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Cholesterol and its metabolism seem to be involved not only in cancer progression but also in immune cells activity. In this comprehensive review, we summarize preclinical, translational, and clinical evidence regarding the crucial role of cholesterol and its metabolism in regulating the immune response against cancer cells, shedding light on the multifaceted mechanisms by which cholesterol influences immune cell function and anti-tumor immunity. By synthesizing findings from preclinical studies, we have elucidated the impact of cholesterol on immune cell activation, differentiation, and effector functions. These investigations have revealed that cholesterol metabolism plays a pivotal role in shaping the immune response, with alterations in cholesterol levels directly impacting immune cell behavior and anti-tumor activity. All the steps related to cholesterol metabolism, including its de-novo synthesis, its influx and efflux mechanisms, as well as its metabolites, have a distinct impact on immune cells function and activity, which, if altered, might influence tumor progression. In addition, we have reviewed clinical studies investigating the role of circulating cholesterol on outcomes of patients with advanced tumors treated with immune checkpoint inhibitors, highlighting again in a clinical scenario the correlation between cholesterol and the immune system. Overall, our review emphasizes the importance of cholesterol and its metabolism in orchestrating the immune response against cancer cells. Herein we have provided a comprehensive overview of this emerging field by illustrating the intricate interplay between cholesterol and immune system., Competing Interests: Declaration of Competing Interest Federica Pecci: none Valeria Cognigni: none Giulia Claire Giudice: none Francesco Paoloni: none Luca Cantini: employee of Fortrea Inc Kamal S. Saini: Consulting fees from the European Commission, iemployee of Fortrea Inc., and stock and/or other ownership interests in Fortrea Inc. and Quantum Health Analytics (UK) Ltd, outside the submitted work. Hassan Mohammed Abushukair: none Abdul Rafeh Naqash: receives funding for trials he is PI on: Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, and NGM Biopharmaceuticals. ARN also received Consultant Editor Compensation from JCO Precision Oncology, Travel Compensation from: SITC/AACR/Conquer CancerFoundation/BinayTara Foundation and Foundation Med, Caris Life Sciences, and serves on the Advisory Board for Foundation Med. Alessio Cortellini: honoraria for consultancies/advisory board role from MSD, BMS, OncoC4, IQVIA, AstraZeneca, REGENERON, Access Infinity, Ardelis Health, Alpha Sight, Guidepoint, Roche; speaker fees from AstraZeneca, Pierre-Fabre, MSD, Sanofi/REGENERON. He also declares honoraria for writing/editorial activity from BMS, MSD, travel support from Sanofi/REGENERON, MSD and research fundings (to institution) from IASLC. Giulia Mazzaschi: none Sonila Alia: none Valentina Membrino: none Elisa Araldi: none Marcello Tiseo: received speakers’ and consultants’ fee from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, Amgen, Merck, Sanofi. Marcello Tiseo received institutional research grants from Astra-Zeneca and Boehringer Ingelheim. Sebastiano Buti: received honoraria as speaker at scientific events and advisory role by Bristol-Myers Squibb (BMS), Pfizer, MSD, Ipsen, Roche, AstraZeneca, and Novartis. Arianna Vignini: none Rossana Berardi: reported serving as a consultant/advisory board member for AstraZeneca, Boehringer Ingelheim, Novartis, Merck, Otsuka, Eli Lilly, and Roche., (Copyright © 2025 Elsevier B.V. All rights reserved.)

No clear evidence supports the advantage of fixed (up to two years (2yICI)) or continuous treatment (more than two years (prolonged ICI)) in cancer patients achieving stable disease or response on immune checkpoint inhibitors (ICIs). We performed a systematic review and meta-analysis of randomized controlled trials reporting the duration of ICIs (alone or in combination with standard of care (SoC)) across various solid tumors. Overall, we identified 28,417 records through database searching. Based on the eligibility criteria, 57 studies were identified for the quantitative synthesis, including 22,977 patients receiving ICIs (with or without SoC). Prolonged ICI correlated with better overall survival (OS) than 2yICI in patients with melanoma (HR:1.55; 95%CI: 1.22,1.98), while 2yICI-SoC led to better OS than prolonged ICI-SoC in patients with NSCLC (HR: 0.84; 95%CI: 0.68,0.89). Prospective randomized trials are needed to assess the most appropriate duration of ICIs. OBJECTIVE: No clear evidence supports the advantage of fixed (up to two years (2yICI)) or continuous treatment (more than two years (prolonged ICI)) in cancer patients achieving stable disease or response on immune checkpoint inhibitors (ICIs). Here, we assessed the optimal treatment duration for ICIs in solid tumors. CONCLUSIONS: Prolonged ICIs administration does not seem to improve the outcomes of patients with NSCLC an RCC., Competing Interests: Declaration of Competing Interest The authors indicate no financial relationship., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) in the era of targeted- (TT) and immuno- (IT) therapy remains controversial., Design: The primary objective of the present systematic, performed according to PRISMA guidelines review, was to assess the prevalence of nephrectomy in mRCC patients enrolled in TT/IT randomized phase II/III clinical trials (RCTs) or expanded access programs (EAPs). Medline database was searched from 2003 to 2019 for studies with available nephrectomy data., Results: We identified 609 studies, subsequently restricted to 57 randomized phase II/III clinical trials and 6 EAPs. Overall, 33,196 patients with mRCC were included, among whom 28,700 (86.4 %) underwent nephrectomy. The trends over time of nephrectomy occurrence remained substantially stable from 2003 to 2019., Conclusions: Our analysis highlighted that data from RCTs and EAPs driving the clinical practice originate from nephrectomized patient populations. This evidence supports the clinical relevance of CN also in mRCC patients candidate to receive TT/IT., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Advanced upper tract urothelial carcinoma (UTUC) has different molecular and genetic features from the commonest carcinoma of the bladder, suggesting a possible different sensitivity to immune-checkpoint inhibitors (ICI)., Methods: A systematic review and meta-analysis of all relevant clinical studies including advanced UTUC patients treated with ICI was conducted according to PRISMA guidelines., Results: Six prospective trials for a total 2537 patients, including 396 (15.6 %) with advanced UTUC, were eligible for the analysis. In UTUC patients, the pooled ORR was 21.2 % (95 % CI, 12.5 %-33.7 %); the risk of death was reduced by 24 % over the standard platinum-based chemotherapy, but this was not statistically significant (hazard ratio = 0.76; 95 % confidence interval, 0.41-1.40; p = 0.37, χ2 = 3.28, p = 0.07; I2 = 70 %)., Conclusions: The current evidence does not support a statistically significant effect from ICI over the standard treatment for advanced UTUC patients. Properly performed pre-planned subgroup analyses from randomized clinical trials are eagerly awaited., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: In the most of cases, for non-small cell lung cancer (NSCLC) patients who progressed to previous immune checkpoint inhibitors (CKI) administered as first- or as second-line therapy, chemotherapy (CT) remains the only viable options in the absence of "druggable" mutations. We aimed to explore the efficacy of salvage chemotherapy after immunotherapy (SCAI) in advanced NSCLC patients., Materials and Methods: We designed a retrospective, multicenter study, involving 20 Italian centers, with the primary objective of describing the clinical outcome of advanced NSCLC patients treated with SCAI at the participating institutions from November 2013 to July 2019. The primary endpoint of the study was represented by overall survival (OS), defined as the time from CT initiation to death. Secondary outcome endpoints of the SCAI (progression free survival, PFS, objective response rate, ORR and toxicity) and explorative biomarkers (lactate dehydrogenase, LDH, and neutrophil-to-lymphocyte ratio, NLR during immunotherapy) were also analyzed., Results: In our study population of 342 NSCLC patients, SCAI obtained a median OS of 6.8 months (95 % confidence interval, CI 5.5-8.1), median PFS of 4.1 months (95 % CI 3.4-4.8) and ORR of 22.8 %. A "Post-CKI score" was constructed by combining significant predictors of OS at the multivariate analyses (sex, ECOG PS, disease control with prior immunotherapy), Harrell'C was 0.65, (95 % CI:0.59-0.71)., Conclusions: Despite the late-line settings, our findings support the hypothesis that previous immunotherapy might increase the sensitivity of the tumor to the subsequent chemotherapy. The "Post-CKI score" was clinically effective in successfully discriminating three distinct prognostic subgroups of patients after the failure of CKI, representing a possibly useful tool for the tailored decision-making process of advanced treatment-line settings in NSCLC., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Upfront criteria to foresee immune checkpoint inhibitors (ICIs) efficacy are far from being identified. Thus, we integrated blood descriptors of pro-inflammatory/immunosuppressive or effective anti-tumor response to non-invasively define predictive immune profiles in ICI-treated advanced non-small cell lung cancer (NSCLC)., Methods: Peripheral blood (PB) was prospectively collected at baseline from 109 consecutive NSCLC patients undergoing ICIs as first or more line treatment. Soluble PD-L1 (sPD-L1) (immunoassay), CD8+PD-1+ and NK (FACS) cells were assessed and interlaced to generate an Immune effector Score (I eff S). Lung Immune Prognostic Index (LIPI) was computed by LDH levels and derived Neutrophil-to-Lymphocyte Ratio (dNLR). All these parameters were correlated with survival outcome and treatment response., Results: High sPD-L1 and low CD8+PD-1+ and NK number had negative impact on PFS (P < 0.001), OS (P < 0.01) and ICI-response (P < 0.05). Thus, sPD-L1 high , CD8+PD-1+ low and NK low were considered as risk factors encompassing I eff S, whose prognostic power outperformed that of individual features and slightly exceeded that of LIPI. Accordingly, the absence of these risk factors portrayed a favorable I eff S characterizing patients with significantly (P < 0.001) prolonged PFS (median NR vs 2.3 months) and OS (median NR vs 4.1) and greater benefit from ICIs (P < 0.01). We then combined each risk parameter composing I eff S and LIPI (LDH high , dNLR high ), thus defining three distinct prognostic classes. A remarkable impact of I eff S-LIPI integration was documented on survival outcome (PFS, HR = 4.61; 95%CI = 2.32-9.18; P < 0.001; OS, HR=4.03; 95%CI=1.91-8.67; P < 0.001) and ICI-response (AUC=0.90, 95%CI=0.81-0.97, P < 0.001)., Conclusion: Composite risk models based on blood parameters featuring the tumor-host interaction might provide accurate prognostic scores able to predict ICI benefit in NSCLC patients., (Copyright © 2020. Published by Elsevier B.V.)

Background: in the setting of metastatic malignancies, the role of concurrent stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT) and immune-checkpoint inhibitors (ICI) is increasing. Few data are available about effectiveness and safety of this strategy., Methods: we used the PRISMA guidelines to perform a systematic review. We selected only articles reporting a "real" concurrent treatment, defined as SRS/SRT performed within 30 days of ICI administration., Results: Despite several limits due to the heterogeneity and retrospective nature of the studies, 1-year local control for brain lesions ranged from 42 to 100% and 1-year regional brain control ranged from 31 to 83%. An interesting rate of local and distant control was reported for concurrent SBRT-ICI on extra-cranial lesions. No relevant signals about toxicity emerged., Conclusions: Based on published evidence, concurrent SRS/SRT and ICI seems to lead intriguing outcomes, without increasing toxicity. Further investigations are warranted to obtain stronger prospective evidence., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Influenza vaccination is recommended for advanced cancer patients, since impaired immunity is presumed to be due not only to the tumor itself but also to immunosuppressive treatments, such as chemotherapy and radiotherapy. The recent advances in the systemic management of metastatic solid tumors, with the introduction of immune checkpoint inhibitors for several indications in clinical practice, has re-actualized simple clinical issues, such as the vaccinal recommendations and counseling, for which common sense is not enough to support pragmatic choices. In the present review, we summarized the evidence about influenza vaccine administration during immune checkpoint blockade, emphasizing the need of prospective data to definitely guide our advices to a growing group of cancer patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Analysis of circulating tumor DNA (ctDNA) for the identification of T790M mutation in advanced EGFR-mutated NSCLC patients can replace tissue re-biopsy for resistance characterization and, being non-invasive, may be applied for disease monitoring. We analysed ctDNA during osimertinib treatment to correlate mutational levels with clinical outcome and to predict pattern of resistance., Materials and Methods: Forty patients with advanced NSCLC receiving osimertinib for T790M + disease after previous EGFR-TKI were enrolled in a pilot study to collect plasma at baseline and every 12 weeks until progression. Molecular analysis of ctDNA was performed by ddPCR and Therascreen®. When feasible at progression, tissue re-biopsy and NGS analysis were performed., Results: Thirty-eight patients had baseline plasma samples suitable for molecular analysis. Patients with low levels of the EGFR activating mutation in ctDNA [< 2200 copies/mL or allele frequency (AF) < 6.1%] showed better progression-free survival (17.8 or 17.8 months vs. 4.3 or 2.7, p = 0.022 or p = 0.018, respectively) and overall survival (23.6 or 23.6 vs. 7.7 or 7.3, p = 0.016 or p = 0.013, respectively) than patients with high levels (≥ 2200 copies/mL or AF ≥ 6.1%). Patients with detectable EGFR mutations in plasma (shedders) presented worse outcome than negative subjects (non-shedders). Low levels of T790M, higher T790M/activating mutation ratio and complete clearance after 2 months were associated with a trend towards better outcome. Tissue re-biopsy at resistance showed 3 patients with EGFR C797S, 1 with MET amplification, 1 with MYC amplification, 1 with PTEN loss, 3 with SCLC transformation., Conclusions: The mutational analysis performed on plasma plays a significant role in prognostic stratification, especially for the EGFR activating mutation, since patients with absence or low levels of mutations presented a better outcome to osimertinib. At progression, tissue re-biopsy remains a crucial issue for the identification of resistance mechanisms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: A prospective investigation of the circulating immune profile in NSCLC patients receiving nivolumab was performed to identify potentially predictive parameters., Methods: Flow Cytometry of peripheral blood (PB) CD3+, CD8+, CD4+, NK, Treg and MDSCs was prospectively performed in 31 consecutive advanced NSCLC patients at baseline (T0) and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. Functional molecules (PD-1, CD3ζ, Granzyme B, Perforin), cell proliferation (Ki67) and NK receptors (NKG2 A, NKG2D, NKp30) were also explored. The immunohistochemical evaluation of PD-L1 and TILs was restricted to available tumor biopsies. Tissue and circulating parameters were correlated to clinico-pathological features and treatment outcomes., Results: KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg., Conclusion: The functional pool of circulating NKs associated with a divergent PD-1 expression in blood and tissue CD8+ lymphocytes portrays an immune profile predictive of anti-PD1 treatment efficacy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Thymic epithelial tumors (TETs) are rare neoplasms with different prognosis lacking consistent molecular alterations possibly leading to targeted therapy. We collected a consecutive series of TETs aimed at investigating the mutational status of druggable genes (EGFR, c-KIT, KRAS, BRAF, PDGFR-alpha and -beta, HER2 and c-MET) and the expression of ALK and PD-L1., Patients and Methods: One hundred twelve consecutive cases of TETs and relative clinico-pathologic features were collected. Immunohistochemical expression of ALK (clone D5F3) and PD-L1 (clone E1L3N), molecular analysis of EGFR (exons 18-21), c-KIT (exons 9,11,13,14,17), KRAS (exon 2), BRAF (exon 15), PDGFR-alpha (exon 12) and -beta (exons 12, 14, 18), HER-2 (exons 19 and 20) and c-MET (exons 14, 17, 18, 19) mutations were performed. Immuno-molecular results were then statistically matched with clinico-pathologic characteristics., Results: Patients were male in 54% of cases, with a median age of 61 years (range 19-83) and affected mainly by thymoma (78%) in stage II (45%). At molecular analysis, there were 4 c-KIT mutations (occurring in exon 11 V559A, L576P, Y553N and exon 17 D820E) in thymic carcinomas (typeC), but not in other tumor types (p=0.003). No mutations were detected in other genes and none case was ALK positive. Twenty-nine (26%) cases were PD-L1 positive (65% of thymic carcinomas and 18% of thymomas). High PD-L1 expression was statistically associated with WHO classification stage type C (p<0.001) and Masaoka stage III-IV disease (p=0.007). In univariate analysis, WHO classification type C, advanced Masaoka stage and absence of myasthenia, but not PD-L1 expressions were correlated with worse survival; at multivariate analysis, only WHO type C confirmed its negative prognostic role., Conclusion: A subset of TETs as thymic carcinomas can harbor c-KIT mutations and elevated PD-L1 expression that could represent targets of potential therapeutic use., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Pemetrexed has been approved for the treatment of advanced non-small cell lung cancer (NSCLC) non-squamous histology, both as first- and second-line therapy. Pemetrexed is an antimetabolite drug, that inhibits enzymes involved in nucleotides bio-synthesis arresting cancer cells cycle. The aim of this study was the evaluation of the impact of pemetrexed on erythrocyte mean corpuscular volume (MCV) change and its possible correlation with disease control rate (DCR), progression free (PFS) and overall survival (OS) in NSCLC patients., Materials and Methods: A retrospective collection of clinical and laboratory data (including basal MCV and maximum MCV occurred during therapy) in advanced NSCLC patients treated with pemetrexed at seven Italian centers was performed. Nonparametric tests, univariate and multivariate analysis were used to assess correlation between variables and to identify predictors of outcomes., Results: 191 patients were enrolled: median age 62, 60% male, 61% performance status (PS) 0, 91% stage IV, 88% adenocarcinoma histotype, 25% never smoker, 62% received pemetrexed as first-line. Mean MCV significantly increased from basal (89fL) to during treatment (94fL), with mean ΔMCV=4fL. The median time from therapy start to maximum MCV was 2.2 months. Median PFS was 7 [CI95% 6-8] and 3 [CI95% 2-4] months [P=0.0016], and median survival was 17 [CI95% 12-23] and 10 [CI95% 8-12] months [P=0.02], in patients with ΔMCV>5fL (n=80) and ΔMCV≤5fL (n=111), respectively. Multivariate analysis identified age ≥62, PS 0, adenocarcinoma histology and ΔMCV>5fL as independent predictors of longer PFS. A ΔMCV>5fL significantly correlates with DCR., Conclusion: Pemetrexed induces macrocytosis. ΔMCV>5fL on pemetrexed therapy correlated with better DCR, PFS and OS. These results deserve further validation in prospective studies., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Hyponatremia is reported in about 15% of small cell lung cancer (SCLC). Variable results of the prognostic significance of low plasmatic sodium (Napl) have been reported. Our study was performed to investigate the prognostic role of hyponatremia in SCLC patients treated in second-line with topotecan chemotherapy., Materials and Methods: Data were retrospectively collected from a database including clinical data from 631 patients enrolled in 6 prospective topotecan iv studies. Final data were obtained from 564 patients in which data on baseline Napl were available. Univariate and multivariate analysis were carried out to study the possible correlation between Napl and second-line clinical outcomes., Results: Hyponatremia (Napl<135mequiv./l) was present in 101 cases (17.9%). Napl was <125mequiv./l in 16 patients (2.8%), 126-130mequiv./l in 11 (2%), 130-134mequiv./l in 74 (13.1%), while 463 patients (82.1%) showed normal values. The median survival was 28.7 weeks in patients with normal Napl, and 21.1 weeks in patients with hyponatremia (p<0.0001, HR=1.67, 95%CI=1.32-2.10). By Cox multivariate analysis, hyponatremia was associated with poorer prognosis (p=0.0024, HR=1.44, 95%CI=1.13-1.82). A not statistically significant trend of correlation between hyponatremia and progression-free survival (p=0.085, HR=1.23, 95%CI 0.97-1.55) and response rate (p=0.5037, OR=0.81, 95%CI 0.44-1.49) was observed., Conclusion: Hyponatremia is an independent prognostic factor for patients with SCLC treated with topotecan in second-line setting. Further studies are needed to prospectically confirm these results and to develop an optimal therapy for hyponatremic patients., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Thymic carcinoma (TC) is a rare intrathoracic malignancy that it can be invasive and refractory to conventional treatment. Comprehensive genomic analysis evidenced a molecularly distinct subset of thymic carcinoma with high prevalence of c-kit mutation, which may behave as a gastrointestinal stromal tumor (GIST). Here, we present a case report of TC with c-Kit mutation, who has relapsed after exposure to multiple lines of combination chemotherapy, but he has shown an impressive and long lasting response to sunitinib after imatinib failure., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: A recent pooled analysis of randomized trials indicated significant improvement in overall survival from cisplatin-based adjuvant chemotherapy for non-small cell lung cancer (NSCLC), depending on disease stage (only in stages II and III) and PS (≤ 1). Post-operative radiotherapy (RT) is optional for pN2 tumours., Patients and Methods: To evaluate opinions and daily clinical practice of Italian Oncologists about adjuvant treatment of NSCLC, a 46-item questionnaire was delivered via e-mail., Results: Seventy-eight physicians from 68 Centers (out of 98 contacted) returned their questionnaire. Seventy-four, 86, 94, and 78% of them give the indication for adjuvant chemotherapy for stage IIA, IIB, IIIA, and IIIB disease, respectively and 14% in stage IB disease. Stage, PS, and age are taken into consideration evaluating adjuvant approach by 97, 95 and 73%, respectively. Cisplatin-vinorelbine (64%) and cisplatin-gemcitabine (33%), for 4 cycles (81%), are the preferred regimens, while 32% use different regimens. Ninety-two percent indicate RT in pN2 disease and/or positive resection margins. Real Number of patients Needed to Treat (NNT) is probably not completely known/understood and/or used by physicians., Conclusions: A substantial adherence between clinical daily practice in Italy and scientific progresses is described in this paper, even with some discordances regarding the most appropriate adjuvant chemotherapy regimen., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)