Search

Background: IL-23 inhibitors were recently approved for the treatment of skin psoriasis and psoriatic arthritis (PsA). Risankizumab, a humanized monoclonal antibody that specifically binds the p19 subunit of IL-23, has proven effective on PsA in two randomized controlled trials. To date, only a few real-world data are available on this topic., Methods: Our study aimed to prospectively evaluate the effectiveness of risankizumab in patients with PsA in a real-world setting. For this purpose, both rheumatologic and dermatologic assessments were performed at baseline and after 28-40 weeks of continuous risankizumab administration. Moreover, joint and entheses ultrasound assessment was performed at the mentioned time points. The rheumatologic assessment was carried out by means of the following scores: (i) clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA); (ii) Leeds Enthesitis Index (LEI); (iii) Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and (iii) Bath Ankylosing Spondylitis Functional Index (BASFI). The degree of skin involvement was measured by both the Psoriasis Area and Severity Index (PASI) and Physician Global Assessment (PGA). Quality of life was assessed by the Health Assessment Questionnaire (HAQ) and Dermatology Life Quality Index (DLQI). Ultrasound assessment of joints and entheses was performed on the basis of the EULAR-OMERACT score., Results: After treatment, cDAPSA decreased from a mean value of 12.9 ± 7.6 to 7.0 ± 6.1 (P < 0.001), and the median PD score significantly decreased from baseline (3; range 1-8) to TP1 (1; range 0-7) (P < 0.001). PASI score also decreased from 8.4 ± 4.9 to 0.3 ± 0.5 (P < 0.001), and PGA from 3.1 ± 1.0 to 0.4 ± 0.5 (P < 0.001)., Conclusion: We can conclude that risankizumab led to substantial improvement in both skin and joint involvement., (© 2024 the International Society of Dermatology.)

Sodium hypochlorite (NaOCl) is widely recognized for its broad-spectrum antimicrobial efficacy in skin wound care. This study investigates the effectiveness of NaOCl against a range of bacterial and fungal isolates from pressure ulcer (PU) patients. We analyzed 20 bacterial isolates from PU patients, comprising carbapenem-resistant Klebsiella pneumoniae (CRKP), multidrug-resistant Acinetobacter baumannii (MDRAB), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible Staphylococcus aureus (MSSA), along with 5 Candida albicans isolates. Antibiotic resistance profiles were determined using standard susceptibility testing. Whole-genome sequencing (WGS) was employed to identify antimicrobial resistance genes (ARGs) and disinfectant resistance genes (DRGs). Genetic determinants of biofilm formation were also assessed. The antimicrobial activity of NaOCl was evaluated by determining the minimum inhibitory concentration (MIC) and the minimal biofilm eradication concentration (MBEC) for both planktonic and biofilm-associated cells. CRKP and MDRAB showed resistance to fluoroquinolones and carbapenems, while MRSA exhibited resistance to β-lactams and levofloxacin. MSSA displayed a comparatively lower resistance profile. WGS identified significant numbers of ARGs in CRKP and MDRAB, with fewer DRGs compared to MRSA and MSSA. All isolates possessed genes associated with fimbriae production and adhesion, correlating with pronounced biofilm biomass production. NaOCl demonstrated substantial antimicrobial activity against both planktonic cells and biofilms. The MIC 90 for planktonic bacterial cells was 0.125 mg/mL, and the MBEC 90 ranged from 0.225 to 0.5 mg/mL. For planktonic C. albicans , the MIC 90 was 0.150 mg/mL, and the MBEC 90 was 0.250 mg/mL. These results highlight the challenge in treating biofilm-associated infections and underscore the potential of NaOCl as a robust antimicrobial agent against difficult-to-treat biofilm infections at concentrations lower than those typically found in commercial disinfectants., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Fabrizio, Sivori, Cavallo, Truglio, Toma, Sperati, Francalancia, Obregon, Pamparau, Kovacs, Pimpinelli and Di Domenico.)

Introduction: When Soft Tissue Sarcomas are localized in the groin area, they pose specific challenges due to their proximity to important structures. These tumors exhibit elevated complication rates and a higher local recurrence rate compared to their locations in other limbs. The objective of this paper is to analyze a series of patients affected by soft tissue sarcomas in the adductor area of the proximal thigh. The analysis aims to elucidate the epidemiology, diagnostic and therapeutic approaches, complications, and outcomes. Additionally, the study seeks potential prognostic factors and to determine patients at a heightened risk of postoperative complications., Patients and Methods: all patients who underwent surgeries for primary soft tissue sarcomas of the adductor area between October 2006 and March 2022 in a tertiary research hospital were valued. Epidemiology, tumor characteristics and therapeutic approaches were analyzed to identify risk factors for complications and local recurrences; survival was considered a secondary outcome., Results: The series comprised 43 patients, 26 males and 17 females, with an average age of 63.3 years. The most frequent histology was liposarcoma, followed by undifferentiated forms. All patients reported the presence of masses, with associated pain in 27.9% of cases. Limb-sparing surgery was performed in 86.0% of cases. Early and late complications were experienced by 34.9% and 20.0% of patients, respectively, with wound dehiscence being the most frequent problem. The recurrence rate was 9.3%, with no recurrences observed in low-grade patients. At an average follow-up of 51 months, 18 patients (41.9%) were alive, two of which with distant metastases., Conclusion: The present series provides evidence that when Soft Tissue Sarcomas localized in the groin area are managed in specialized centers, the rates of recurrence and complications are not significantly different from those observed in other anatomical sites., Competing Interests: none., (© 2024 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: The purpose of this study is to evaluate the clinical determinants of complete response in locally advanced basal cell carcinoma (laBCC) patients receiving Sonidegib in a real-life, retrospective, observational study.  Hedgehog pathway inhibitors (Vismodegib and Sonidegib) are approved for the systemic treatment of locally advanced basal cell carcinoma (laBCC). The objective response rate was the primary endpoint of the trials for both drugs., Patients and Methods: Adult patients with laBCC treated with Sonidegib at the Dermato-Oncology Unit of IFO San Gallicano between June 2020 and September 2022 were included in the study. Patient, tumor, and treatment characteristics were recorded. The complete response rate was the primary outcome. The median time to the best response and complete response were the secondary outcomes. Treatment-related adverse events (TRAEs) and dose adjustments were recorded., Results: Of the 19 patients included in the study, eight (42.1%) achieved a complete response, seven (36.8%) had a partial response, and four experienced progressive disease (21%). The median time to the best response was 3 months in the group of patients with partial response (range 2.0-4.0, with three patients not evaluable) and 3.5 months in the group of patients with complete response (range 2-5). TRAEs occurred in 14 (73.6%) patients, with 8 (57.1%) reporting ≤2 TRAE categories and 6 (42.8%) >2. A total of 78.9% of patients received a modified treatment schedule; 12.5% of patients who achieved a complete response received full dosage from the beginning to the end of treatment, compared with 27.3% of those with a partial response., Conclusions: The associations between the clinical outcome of interest (objective response rate) and the clinicopathological and treatment characteristics were evaluated. No statistically significant association was observed. Our analysis confirms the observation that no statistically significant correlation exists between clinical response and Sonidegib alternate dose regimen.

Objective: Lichen sclerosus is a chronic, inflammatory, progressive skin disease predominantly affecting anogenital areas. Vulvar lichen sclerosus (VLS) is one of the most common conditions treated in vulvar clinics; most patients report distressing symptoms of itching, burning, stinging, and pain (particularly during or after sexual intercourse). A preliminary, prospective, single-center study was performed to investigate the efficacy of hyaluronan hybrid cooperative complex (HCC) comprising high and low molecular weight hyaluronic acid to treat menopausal women with VLS., Patients and Methods: Patients (N = 30) received two HCC injections at 32 mg/ml (one month apart). At baseline and one and six months after treatment, patients completed validated psychometric questionnaires to assess their self-reported pain, itching, and dryness using the Visual Analogue Scale (VAS) and sexual function by the Female Sexual Function Index (FSFI)., Results: After treatment with HCC, no side effects or complications were reported. VAS scores showed a trend towards reduced pain and itching intensity, and there was a statistically significant reduction in median VAS score for dryness at follow-up vs. baseline (p=0.038). For sexual function, there was a statistically significant improvement in lubrication (p=0.001) and orgasm (p=0.001) FSFI domains., Conclusions: Overall, this preliminary study demonstrated the promising efficacy of HCC in menopausal women with VLS without side effects.

Background: Molecular Tumor Boards (MTB) operating in real-world have generated limited consensus on good practices for accrual, actionable alteration mapping, and outcome metrics. These topics are addressed herein in 124 MTB patients, all real-world accrued at progression, and lacking approved therapy options., Methods: Actionable genomic alterations identified by tumor DNA (tDNA) and circulating tumor DNA (ctDNA) profiling were mapped by customized OncoKB criteria to reflect diagnostic/therapeutic indications as approved in Europe. Alterations were considered non-SoC when mapped at either OncoKB level 3, regardless of tDNA/ctDNA origin, or at OncoKB levels 1/2, provided they were undetectable in matched tDNA, and had not been exploited in previous therapy lines., Results: Altogether, actionable alterations were detected in 54/124 (43.5%) MTB patients, but only in 39 cases (31%) were these alterations (25 from tDNA, 14 from ctDNA) actionable/unexploited, e.g. they had not resulted in the assignment of pre-MTB treatments. Interestingly, actionable and actionable/unexploited alterations both decreased (37.5% and 22.7% respectively) in a subset of 88 MTB patients profiled by tDNA-only, but increased considerably (77.7% and 66.7%) in 18 distinct patients undergoing combined tDNA/ctDNA testing, approaching the potential treatment opportunities (76.9%) in 147 treatment-naïve patients undergoing routine tDNA profiling for the first time. Non-SoC therapy was MTB-recommended to all 39 patients with actionable/unexploited alterations, but only 22 (56%) accessed the applicable drug, mainly due to clinical deterioration, lengthy drug-gathering procedures, and geographical distance from recruiting clinical trials. Partial response and stable disease were recorded in 8 and 7 of 19 evaluable patients, respectively. The time to progression (TTP) ratio (MTB-recommended treatment vs last pre-MTB treatment) exceeded the conventional Von Hoff 1.3 cut-off in 9/19 cases, high absolute TTP and Von Hoff values coinciding in 3 cases. Retrospectively, 8 patients receiving post-MTB treatment(s) as per physician's choice were noted to have a much longer overall survival from MTB accrual than 11 patients who had received no further treatment (35.09 vs 6.67 months, p = 0.006)., Conclusions: MTB-recommended/non-SoC treatments are effective, including those assigned by ctDNA-only alterations. However, real-world MTBs may inadvertently recruit patients electively susceptible to diverse and/or multiple treatments., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The COVID-19 outbreak had a negative psychological impact on cancer patients. In this study, we analyzed emotional distress and quality of life in patients diagnosed with sarcoma during the first year of the pandemic compared to the previous year., Methods: We retrospectively enrolled patients with soft tissue, bone sarcoma, and aggressive benign musculoskeletal diseases diagnosed during the pandemic (COVID group) or the year before (control group) at the IRCCS Regina Elena National Cancer Institute in Rome. Patients who had undergone a psychological assessment with the EORTC QLQ-C30 and the Distress Thermometer at diagnosis were included in the final analysis. We analyzed whether there is a difference in the various domains of quality of life between the two groups and whether there are changes over time in each group., Results: We enrolled 114 patients (72 control group; 42 COVID group), affected by soft tissue (64%), bone sarcoma (29%), and aggressive benign musculoskeletal diseases (7%). We did not observe significant differences in the health-related quality of life domains in the control and COVID groups, except for the financial domain ( p  = 0.039), with 9.7% vs. 23.8% of patients with a score > 0 in the control and COVID groups, respectively. We observed emotional distress at diagnosis in 48.6% of patients in the control group vs. 69.0% in the COVID group ( p = 0.034). In the control group, we observed an improvement in physical function ( p = 0.043) and in QoL ( p = 0.022), while in the COVID group, we observed a deterioration in role function ( p = 0.044) during follow-up. In the COVID group, 22.2% of patients were concerned about COVID-19, 61.1% by tumor, 91.1% stated that the pandemic worsened their subjective perception of cancer, and 19.4% perceived that their quality of care had worsened., Conclusion: We observed a higher level of distress among patients diagnosed during the pandemic compared to the year before, probably due to the increased concern for both infection and cancer, the worsened perception of health status, and the perception of a poorer quality of health care., 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 © 2023 Onesti, Vari, Minghelli, Nardozza, Rossi, Sperati, Checcucci, Faltyn, Cercato, Cosimati, Salvatori, Biagini, Ciliberto, Ferraresi and Maggi.)

Purpose: In our institution, stereotactic radiosurgery of multiple brain metastases is performed with the CyberKnife® (CK) device, using fixed/Iris collimators. In this study, nineteen fixed/Iris plans were recalculated with the multileaf collimator (MLC), to assess if it is possible to produce plans with comparable dosimetric overall quality., Materials and Methods: For consistent comparisons, MLC plans were re-optimized and re-normalized in order to achieve the same minimum dose for the total planning target volume (PTV tot ). Conformation number (CN), homogeneity index (HI) and dose gradient index (DGI) metrics were evaluated. The dose to the brain was evaluated as the volume receiving 12 Gy (V 12 ) and as the integral dose (ID). The normal tissue complication probability (NTCP) for brain radionecrosis was calculated as a function of V 12 ., Results: The reoptimized plans were reviewed by the radiation oncologist and were found clinically acceptable according to the The American Association of Physicists in Medicine (AAPM) Task Group-101 protocol. However, fixed/Iris plans provided significantly higher CN (+8.6%), HI (+2.2%), and DGI (+44.0%) values, and significantly lower ID values (-35.9%). For PTV tot less than the median value of 2.58cc, fixed/Iris plans provided significantly lower NTCP values. On the other side, MLC plans provided significantly lower treatment times (-18.4%), number of monitor units (-33.3%), beams (-46.0%) and nodes (-21.3%)., Conclusions: CK-MLC plans for the stereotactic treatment of brain multi metastases could provide an important advantage in terms of treatment duration. However, to contain the increased risk for brain radionecrosis, it could be useful to calculate MLC plans only for patients with large PTV tot ., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Medical Physics.)

Background: Lichen sclerosus is a chronic relapsing inflammatory skin disease, which involves most commonly the anogenital region. The gold standard in treatment is ultra-potent topical steroids (clobetasol propionate): it aims at controlling the symptoms, stopping further scarring and distortion, and reducing the risk of cancer., Objectives: The aim of this preliminary study is to evaluate the efficacy of injecting Hybrid Cooperative Complexes of Hyaluronic Acid (HCC) for the treatment of vulvar lichen sclerosus (VLS)., Methods: Twenty female adult patients (range: 21-78 years), aged over 18, with histopathological diagnosis of lichen sclerosus and good general conditions were enrolled. Patients underwent HCC infiltration every month, for 3 times. Patients were evaluated at baseline (T0) and after one (T1) and six months (T2) after treatment. During every visit, each patient was studied clinically and with videothermography. Itching, burning sensation, pain, and dyspareunia were reported by patients at T0, T1, and T2. The effectiveness of the treatment on patients' quality of life and sexual function was evaluated using the Dermatology Life Quality Index (DLQI) and the Female Sexual Function Index (FSFI) at T0 and at T2., Results: The results of this preliminary study are very promising, in fact, all patients had a significant reduction in most symptoms after 1 and 6 months of HCC treatment. The reduction of patients with itching (p value ≤ 0.001), pain (p value = 0.031), and burning sensation (p = 0.004) at 6 months is significant. The analysis of DLQI scores revealed a significant improvement in patients' quality of life. At baseline, the average score of DLQI (±SD) was 5.89 ± 3.68 while at follow-up it was 3.42 ± 2.36 (p = 0.002)., Conclusions: Our preliminary study has demonstrated the validity and tolerability of HCC infiltrations in patients with VLS, and the effectiveness of HCC in reducing symptoms and, thus, to improve sexuality and patient quality of life., (© 2022 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Rationale: Metastatic melanoma is the most aggressive and dangerous form of skin cancer. The introduction of immunotherapy with Immune checkpoint Inhibitors (ICI) and of targeted therapy with BRAF and MEK inhibitors for BRAF mutated melanoma, has greatly improved the clinical outcome of these patients. Nevertheless, response to therapy remains highly variable and the development of drug resistance continues to be a daunting challenge. Within this context there is a need to develop diagnostic tools capable of predicting response or resistance to therapy in order to select the best therapeutic approach. Over the years, accumulating evidence brought to light the role of microRNAs (miRNAs) as disease biomarkers. Methods: In particular, the detection of miRNAs in whole blood or specific blood components such as serum or plasma, allows these molecules to be good candidates for diagnosis, prognosis and for monitoring response to anticancer therapy. In this paper, we evaluated circulating basal levels of 6 previously identified miRNAs in serum samples of 70 BRAF-mutant melanoma patients before starting targeted therapy. Results: Results show that the circulating levels of the oncosuppressor miR-579-3p and of the oncomiR miR-4488 are able to predict progression free survival (PFS) but not overall survival (OS). Most importantly, we observed that the best predictor of disease outcome is represented by the ratio of circulating miR-4488 vs. miR-579-3p (miRatio). Finally, the combination of the Lactate dehydrogenase (LDH) blood levels with the two circulating miRNAs alone or together did not produce any improvement in predicting PFS indicating that miR-579-3p and miR-4488 are independent predictors of PFS as compared to LDH. Conclusions: All together these data underscored the relevance of circulating miRNAs as suitable tools to predict therapy response in melanoma and maybe further developed as companion diagnostics in the clinic., Competing Interests: Competing Interests: All the authors declare no conflict of interest with the exception of P.A.A. Paolo A. Ascierto has/had a consultant/advisory role for Bristol MyersSquibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. Travel support by Pfizer. The funders of this study had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (© The author(s).)

The Hippo pathway and its two key effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are consistently altered in breast cancer. Pivotal regulators of cell metabolism such as the AMP-activated protein kinase (AMPK), Stearoyl-CoA-desaturase 1 (SCD1), and HMG-CoA reductase (HMGCR) are relevant modulators of TAZ/YAP activity. In this prospective study, we measured the tumor expression of TAZ, YAP, AMPK, SCD1, and HMGCR by immunohistochemistry in 65 Her2+ breast cancer patients who underwent trastuzumab-based neoadjuvant treatment. The aim of the study was to assess the impact of the immunohistochemical expression of the Hippo pathway transducers and cell metabolism regulators on pathological complete response. Low expression of cytoplasmic TAZ, both alone and in the context of a composite signature identified by machine learning including also low nuclear levels of YAP and HMGCR and high cytoplasmic levels of SCD1, was a predictor of residual disease in the univariate logistic regression. This finding was not confirmed in the multivariate model including estrogen receptor > 70% and body mass index > 20. However, our findings were concordant with overall survival data from the TCGA cohort. Our results, possibly affected by the relatively small sample size of this study population, deserve further investigation in adequately sized, ad hoc prospective studies.

Background: The COVID-19 pandemic led to a rapid reorganization of healthcare activities, leading to reduced access to clinics, interruption of screenings, and treatment schedule modifications in several cancer types. Few data are available on sarcomas. We analyzed COVID-19-related diagnostic delay in a sarcoma referral center in Italy., Methods: We retrospectively enrolled in this study patients with histological diagnosis of soft tissue or bone sarcoma and aggressive benign musculoskeletal diseases obtained during the first year of the pandemic (Covid group) or the year before (Control group) and followed at the Regina Elena National Cancer Institute in Rome. The primary endpoint was the time from the first symptom to histological diagnosis., Results: We evaluated 372 patients, 185 of whom were eligible for primary endpoint analysis (92 patients in the Control group and 93 patients in the Covid group). The patients were affected by soft tissue sarcoma in most cases (63.0% and 66.7% in Covid and Control groups, respectively). We observed a diagnostic delay in the Covid group with a median time from the first symptom to the definitive histological diagnosis of 103.00 days (95% CI 92.77-113.23) vs . 90.00 days (95% CI 69.49-110.51) in the Control group ( p = 0.024), but not a delay in treatment beginning (151 days, 95% CI 132.9-169.1 vs . 144 days, 95% CI 120.3-167.7, respectively, p = 0.208). No differences in stage at diagnosis were observed (12% vs . 16.5% of patients with metastatic disease at diagnosis in the Covid and Control groups, respectively, p = 0.380). Progression-free survival ( p = 0.897) and overall survival ( p = 0.725) were comparable in the subgroup of patients affected by soft tissue sarcoma., Conclusions: A delay in sarcoma diagnosis but not in starting treatment has been observed during the first year of the COVID-19 pandemic. Nevertheless, no difference in stage at diagnosis or in terms of survival has been observed., 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. The reviewer DM declared a past co-authorship with the author SV and a shared parent affiliation with the author AC to the handling editor at the time of review. The author CEO declared past co-authorships with the Editor RG., (Copyright © 2022 Onesti, Vari, Nardozza, Maggi, Minghelli, Rossi, Sperati, Checcucci, Faltyn, Cercato, Cosimati, Biagini, Ciliberto and Ferraresi.)

Introduction: Psoriasis has not been directly linked to a poor prognosis for COVID-19, yet immunomodulatory agents used for its management may lead to increased vulnerability to the dangerous complications of SARS-CoV-2 infection, as well as impair the effectiveness of the recently introduced vaccines. The three-dose antibody response trend and the safety of BNT162b2 mRNA vaccine in psoriasis patients treated with biologic drugs have remained under-researched., Materials and Methods: Forty-five psoriatic patients on biologic treatment were enrolled to evaluate their humoral response to three doses of BNT162b2. IgG titers anti-SARS-CoV-2 spike protein were evaluated at baseline (day 0, first dose), after 3 weeks (second dose), four weeks post-second dose, at the time of the third dose administration and 4 weeks post-third dose. Seropositivity was defined as IgG ≥15 antibody-binding units (BAU)/mL. Data on vaccine safety were also collected by interview at each visit., Results: A statistically significant increase in antibody titers was observed after each dose of vaccine compared with baseline, with no significant differences between patients and controls. Methotrexate used in combination with biologics has been shown to negatively influence the antibody response to the vaccine. On the contrary, increasing body mass index (BMI) positively influenced the antibody response. No adverse effects were reported, and no relapses of psoriasis were observed in the weeks following vaccine administration in our study population., Conclusions: Our data are largely consistent with the recent literature on this topic confirming the substantial efficacy and safety of BNT162b2 mRNA vaccine on psoriatic patients treated with biologics of different types and support the recommendation to perform additional doses in this specific subgroup of patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Graceffa, Sperati, Bonifati, Spoletini, Lora, Pimpinelli, Pontone, Pellini, Di Bella, Morrone and Cristaudo.)

Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I → KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy., (© 2022. The Author(s).)

Lichen Sclerosus is a chronic-relapsing inflammatory skin disease usually involving the anogenital region lacking a resolutive therapy. Potent to high-potent topical corticosteroids are considered to be the standard first-line treatment. The objective of this preliminary study is to evaluate the efficacy of injecting Hybrid Cooperative Complexes of Hyaluronic Acid (HCC) in the treatment of Vulvar Lichen Sclerosus (VLS). Twenty-female patients (range 21-78 years) with histopathologic diagnosis of lichen sclerosus and good general conditions were enrolled. Patients underwent HCC infiltration every month, for three times. Patients had been assessed at baseline (T0) and after 1 and 6 months from treatment (T1 and T2, respectively). Clinical evaluation was executed in every visit. Itching, burning sensation, pain and dyspareunia were reported by a patient at T0, T1, and at T2. The effectiveness of the treatment on patients' quality life and sexual life was assessed using the Dermatology Life Quality Index (DLQI) at T0 and at T2. During or after the treatment no complications or side-effects were observed. All patients had a significant reduction in most symptoms after 1 and 6 months of HCC treatment. The reduction of patients with itching (p ≤ 0.001), pain (p = 0.031), burning sensation (p = 0.004) at 6 months is significant. The analysis of DLQI scores revealed a significant improvement in patients' quality of life. The DLQI mean score (±SD) at baseline and at follow-up was 5.89 ± 3.68 and 3.42 ± 2.36 (p = 0.002), respectively. Our preliminary study has demonstrated the safety and tolerability of HCC infiltrations in patients with VLS, and the effectiveness of HCC in reducing symptoms and, thus, to improve patient Quality of Life., (© 2022 Wiley Periodicals LLC.)

Introduction: To assess the diagnostic accuracy of CESM and 3T MRI compared to full-field digital mammography (FFDM), plus US, in the evaluation of advanced breast lesions. Materials and Methods: Consenting women with suspicious findings underwent FFDM, US, CESM and 3T MRI. Breast lesions were histologically assessed, with histology being the gold standard. Two experienced breast radiologists, blinded to cancer status, read the images. Diagnostic accuracy of (1) CESM as an adjunct to FFDM and US, and (2) 3T MRI as an adjunct to CESM compared to FFDM and US, was assessed. Measures of accuracy were sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). Results: There were 118 patients included along with 142 histologically characterized lesions. K agreement values were 0.69, 0.68, 0.63 and 0.56 for concordance between the gold standard and FFDM, FFDM + US, CESM and MRI, respectively (p < 0.001, for all). K concordance for CESM was 0.81 with FFDM + US and 0.73 with MRI (p value < 0.001 for all). Conclusions: CESM may represent a valuable alternative and/or an integrating technique to MRI in the evaluation of breast cancer patients.

Background: Compared with people without cancer, people with cancer who receive anticoagulant treatment for venous thromboembolism (VTE) are more likely to develop recurrent VTE., Objectives: To compare the efficacy and safety of three types of parenteral anticoagulants (i.e. fixed-dose low molecular weight heparin (LMWH), adjusted-dose unfractionated heparin (UFH), and fondaparinux) for the initial treatment of VTE in people with cancer., Search Methods: We performed a comprehensive search in the following major databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid) and Embase (via Ovid). We also handsearched conference proceedings, checked references of included studies, and searched for ongoing studies. This update of the systematic review is based on the findings of a literature search conducted on 14 August 2021., Selection Criteria: Randomised controlled trials (RCTs) assessing the benefits and harms of LMWH, UFH, and fondaparinux in people with cancer and objectively confirmed VTE., Data Collection and Analysis: Using a standardised form, we extracted data - in duplicate - on study design, participants, interventions, outcomes of interest, and risk of bias. Outcomes of interest included all-cause mortality, symptomatic VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia. We assessed the certainty of evidence for each outcome using the GRADE approach., Main Results: Of 11,484 identified citations, 3073 were unique citations and 15 RCTs fulfilled the eligibility criteria, none of which were identified in the latest search. These trials enrolled 1615 participants with cancer and VTE: 13 compared LMWH with UFH; one compared fondaparinux with UFH and LMWH; and one compared dalteparin with tinzaparin, two different types of low molecular weight heparin. The meta-analyses showed that LMWH may reduce mortality at three months compared to UFH (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.40 to 1.10; risk difference (RD) 57 fewer per 1000, 95% CI 101 fewer to 17 more; low certainty evidence) and may reduce VTE recurrence slightly (RR 0.69, 95% CI 0.27 to 1.76; RD 30 fewer per 1000, 95% CI 70 fewer to 73 more; low certainty evidence). There were no data available for bleeding outcomes, postphlebitic syndrome, quality of life, or thrombocytopenia. The study comparing fondaparinux with heparin (UFH or LMWH) found that fondaparinux may increase mortality at three months (RR 1.25, 95% CI 0.86 to 1.81; RD 43 more per 1000, 95% CI 24 fewer to 139 more; low certainty evidence), may result in little to no difference in recurrent VTE (RR 0.93, 95% CI 0.56 to 1.54; RD 8 fewer per 1000, 95% CI 52 fewer to 63 more; low certainty evidence), may result in little to no difference in major bleeding (RR 0.82, 95% CI 0.40 to 1.66; RD 12 fewer per 1000, 95% CI 40 fewer to 44 more; low certainty evidence), and probably increases minor bleeding (RR 1.53, 95% CI 0.88 to 2.66; RD 42 more per 1000, 95% CI 10 fewer to 132 more; moderate certainty evidence). There were no data available for postphlebitic syndrome, quality of life, or thrombocytopenia. The study comparing dalteparin with tinzaparin found that dalteparin may reduce mortality slightly (RR 0.86, 95% CI 0.43 to 1.73; RD 33 fewer per 1000, 95% CI 135 fewer to 173 more; low certainty evidence), may reduce recurrent VTE (RR 0.44, 95% CI 0.09 to 2.16; RD 47 fewer per 1000, 95% CI 77 fewer to 98 more; low certainty evidence), may increase major bleeding slightly (RR 2.19, 95% CI 0.20 to 23.42; RD 20 more per 1000, 95% CI 14 fewer to 380 more; low certainty evidence), and may reduce minor bleeding slightly (RR 0.82, 95% CI 0.30 to 2.21; RD 24 fewer per 1000, 95% CI 95 fewer to 164 more; low certainty evidence). There were no data available for postphlebitic syndrome, quality of life, or thrombocytopenia., Authors' Conclusions: Low molecular weight heparin (LMWH) is probably superior to UFH in the initial treatment of VTE in people with cancer. Additional trials focusing on patient-important outcomes will further inform the questions addressed in this review. The decision for a person with cancer to start LMWH therapy should balance the benefits and harms and consider the person's values and preferences., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Introduction: The connection between driver mutations and the efficacy of immune checkpoint inhibitors is the focus of intense investigations. In lung adenocarcinoma (LUAD), KEAP1/STK11 alterations have been tied to immunoresistance. Nevertheless, the heterogeneity characterizing immunotherapy efficacy suggests the contribution of still unappreciated events., Methods: Somatic interaction analysis of top-ranking mutant genes in LUAD was carried out in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) (N = 6208). Mutational processes, intratumor heterogeneity, evolutionary trajectories, immunologic features, and cancer-associated signatures were investigated, exploiting multiple data sets (AACR GENIE, The Cancer Genome Atlas [TCGA], TRAcking Cancer Evolution through therapy [Rx]). The impact of the proposed subtyping on survival outcomes was assessed in two independent cohorts of immune checkpoint inhibitor-treated patients: the tissue-based sequencing cohort (Rome/Memorial Sloan Kettering Cancer Center/Dana-Farber Cancer Institute, tissue-based next-generation sequencing [NGS] cohort, N = 343) and the blood-based sequencing cohort (OAK/POPLAR trials, blood-based NGS cohort, N = 304)., Results: Observing the neutral interaction between KEAP1 and TP53, KEAP1/TP53-based subtypes were dissected at the molecular and clinical levels. KEAP1 single-mutant (KEAP1 SM) and KEAP1/TP53 double-mutant (KEAP1/TP53 DM) LUAD share a transcriptomic profile characterized by the overexpression of AKR genes, which are under the control of a productive superenhancer with NEF2L2-binding signals. Nevertheless, KEAP1 SM and KEAP1/TP53 DM tumors differ by mutational repertoire, degree of intratumor heterogeneity, evolutionary trajectories, pathway-level signatures, and immune microenvironment composition. In both cohorts (blood-based NGS and tissue-based NGS), KEAP1 SM tumors had the shortest survival; the KEAP1/TP53 DM subgroup had an intermediate prognosis matching that of pure TP53 LUAD, whereas the longest survival was noticed in the double wild-type group., Conclusions: Our data provide a framework for genomically-informed immunotherapy, highlighting the importance of multimodal data integration to achieve a clinically exploitable taxonomy., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Oral anticoagulants may improve the survival of people with cancer through an antithrombotic effect, yet increase the risk of bleeding., Objectives: To evaluate the efficacy and safety of oral anticoagulants in ambulatory people with cancer undergoing chemotherapy, targeted therapy, immunotherapy, or radiotherapy (either alone or in combination), with no standard therapeutic or prophylactic indication for anticoagulation., Search Methods: We conducted comprehensive searches on 14 June 2021, following the original electronic searches performed in February 2016 (last major search). We electronically searched the following databases: CENTRAL, MEDLINE, Embase. In addition, we handsearched conference proceedings, checked references of included studies, and searched for ongoing studies. As part of the living systematic review approach, we are running continual searches and will incorporate new evidence rapidly after it is identified., Selection Criteria: We included randomised controlled trials (RCTs) assessing the benefits and harms of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) in ambulatory people with cancer (i.e., not hospital inpatients during the time of their participation in trials) These people are typically undergoing systemic anticancer therapy, possibly including chemotherapy, targeted therapy, immunotherapy, or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation., Data Collection and Analysis: Using a standardised form, two review authors independently extracted data on study design, participants, intervention outcomes of interest, and risk of bias. Outcomes of interest included all-cause mortality, pulmonary embolism, symptomatic deep vein thrombosis (DVT), major bleeding, minor bleeding and health-related quality of life. We assessed the certainty of evidence for each outcome using the GRADE approach., Main Results: Of 12,620 identified citations, 10 RCTs fulfilled the inclusion criteria. The oral anticoagulant was a vitamin K antagonist (VKA) in six of these RCTs, and a direct oral anticoagulant (DOAC) in the remaining four RCTs (three studies used apixaban; one used rivaroxaban). The comparator was either placebo or no prophylaxis. Compared to no prophylaxis, vitamin K antagonists (VKAs) probably reduce mortality at six months slightly (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.77 to 1.13; risk difference (RD) 22 fewer per 1000, 95% CI 72 fewer to 41 more; moderate-certainty evidence), and probably reduce mortality at 12 months slightly (RR 0.95, 95% CI 0.87 to 1.03; RD 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate-certainty evidence). One study assessed the effect of a VKA compared to no prophylaxis on thrombosis; the evidence was very uncertain about the effect of VKA compared to no VKA on pulmonary embolism and symptomatic DVT (RR 1.05, 95% CI 0.07 to 16.58; RD 0 fewer per 1000, 95% CI 6 fewer to 98 more; very low-certainty evidence; RR 0.08, 95% CI 0.01 to 1.42; RD 35 fewer per 1000, 95% CI 37 fewer to 16 more; very low-certainty evidence, respectively). Also, VKAs probably increase major and minor bleeding at 12 months (RR 2.93, 95% CI 1.86 to 4.62; RD 107 more per 1000, 95% CI 48 more to 201 more; moderate-certainty evidence for major bleeding, and RR 3.14, 95% CI 1.85 to 5.32; RD 167 more per 1000, 95% CI 66 more to 337 more; moderate-certainty evidence for minor bleeding). Compared to no prophylaxis, at three to six months, direct oral anticoagulants (DOACs) probably reduce mortality slightly (RR 0.94, 95% CI 0.64 to 1.38, RD 11 fewer per 1000, 95% CI 67 fewer to 70 more; moderate-certainty evidence), probably reduce the risk of pulmonary embolism slightly compared to no prophylaxis (RR 0.48, 95% CI 0.24 to 0.98; RD 24 fewer per 1000, 95% CI 35 fewer to 1 fewer; moderate-certainty evidence), probably reduce symptomatic DVT slightly (RR 0.58, 95% CI 0.30 to 1.15; RD 21 fewer per 1000, 95% CI 35 fewer to 8 more; moderate-certainty evidence), probably do not increase major bleeding (RR 1.65, 95% CI 0.72 to 3.80; RD 9 more per 1000, 95% CI 4 fewer to 40 more; moderate-certainty evidence), and may increase minor bleeding (RR 3.58, 95% CI 0.55 to 23.44; RD 55 more per 1000, 95% CI 10 fewer to 482 more; low-certainty evidence)., Authors' Conclusions: In ambulatory people with cancer undergoing chemotherapy, targeted therapy, immunotherapy, or radiotherapy (either alone or in combination), the current evidence on VKA thromboprophylaxis suggests that the harm of major bleeding might outweigh the benefit of reduction in venous thromboembolism. With DOACs, the benefit of reduction in venous thromboembolic events outweighs the risk of major bleeding. Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the 'What's new' section in the  Cochrane Database of Systematic Reviews for the current status of this review., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Multiple myeloma is a malignant plasma cell disorder characterised by clonal plasma cells that cause end-organ damage such as renal failure, lytic bone lesions, hypercalcaemia and/or anaemia. People with multiple myeloma are treated with immunomodulatory agents including lenalidomide, pomalidomide, and thalidomide. Multiple myeloma is associated with an increased risk of thromboembolism, which appears to be further increased in people receiving immunomodulatory agents., Objectives: (1) To systematically review the evidence for the relative efficacy and safety of aspirin, oral anticoagulants, or parenteral anticoagulants in ambulatory patients with multiple myeloma receiving immunomodulatory agents who otherwise have no standard therapeutic or prophylactic indication for anticoagulation. (2) To maintain this review as a living systematic review by continually running the searches and incorporating newly identified studies., Search Methods: We conducted a comprehensive literature search that included (1) a major electronic search (14 June 2021) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE via Ovid, and Embase via Ovid; (2) hand-searching of conference proceedings; (3) checking of reference lists of included studies; and (4) a search for ongoing studies in trial registries. As part of the living systematic review approach, we are running continual searches, and we will incorporate new evidence rapidly after it is identified., Selection Criteria: Randomised controlled trials (RCTs) assessing the benefits and harms of oral anticoagulants such as vitamin K antagonist (VKA) and direct oral anticoagulants (DOAC), anti-platelet agents such as aspirin (ASA), and parenteral anticoagulants such as low molecular weight heparin (LMWH)in ambulatory patients with multiple myeloma receiving immunomodulatory agents., Data Collection and Analysis: Using a standardised form, we extracted data in duplicate on study design, participants, interventions, outcomes of interest, and risk of bias. Outcomes of interest included all-cause mortality, symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, and minor bleeding. For each outcome we calculated the risk ratio (RR) with its 95% confidence interval (CI) and the risk difference (RD) with its 95% CI. We then assessed the certainty of evidence at the outcome level following the GRADE approach (GRADE Handbook)., Main Results: We identified 1015 identified citations and included 11 articles reporting four RCTs that enrolled 1042 participants. The included studies made the following comparisons: ASA versus VKA (one study); ASA versus LMWH (two studies); VKA versus LMWH (one study); and ASA versus DOAC (two studies, one of which was an abstract). ASA versus VKA One RCT compared ASA to VKA at six months follow-up. The data did not confirm or exclude a beneficial or detrimental effect of ASA relative to VKA on all-cause mortality (RR 3.00, 95% CI 0.12 to 73.24; RD 2 more per 1000, 95% CI 1 fewer to 72 more; very low-certainty evidence); symptomatic DVT (RR 0.57, 95% CI 0.24 to 1.33; RD 27 fewer per 1000, 95% CI 48 fewer to 21 more; very low-certainty evidence); PE (RR 1.00, 95% CI 0.25 to 3.95; RD 0 fewer per 1000, 95% CI 14 fewer to 54 more; very low-certainty evidence); major bleeding (RR 7.00, 95% CI 0.36 to 134.72; RD 6 more per 1000, 95% CI 1 fewer to 134 more; very low-certainty evidence); and minor bleeding (RR 6.00, 95% CI 0.73 to 49.43; RD 23 more per 1000, 95% CI 1 fewer to 220 more; very low-certainty evidence). One RCT compared ASA to VKA at two years follow-up. The data did not confirm or exclude a beneficial or detrimental effect of ASA relative to VKA on all-cause mortality (RR 0.50, 95% CI 0.05 to 5.47; RD 5 fewer per 1000, 95% CI 9 fewer to 41 more; very low-certainty evidence); symptomatic DVT (RR 0.71, 95% CI 0.35 to 1.44; RD 22 fewer per 1000, 95% CI 50 fewer to 34 more; very low-certainty evidence); and PE (RR 1.00, 95% CI 0.25 to 3.95; RD 0 fewer per 1000, 95% CI 14 fewer to 54 more; very low-certainty evidence). ASA versus LMWH Two RCTs compared ASA to LMWH at six months follow-up. The pooled data did not confirm or exclude a beneficial or detrimental effect of ASA relative to LMWH on all-cause mortality (RR 1.00, 95% CI 0.06 to 15.81; RD 0 fewer per 1000, 95% CI 2 fewer to 38 more; very low-certainty evidence); symptomatic DVT (RR 1.23, 95% CI 0.49 to 3.08; RD 5 more per 1000, 95% CI 11 fewer to 43 more; very low-certainty evidence); PE (RR 7.71, 95% CI 0.97 to 61.44; RD 7 more per 1000, 95% CI 0 fewer to 60 more; very low-certainty evidence); major bleeding (RR 6.97, 95% CI 0.36 to 134.11; RD 6 more per 1000, 95% CI 1 fewer to 133 more; very low-certainty evidence); and minor bleeding (RR 1.42, 95% CI 0.35 to 5.78; RD 4 more per 1000, 95% CI 7 fewer to 50 more; very low-certainty evidence). One RCT compared ASA to LMWH at two years follow-up. The pooled data did not confirm or exclude a beneficial or detrimental effect of ASA relative to LMWH on all-cause mortality (RR 1.00, 95% CI 0.06 to 15.89; RD 0 fewer per 1000, 95% CI 4 fewer to 68 more; very low-certainty evidence); symptomatic DVT (RR 1.20, 95% CI 0.53 to 2.72; RD 9 more per 1000, 95% CI 21 fewer to 78 more; very low-certainty evidence); and PE (RR 9.00, 95% CI 0.49 to 166.17; RD 8 more per 1000, 95% CI 1 fewer to 165 more; very low-certainty evidence). VKA versus LMWH One RCT compared VKA to LMWH at six months follow-up. The data did not confirm or exclude a beneficial or detrimental effect of VKA relative to LMWH on all-cause mortality (RR 0.33, 95% CI 0.01 to 8.10; RD 3 fewer per 1000, 95% CI 5 fewer to 32 more; very low-certainty evidence); symptomatic DVT (RR 2.32, 95% CI 0.91 to 5.93; RD 36 more per 1000, 95% CI 2 fewer to 135 more; very low-certainty evidence); PE (RR 8.96, 95% CI 0.49 to 165.42; RD 8 more per 1000, 95% CI 1 fewer to 164 more; very low-certainty evidence); and minor bleeding (RR 0.33, 95% CI 0.03 to 3.17; RD 9 fewer per 1000, 95% CI 13 fewer to 30 more; very low-certainty evidence). The study reported that no major bleeding occurred in either arm. One RCT compared VKA to LMWH at two years follow-up. The data did not confirm or exclude a beneficial or detrimental effect of VKA relative to LMWH on all-cause mortality (RR 2.00, 95% CI 0.18 to 21.90; RD 5 more per 1000, 95% CI 4 fewer to 95 more; very low-certainty evidence); symptomatic DVT (RR 1.70, 95% CI 0.80 to 3.63; RD 32 more per 1000, 95% CI 9 fewer to 120 more; very low-certainty evidence); and PE (RR 9.00, 95% CI 0.49 to 166.17; RD 8 more per 1000, 95% CI 1 fewer to 165 more; very low-certainty evidence). ASA versus DOAC One RCT compared ASA to DOAC at six months follow-up. The data did not confirm or exclude a beneficial or detrimental effect of ASA relative to DOAC on DVT, PE, and major bleeding and minor bleeding (minor bleeding: RR 5.00, 95% CI 0.31 to 79.94; RD 4 more per 1000, 95% CI 1 fewer to 79 more; very low-certainty evidence). The study reported that no DVT, PE, or major bleeding events occurred in either arm. These results did not change in a meta-analysis including the study published as an abstract., Authors' Conclusions: The certainty of the available evidence for the comparative effects of ASA, VKA, LMWH, and DOAC on all-cause mortality, DVT, PE, or bleeding was either low or very low. People with multiple myeloma considering antithrombotic agents should balance the possible benefits of reduced thromboembolic complications with the possible harms and burden of anticoagulants. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by pruritus, xerosis, and skin barrier dysfunction. Skin barrier alteration is associated with an increase in trans-epidermal water loss (TEWL) and reduction in skin hydration. Dupilumab is a monoclonal antibody targeting interleukin-13 modulating pro-inflammatory signal transduction, which has been approved for moderate to severe AD. The aim of this study is to evaluate the effects of Dupilumab on skin barrier functions, using non-invasive instruments and clinical evaluation., Materials and Methods: Thirty patients affected by moderate-severe AD, who had been administered dupilumab, were evaluated by clinical examination and through the instrumental measurements of TEWL and corneometry at the baseline (T0) and 8 weeks (T1) on lesional skin. The clinical evaluation was performed using the Eczema Area and Severity Index (EASI) score. Moreover, a Dermatology Life Quality Index (DLQI) and 7-day numeric rating scale (NRS) questionnaires were administered to each patient., Results: The instrumental parameters of skin barrier recovery confirmed the clinical improvement outcomes with a statistically significant reduction of TEWL at T1., Conclusion: Our data confirm the clinical outcomes already reported in the literature and show that there was an inverse proportional correlation between TEWL levels and clinical severity after 8 weeks of treatment with dupilumab., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with glioma have a poor prognosis and, in a short period of time, have to deal with severe forms of disability, which compromise their psychological distress and quality of life. The caregivers of these patients consequently carry a heavy burden in terms of emotional and patient care. The study aims to evaluate the coping strategies of patients and their caregivers during the course of the disease in order to frame the adaptation process in a rapidly progressing pathology. Methods: A prospective study on 24 dyads of patients affected by malignant glioma and their caregivers was conducted between May 2016 and July 2018. Questionnaires designed to identify the coping style (MINI-MaC Scale) and psychological distress (HADS scores) and assess QOL (EQ-5D) were administered at two time points: at first lines of treatment and at disease recurrence. Results: Patients and their caregiver structure adaptive coping strategies during the disease: a coping style oriented toward a fighting spirit prevails at baseline (Mini-Mac Mean 3.23); fatalism prevails at recurrence (Mini-Mac Mean 3.03). Psychological distress affects the coping style expressed: high levels of anxiety symptoms were found to be significantly associated with a coping style oriented toward anxious preoccupation, helpless-hopeless, and fatalism; low depressive symptoms were inversely correlated with fighting spirit coping style. Patients' and caregivers' perceptions of quality of life were correlated between them and with performance status assessed by clinicians. In a dyadic perspective, the adaptation of a member of the couple varies as a function of the other partner's coping style. Conclusions: Our data are in line with previous literature on cancer patients, demonstrating that coping style is not a persistent dimension of personality, but can change depending on the situation. Despite the disease rapid course, patients and their caregivers can structure adaptive and functional defenses to manage the disease., 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 Guariglia, Ieraci, Villani, Tanzilli, Benincasa, Sperati, Terrenato and Pace.)

The aim of this paper is to define the pre-treatment radiological characteristics of oropharyngeal squamous cell carcinoma (OPSCC) using morphological and non-morphological magnetic resonance imaging (MRI), based on HPV status, in a single-institution cohort. In total, 100 patients affected by OPSCC were prospectively enrolled in the present study. All patients underwent 1.5T MR with standard sequences, including diffusion-weighted imaging with and intravoxel incoherent motion (IVIM-DWI) technique and a dynamic contrast-enhanced (DCE) MRI. For all patients, human papillomavirus (HPV) status was available. No statistically significant differences in the volume of primary tumors (PTs) and lymph nodes (LNs) were observed based on HPV status. When comparing the two patient groups, no significant differences were found for the PT radiologic characteristics (presence of well-defined borders, exophytic growth, ulceration, and necrosis) and LN morphology (solid/cystic/necrotic). Tumor subsite, smoking status, and alcohol intake significantly differed based on HPV status, as well as ADC and D t values of both PTs and LNs. We detected no significant difference in DCE-MRI parameters by HPV status. Based on a multivariate logistic regression model, the combination of clinical factors, such as tumor subsite and alcohol habits, with the perfusion-free diffusion coefficient D t of LNs, may help to accurately discriminate OPSCC by HPV status.

Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations.

Osteoarthritis is a degenerative disease considered a leading cause of functional disability. Its treatment is based on a combination of pharmacological and non-pharmacological interventions, but the role of these latter is still debated. This overview of systematic reviews aimed at evaluating the short-term efficacy of different thermal modalities in patients with osteoarthritis. We searched PubMed, Scopus, CINHAL, Web of Science, ProQuest and the Cochrane Database of Systematic Reviews from inception until October 2020, with no language restrictions. We selected the following outcomes a priori: pain, stiffness and quality of life. Seventeen systematic reviews containing 27 unique relevant studies were included. The quality of the reviews ranged from low to critically low. Substantial variations in terms of interventions studied, comparison groups, population, outcomes and follow-up between the included SRs were found. From a re-analysis of primary data, emerged that balneotherapy was effective in reducing pain and improving stiffness and quality of life, mud therapy significantly reduced pain and stiffness, and spa therapy showed pain relief. However, the evidence supporting the efficacy of different thermal modalities could be seriously flawed due to methodological quality and sample size, to the presence of important treatment variations, and to the high level of heterogeneity and the absence of a double-blind design. There is some encouraging evidence that deserves clinicians' consideration, suggesting that thermal modalities are effective on a short-term basis for treating patients with AO.

Cancer stem cells (CSCs) drive not only tumor initiation and expansion, but also therapeutic resistance and tumor relapse. Therefore, CSC eradication is required for effective cancer therapy. In preclinical models, CSCs demonstrated high capability to tolerate even extensive genotoxic stress, including replication stress, because they are endowed with a very robust DNA damage response (DDR). This favors the survival of DNA-damaged CSCs instead of their inhibition via apoptosis or senescence. The DDR represents a unique CSC vulnerability, but the abrogation of the DDR through the inhibition of the ATR-CHK1 axis is effective only against some subtypes of CSCs, and resistance often emerges. Here, we analyzed the impact of druggable DDR players in the response of patient-derived colorectal CSCs (CRC-SCs) to CHK1/2 inhibitor prexasertib, identifying RAD51 and MRE11 as sensitizing targets enhancing prexasertib efficacy. We showed that combined inhibition of RAD51 and CHK1 (via B02+prexasertib) or MRE11 and CHK1 (via mirin+prexasertib) kills CSCs by affecting multiple genoprotective processes. In more detail, these two prexasertib-based regimens promote CSC eradication through a sequential mechanism involving the induction of elevated replication stress in a context in which cell cycle checkpoints usually activated during the replication stress response are abrogated. This leads to uncontrolled proliferation and premature entry into mitosis of replication-stressed cells, followed by the induction of mitotic catastrophe. CRC-SCs subjected to RAD51+CHK1 inhibitors or MRE11+CHK1 inhibitors are eventually eliminated, and CRC-SC tumorspheres inhibited or disaggregated, via a caspase-dependent apoptosis. These results support further clinical development of these prexasertib-based regimens in colorectal cancer patients.

Introduction: p53 and antiapoptotic B-cell leukemia/lymphoma 2 (BLC2) have been proposed as prognostic markers for early breast cancer (BC), although their relationship with conventional parameters and patient prognosis, as well as their distribution within the molecular BC subtypes remains uncertain., Patients and Methods: In this observational study, we analyzed the immunohistochemical expression of p53 and BLC2 in 1099 early BC patients surgically treated between 2000 and 2006 and followed for at least 5 years, also considering their association with pathologic factors and molecular subtypes, as well as their influence on disease-free survival., Results: p53 and BLC2 are distributed differently across molecular subtypes (P < .0001); in particular, p53 positivity and BLC2 negativity seems to be associated with more aggressive conventional tumor phenotypes. Moreover, BLC2 negativity seems to be a significant discriminating factor for disease-free survival (P = .003) according to Kaplan-Meier analysis, while p53 seems to have no discriminating effect. Among patients with discordant p53/BLC2 phenotype, the combination p53 + BLC2 - seems to be associated with the worst outcomes (P = .007) and significantly influenced the clinical course of node-negative patients treated only with hormone therapy (P = .004)., Conclusion: These two biomarkers, in addition to conventional pathologic factors and molecular subtype, could help define the risk and outcome of BC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy., Patients and Methods: KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study., Results: On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes., Conclusions: This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease., Competing Interests: Disclosure LP received travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees from Roche, Pfizer, Novartis, Gentili. PVici received travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees/advisory boards from Roche, Pfizer, Novartis, Gentili. RG received advisory boards/honoraria/speakers' fee from Astra Zeneca and Roche. RDM is a scientific advisory board member at Exosomics SpA (Siena IT), HiberCell Inc. (New York, NY), Kiromic Inc. (Houston, TX) and Exiris Inc. (Rome, IT). All other authors declare no conflicts of interest. Data sharing Data concerning the Rome cohort are provided in supplementary Data File S1, available at https://doi.org/10.1016/j.annonc.2020.08.2105. The MSKCC and DFCI studies are available at www.cbioportal.org. The OAK and POPLAR trials are available as supplementary information in Gandara DR et al.(23) Immunogenomic features related to the TCGA LUAD study were downloaded from the CRI iAtlas Portal (available at www.cri-iatlas.org)., (Copyright © 2020 European Society for Medical Oncology. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) provide significant survival benefits in non-small cell lung cancer (NSCLC). Nevertheless, while some patients obtain a prolonged benefit, a non-negligible fraction of patients experiences an ultrarapid disease progression. Identifying specific molecular backgrounds predicting opposite outcomes is instrumental to optimize the use of these agents in clinical practice., Methods: We carried out an observational study with prospective design envisioning targeted next-generation sequencing (NGS) with an approved assay in 55 patients with metastatic NSCLC (Rome cohort), of whom 35 were treated with ICIs. Data from three clinically comparable datasets were collected and combined into a metadataset containing 779 patients. The datasets were related to the Memorial Sloan Kettering Cancer Center (MSKCC) cohort (tissue-based NGS) and the randomized phase II and III POPLAR and OAK trials (blood-based NGS)., Results: In patients treated with ICIs in the Rome cohort, co-occurring mutations in NOTCH1-3 and homologous repair (HR) genes were associated with durable clinical benefit. Using the MSKCC/POPLAR/OAK metadaset, we confirmed the relationship between the NOTCH mut /HR mut signature and longer progression-free survival (PFS) in ICI-treated patients (multivariate Cox: HR 0.51, 95% CI 0.34 to 0.76, p=0.001). The NOTCH mut /HR mut genomic predictor was also associated with longer survival (log-rank p=0.008), despite patients whose tumors carried the NOTCH mut /HR mut signature had higher metastatic burden as compared with their negative counterpart. Finally, we observed that this genomic predictor was also associated with longer survival in patients with other tumor types treated with ICIs (n=1311, log-rank p=0.002)., Conclusions: Co-occurring mutations in the NOTCH and HR pathways are associated with increased efficacy of immunotherapy in advanced NSCLC. This genomic predictor deserves further investigation to fully assess its potential in informing therapeutic decisions., Competing Interests: Competing interests: MM, MF, MO, DM, SS, IT, FS, MP, FR, AG, AB, GS, ADN, EK, MB, SC, MF, FDN, LC, FG, AV, GC, PM and MM-S declare no conflicts of interest. LP received travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees from Roche, Pfizer, Novartis, Gentili. PV received travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees/advisory boards from Roche, Pfizer, Novartis, Gentili. RDM declares to be a scientific advisory board member at ExosomicsSpA (Siena IT), Hibercell Inc. (New York, New York USA), Kiromic Inc. (Houston, Texas, USA) and at Exiris Inc. (Rome, Italy). RG received advisory boards/honoraria/speakers’ fee from AstraZeneca and Roche., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate the correlation between histogram-based Dynamic Contrast-Enhanced magnetic resonance imaging (DCE-MRI) parameters and positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG-PET) values in oropharyngeal squamous cell carcinoma (OPSCC), both in primary tumors (PTs) and in metastatic lymph nodes (LNs)., Methods: 52 patients with a new pathologically-confirmed OPSCC were included in the present retrospective cohort study. Imaging including DCE-MRI and 18F-FDG PET/CT scans were acquired in all patients. Both PTs and the largest LN, if present, were volumetrically contoured. Quantitative parameters, including the transfer constants, Ktrans and Kep, and the volume of extravascular extracellular space, ve, were calculated from DCE-MRI. The percentiles (P), P10, P25, P50, P75, P90, and skewness, kurtosis and entropy were obtained from the histogram-based analysis of each perfusion parameter. Standardized uptake values (SUV), SUVmax, SUVpeak, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated applying a SUV threshold of 40%. The correlations between all variables were investigated with the Spearman-rank correlation test. To exclude false positive results under multiple testing, the Benjamini-Hockberg procedure was applied., Results: No significant correlations were found between any parameters in PTs, while significant associations emerged between Ktrans and 18F-FDG PET parameters in LNs., Conclusions: Evident relationships emerged between DCE-MRI and 18F-FDG PET parameters in OPSCC LNs, while no association was found in PTs. The complex relationships between perfusion and metabolic biomarkers should be interpreted separately for primary tumors and lymph-nodes. A multiparametric approach to analyze PTs and LNs before treatment is advisable in head and neck squamous cell carcinoma (HNSCC)., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To investigate the relationships between imaging parameters derived from intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and HPV status in oropharyngeal squamous cell carcinoma (OPSCC)., Materials and Methods: 73 patients with a new diagnosis of OPSCC were enrolled in the present study. MRI including IVIM-DWI with nine b value (range 0-800 s/mm 2 ) was acquired in all patients. Primary tumor (PT) and the largest metastatic lymph node (LN), if present, were volumetrically contoured and the tissue diffusion coefficient D t , perfusion fraction f and perfusion-related diffusion coefficient D* were estimated by a bi-exponential fit. The apparent diffusion coefficient (ADC) was also estimated by a mono-exponential fit. The predictive power of the most relevant patient/tumor characteristics and image-based features in determining the HPV status was assessed., Results: 67 PTs and 67 metastatic LNs were analyzed. Significant differences in ADC and D t values among HPV-positive and HPV-negative patients were found for PTs (p = 0.003 and p < 0.001, respectively), while a trend toward significance in D t was reported for LNs (p = 0.066). The perfusion-related parameters, f, D* and D*× f, were not related to HPV status. The best predictive model for HPV positivity was obtained combining alcohol intake and smoke habits with D t values of PTs (accuracy = 80.8%, sensitivity = 85.7%, specificity = 64.7%)., Conclusion: Significant correlations were found between IVIM-DWI and HPV status in OPSCCs. The perfusion-free diffusion coefficient, D t , may better reflect the HPV-related tumor differences compared to ADC, whereas the perfusion-related parameters were not able to reliably discriminate HPV-positive from HPV-negative OPSCC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The logic behind the outcome of endocrine therapy in breast cancer has long remained poorly understood. The prognostic role of DNA damage and repair biomarkers (DDR) was explored in postmenopausal, hormone-receptor-positive breast cancer patients treated with neoadjuvant hormone therapy (NAHT)., Methods: Data on 55 patients were included. The phosphorylated ataxia-teleangectasia and Rad3-related protein (pATR), phosphorylated ataxia-telangiectasia mutated (ATM) kinase, and phosphorylated H2A Histone Family Member X (γ-H2AX) were evaluated by immunohistochemistry in paired tissues collected at baseline and following NAHT. Biomarkers were considered both singularly and within signatures. Ki-67 percentage change was the primary biomarker endpoint. Classical endpoints were also considered., Results: The most favorable Ki-67 outcome was associated with the γ-H2AX/pATM signature ( p = 0.011). In models of Ki-67 reduction, 'luminal B' subtype, higher grade of anaplasia, and the γ-H2AX/pATM signature tested as significant ( p < 0.05 for all). Results were confirmed in multivariate analysis. No association was observed with pathologic response. An increase of ∆γ-H2AX in paired breast tissues was associated with longer event-free survival ( p = 0.027) and overall survival ( p = 0.042). In Cox models, both survival outcomes were solely affected by grade of anaplasia, with less favorable prognosis in the highest grades ( p < 0.05 for both)., Conclusions: We report novel evidence of the prognostic role of DDR biomarkers on important patient outcomes in postmenopausal hormone-receptor-positive breast cancer patients treated with NAHT. If confirmed in future and adequately sized trials, our results may help inform therapeutic decisions and clarify underlying biological mechanisms., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.