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The study investigated the relationship between serum proinflammatory cytokine levels, cholesterol metabolism, and clinical outcome in cancer patients undergoing immune checkpoint inhibitors (ICIs). Peripheral blood was collected before therapy from ICI-treated advanced cancer patients. We retrospectively assessed plasma total cholesterol (TC), ABCA1- and ABCG1-mediated cholesterol efflux (CE), passive diffusion (PD), cholesterol loading capacity (CLC), and serum IL-6, IL-10, and TNF-α. The association between blood cholesterol parameters and inflammatory cytokines and their effect on overall survival (OS), progression-free survival (PFS), and clinical benefit (CB) from ICIs were statistically assessed. Among 70 consecutively enrolled patients (nonsmall cell lung cancer: 94%; renal cell carcinoma: 6%), TC, CLC, and cholesterol PD resulted significantly higher in IL-6 low and IL-10 low cases ( P <0.05), whereas ABCA1-mediated CE was increased in IL-10 high patients ( P =0.018). Uni- and multivariable analysis revealed meaningfully longer OS and PFS in IL-6 low (HR 2.13 and 2.97, respectively) and IL-10 low (HR 3.17 and 2.62) groups. At univariate analysis all cholesterol-related indices significantly correlated with OS and PFS, whereas at multivariate only high PD was validated as a protection factor (OS, HR 0.75; PFS, HR 0.84). Finally, uni- and multivariable showed a statistically significant inverse association of CB with ABCG1-CE (OR 0.62), as with IL-6 (OR 0.13) and IL-10 (OR 0.10). In-depth characterization of the interplay between blood cholesterol metabolism and immune-inflammatory cytokines might provide novel insights into the complex relationship among cancer, inflammation, lipids profile, and response to immunotherapy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Immune checkpoint inhibitors (ICIs) are standard treatments for advanced solid cancers. Resistance to ICIs, both primary and secondary, poses challenges, with early mortality (EM) within 30-90 days indicating a lack of benefit. Prognostic factors for EM, including the lung immune prognostic index (LIPI), remain underexplored., Methods: We performed a retrospective, observational study including patients affected by advanced solid tumors, treated with ICI as single agent or combined with other agents. Logistic regression models identified factors associated with EM and 90-day progression risks. A nomogram for predicting 90-day mortality was built and validated within an external cohort., Results: In total, 637 patients received ICIs (single agent or in combination with other drugs) for advanced solid tumors. Most patients were male (61.9%), with NSCLC as the prevalent tumor (61.8%). Within the cohort, 21.3% died within 90 days, 8.4% died within 30 days, and 34.5% experienced early progression. Factors independently associated with 90-day mortality included ECOG PS 2 and a high/intermediate LIPI score. For 30-day mortality, lung metastasis and a high/intermediate LIPI score were independent risk factors. Regarding early progression, high/intermediate LIPI score was independently associated. A predictive nomogram for 90-day mortality combining LIPI and ECOG PS achieved an AUC of 0.76 (95% CI 0.71-0.81). The discrimination ability of the nomogram was confirmed in the external validation cohort (n = 255) (AUC 0.72, 95% CI 0.64-0.80)., Conclusion: LIPI and ECOG PS independently were able to estimate 90-day mortality, with LIPI also demonstrating prognostic validity for 30-day mortality and early progression., (© 2024. The Author(s).)

Background: While concomitant medications can affect the efficacy of immune checkpoint inhibitors (ICIs), few studies have assessed associations of concomitant medications with the occurrence and profile of immune-related adverse events (irAEs)., Methods: This study assessed associations of concomitant medication (antibiotics/proton pump inhibitors (PPIs)/corticosteroids)-based risk model termed the "drug score" with survival and the occurrence and profile of irAEs in 851 patients with advanced cancer treated with ICIs (with or without other agents). The study also assessed the survival impact of the occurrence of irAEs, using a landmark analysis to minimize immortal time bias. Multivariable Cox proportional hazard analyses were conducted for progression-free survival (PFS) and overall survival (OS)., Results: The drug score classified patients into three risk groups, with significantly different PFS and OS. Notably, the score's predictive capability was better in patients treated with ICIs only than in those treated with ICIs plus other agents. The landmark analysis showed that patients who developed irAEs had significantly longer PFS and OS than those without irAEs. Generally, concomitant medications were negatively associated with the occurrence of irAEs, especially endocrine irAEs, whereas PPI use was positively associated with gastrointestinal irAEs, as an exception., Conclusions: Using a large pan-cancer cohort, the prognostic ability of the drug score was validated, as well as that of the occurrence of irAEs. The negative association between concomitant medications and irAE occurrence could be an indirect measure of the detrimental effect on the immune system induced by one or more concomitant drugs., Competing Interests: Competing interests: Professor Sebastiano Buti has received honoraria for speaking at scientific events and advisory roles from AstraZeneca, Bristol Myers Squibb, Ipsen, Merck, Eisai, MSD, Novartis, and Pfizer and research funding from Novartis and Pfizer, outside the present work. The other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Specific components of lipid profile seem to differently impact on immune activity against cancer and unraveling their prognostic role in patients with solid cancer treated with immune checkpoint inhibitors (ICIs) is needed., Materials and Methods: We retrospectively collected baseline clinicopathological characteristics including circulating lipid profile (total cholesterol [TC], triglycerides [TG], low-density lipoproteins [LDL], high-density lipoproteins [HDL]) of patients with consecutive solid cancer treated with ICIs, and we investigated their role in predicting clinical outcomes., Results: At a median follow-up of 32.9 months, among 430 enrolled patients, those with TC ≥ 200 mg/dl showed longer median progression-free survival (mPFS; 6.6 vs. 4.7 months, P = .4), although not reaching statistical significance, and significantly longer median overall survival (mOS; 19.4 vs. 10.8 months, P = .02) compared to those with TC < 200 mg/dl. Conversely, patients with TG ≥150 mg/dl displayed shorter PFS (3.4 vs. 5.1 months, P = .02) and OS (7.1 vs. 12.9 months, P = .009) compared to those with TG <150 mg/dl. TC and TG were then combined in a "LIPID score" identifying three subgroups: good-risk (GR) (TC ≥200 mg/dl and TG <150 mg/dl), intermediate-risk (IR) (TC <200 mg/dl and TG <150 mg/dl or TC ≥200 mg/dl and TG ≥150 mg/dl) and poor-risk (PR) (TC <200 mg/dl and TG ≥150 mg/dl). The mPFS of GR, IR, and PR groups was 7.8, 4.3, and 2.5 months, respectively (P = .005); mOS of GR, IR, and PR was 20.4, 12.4, and 5.3 months, respectively (P < .001). At multivariable analysis, the PR profile represented an independent poor prognostic factor for both PFS and OS., Conclusions: We developed a lipid score that defined subgroups of patients with cancer who differently benefit from ICIs. Further mechanistic insights are warranted to clarify the prognostic and predictive role of lipid profile components in patients treated with ICIs., (© The Author(s) 2023. Published by Oxford University Press.)

Aim: To investigate the different impact of each component of lipid profile in advanced cancer patients treated with immune checkpoints inhibitors (ICIs) according to neutrophil-to-lymphocyte ratio (NLR) value. Methods: We retrospectively collected total cholesterol (TC), triglycerides (TGs), low-density lipoproteins (LDL), high-density lipoproteins (HDL). Results: 407 patients were enrolled. In NLR <4 subgroup, TGs <150 mg/dl led to longer PFS ( p  = 0.01) and OS ( p  = 0.02) compared with TGs ≥150 mg/dl; LDL <100 mg/dl led to longer PFS ( p  = 0.004) and OS ( p  = 0.007) compared with LDL ≥100 mg/dl. In NLR ≥4 subgroup, TC >200 mg/dl led to longer PFS ( p  = 0.008) and OS ( p  = 0.004) compared with TC <200 mg/dl. Conclusion: We showed a distinct prognostic impact of lipid profile according to NLR.

Background: Hypovitaminosis D can have a negative prognostic impact in patients with cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation. We hypothesized that systematic vitamin D repletion could impact clinical outcomes in patients with cancer receiving immune-checkpoint inhibitors (ICIs)., Methods: We planned a prospective observational study (PROVIDENCE) to assess serum vitamin D levels in patients with advanced cancer receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on survival and toxicity outcomes. In an exploratory analysis, we compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centers who did not receive systematic vitamin D repletion., Results: Overall, 164 patients were prospectively recruited in the PROVIDENCE study. In cohort 1, consisting of 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, adequate repletion with cholecalciferol was obtained in 70.1% at the three months re-assessment. Cohort 2 consisted of 63 patients assessed for vitamin D at a median time of 3.7 months since immunotherapy initiation, with no patients having adequate levels (> 30 ng/ml). Even in cohort 2, systematic supplementation led to adequate levels in 77.8% of patients at the three months re-assessment. Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS, p = 0.013), time to treatment failure (TTF, p = 0.017), and higher disease control rate (DCR, p = 0.016). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55, 95%CI: 0.34-0.90) and treatment discontinuation (HR 0.61, 95%CI: 0.40-0.91) for patients from PROVIDENCE cohort 1 in comparison to the control cohort. In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16, 95%CI: 0.03-0.85)., Conclusion: The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs., (© 2023. The Author(s).)

Background/aim: Recent evidence suggests potential synergistic antitumor effects of the combination of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors with the oral hypoglycemic agent metformin. The aim of this study was to investigate the safety and activity of metformin combined with nivolumab in diabetic cancer patients., Patients and Methods: Patients with advanced melanoma, renal cell carcinoma or lung cancer receiving nivolumab with concurrent diabetes treated with metformin were retrospectively collected. The primary endpoint was the safety of nivolumab plus metformin combination., Results: We collected 40 patients with solid tumors who received metformin for concomitant diabetes and nivolumab as anticancer therapy in four Italian Hospitals. The concomitant use of nivolumab and metformin was well tolerated; adverse events (AEs) of any grade occurred in 75% of patients (mainly fatigue, pruritus, rash, and asthenia). Grade 3 AEs occurred only in 20% of cases; no grade 4 AEs were observed. A statistically significant correlation was found between higher doses of metformin (>1,000 mg daily) and longer progression-free survival (p=0.021), overall survival (p=0.037) and higher overall response rate., Conclusion: The combination of nivolumab and metformin was safe and might have an antitumor activity, supporting further investigations on the synergistic antitumor effect of this combination., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The predictive ability of metabolic conditions, such as hypercholesterolemia, on the outcome of cancer patients to immune-checkpoint inhibitors (ICIs) therapy, has been recently explored. The reasons for their value in this setting are to be searched in the individual himself more than in his tumor, as the target of the immune-checkpoint blockade is the immune system. The efficacy of ICIs on the tumor may be based on two simple premises: 1) the physiological immune function has been blocked, and 2) the tumor progression (mainly) depends on this block. The metabolic syndrome may represent the epiphenomenon of an "inflamed patient," no longer able of physiological functions required to prevent chronic inflammatory events. The metabolic dysfunction could represent merely "a biomarker" of the patient who satisfies both the two premises reported above. Suggestions from preclinical and translational researches should be transferred in the clinical setting, implementing randomized clinical trials with observational endpoints such as the effect of concomitant drug medications and the impact of blood cholesterol levels and other metabolic conditions on the outcome of ICI treatment.

Background: Until now, no robust data supported the efficacy, safety and recommendation for influenza vaccination in patients with cancer receiving immune checkpoint inhibitors (ICIs)., Methods: The prospective multicenter observational INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors (INVIDIa-2) study investigated the clinical effectiveness of influenza vaccination in patients with advanced cancer receiving ICIs, enrolled in 82 Italian centers from October 2019 to January 2020. The primary endpoint was the time-adjusted incidence of influenza-like illness (ILI) until April 30, 2020. Secondary endpoints regarded ILI severity and vaccine safety., Results: The study enrolled 1279 patients; 1188 patients were evaluable for the primary endpoint analysis. Of them, 48.9% (581) received influenza vaccination. The overall ILI incidence was 8.2% (98 patients). Vaccinated patients were significantly more frequently elderly (p<0.0001), males (p=0.004), with poor European Cooperative Oncology Group performance status (p=0.009), affected by lung cancer (p=0.01), and by other non-cancer comorbidities (p<0.0001) when compared with unvaccinated. ILI incidence was not different basing on influenza vaccination: the time-to-ILI was similar in vaccinated and unvaccinated patients (p=0.62). ILI complications were significantly less frequent for patients receiving the vaccination (11.8% vs 38.3% in unvaccinated, p=0.002). ILI-related intravenous therapies were significantly less frequent in vaccinated patients than in unvaccinated (11.8% vs 29.8%, p=0.027). ILI lethality was, respectively, 0% in vaccinated and 4.3% in unvaccinated patients. Vaccine-related adverse events were rare and mild (1.5%, grades 1-2)., Conclusion: The INVIDIa-2 study results support a positive recommendation for influenza vaccination in patients with advanced cancer receiving immunotherapy., Competing Interests: Competing interests: The Federation of Italian Cooperative Oncology Groups (FICOG) received funding for the present study by Seqirus and Roche S.p.A.; also received funding outside the present study by Astra Zeneca, Bristol-Myers Squibb (BMS), Sanofi.Melissa Bersanelli received funding for the present study by Seqirus and Roche S.p.A. (FICOG as Institution, no personal fees). She also received, outside the present work, research funding from Pfizer and Novartis (Institution); honoraria as a speaker at scientific events (personal fees) by Astra Zeneca, Bristol-Myers Squibb (BMS), Novartis and Pfizer; as consultant for advisory role (personal fees) by Novartis, BMS and Pfizer; for copyright transfer by Sciclone Pharmaceuticals.Ugo De Giorgi has served as a consultant for Astellas, Bayer, BMS, Ipsen, Janssen, Novartis, Pfizer, Sanofi and Pharmamar; he received research funding from AstraZeneca, Roche, and Sanofi; and received travel funds from BMS, Ipsen, Janssen, Pfizer, and Roche during the conduct of the study.Massimo Di Maio reports personal fees from Bristol Myers Squibb, personal fees from Merck Sharp MSD, Ipsen, Roche S.p.A., Eli-Lilly, AstraZeneca and Novartis; he also received research funding from Novartis.Vieri Scotti participated, with personal fees, to advisory boards and speaker’s bureaus for Roche S.p.A. Saverio Cinieri declared international board for Eli Lilly international. Paolo Andrea Zucali acts in a consultant or advisory role for Sanofi, BMS, Pfizer, MSD, Astellas, Janssen, Ipsen, Novartis, all outside the scope of work. Marcello Tiseo received speakers’ and consultants’ fee from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, and institutional research grants from Astra-Zeneca, Boehringer Ingelheim. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We presented the rationale for the use of thymosin α1 as prophylaxis of severe COVID-19 in cancer patients undergoing active treatment, constituting the background for the PROTHYMOS study, a prospective, multicenter, open-label, Phase II randomized study, currently in its start-up phase (Eudract no. 2020-006020-13). We aim to offer new hope for this incurable disease, especially to frail patient population, such as patients with cancer. The hypothesis of an effective prophylactic approach to COVID-19 would have immediate clinical relevance, especially given the lack of curative approaches. Moreover, in the 'COVID-19 vaccine race era' both clinical and biological results coming from the PROTHYMOS trials could even support the rationale for future combinatorial approaches, trying to rise vaccine efficacy in frail individuals.

Aim: Evaluating the incidence and course of COVID-19 in cancer patients treated with immunotherapy. Patients & methods: We reported the influenza-like illness events with diagnosis of COVID-19 within the patient cohort enrolled in the prospective observational multicenter INVIDIa-2 study in the single center of Parma. Results: Among 53 patients, eight experienced influenza-like illness during the influenza season 2019/2020, and three of them had diagnosis of COVID-19. They were males, elderly, with cardiovascular disease. Radiological features of COVID-19 pneumonitis were found in all of three cases, although the pharyngeal swab resulted positive in only two. Two of these three patients died due to respiratory failure. Conclusion: Cancer patients are at high risk of severe events from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Immune checkpoint inhibitors (ICI) have improved survival in numerous types of cancer. However, a great number of unselected patients still do not respond to ICI. Moreover, there is a need to identify biomarkers that could predict the prognosis of immunotherapy-treated patients. The aim of our study is to evaluate the prognostic value of baseline plasmatic cholesterol levels in metastatic cancer patients treated with immunotherapy. We retrospectively enrolled advanced cancer patients consecutively treated with ICI at our center between October 2013 and October 2018 to correlate the blood cholesterol level before treatment with overall survival (OS, primary endpoint). The secondary endpoints were the correlation between baseline cholesterol and progression-free survival (PFS), objective response rate, and toxicity (immune-related adverse events). Among 187 patients with availability of baseline plasmatic cholesterol, 58 had cholesterol levels >200 mg/dL. The median age was 70 years. Primary tumors were as follows: non-small cell lung cancer (70.0%), melanoma (15.0%), renal cell carcinoma (9.1%), urothelial cancer (4.6%), head-neck carcinoma (0.9%), and others (0.4%). The median follow-up was 21.3 months. Both OS and PFS were better in patients with high plasmatic cholesterol levels: the median OS was 19.4 versus 5.5 months (P=0.001) and the median PFS was 6.1 versus 2.4 months (P=0.002). The multivariate analysis confirmed the prognostic role of hypercholesterolemia in terms of OS, but not PFS. Hypercholesterolemia was associated with better outcomes in ICI-treated cancer patients and, as an expression of low-grade inflammation state, it could identify tumors more likely to be responsive to immunotherapy.

Background: Several studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients., Patients and Methods: We conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI., Results: One thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21-92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6-46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events [irAEs] (p < 0.0001), G3/G4 irAEs (p < 0.0001) and irAEs leading to discontinuation (LTD) (p < 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5-14.9 for overweight, and 16.6 (95%CI: 10.3-26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 [95%CI: 6.4-22.3], p < 0.0001) and LTD irAEs (OR = 8.8 [95%CI: 4.3-18.2], p < 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients., Conclusions: Considering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'., Competing Interests: Declaration of competing interest Dr Alessio Cortellini received grants as speaker by MSD and Astra-Zeneca, grant consultancies by MSD, BMS, Roche, Novartis, Istituto Gentili, Astellas and Ipsen; Prof Clara Natoli received travel grants/personal fees from Pfizer, EISAI, Novartis, MSD, BMS and Astra-Zeneca; Dr Maria G Vitale received grant as consultant for advisory role, travel and speaker fees by BMS, Ipsen, Novartis and Pfizer, Jansen, Astellas and Pierre Fabre; Dr Raffaele Giusti received honoraria for lectures, consultation or advisory board participation from Kiowakirin, Angelini, Bristol-Myers Squibb, Boehringer-Ingelheim, MSD, Roche and Astra-Zeneca; Dr Melissa Bersanelli received research funding by Sanofi Genzyme, BMS, MSD, AstraZeneca, Seqirus, Roche, Novartis, Pfizer; honoraria as scientific speaker and advisory board consultant for BMS, Novartis, Pfizer. All other authors declared no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aim: INVIDIa was a retrospective, multicenter study, exploring the clinical efficacy of influenza vaccine in 300 cancer patients undergoing immunotherapy. Overall survival (OS) was immature at the initial report. Methods: We reported the final OS analysis from the original study population and within subgroups. Results: Both at the univariate and multivariate analysis, the occurrence of influenza syndrome (IS) was significantly related to better OS in the overall population (OR: 0.53 [95% CI: 0.32-0.88]; p = 0.01). In the lung cancer subgroup, receiving flu vaccine and/or developing IS was related to better OS (p = 0.04). Within elderly patients, the flu vaccine was the main variable for the relative OS advantage (p = 0.05). Conclusion: Receiving the flu vaccine and/or developing IS was related to better OS within the INVIDIa population.

Background : We investigate the role of family history of cancer (FHC) and diagnosis of metachronous and/or synchronous multiple neoplasms (MN), during anti-PD-1/PD-L1 immunotherapy. Design : This was a multicenter retrospective study of advanced cancer patients treated with anti-PD-1/PD-L1 immunotherapy. FHC was collected in lineal and collateral lines, and patients were categorized as follows: FHC-high (in case of cancer diagnoses in both the lineal and collateral family lines), FHC-low (in case of cancer diagnoses in only one family line), and FHC-negative. Patients were also categorized according to the diagnosis of MN as follows: MN-high (>2 malignancies), MN-low (two malignancies), and MN-negative. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and incidence of immune-related adverse events (irAEs) of any grade were evaluated. Results : 822 consecutive patients were evaluated. 458 patients (55.7%) were FHC-negative, 289 (35.2%) were FHC-low, and 75 (9.1%) FHC-high, respectively. 29 (3.5%) had a diagnosis of synchronous MN and 94 (11.4%) of metachronous MN. 108 (13.2%) and 15 (1.8%) patients were MN-low and MN-high, respectively. The median follow-up was 15.6 months. No significant differences were found regarding ORR among subgroups. FHC-high patients had a significantly longer PFS (hazard ratio [HR] = 0.69 [95% CI: 0.48-0.97], p = .0379) and OS (HR = 0.61 [95% CI: 0.39-0.93], p = .0210), when compared to FHC-negative patients. FHC-high was confirmed as an independent predictor for PFS and OS at multivariate analysis. No significant differences were found according to MN categories. FHC-high patients had a significantly higher incidence of irAEs of any grade, compared to FHC-negative patients ( p = .0012). Conclusions : FHC-high patients seem to benefit more than FHC-negative patients from anti-PD-1/PD-L1 checkpoint inhibitors., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Objective : Hypertension is a common adverse event with targeted agents in cancer patients and can lead to serious and sometimes lethal cardiovascular complications. The authors performed a meta-analysis of clinical trials aiming to evaluate the incidence and Relative Risk (RR) of developing all-grade and high-grade Hypertension Events (HE) in patients with solid tumors receiving targeted therapy. Methods : A review of citations from PubMed was performed and studies were selected based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The search was limited to randomized phase III trials published in English focused on the efficacy and safety of targeted agents in cancer patients, reporting data on HE. Incidence, RR and relative 95% CIs were analyzed using random or fixed-effects models. Overall incidences were calculated and further compared with the chi-squared test for proportions. Results : Ninety-three phase III trials were included, with a total of 68,077 patients. Prostate cancer was the most represented (18.9%), followed by breast cancer (17.3%) and colorectal cancer (16.4%). The incidence of all- and high-grade HE was 23.47% and 8.57%, respectively, with the highest incidence of serious HE reported by adjuvant Sunitib/Sorafenib (29.03%). The highest RR of high-grade HE was observed with Bevacizumab in patients with advanced cervical cancer. By drug category, the highest RR of high-grade HE was reported by VEGFR/EGFR TKIs. Conclusion : According to these data, monitoring this class of toxicities is of primary importance to avoid hypertension worsening and, thus, the risk of major cardiovascular events.

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.)

The correlation between clinical outcomes and treatment-related adverse events (AEs) has always been a debated topic in clinical oncology. Despite toxicities pharmacodynamics effects, the misunderstanding has always been around the corner: AEs themselves could lead to morbidity and mortality; on the other hand, the choice of the clinical outcomes to measure is not univocal. After the advent of immune checkpoint inhibitors (ICIs), such as anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed death-1/programmed death ligand-1, new class-specific AEs have emerged, called immune-related AEs (irAEs). With irAEs, the correlation between toxicity and clinical outcomes has suddenly been suggested, but it is still to be proven. We conducted a systematic literature review regarding this emerging association, pointing out all the available data and speculating on the possible underlying mechanisms. Thirty-six studies were included in the analysis, involving different malignancies (mostly melanoma and lung cancer), with different measured clinical outcomes. The most of them were retrospective. Despite the high heterogeneity, and the enormous biases of the revised studies, we can assume that irAEs occurrence is linked to the therapeutic activity of immune checkpoint inhibitors, with a (certain) direct proportionality, maybe subtending the likelihood of an immunogenic phenotype. This phenomenon seems to occur with both anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed death-1/programmed death ligand-1, and across different solid malignancies., (Copyright © 2019 Elsevier Inc. 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.)

Background: Patients with a history of autoimmune diseases (AIDs) have not usually been included in clinical trials with immune checkpoint inhibitors., Materials and Methods: Consecutive patients with advanced cancer, treated with anti-programmed death-1 (PD-1) agents, were evaluated according to the presence of pre-existing AIDs. The incidence of immune-related adverse events (irAEs) and clinical outcomes were compared among subgroups., Results: A total of 751 patients were enrolled; median age was 69 years. Primary tumors were as follows: non-small cell lung cancer, 492 (65.5%); melanoma, 159 (21.2%); kidney cancer, 94 (12.5%); and others, 6 (0.8%). Male/female ratio was 499/252. Eighty-five patients (11.3%) had pre-existing AIDs, further differentiated in clinically active (17.6%) and inactive (82.4%). Among patients with pre-existing AIDs, incidence of irAEs of any grade was significantly higher when compared with patients without AIDs (65.9% vs. 39.9%). At multivariate analysis, both inactive ( p  = .0005) and active pre-existing AIDs ( p  = .0162), female sex ( p  = .0004), and Eastern Cooperative Oncology Group Performance Status <2 ( p  = .0030) were significantly related to a higher incidence of irAEs of any grade. No significant differences were observed regarding grade 3/4 irAEs and objective response rate among subgroups. Pre-existing AIDs were not significantly related with progression-free survival and overall survival., Conclusion: This study quantifies the increased risk of developing irAEs in patients with pre-existing AIDs who had to be treated with anti-PD-1 immunotherapy. Nevertheless, the incidence of grade 3/4 irAEs is not significantly higher when compared with control population. The finding of a greater incidence of irAEs among female patients ranks among the "hot topics" in gender-related differences in immuno-oncology., Implications for Practice: Patients with a history of autoimmune diseases (AIDs) have not usually been included in clinical trials with immune checkpoint inhibitors but are frequent in clinical practice. This study quantifies the increased risk of developing immune-related adverse events (irAEs) in patients with pre-existing AIDs who had to be treated with anti-programmed death-1 immunotherapy. Nevertheless, their toxicities are mild and the incidence of grade 3/4 irAEs is not significantly higher compared with those of controls. These results will help clinicians in everyday practice, improving their ability to offer a proper counselling to patients, in order to offer an immunotherapy treatment even to patients with pre-existing autoimmune disease., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Several urinary disorders, including overactive bladder, urinary incontinence, and interstitial cystitis, are often characterized by negative urine cultures. The application of metagenomics (i.e., 16S rRNA microbial profiling or whole-genome shotgun sequencing) to urine samples has enabled the identification of previously undetected bacteria, contributing to the discovery and characterization of the urinary microbiome. The most frequent species isolated are Lactobacillus (15%), Corynebacterium (14.2%), Streptococcus (11.9%), Actinomyces (6.9%), and Staphylococcus (6.9%). Although several studies are emerging in this context, the role of urinary microbiota in the pathogenesis of infections and in tumor carcinogenesis remains unclear. Furthermore, data on the activity of gut microbiota in modulating sensitivity to immune checkpoint inhibitors in advanced cancer patients suggest that the influence of urinary microbiota on tumor response to anticancer therapy should also be investigated. Moreover, its possible relationship with tumor mutational burden, which is in turn correlated with response to immunotherapy, should be the focus of future studies. Of note, the effect of antibiotics on this complex scenario seems to deserve careful consideration.

Immunotherapy, and in particular immune-checkpoints blockade therapy (ICB), represents a new pillar in cancer therapy. Antibodies targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and Programmed Death 1 (PD-1)/Programmed Death Ligand-1 (PD-L1) demonstrated a relevant clinical value in a large number of solid tumors, leading to an improvement of progression free survival and overall survival in comparison to standard chemotherapy. However, across different solid malignancies, the immune-checkpoints inhibitors efficacy is limited to a relative small number of patients and, for this reason, the identification of positive or negative predictive biomarkers represents an urgent need. Despite the expression of PD-L1 was largely investigated in various malignancies, (i.e., melanoma, head and neck malignancies, urothelial and renal carcinoma, metastatic colorectal cancer, and pancreatic cancer) as a biomarker for ICB treatment-patients selection, it showed an important, but still imperfect, role as positive predictor of response only in nonsmall cell lung cancer (NSCLC). Importantly, other tumor and/or microenvironments related characteristics are currently under clinical evaluation, in combination or in substitution of PD-L1 expression. In particular, tumor-infiltrating immune cells, gene expression analysis, mismatch- repair deficiency, and tumor mutational landscape may play a central role in predicting clinical benefits of CTLA-4 and/or PD-1/PD-L1 checkpoint inhibitors. In this review, we will focus on the clinical evaluation of emerging biomarkers and how these may improve the naïve vision of a single- feature patients-based selection.

Background: Recent evidence suggested a potential correlation between overweight and the efficacy of immune checkpoint inhibitors (ICIs) in cancer patients., Patients and Methods: We conducted a retrospective study of advanced cancer patients consecutively treated with anti-PD-1/PD-L1 inhibitors, in order to compare clinical outcomes according to baseline BMI levels as primary analysis. Based on their BMI, patients were categorized into overweight/obese (≥ 25) and non-overweight (< 25). A gender analysis was also performed, using the same binomial cut-off. Further subgroup analyses were performed categorizing patients into underweight, normal weight, overweight and obese., Results: Between September 2013 and May 2018, 976 patients were evaluated. The median age was 68 years, male/female ratio was 663/313. Primary tumors were: NSCLC (65.1%), melanoma (18.7%), renal cell carcinoma (13.8%) and others (2.4%). ECOG-PS was ≥2 in 145 patients (14.9%). PD-1/PD-L1 inhibitors were administered as first-line treatment in 26.6% of cases. Median BMI was 24.9: 492 patients (50.6%) were non-overweight, 480 patients (50.4%) were overweight/obese. 25.2% of non-overweight patients experienced irAEs of any grade, while 55.6% of overweight/obese patients (p < 0.0001). ORR was significantly higher in overweight/obese patients compared to non-overweight (p < 0.0001). Median follow-up was 17.2 months. Median TTF, PFS and OS were significantly longer for overweight/obese patients in univariate (p < 0.0001, for all the survival intervals) and multivariate models (p = 0.0009, p < 0.0001 and p < 0.0001 respectively). The significance was confirmed in both sex, except for PFS in male patients (p = 0.0668)., Conclusions: Overweight could be considered a tumorigenic immune-dysfunction that could be effectively reversed by ICIs. BMI could be a useful predictive tool in clinical practice and a stratification factor in prospective clinical trials with ICIs.

Influenza vaccination is recommended by national and international guidelines in cancer patients, due to the likely compromised immune status and the risk of major complications from the infection. Nevertheless, the infectious morbidity and mortality of cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors have not been explored. Currently, no solid data support the efficacy and safety of influenza vaccination in this subgroup. The few available retrospective studies suggest a low efficacy of the vaccine, posing legitimate doubts about its safety. On the other hand, influenza vaccination does not seem to compromise the efficacy of immunotherapy. In conclusion, current data are limited and do not allow a unique recommendation about influenza vaccination during cancer immunotherapy, suggesting a conservative attitude and a personalized assessment of risks and benefits pending prospective data.

Aim: We aimed to assess the incidence and relative risk (RR) of fatigue in cancer patients treated with anti programmed cell death-1 (PD-1) and anti programmed cell death ligand-1 (PD-L1) agents., Patients & Methods: Eligible studies were selected according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Incidence, RR and 95% CIs were calculated using random or fixed-effects models., Results: Thirty-eight studies were included in this analysis, with a total of 11,719 patients. The incidences were 23.4 and 2.1% for all- and high-grade fatigue, respectively. The highest incidence of high-grade fatigue was reported by the combination of nivolumab and ipilimumab. Overall RR of high-grade fatigue with anti-PD-1/PD-L1 compared with chemotherapy or targeted therapy was 0.48., Conclusion: Treatment with anti-PD-1/PD-L1 agents correlates with lower incidence and RR of fatigue compared with standard therapies.

Aim: Considering the unmet need for the counseling of cancer patients treated with immune checkpoint inhibitors (CKI) about influenza vaccination, an explorative study was planned to assess flu vaccine efficacy in this population., Methods: INVIDIa was a retrospective, multicenter study, enrolling consecutive advanced cancer outpatients receiving CKI during the influenza season 2016-2017., Results: Of 300 patients, 79 received flu vaccine. The incidence of influenza syndrome was 24.1% among vaccinated, versus 11.8% of controls; odds ratio: 2.4; 95% CI: 1.23-4.59; p = 0.009. The clinical ineffectiveness of vaccine was more pronounced among elderly: 37.8% among vaccinated patients, versus 6.1% of unvaccinated, odds ratio: 9.28; 95% CI: 2.77-31.14; p < 0.0001., Conclusion: Although influenza vaccine may be clinically ineffective in advanced cancer patients receiving CKI, it seems not to negatively impact the efficacy of anticancer therapy.

Immune checkpoint inhibitors (CKIs) are therapeutic weapons in several advanced malignancies. Performance status is a validated prognostic variable in cancer patients; it possibly affects the efficiency of the immune system. We performed a systematic review and meta-analysis to investigate the predictive role of PS toward treatment with CKIs in cancer patients. Following PRISMA guidelines, an electronic search from PubMed, The Cochrane Library and Embase was performed, from the inception of each database to May 31, 2018. Inclusion criteria were (1) randomized trials comparing CKI with standard therapy for the treatment of patients with solid tumors; (2) information on overall survival (OS) according to PS; (3) full text available; and (4) reported in English language. Data were pooled using HRs for OS according to random effect model. The effect of experimental versus control arms was evaluated in PS = 0 and 1-2 subgroups, and the heterogeneity between the two estimates was assessed using an interaction test. The OS differences between PS = 0 and PS = 1-2 strata were evaluated in all studies and according to predefined subgroups. Eighteen studies were eligible, with 11,354 patients [PS = 0 group 5217 patients (46%); PS = 1-2 group 6137 patients (54%)]. The pooled HR for OS was 0.78 (95% CI 0.69-0.89) in PS = 0 patients. In PS = 1-2 patients, the pooled OS HR was 0.78 (95% CI 0.71-0.86). The OS difference between PS = 0 and PS = 1-2 patients treated with CKI was not significant (P = 0.99). CKI improves survival irrespective of patients' PS. PS should not guide treatment choice for anticancer immunotherapy.