ADC-B categories were identified: ADC-B0-ADC cannot be assessed; ADC-B1-no contrast-enhancing lesion; ADC-B2-ADC ≥ 1.9 (cumulative malignancy rate < 0.1%); ADC-B3-ADC 1.5 to < 1.9 (0.1-1.7%); ADC-B4-ADC 1.0 to < 1.5 (10-24.5%); and ADC-B5-ADC < 1.0 (> 24.5%). At the latter threshold, a positive predictive value of 95.8% (95% CI 0.94-0.97) for invasive versus non-invasive breast carcinomas was reached., Conclusions: The breast apparent diffusion coefficient system (ADC-B) provides a simple and widely applicable categorization scheme for assessment, documentation, and reporting of apparent diffusion coefficient values in contrast-enhancing breast lesions on MRI., Clinical Relevance Statement: The ADC-B system, based on diverse MRI examinations, is clinically relevant for stratifying breast cancer risk via apparent diffusion coefficient measurements, and complements BI-RADS for improved clinical decision-making and patient outcomes., Key Points: • The breast apparent diffusion coefficient category system (ADC-B) is a simple tool for the assessment, documentation, and reporting of ADC values in contrast-enhancing breast lesions on MRI. • The categories comprise ADC-B0 for non-diagnostic examinations, ADC-B1 for examinations without an enhancing lesion, and ADC-B2-5 for enhancing lesions with an increasing malignancy rate. • The breast apparent diffusion coefficient category system may be used to complement BI-RADS in clinical decision-making., (© 2023. The Author(s).)

Photodynamic inhibition (PDI) of bacteria represents a powerful strategy for dealing with multidrug-resistant pathogens and infections, as it exhibits minimal development of antibiotic resistance. The PDI action stems from the generation of a triplet state in the photosensitizer (PS), which subsequently transfers energy or electrons to molecular oxygen, resulting in the formation of reactive oxygen species (ROS). These ROS are then able to damage cells, eventually causing bacterial eradication. Enhancing the efficacy of PDI includes the introduction of heavy atoms to augment triplet generation in the PS, as well as membrane intercalation to circumvent the problem of the short lifetime of ROS. However, the former approach can pose safety and environmental concerns, while achieving stable membrane partitioning remains challenging due to the complex outer envelope of bacteria. Here, we introduce a novel PS, consisting of a metal-free donor-acceptor thiophene-based conjugate molecule (BV-1). It presents several advantageous features for achieving effective PDI, namely: (i) it exhibits strong light absorption due to the conjugated donor-acceptor moieties; (ii) it exhibits spontaneous and stable membrane partitioning thanks to its amphiphilicity, accompanied by a strong fluorescence turn-on; (iii) it undergoes metal-free intersystem crossing, which occurs preferentially when the molecule resides in the membrane. All these properties, which we rationalized via optical spectroscopies and calculations, enable the effective eradication of Escherichia coli , with an inhibition concentration that is below that of current state-of-the-art treatments. Our approach holds significant potential for the development of new PS for controlling bacterial infections, particularly those caused by Gram-negative bacteria., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Non-genetic photostimulation, which allows for control over cellular activity via the use of cell-targeting phototransducers, is widely used nowadays to study and modulate/restore biological functions. This approach relies on non-covalent interactions between the phototransducer and the cell membrane, thus implying that cell conditions and membrane status can dictate the effectiveness of the method. For instance, although immortalized cell lines are traditionally used in photostimulation experiments, it has been demonstrated that the number of passages they undergo is correlated to the worsening of cell conditions. In principle, this could impact cell responsivity against exogenous stressors, including photostimulation. However, these aspects have usually been neglected in previous experiments. In this work, we investigated whether cell passages could affect membrane properties (such as polarity and fluidity). We applied optical spectroscopy and electrophysiological measurements in two different biological models: (i) an epithelial immortalized cell line (HEK-293T cells) and (ii) liposomes. Different numbers of cell passages were compared to a different morphology in the liposome membrane. We demonstrated that cell membranes show a significant decrease in ordered domains upon increasing the passage number. Furthermore, we observed that cell responsivity against external stressors is markedly different between aged and non-aged cells. Firstly, we noted that the thermal-disordering effect that is usually observed in membranes is more evident in aged cells than in non-aged ones. We then set up a photostimulation experiment by using a membrane-targeted azobenzene as a phototransducer (Ziapin2). As an example of a functional consequence of such a condition, we showed that the rate of isomerization of an intramembrane molecular transducer is significantly impaired in aged cells. The reduction in the photoisomerization rate translates in cells with a sustained reduction of the Ziapin2-related hyperpolarization of the membrane potential and an overall increase in the molecule fluorescence. Overall, our results suggest that membrane stimulation strongly depends on membrane order, highlighting the importance of cell passage during the characterization of the stimulation tools. This study can shine light on the correlation between aging and the development of diseases driven by membrane degradation as well as on the different cell responsivities against external stressors, such as temperature and photostimulation., Competing Interests: The authors declare no conflicts of interest.

Purpose: No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog ( NRAS )-mutant melanoma is currently available., Patients and Methods: In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF -mutant non-small-cell lung cancer (escalation arm) or NRAS -mutant melanoma (escalation and expansion arms)., Results: Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily., Conclusion: Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS -mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.

Despite some notable successes, there are still relatively few agents approved for cancer prevention. Here we review progress thus far in the development of medicines for cancer prevention, and we outline some key concepts that could further enable or accelerate drug development for cancer prevention in the future. These are summarized under six key themes: (i) unmet clinical need, (ii) patient identification, (iii) risk stratification, (iv) pharmacological intervention, (v) clinical trials, and (vi) health care policy. These concepts, if successfully realized, may help to increase the number of medicines available for cancer prevention., Significance: The huge potential public health benefits of preventing cancer, combined with recent advances in the availability of novel early detection technologies and new treatment modalities, has caused us to revisit the opportunities and challenges associated with developing medicines to prevent cancer. Here we review progress in the field of developing medicines to prevent cancer to date, and we present a series of ideas that might help in the development of more medicines to prevent cancer in the future., (©2023 American Association for Cancer Research.)

Background: Age- and height-adjusted total kidney volume is currently considered the best prognosticator in patients with autosomal dominant polycystic kidney disease. We tested the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for the prediction of the Mayo Clinic Imaging Classes., Methods: Urinary epidermal growth factor and monocyte chemotactic peptide 1 levels were measured in two independent cohorts (discovery, n = 74 and validation set, n = 177) and healthy controls (n = 59) by immunological assay. Magnetic resonance imaging parameters were used for total kidney volume calculation and the Mayo Clinic Imaging Classification defined slow (1A-1B) and fast progressors (1C-1E). Microarray and quantitative gene expression analysis were used to test epidermal growth factor and monocyte chemotactic peptide 1 gene expression., Results: Baseline ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 correlated with total kidney volume adjusted for height (r = - 0.6, p < 0.001), estimated glomerular filtration rate (r = 0.69 p < 0.001), discriminated between Mayo Clinic Imaging Classes (p < 0.001), and predicted the variation of estimated glomerular filtration rate at 10 years (r = - 0.51, p < 0.001). Conditional Inference Trees identified cut-off levels of the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for slow and fast progressors at > 132 (100% slow) and < 25.76 (89% and 86% fast, according to age), with 94% sensitivity and 66% specificity (p = 6.51E-16). Further, the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 at baseline showed a positive correlation (p = 0.006, r = 0.36) with renal outcome (delta-estimated glomerular filtration rate per year, over a mean follow-up of 4.2 ± 1.2 years). Changes in the urinary epidermal growth factor and monocyte chemotactic peptide 1 were mirrored by gene expression levels in both human kidney cysts (epidermal growth factor: - 5.6-fold, fdr = 0.001; monocyte chemotactic peptide 1: 3.1-fold, fdr = 0.03) and Pkd1 knock-out mouse kidney (Egf: - 14.8-fold, fdr = 2.37E-20, Mcp1: 2.8-fold, fdr = 6.82E-15)., Conclusion: The ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 is a non-invasive pathophysiological biomarker that can be used for clinical risk stratification in autosomal dominant polycystic kidney disease., (© 2022. The Author(s).)

Aim of this study is to compare early post-operative outcomes and patient's satisfaction after skin-sparing and/or nipple-sparing mastectomy (SSM/SNSM) followed either by breast reconstruction with one-stage prepectoral implantation or two-stage technique for breast cancer (BC) or BRCA1/2 mutation.From January 2018 to December 2021, 96 patients (mean age of 51.12 ± 10.9) underwent SSM/SNSM and were divided into two groups: in group A (65 patients, 67.7%), mastectomy was followed by one-stage reconstruction; in group B (31 patients, 32.3%) by two-stage. Operative time was significantly longer in A vs. B (307.6 ± 95.7 vs. 254.4 ± 90.91; P < 0.05). Previous breast surgery was more common in B vs. A (29.0% vs. 7.7%; P < 0.05), while bilateral surgery was performed more frequently in A vs. B (40% vs. 6.5%; P = 0.001). All SSM/SNSM for BRCA1/2 mutation were followed by immediate prepectoral implantation. No significant differences were found between groups in terms of post-operative complications. At pathology, DCIS and invasive ST forms, such as multicentric/multifocal forms, were detected more frequently in B, while NST type in A (all P < 0.05). A multivariate analysis showed improved post-operative satisfaction at BREAST-Q survey in Group A (P = 0.001). Encouraging oncologic outcomes after SSM/SNSM for BC enabled the improvement of breast reconstructive techniques. One-stage reconstruction is characterized by better aesthetic outcomes and by greater patient's satisfaction. When SSM/SNSM is technically difficult to perform, as in multicentric/multifocal forms or previous breast surgery, mastectomy followed by two-stage reconstruction should be considered to achieve a radical surgery., (© 2022. The Author(s).)

Ovarian cancer has become the largest cause of gynaecological cancer-related mortality. It is typically diagnosed at a late stage and has no effective screening strategy. Ovarian cancer is a highly heterogeneous disease that can be subdivided into several molecular subsets. As a result of a greater understanding of molecular pathways involved in carcinogenesis and tumor growth, targeted agents have been approved or are in several stages of development. Poly(ADP-ribose) polymerase (PARP) inhibitors and the anti-vascular endothelial growth factor (VEGF)-A antibodies are two types of approved and most effective targeted drugs for ovarian cancer at present. With the success of bevacizumab, tyrosine kinase inhibitors which could target alternate angiogenic pathways are being studied. Furthermore, many treatments targeting the PI3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways, are being developed or are already in clinical studies. MicroRNAs have also become novel biomarkers for the therapy and clinical diagnosis of ovarian cancer. This manuscript reviews the molecular, preclinical and clinical evidence supporting the targeting of growth-dependent pathways in ovarian cancer and assesses current data related to targeted treatments beyond PARP inhibitors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Synapsin I (SynI) is a synaptic vesicle (SV)-associated phosphoprotein that modulates neurotransmission by controlling SV trafficking. The SynI C-domain contains a highly conserved ATP binding site mediating SynI oligomerization and SV clustering and an adjacent main Ca 2+ binding site, whose physiological role is unexplored. Molecular dynamics simulations revealed that the E373K point mutation irreversibly deletes Ca 2+ binding to SynI, still allowing ATP binding, but inducing a destabilization of the SynI oligomerization interface. Here, we analyzed the effects of this mutation on neurotransmitter release and short-term plasticity in excitatory and inhibitory synapses from primary hippocampal neurons. Patch-clamp recordings showed an increase in the frequency of miniature excitatory postsynaptic currents (EPSCs) that was totally occluded by exogenous Ca 2+ chelators and associated with a constitutive increase in resting terminal Ca 2+ concentrations. Evoked EPSC amplitude was also reduced, due to a decreased readily releasable pool (RRP) size. Moreover, in both excitatory and inhibitory synapses, we observed a marked impaired recovery from synaptic depression, associated with impaired RRP refilling and depletion of the recycling pool of SVs. Our study identifies SynI as a novel Ca 2+ buffer in excitatory terminals. Blocking Ca 2+ binding to SynI results in higher constitutive Ca 2+ levels that increase the probability of spontaneous release and disperse SVs. This causes a decreased size of the RRP and an impaired recovery from depression due to the failure of SV reclustering after sustained high-frequency stimulation. The results indicate a physiological role of Ca 2+ binding to SynI in the regulation of SV clustering and trafficking in nerve terminals., (© 2022. The Author(s).)

Organic semiconductors have shown great potential as efficient bioelectronic materials. Specifically, photovoltaic polymers such as the workhorse poly(thiophene) derivatives, when stimulated with visible light, can depolarize neurons and generate action potentials, an effect that has been also employed for rescuing vision in blind rats. In this context, however, the coupling of such materials with optically resonant structures to enhance those photodriven biological effects is still in its infancy. Here, we employ the optical coupling between a nanostructured metasurface and poly(3-hexylthiophene) (P3HT) to improve the bioelectronic effects occurring upon photostimulation at the abiotic-biotic interface. In particular, we designed a spectrally tuned aluminum metasurface that can resonate with P3HT, hence augmenting the effective field experienced by the polymer. In turn, this leads to an 8-fold increase in invoked inward current in cells. This enhanced activation strategy could be useful to increase the effectiveness of P3HT-based prosthetic implants for degenerative retinal disorders., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

DNA damage repair (DDR) defects are common in different cancer types, and these alterations can be exploited therapeutically. Epithelial ovarian cancer (EOC) is among the tumours with the highest percentage of hereditary cases. BRCA1 and BRCA2 predisposing pathogenic variants (PVs) were the first to be associated with EOC, whereas additional genes comprising the homologous recombination (HR) pathway have been discovered with DNA sequencing technologies. The incidence of DDR alterations among patients with metastatic prostate cancer is much higher compared to those with localized disease. Genetic testing is playing an increasingly important role in the treatment of patients with ovarian and prostate cancer. The development of poly (ADP-ribose) polymerase (PARP) inhibitors offers a therapeutic strategy for patients with EOC. One of the mechanisms of PARP inhibitors exploits the concept of synthetic lethality. Tumours with BRCA1 or BRCA2 mutations are highly sensitive to PARP inhibitors. Moreover, the synthetic lethal interaction may be exploited beyond germline BRCA mutations in the context of HR deficiency, and this is an area of ongoing research. PARP inhibitors are in advanced stages of development as a treatment for metastatic castration-resistant prostate cancer. However, there is a major concern regarding the need to identify reliable biomarkers predictive of treatment response. In this review, we explore the mechanisms of DDR, the potential for genomic analysis of ovarian and prostate cancer, and therapeutics of PARP inhibitors, along with predictive biomarkers.

Objective: In the hybrid Positron Emission Tomography/Computed Tomography (PET/CT) method, the functional evaluation is integrated with the morphological information provided by co-registered CT, still performed for attenuation correction and lesion localization. However, co-registered CT images could provide additional diagnostic information that PET alone could underestimate. To optimize the diagnostic potential of this hybrid examination, we evaluated the prevalence and the clinical significance of incidental findings detected on co-registered CT images in a cohort of multiple myeloma (MM) patients., Patients and Methods: We evaluated 112 MM patients (mean age 65.8 y), who underwent [18F]FDG-PET/CT during their regular workup. All co-registered CT images were retrospectively reviewed by two expert radiologists and each non-myelomatous incidental finding (nM-IF) was collected and clinically graded according to a nM-IF Reporting and Data System (nM-RADS). In addition, nM-IFs were classified according to anatomic localization (skull, lung, mediastinum, abdomen, breast, gastrointestinal, genitourinary and cardiovascular system and muscle/soft tissue)., Results: 163 nM-IFs were detected in 94/112 patients (83.9%) (mean value: 1.5 IFs per patient). The most interested anatomic districts were the lung (n=33; 20.2%), genitourinary (n=33; 20.2%) and gastrointestinal (n=30; 18.4%) systems. Focusing on the clinically significant findings (nM3+nM4), 92/163 (56.4%) IFs could have been required further investigations, of which 38/163 (23.3%) were potentially important and detected in 33/112 (29.5%) patients., Conclusions: The high percentage of potentially clinically significant IFs detected in MM patients emphasizes that co-registered CT images hold precious information often missed. Giving more relevance to co-registered CT with tailored acquisition and reconstruction protocols and dedicated reporting could optimize the potentiality of this multimodality imaging method with impact on clinical management.

Purpose: To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib., Patients and Methods: This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non-small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding; (ii) monotherapy dose expansion; (iii) AZD8186/abiraterone acetate (with prednisone); and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses., Results: In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID; 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction., Conclusions: AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate/prednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway-dependent cancers., (©2022 The Authors; Published by the American Association for Cancer Research.)

The ability to identify ovarian cancer (OC) at its earliest stages remains a challenge. The patients present an advanced stage at diagnosis. This heterogeneous disease has distinguishable etiology and molecular biology. Next-generation sequencing changed clinical diagnostic testing, allowing assessment of multiple genes, simultaneously, in a faster and cheaper manner than sequential single gene analysis. Technologies of proteomics, such as mass spectrometry (MS) and protein array analysis, have advanced the dissection of the underlying molecular signaling events and the proteomic characterization of OC. Proteomics analysis of OC, as well as their adaptive responses to therapy, can uncover new therapeutic choices, which can reduce the emergence of drug resistance and potentially improve patient outcomes. There is an urgent need to better understand how the genomic and epigenomic heterogeneity intrinsic to OC is reflected at the protein level, and how this information could potentially lead to prolonged survival.

On 12 March 2020, the World Health Organization (WHO) declared the novel Coronavirus (CoV) disease a global Pandemic and an emerging risk. In order to understand patterns that are typical in COVID-19 pneumonia and track the evolution of the disease, the role of the chest computed tomography (CT) is pivotal. The impact of the illness as well as the efficiency of the therapy are also monitored carefully when performing this imaging exam. Coronaviruses, specifically CoV-2, as RNA viruses, have a tendency to frequently change their genome, giving the virus beneficial characteristics such as greater transmissibility, pathogenicity and the possibility to escape the previously acquired immunity. Therefore, genome evaluation became an extremely important routine practice worldwide. In particular, in Italy, four variants have been recognised and each of them represent a specific temporal wave of the disease. Hence, our goal was to describe imaging findings of COVID-19 pneumonia, specifically its most typical imaging identified during the period of our study, and to assess whether or not SARS-CoV-2 variants determine different CT patterns. Our analyses revealed that the SARS-CoV-2 genotype seems not to interfere with the severity of CT patterns and, in particular, bilateral Ground Glass Opacities (GGOs) are the most frequent findings in all COVID-19 waves.

Purpose: To assess the role of ultrasound (US) in detecting and characterizing ductal carcinoma in situ (DCIS) of the breast and to investigate the correlation between ultrasonographic and biological features of DCIS., Methods: In total, 171 patients (mean age 44; range 39-62) with 178 lesions were retrospectively evaluated by two independent radiologists searching for US mass or non-mass lesions. Immunohistochemistry analysis was performed to determine estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. The US detection rate and pattern distribution among the lesion types were evaluated. The χ 2 test was used to evaluate the correlation between the US findings and the biological factors. Statistical significance was indicated by p values < 0.05. Inter-observer agreement was calculated by Kohen's k test., Results: US detected 35% (63/178) of all lesions. Fifty-two (83%) lesions were classified as mass lesions, and 11 (17%) as non-mass lesions (p < 0.0001). Among the mass lesions, the most common shape was irregular (79%; p < 0.0001), with 45 (87%) lesions having indistinct margins. Hypoechogenicity was the most common echo pattern (49 cases, 94%; p < 0.0001). Microcalcifications were found in 23 cases (37%; p = 0.004) and were associated with mass lesions in 15 cases (65%) and with non-mass lesions in 8 cases (35%) (p = 0.21). An almost perfect inter-observer agreement (k = 0.87) was obtained between the two radiologists. A significant ER expression was found in mass lesions (83%; p < 0.0001), with no significant PR (p = 0.89) or HER2 expression (p = 0.81). Among the lesions with microcalcifications, only 7 out of 23 cases (30%) were positive for HER2 (p = 0.09)., Conclusion: DCIS represents a heterogeneous pathological process with variable US appearance (mass-like, non-mass-like, or occult). The most common US finding is represented by mass-type, hypoechogenic lesions with indistinct margins. A significant ER expression exists among mass-type lesions, while microcalcifications seem not to be associated with HER2 expression., (© 2021. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

Background: Psycho-oncology literature pointed out that individual health outcomes may depend on patients' propensity to adopt approach or, conversely, avoidant coping strategies. Nevertheless, coping factors associated with postoperative distress remain unclear, unfolding the lack of tailored procedures to help breast cancer patients manage the psychological burden of scheduled surgery. In view of this, the present study aimed at investigating: 1. pre-/post-surgery distress variations occurring among women diagnosed with breast cancer; 2. the predictivity of approach and avoidant coping strategies and factors in affecting post-surgery perceived distress., Methods: N = 150 patients (mean age = 59.37; SD =  ± 13.23) scheduled for breast cancer surgery were administered a screening protocol consisting of the Distress Thermometer (DT) and the Brief-COPE. The DT was used to monitor patients' distress levels before and after surgery (± 7 days), whereas the Brief-COPE was adopted only preoperatively to evaluate patients' coping responses to the forthcoming surgical intervention. Non-parametric tests allowed for the detection of pre-/post-surgery variations in patients' perceived distress. Factor analysis involved the extraction and rotation of principal components derived from the Brief-COPE strategies. The predictivity of such coping factors was investigated through multiple regression (Backward Elimination)., Results: The Wilcoxon Signed-Rank Test yielded a significant variation in DT mean scores (TW = -5,68 < -zα/2 = -1,96; p < .001) indicative of lower perceived distress following surgery. The four coping factors extracted and Varimax-rotated were, respectively: 1. cognitive processing (i.e., planning + acceptance + active coping + positive reframing); 2. support provision (i.e., instrumental + emotional support); 3. emotion-oriented detachment (i.e., self-blame + behavioral disengagement + humor + denial); 4. goal-oriented detachment (i.e., self-distraction). Among these factors, support provision (B = .458; β = - .174; t = - 2.03; p = .045), encompassing two approach coping strategies, and goal-oriented detachment (B = .446; β = - .176; t = - 2.06; p = .042), consisting of one avoidant strategy, were strongly related to post-surgery distress reduction., Conclusion: The present investigation revealed that the pre-surgery adoption of supportive and goal-oriented strategies led to postoperative distress reduction among breast cancer patients. These findings highlight the importance of timely psychosocial screening and proactive interventions in order to improve patients' recovery and prognosis., (© 2021. The Author(s).)

Alterations in KRAS have been identified as the most recurring somatic variants in the multiple myeloma (MM) mutational landscape. Combining DNA and RNA sequencing, we studied 756 patients and observed KRAS as the most frequently mutated gene in patients at diagnosis; in addition, we demonstrated the persistence or de novo occurrence of the KRAS aberration at disease relapse. Small-molecule inhibitors targeting KRAS have been developed; however, they are selective for tumors carrying the KRASG12C mutation. Therefore, there is still a need to develop novel therapeutic approaches to target the KRAS mutational events found in other tumor types, including MM. We used AZD4785, a potent and selective antisense oligonucleotide that selectively targets and downregulates all KRAS isoforms, as a tool to dissect the functional sequelae secondary to KRAS silencing in MM within the context of the bone marrow niche and demonstrated its ability to significantly silence KRAS, leading to inhibition of MM tumor growth, both in vitro and in vivo, and confirming KRAS as a driver and therapeutic target in MM., (© 2021 by The American Society of Hematology.)

Background: Bilateral risk-reducing mastectomy (BRRM) has increased its popularity in the last years because of its aim to minimise the chances of developing breast cancer in high-risk patients. Women undergoing this procedure must be considered highly demanding patients given the need to combine aesthetical, functional and preventive desires. This study aims to present the authors' experience in performing BRRM followed by single-stage prepectoral reconstruction (PPBR) with implant completely covered by acellular dermal matrix (ADM) and to report indications, surgical techniques, functional and aesthetic results., Methods: A single-centre prospective data collection was carried out from January 2017 to January 2021 of patients at high risk of developing breast cancer undergoing BRRM and immediate PPBR with ADM. Patients were subdivided into two groups according to the breast shape: Group A had small and medium size breasts and Group B had large and ptotic breasts. Oncological and surgical outcomes were collected. Satisfaction with reconstruction and related quality of life were evaluated through the BREAST-Q questionnaire., Results: A total of twenty-three patients met the inclusion criteria. Seventeen patients were included in group A and six patients in group B. Average follow-up was 18.4 months. Minor complications occurred in four breasts: one seroma, one hematoma and two cases of wound dehiscence. Capsular contracture was not observed. All patients were satisfied with the final result according to the post-operative BREAST-Q questionnaire., Conclusions: Immediate prepectoral breast reconstruction could represent the ideal reconstruction option after BRRM and should be offered to all women that fulfil the inclusion criteria., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/gs-21-339). The authors have no conflicts of interest to declare., (2021 Gland Surgery. All rights reserved.)

The use of composite biomaterials as innovative bio-friendly neuronal interfaces has been poorly developed so far. Smart strategies to target neuro-pathologies are currently exploiting the mixed and complementary characteristics of composite materials to better design future neural interfaces. Here we present a polymer-based scaffold that has been rendered suitable for primary neurons by embedding graphene nanoplatelets (GnP). In particular, the growth, network formation, and functionality of primary neurons on poly(3-hydroxybutyrate) [P(3HB)] polymer supports functionalized with various concentrations of GnP were explored. After growing primary cortical neurons onto the supports for 14 days, all specimens were found to be biocompatible, revealing physiological growth and maturation of the neuronal network. When network functionality was investigated by whole patch-clamp measurements, pure P(3HB) led to changes in the action potential waveform and reduction in firing frequency, resulting in decreased neuronal excitability. However, the addition of GnP to the polymer matrix restored the electrophysiological parameters to physiological values. Interestingly, a low concentration of graphene was able to promote firing activity at a low level of injected current. The results indicate that the P(3HB)/GnP composites show great potential for electrical interfacing with primary neurons to eventually target central nervous system disorders., 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 © 2021 Moschetta, Chiacchiaretta, Cesca, Roy, Athanassiou, Benfenati, Papadopoulou and Bramini.)

Prostate cancer (PC) is the most common cancer in men and the second leading cause of cancer-related death worldwide. Many therapeutic advances over the last two decades have led to an improvement in the survival of patients with metastatic PC, yet the majority of these patients still succumb to their disease. Antiagiogenic therapies have shown substantial benefits for many types of cancer but only a marginal benefit for PC. Ongoing clinical trials investigate antiangiogenic monotherapies or combination therapies. Despite the important role of angiogenesis in PC, clinical trials in refractory castration-resistant PC (CRPC) have demonstrated increased toxicity with no clinical benefit. A better understanding of the mechanism of angiogenesis may help to understand the failure of trials, possibly leading to the development of new targeted anti-angiogenic therapies in PC. These could include the identification of specific subsets of patients who might benefit from these therapeutic strategies. This paper provides a comprehensive review of the pathways involved in the angiogenesis, the chemotherapeutic agents with antiangiogenic activity, the available studies on anti-angiogenic agents and the potential mechanisms of resistance., Competing Interests: The authors declare no conflict of interest.

Prostate cancer (PC) is the second most common cancer in men worldwide. Due to the large-scale sequencing efforts, there is currently a better understanding of the genomic landscape of PC. The identification of defects in DNA repair genes has led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients. The identification of molecularly defined subgroups of patients has also other clinical implications; for example, we now know that carriers of breast cancer 2 ( BRCA2 ) pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate; BRCA2 PSVs confer lower overall survival (OS). Distinct tumor PSV, methylation, and expression patterns have been identified in BRCA2 compared with non- BRCA2 mutant prostate tumors. Several DNA damage response and repair (DDR)-targeting agents are currently being evaluated either as single agents or in combination in patients with PC. In this review article, we highlight the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC and offer an overview of new agents being developed for the treatment of PC.

The use of biomarkers in medicine has become essential in clinical practice in order to help with diagnosis, prognostication and prediction of treatment response. Since Alexander Breslow's original report on "melanoma and prognostic values of thickness", providing the first biomarker for melanoma, many promising new biomarkers have followed. These include serum markers, such as lactate dehydrogenase and S100 calcium-binding protein B. However, as our understanding of the DNA mutational profile progresses, new gene targets and proteins have been identified. These include point mutations, such as mutations of the BRAF gene and tumour suppressor gene tP53. At present, only a small number of the available biomarkers are being utilised, but this may soon change as more studies are published. The aim of this article is to provide a comprehensive review of melanoma biomarkers and their utility for current and, potentially, future clinical practice.

Suppressive myeloid cells mediate resistance to immune checkpoint blockade. PI3Kγ inhibition can target suppressive macrophages, and enhance efficacy of immune checkpoint inhibitors. However, how PI3Kγ inhibitors function in different tumor microenvironments (TME) to activate specific immune cells is underexplored. The effect of the novel PI3Kγ inhibitor AZD3458 was assessed in preclinical models. AZD3458 enhanced antitumor activity of immune checkpoint inhibitors in 4T1, CT26, and MC38 syngeneic models, increasing CD8 + T-cell activation status. Immune and TME biomarker analysis of MC38 tumors revealed that AZD3458 monotherapy or combination treatment did not repolarize the phenotype of tumor-associated macrophage cells but induced gene signatures associated with LPS and type II INF activation. The activation biomarkers were present across tumor macrophages that appear phenotypically heterogenous. AZD3458 alone or in combination with PD-1-blocking antibodies promoted an increase in antigen-presenting (MHCII + ) and cytotoxic (iNOS + )-activated macrophages, as well as dendritic cell activation. AZD3458 reduced IL-10 secretion and signaling in primary human macrophages and murine tumor-associated macrophages, but did not strongly regulate IL-12 as observed in other studies. Therefore, rather than polarizing tumor macrophages, PI3Kγ inhibition with AZD3458 promotes a cytotoxic switch of macrophages into antigen-presenting activated macrophages, resulting in CD8 T-cell-mediated antitumor activity with immune checkpoint inhibitors associated with tumor and peripheral immune activation., (©2021 American Association for Cancer Research.)

Clonal evolution drives tumor progression, dissemination, and relapse in multiple myeloma (MM), with most patients dying of relapsed disease. This multistage process requires tumor cells to enter the circulation, extravasate, and colonize distant bone marrow (BM) sites. Here, we developed a fluorescent or DNA-barcode clone-tracking system on MM PrEDiCT (progression through evolution and dissemination of clonal tumor cells) xenograft mouse model to study clonal behavior within the BM microenvironment. We showed that only the few clones that successfully adapt to the BM microenvironment can enter the circulation and colonize distant BM sites. RNA sequencing of primary and distant-site MM tumor cells revealed a progression signature sequentially activated along human MM progression and significantly associated with overall survival when evaluated against patient data sets. A total of 28 genes were then computationally predicted to be master regulators (MRs) of MM progression. HMGA1 and PA2G4 were validated in vivo using CRISPR-Cas9 in the PrEDiCT model and were shown to be significantly depleted in distant BM sites, indicating their role in MM progression and dissemination. Loss of HMGA1 and PA2G4 also compromised the proliferation, migration, and adhesion abilities of MM cells in vitro. Overall, our model successfully recapitulates key characteristics of human MM disease progression and identified potential new therapeutic targets for MM., (© 2021 by The American Society of Hematology.)

Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co-mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.

Purpose: Diffusion-weighted imaging with the calculation of an apparent diffusion coefficient (ADC) has been proposed as a quantitative biomarker on contrast-enhanced MRI (CE-MRI) of the breast. There is a need to approve a generalizable ADC cutoff. The purpose of this study was to evaluate whether a predefined ADC cutoff allows downgrading of BI-RADS 4 lesions on CE-MRI, avoiding unnecessary biopsies., Experimental Design: This was a retrospective, multicentric, cross-sectional study. Data from five centers were pooled on the individual lesion level. Eligible patients had a BI-RADS 4 rating on CE-MRI. For each center, two breast radiologists evaluated the images. Data on lesion morphology (mass, non-mass), size, and ADC were collected. Histology was the standard of reference. A previously suggested ADC cutoff (≥1.5 × 10 -3 mm 2 /second) was applied. A negative likelihood ratio of 0.1 or lower was considered as a rule-out criterion for breast cancer. Diagnostic performance indices were calculated by ROC analysis., Results: There were 657 female patients (mean age, 42; SD, 14.1) with 696 BI-RADS 4 lesions included. Disease prevalence was 59.5% (414/696). The area under the ROC curve was 0.784. Applying the investigated ADC cutoff, sensitivity was 96.6% (400/414). The potential reduction of unnecessary biopsies was 32.6% (92/282)., Conclusions: An ADC cutoff of ≥1.5 × 10 -3 mm 2 /second allows downgrading of lesions classified as BI-RADS 4 on breast CE-MRI. One-third of unnecessary biopsies could thus be avoided., (©2021 American Association for Cancer Research.)

Vaccines, cytokines, and adoptive cellular therapies (ACT) represent immuno-therapeutic modalities with great development potential, and they are currently approved for the treatment of a limited number of advanced malignancies. The most up-to-date knowledge on the regulation of the anti-cancer immune response has recently led to the development and approval of inhibitors of immune checkpoints, which have produced unprecedented clinical activity in several hard to treat solid malignancies. However, severe adverse events (AEs) represent a limitation to the use of these drugs. Currently approved checkpoint inhibitors block cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand (PD-L1), resulted in increased survival of patients with several solid and hematologic malignancies. The most common treatment AEs associated with these drugs are fatigue, rash, and auto-immune/inflammatory reactions. Many of the immune-related AEs are reversible and the strategies for their management include supportive care either with or without treatment withdrawal; nevertheless, in severe cases, hospitalization and treatment with immune suppressants, and/or immunomodulators may be required. Steroid therapy is a critical component of the treatment algorithm; nevertheless, the associated immunosuppression may compromise the antitumor response. This article provides a comprehensive and narrative review of luminal gastrointestinal and hepatic complications, including recommendations for their investigation and management., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-7361). SB serves as an unpaid editorial board member of Annals of Translational Medicine from Nov 2019 to Oct 2021. The other authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Neuroinflammation is associated with synapse dysfunction and cognitive decline in patients and animal models. One candidate for translating the inflammatory stress into structural and functional changes in neural networks is the transcriptional repressor RE1-silencing transcription factor (REST) that regulates the expression of a wide cluster of neuron-specific genes during neurogenesis and in mature neurons. To study the cellular and molecular pathways activated under inflammatory conditions mimicking the experimental autoimmune encephalomyelitis (EAE) environment, we analyzed REST activity in neuroblastoma cells and mouse cortical neurons treated with activated T cell or microglia supernatant and distinct pro-inflammatory cytokines. We found that REST is activated by a variety of neuroinflammatory stimuli in both neuroblastoma cells and primary neurons, indicating that a vast transcriptional change is triggered during neuroinflammation. While a dual activation of REST and its dominant-negative splicing isoform REST4 was observed in N2a neuroblastoma cells, primary neurons responded with a pure full-length REST upregulation in the absence of changes in REST4 expression. In both cases, REST upregulation was associated with activation of Wnt signaling and increased nuclear translocation of β-catenin, a well-known intracellular transduction pathway in neuroinflammation. Among single cytokines, IL-1β caused a potent and prompt increase in REST transcription and translation in neurons, which promoted a delayed and strong synaptic downscaling specific for excitatory synapses, with decreased frequency and amplitude of spontaneous synaptic currents, decreased density of excitatory synaptic connections, and decreased frequency of action potential-evoked Ca 2+ transients. Most important, the IL-1β effects on excitatory transmission were strictly REST dependent, as conditional deletion of REST completely occluded the effects of IL-1β activation on synaptic transmission and network excitability. Our results demonstrate that REST upregulation represents a new pathogenic mechanism for the synaptic dysfunctions observed under neuroinflammatory conditions and identify the REST pathway as therapeutic target for EAE and, potentially, for multiple sclerosis.

Melanoma of unknown primary site (MUP) comprises 3-4 % of all melanomas. It mostly presents in lymph nodes (LNs), followed by subcutaneous sites, and visceral organs; nevertheless, there is a trend of increase in the relative incidence of visceral counterpart in recent years. Spontaneous regression of the primary lesion is a well-established theory, based on the evidence that melanoma can undergo regression at the primary site. MUP and stage-matched melanoma of known primary site (MKP) share similar prognostic factors. The survival rate of patients with MUP has been compared to those with stage-matched MKP. Multiple studies conducted before the era of novel therapy with immune checkpoint or BRAF/MEK inhibitors found improved survival in favor of MUP, whereas others reported equivalent or poorer outcomes. Here, we discuss the genetic and molecular features, epidemiology, diagnosis, prognostic factors, survival, and treatment of MUP in comparison with MKP, in the pre- and post-novel therapy era., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)