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Association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated. Indeed, DM2 can be both an epiphenomenon of PDAC and a risk factor. The present study aimed to investigate the correlation between overall survival (OS) and antidiabetic drugs in patients with metastatic pancreatic ductal adenocarcinoma and DM2.Data from 232 patients were collected retrospectively from 2014 to 2021. 174 from AOU Cagliari Medical Oncology and 58 from AOU Ancona Medical Oncology. All patients received gemcitabine plus nab-paclitaxel first-line chemotherapy. We aimed to evaluate the correlation between DM2, anti-diabetic medications and overall survival. Survival distribution was assessed by Kaplan-Meier curves.Median age was 68±9, 127 (55%) were male. 138/232 (59%) patients were not affected by DM2, 94/232 (41%) were affected by DM2. 57 were insulin-treated and 37 were metformin-treated. DM2 treated patients showed an higher median overall survival (26 vs 12 months, p = 0,0002). Among DM2 patients insulin-treated and metformin-treated showed an mOS of 21 months and 33 months, respectively.Results showed a correlation between treated DM2 and higher mOS in patients with mPDAC. Limitations due to retrospective data collection must be considered. Further studies in this setting are needed.

IDH1-mutated intrahepatic cholangiocarcinomas (IDH1m iCCAs) could be treated with anti-IDH1 drugs, although the high heterogeneity in this class of tumours could limit treatment efficacy.We selected 125 IDH1m iCCAs that were treated as resectable, locally advanced, or metastatic and were screened by the NGS-based FoundationOne gene panel. We conducted a mutation-based clustering of tumours and survival analysis.Three main clusters were identified. The most altered pathways in cluster 1 were cell cycle and apoptosis, RTK/RAS, PI3K, and chromatin modification. Of note, CDKN2A/2B were mutated in 41/44 patients of this cluster. In cluster 2, the most affected pathways were as follows: Chromatin modification, DNA damage control, PI3K, and RTK/RAS. In this cluster, the most frequently mutated genes were ARID1A and PBRM1. The most altered pathways in cluster 3 were as follows: Cell cycle and apoptosis, DNA damage control, TP53, and chromatin modification. Importantly, TP53 was mutated only in cluster 3 patients. In the cohort of patients treated with surgery, cluster 2 showed statistically significant better disease-free survival (DFS) and overall survival (OS) compared with patients in cluster 3 and cluster 1 (p = 0.0014 and p = 0.0003, respectively). In the advanced setting, cluster 2 experienced a statistically significant better PFS (p = 0.0012), a tendency toward a better OS from first-line treatment, and a better OS from first-line progression compared with patients in cluster 1 and cluster 3 (p = 0.0017). We proposed an easy-to-use algorithm able to stratify patients in the three clusters on the basis of the genomic profile.We highlighted three different mutation-based clusters with prognostic significance in a cohort of IDH1m iCCAs.

Biliary tract cancers are rare malignancies with a poor prognosis and scarce therapeutic strategies. The significance of BRCAness in this setting is already unknown.Tissue specimens of BTC patients treated with platinum-based chemotherapy have been analyzed through the FOUNDATIONPne assay.72/150 (48%) BRCAness mutated and 78/150 (52.0%) wild type (WT) patients were included. The most commonly mutated genes in the BRCAness mutated group were: ARID1A (N = 32, 44%), CDKN2A (N = 23, 32%), KRAS/NRAS (N = 16, 22%), CDKN2B (N = 13, 18%), BRCA2 (N = 13, 18%), PBRM1 (N = 12, 17%), ATM (N = 11, 15%), FGFR2 (N = 10, 14%), TP53 (N = 8, 11%), IRS2 (N = 7, 10%), CREBBP (N = 7, 10%) (table 3, figure 1). At the univariate analysis BRCAness mutation was associated with longer median Progression Free Survival (mPFS) (HR 0.68; 95% CI 0.49-0.95; p = 0.0254); it was not associated with longer mOS but a trend toward a benefit in survival was found (HR 0.77; 95% CI 0.50-1.19; p = 0.2388). Patients with BRCAness mutation showed a higher percentage of disease control rate (77.8 vs 67.9; p = 0.04) compared to patients WT. Multivariate analysis confirmed BRCAness mutation (HR 0.66; 95% CI: 0.45-0.98; p = 0.0422) as independent favorable prognostic factors for PFS and a positive trend was found for OS (HR 0.84; 95% CI: 0.53-1.33; p = 0.3652).BRCAness BTC patients showed a better PFS compared BRCAnessWT patients after exposure to platinum-based chemotherapy. Moreover, the OS curves' trend showed in our analysis suggests that BRCAness mutated patients could benefit from a maintenance therapy with PARPi.

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Biliary tract cancer’s (BTC) treatment main stone for advanced stages is constituted by chemotherapy. Surgical centralization and physicians’ confidence in the use of new technologies and molecular analysis turned out to be of interest and potentially influencing survival. After applying a random-effect model, the relationship between each clinical variable on the main outcome was investigated through multilevel mixed-effects logistic regression. The risk-standardized outcomes were calculated for each centre involved. In the unadjusted cohort the median survival was 8.6 months (95%C.I.: 7.8–9.3) with a 9-month survival rate of 48.3% (95%C.I.: 45.0–51.5). A substantial heterogeneity across hospitals was found (I2: 70.3%). In multilevel mixed effect logistic regression, male, being treated for gallbladder cancer, higher ECOG, increased NLR, CEA and Ca 19.9 and low value of haemoglobin showed to increase the odds for 9-month mortality. The model estimated that the residual variance observed in 9-month mortality was attributable for the 2.6% to the treating hospital. Through a multilevel mixed effect model, average risk-standardized mortality within 9 months was 50.1%. As noticeable, all hospital’s risk-standardized mortality falls within 95%C.I., thus all participating centres provided similar outcomes when adjusted for patient case-mix. Heterogenicity between hospital did not affect the outcome in term of overall survival.

Background: The transmembrane glycoprotein CD44, the major hyaluronan (HA) receptor, has been proven to regulate cell growth, survival, differentiation, and migration. It is therefore widely considered to be involved in carcinogenesis. Its role as a new therapeutic target in solid tumors is under evaluation in clinical trials. The prognostic value remains controversial. Here, we aimed to investigate the correlation between CD44 expression and the clinicopathological features and survival in metastatic colorectal cancer (mCRC) patients. Methods: Data from 65 mCRC patients of the Medical Oncology Unit, University Hospital and University of Cagliari were retrospectively collected from 2008 to 2021. Immunohistochemical analysis was performed at the Pathology Division, University Hospital of Cagliari on 3 μm thick sections obtained from paraffin blocks. The intensity of immunohistochemical staining was subclassified into four groups: score 0 if negative or weak membrane staining in less than 10% of tumor cells; score 1+ if weak membrane staining in at least 10% of tumor cells or moderate membrane staining in less than 10% of tumor cells; score 2+ if moderate membrane staining in at least 10% of tumor cells or intensive membrane staining in less than 10% of tumor cells; score 3+ if intense membrane staining in at least 10% of tumor cells. Based on this score, we distinguished patients into low CD44 expression (score 0, 1+, 2+) and high CD44 expression (score 3+). Statistical analysis was performed with MedCalc (survival distribution: Kaplan–Meier; survival comparison: log-rank test; association between categorical variables: Fisher’s exact test). Results: Patients’ median age was 66 years (range 49–85). Regarding CD44 expression, score was 0 in 18 patients, 1+ in 15 patients, 2+ in 18 patients, and 3+ in 14 patients. Median overall survival (mOS) was 28.1 months (95%CI: 21.3–101). CD44 overexpression (3+) was correlated with poor prognosis (p = 0.0011; HR = 0.2), with a mOS of 14.5 months (95%CI 11.7 to 35.9) versus 30.7 months (95%CI 27.8 to 101) in lower CD44 expression. Higher CD44 expression was associated with clinically poor prognostic features: age ≥ 70 years (p = 0.0166); inoperable disease (p = 0.0008); stage IV at diagnosis (p = 0.0241); BRAF mutated (p = 0.0111), high-grade tumor (p = 0.0084). Conclusions: CD44 markedly correlated with aggressive tumor behavior and contributed to the earlier progression of disease, thus suggesting its role as a novel prognostic marker and potential therapeutic target for mCRC patients.

Immune checkpoint inhibitor (ICI)-based immunotherapy has significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC); however, a significant percentage of patients do not benefit from this approach, and predictive biomarkers are needed. Increasing evidence demonstrates that cachexia, a complex syndrome driven by cancer-related chronic inflammation often encountered in patients with NSCLC, may impair the immune response and ICI efficacy. Herein, we carried out a prospective study aimed at evaluating the prognostic and predictive role of cachexia with the related changes in nutritional, metabolic, and inflammatory parameters (assessed by the multidimensional miniCASCO tool) on the survival and clinical response (i.e., disease control rate) to ICI-based immunotherapy in patients with advanced NSCLC. We included 74 consecutive patients. Upon multivariate regression analysis, we found a negative association between IL-6 levels (odds ratio (OR) = 0.9036; 95%CI = 0.8408–0.9711; p = 0.0025) and the miniCASCO score (OR = 0.9768; 95%CI = 0.9102–0.9999; p = 0.0310) with the clinical response. As for survival outcomes, multivariate COX regression analysis found that IL-6 levels and miniCASCO-based cachexia severity significantly affected PFS (hazard ratio (HR) = 1.0388; 95%CI = 1.0230–1.0548; p < 0.001 and HR = 1.2587; 95%CI = 1.0850–1.4602; p = 0.0024, respectively) and OS (HR = 1.0404; 95%CI = 1.0221–1.0589; p < 0.0001 and HR = 2.3834; 95%CI = 1.1504–4.9378; p = 0.0194, respectively). A comparison of the survival curves by Kaplan–Meier analysis showed a significantly lower OS in patients with cachexia versus those without cachexia (p = 0.0323), as well as higher miniCASCO-based cachexia severity (p = 0.0428), an mGPS of 2 versus those with a lower mGPS (p = 0.0074), and higher IL-6 levels (>6 ng/mL) versus those with lower IL-6 levels (≤6 ng/mL) (p = 0.0120). In conclusion, our study supports the evidence that cachexia, with its related changes in inflammatory, body composition, and nutritional parameters, is a key prognostic and predictive factor for ICIs. Further larger studies are needed to confirm these findings and to explore the potential benefit of counteracting cachexia to improve immunotherapy efficacy.

Background: Information about the adherence to scientific societies guidelines in the ‘real-world’ therapeutic management of oncological patients are lacking. This multicenter, prospective survey was aimed to improve the knowledge relative to 2017-2018 recommendations of the Italian Association of Medical Oncology (AIOM). Patients and methods: Treatment-naive adult patients with pancreatic adenocarcinoma were enrolled. Group A received adjuvant therapy, group B received primary chemotherapy, and group C had metastatic disease. The results on patients accrued until 31 October 2019 with a mature follow-up were presented. Results: Since July 2017, 833 eligible patients of 923 (90%) were enrolled in 44 Italian centers. The median age was 69 years (range 36-89 years; 24% >75 years); 48% were female; 93% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; group A: 16%, group B: 30%; group C: 54%; 72% Nord, 13% Center, 15% South. In group A, guidelines adherence was 68% [95% confidence interval (CI) 59% to 76%]; 53% of patients received gemcitabine and 15% gemcitabine þ capecitabine; median CA19.9 was 29 (range 0-7300; not reported 15%); median survival was 36.4 months (95% CI 27.5-47.3 months). In group B, guidelines adherence was 96% (95% CI 92% to 98%); 55% of patients received nab-paclitaxel þ gemcitabine, 27% FOLFIRINOX, 12% gemcitabine, and 3% clinical trial; median CA19.9 was 337 (range 0-20220; not reported 9%); median survival was 18.1 months (95% CI 15.6-19.9 months). In group C, guidelines adherence was 96% (95% CI 94% to 98%); 71% of patients received nabpaclitaxel þ gemcitabine, 16% gemcitabine, 8% FOLFIRINOX, and 4% clinical trial; liver and lung metastases were reported in 76% and 23% of patients, respectively; median CA19.9 value was 760 (range 0-1374500; not reported 9%); median survival was 10.0 months (95% CI 9.1-11.1 months). Conclusions: The GARIBALDI survey shows a very high rate of adherence to guidelines and survival outcome in line with the literature. CA19.9 testing should be enhanced; nutritional and psychological counseling represent an unmet need. Enrollment to assess adherence to updated AIOM guidelines is ongoing.

The evaluation of circulating tumor DNA (ctDNA) is increasingly integrated into the management of diagnosis and treatment of gastrointestinal cancer as it represents an innovative and minimally invasive biomarker that could allow us to reach clinical needs not met yet in randomized clinical trials. Recent research provided an interesting overview of the role of circulating tumor DNA in gastric, biliary, liver, pancreatic, and colorectal cancer. Data regarding upper gastrointestinal tumors are currently not practice changing. Tumor detection rates are low in the early stages, while in advanced stages ctDNA is useful for molecular tracking evaluation. Most of the evidence comes from colorectal cancer studies, where ctDNA was evaluated both in the early and advanced stages with the post-surgery minimal residual disease assessment and the response assessment, respectively. ctDNA qualifies as a promising tool in the era of precision medicine, with potential applications in the entire management of gastrointestinal cancer patients. Further evidence is needed to establish which setting may be influenced greatly by liquid biopsy in clinical practice. ispartof: WORLD JOURNAL OF CLINICAL ONCOLOGY vol:13 issue:12 pages:980-983 ispartof: location:United States status: published

Introduction In the past, targeted therapies have not shown positive results as they have been used without adequate molecular selection of patients with biliary tract cancer (BTC). This has led to an expansion of research on characteristics and molecular selection to identify new effective strategies in this setting. Improved knowledge of the molecular biology of these neoplasms has highlighted their extraordinary heterogeneity and has made it possible to identify targetable gene alterations, including fibroblast growth factor receptor (FGFR) 2 gene fusions, and isocitrate dehydrogenase (IDH) mutations. The FDA recently approved ivosidenib and pemigatinib for the treatment of BTCs. Areas covered We review data in the literature regarding targeted therapies for the treatment of BTCs, as well as on the prospects deriving from the extraordinary molecular heterogeneity of these neoplasms. Expert opinion At present, it is essential to evaluate the expression of the genetic alterations expressed by these neoplasms to offer patients an increasingly personalized therapeutic approach. Studies are needed to better define the limits and potentials of targeted therapies and their role in the therapeutic algorithm to improve the poor prognosis of these patients.

Despite continued research, pancreatic ductal adenocarcinoma (PDAC) remains one of the main causes of cancer death. Interest is growing in the role of the tumour suppressors breast cancer 1 (BRCA1) and BRCA2—typically associated with breast and ovarian cancer—in the pathogenesis of PDAC. Indeed, both germline and sporadic mutations in BRCA1/2 have been found to play a role in the development of PDAC. However, data regarding BRCA1/2-mutant PDAC are lacking. In this review, we aim to outline the specific landscape of BRCA-mutant PDAC, focusing on heritability, clinical features, differences between BRCA1 and 2 mutations and between germline and sporadic alterations, as well as established therapeutic strategies and those that are still under evaluation.

Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic colorectal cancer (mCRC) with mismatch-repair deficiency or high microsatellite instability (dMMR-MSI-H). Unfortunately, a patient’s subgroup did not benefit from immunotherapy. Caudal-related homeobox transcription factor 2 (CDX-2) would seem to influence immunotherapy’s sensitivity, promoting the chemokine (C-X-C motif) ligand 14 (CXCL14) expression. Therefore, we investigated CDX-2 role as a prognostic-predictive marker in patients with mCRC MSI-H. We retrospectively collected data from 14 MSI-H mCRC patients treated with ICIs between 2019 and 2021. The primary endpoint was the 12-month progression-free-survival (PFS) rate. The secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and disease control rate (DCR). The PFS rate at 12 months was 81% in CDX-2 positive patients vs 0% in CDX-2 negative patients (p = 0.0011). The median PFS was not reached (NR) in the CDX-2 positive group versus 2.07 months (95%CI 2.07–10.8) in CDX-2 negative patients (p = 0.0011). Median OS was NR in CDX-2-positive patients versus 2.17 months (95% Confidence Interval [CI] 2.17–18.7) in CDX2-negative patients (p = 0.026). All CDX-2-positive patients achieved a disease response, one of them a complete response. Among CDX-2-negative patients, one achieved stable disease, while the other progressed rapidly (ORR: 100% vs 0%, p = 0.0005; DCR: 100% vs 50%, p = 0.02). Twelve patients received 1st-line pembrolizumab (11 CDX-2 positive and 1 CDX-2 negative) not reaching median PFS, while two patients (1 CDX-2 positive and 1 CDX-2 negative) received 3rd-line pembrolizumab reaching a median PFS of 10.8 months (95% CI, 10.8–12.1; p = 0.036). Although our study reports results on a small population, the prognostic role of CDX-2 in CRC seems confirmed and could drive a promising predictive role in defining the population more sensitive to immunotherapy treatment. Modulating the CDX-2/CXCL14 axis in CDX-2-negative patients could help overcome primary resistance to immunotherapy.

Testicular cancer (TC) is the most common solid tumor in young adults. 95% of patients are cured, but they may experience late adverse effects (anxiety, fear of recurrence, and sexual dysfunction) with an impact on daily life. We attempted to assess Patient Reported Outcomes (PROMs), long-term sexual disorders, and difficulties in achieving fatherhood in a cohort of TC survivors, as well as their possible correlation with previous cancer treatments.Different questionnaires, such as the Impact of Cancer (IOC) and the Body Image Scale (BIS), were used to investigate the distinct areas of the PROMs. International Index of Erectile Function (IIEF15) and the Premature Ejaculation Diagnostic Tool (PEDT) focused on sexuality and fertility. Patients were prospectively recruited between February 2020 and February 2022.144 participants completed all the questionnaires. Results showed a good QoL, a moderate fear of TC recurrence, a good satisfaction with their personal body image, low incidence of premature ejaculation and erectile dysfunction. 19.5% of patients who had a testicular implant reported general dissatisfaction. Only 18% of patients had unsuccessfully attempted fatherhood, while the majority had not yet tried, and 23.4% succeeded. A low percentage of patients used procedures assisted reproduction and adoption.This trial supports the use of various questionnaires as a multifactorial tool capable of investigating all the aspects of long-term cancer survivorship. The assessment of medical and psychosocial sequelae is an essential part of patient care and is important for the development of a comprehensive care plan for TC survivors.

Lung cancer is a leading cause of cancer-related deaths worldwide. About 10-30% of patients with non-small cell lung cancer (NSCLC) harbor mutations of the EGFR gene. The Tumor Microenvironment (TME) of patients with NSCLC harboring EGFR mutations displays peculiar characteristics and may modulate the antitumor immune response. EGFR activation increases PD-L1 expression in tumor cells, inducing T cell apoptosis and immune escape. EGFR-Tyrosine Kinase Inhibitors (TKIs) strengthen MHC class I and II antigen presentation in response to IFN-γ, boost CD8+ T-cells levels and DCs, eliminate FOXP3+ Tregs, inhibit macrophage polarization into the M2 phenotype, and decrease PD-L1 expression in cancer cells. Thus, targeted therapy blocks specific signaling pathways, whereas immunotherapy stimulates the immune system to attack tumor cells evading immune surveillance. A combination of TKIs and immunotherapy may have suboptimal synergistic effects. However, data are controversial because activated EGFR signaling allows NSCLC cells to use multiple strategies to create an immunosuppressive TME, including recruitment of Tumor-Associated Macrophages and Tregs and the production of inhibitory cytokines and metabolites. Therefore, these mechanisms should be characterized and targeted by a combined pharmacological approach that also concerns disease stage, cancer-related inflammation with related systemic symptoms, and the general status of the patients to overcome the single-drug resistance development. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:23 issue:12 ispartof: location:Switzerland status: published

Aim The identification of new prognostic factors able to stratify hepatocellular carcinoma patients candidate to first-line therapy is urgent. In the present work we validated the prognostic value of the lenvatinib prognostic index. Methods Data of Eastern and Western patients treated with lenvatinib as first-line for Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma were recollected. The lenvatinib prognostic index was composed by three classes of risk according with our previous study. The "low risk" group includes patients with prognostic nutritional index (PNI) >43.3 and with previous transarterial chemoembolization. The "medium risk" group includes patients with PNI >43.3, but without previous transarterial chemoembolization and patients with PNI

Background Biliary tract cancers (BTC) are rare but highly aggressive tumours with poor prognosis, usually detected at advanced stages. Herein, we aimed at identifying BTC-specific DNA methylation alterations. Methods Study design included statistical power and sample size estimation. A genome-wide methylation study of an explorative cohort (50 BTC and ten matched non-tumoral tissue samples) has been performed. BTC-specific altered CpG islands were validated in over 180 samples (174 BTCs and 13 non-tumoral controls). The final biomarkers, selected by a machine-learning approach, were validated in independent tissue (18 BTCs, 14 matched non-tumoral samples) and bile (24 BTCs, five non-tumoral samples) replication series, using droplet digital PCR. Results We identified and successfully validated BTC-specific DNA methylation alterations in over 200 BTC samples. The two-biomarker panel, selected by an in-house algorithm, showed an AUC > 0.97. The best-performing biomarker (chr2:176993479-176995557), associated with HOXD8, a pivotal gene in cancer-related pathways, achieved 100% sensitivity and specificity in a new series of tissue and bile samples. Conclusions We identified a novel fully efficient BTC biomarker, associated with HOXD8 gene, detectable both in tissue and bile by a standardised assay ready-to-use in clinical trials also including samples from non-invasive matrices.

648 Background: The oral tyrosine kinase inhibitor Cabozantinib (CABO) is frequently used to treat patients with metastatic RCC. Polypharmacy is common in elderly pts, thus several drug-drug interactions (DDIs) with cabozantinib may ensue. Methods: ZEBRA /MEET-URO 9 was a prospective, real world trial enrolling pts ≥ 70 years with mRRC treated with CABO at 13 Italian Oncology Centers. All concomitants drugs administered to pts were collected and categorized according to active principles and indication. DDIs were identified through a dedicated software (Lexicomp), scientific databases (Sider4.1) and published articles. Results: we enrolled 104 pts, median age 75.8 years (range 70.2-87.4 yrs). Overall, 91.4% of the cohort was treated at a reduced dose either upfront or due to side effects. Pts took a median of 6 concomitant drugs (IQR: 4-9), for a total of 131 active principles. Software analysis identified 4 DDIs (warfarin, apixaban, diltiazem and furosemide); whereas scientific reports allowed us to identify 15 additional DDIs involving metoprolol, nebivolol, olmesartan, amiloride, simvastatin, rosuvastatin, polyenoic omega-3 fatty acids, loperamide, metoclopramide, metformin, dutasteride, dexamethasone, prednisone, cetirizine and doxazosin. Seventy pts with potential DDIs experienced a trend for higher rate of grade 3-4 adverse events compared to other pts, although difference was not statistically significant (48.7% v 23.5 %, p=0.485). The table summarizes the main DDIs and suggestions to avoid or mitigate their effects Conclusions: the risk of DDIs was not negligible in our cohort of elderly mRCC pts treated with CABO, although the frequent dose reductions of CABO probably confounded their impact on toxicities. Unremitting attention to concomitant medications in the elderly is thus warranted. [Table: see text]

688 Background: Pembrolizumab/axitinib (PAXI) combination is an approved option as first-line therapy of mRCC. The aim of this analysis is to evaluate safety profile of PAXI combo in the real-world experience in Italy. Methods: This is a prospective study including patients (pts) diagnosed with mRCC who received PAXI as first-line therapy in recruiting Italian Centers. Safety data about clinically significant adverse events (AEs), defined as AE requiring corticosteroids, hormone replacement, drug delay, discontinuation or dose reduction were collected. Results: Data from 122 pts treated from January 2021 to September 2022 have been analyzed. With a median follow-up of 10 mos (range 0.2 - 21) and treatment interruption in 35 pts (29%), at landmark 6-mos and 12-mos the treatment was ongoing in 76% (95%CI 0.67-0.83) and 66% of pts (95%CI 0.56-0.75) respectively. In 11% of pts a starting dose of Axi

164 Background: ARSI [enzalutamide (ENZA) and abiraterone (ABI)] demonstrated to be efficacious as a first-line therapy for mCRPC, showing a median progression-free survival of 16 and 20 months (mos) in pivotal trials, respectively. Nevertheless, some pts of daily clinical practice show exceptionally prolonged disease control with very long duration of treatment. The present study aimed at identifying the characteristics of LTR pts who received one ARSI as a first-line for mCRPC. Methods: We retrospectively reviewed the clinical records of a consecutive series of 647 pts treated in the daily clinical practice with one ARSI as first-line mCRPC in four Italian high-volume Institutions. Pts who had previously received docetaxel in castration-sensitive setting were excluded. Pts received standard AA or ENZA doses (1,000 mg po daily plus prednisone 10 mg po daily or 160 mg po daily, respectively). ARSI were administered until progression and were followed according to each Institution policy. For each pt we recorded pre and post-ARSI clinical history, baseline characteristics, treatment details and clinical outcomes. Pts were considered as LTR in presence of an ARSI exposure ≥ 36 mos. LTR were compared to the progressed pts with an ARSI exposure < 36 mos. On-treatment pts with an ARSI exposure < 36 mos were not considered. Results: We identified 81 LTR pts (53 treated with ENZA and 28 treated with ABI). The median age was 76 yrs (range 56-89). The median treatment duration was 46.1 mos (range 36.4-88.6) and 52 pts were still on treatment. LTR were compared to no-LTR 415 pts (233 treated with ENZA and 182 treated with ABI). Compared to no-LTR, LTR pts showed longer PSA doubling time (PSADT) (PSADT) (p = 0.001) and time to mCRPC (p < 0.0001), lower levels of basal PSA (p = 0.01), and alkaline phosphatase (ALP) (p = 0.01), better ECOG PS (p = 0.01), lower Gleason score (p = 0.01), and less pain level (p = 0.04). ECOG PS, ALP, time to mCRPC and PSADT were all identified as independent predictors of time to treatment interruption in multivariate analysis. LTR showed an 89% decreased risk of death compared to no-LTR (HR = 0.11 IC95% 0.06-0.18). Conclusions: In our experience, several variables, which are usually considered as having a prognostic value, demonstrated to be able to predict the probability of prolonged disease control in mCRPC pts treated with first-line ARSI.

752 Background: Glucose and other metabolites (lactates and glutamine) in the tumor microenvironment (TME) may alter the activity of the immune system cells. Cancer cells consume glucose and its decrease in the TME affects the function of tumour-infiltrating lymphocytes (TILs). Moreover, tumor-infiltrated immunosuppressive cells and vascular endothelial cells also deplete nutrients, in the TME, enhancing an immunosuppressive environment. On the basis of the results coming from our previous works regarding lymphocytes to monocytes ratio (LMr) and diabetes, suggesting a role for each of them as predictors of better outcomes, in this study we evaluate both of them in order to establish a possible role of them as outcomes predictive factors. Methods: Data from 228 patients (pts) were collected retrospectively from 2016 to 2021: 175 from the Medical Oncology Unit of University Hospital of Cagliari; 53 from the Medical Oncology Unit, AOU Ospedali Riuniti di Ancona. All pts had stage IV disease and received gemcitabine plus nab-paclitaxel 1st line chemotherapy. Statistical analysis was performed with the MedCalc package. We aimed to evaluate the correlation between treated DM2 and lymphocytes to monocytes ratio (LMr) ≥ 4 with outcomes. Survival distribution was assessed by Kaplan-Meier curves. Multivariate analysis was performed taking into consideration the following prognostic factors: sex, ECOG-PS, LMr, NLr, LDH, Ca19.9, and metastatic sites. Results: Median age was 68 (±9), 123/228 (54%) were male, 94/232 (40,6%) were affected by DM2 (insulin or metfomin-treated) and 138 (59,4%) pts were not affected by DM2. 52/228 (23%) pts had a LMr ≥ 4, 176/228 (77%) pts had a LMr < 4. In multivariate analysis, DM2 and LM ratio ≥ 4 were found to be independent factors associated with higher overall survival. Therefore, we divided the pts into 3 groups: co-presence DM2 and LM ≥ 4 (DM+LM+); absence of DM2 and LM ≥ 4 (DM-LM-); presence of DM2 or LM ≥ 4 (DM+LM- or DM-LM+). DM+LM+ demonstrated statistically significantly higher median OS than DM+LM-/DM-LM+ and DM-LM- (not reached versus 21 versus 9 months, respectively, p < 0.0001). Furthermore, DM+LM+ showed a statistically significant better median PFS than DM+LM-/DM-LM+ and DM-LM- (11 versus 9 versus 6 months, respectively, p = 0,0036). Conclusions: Results showed a correlation between pts with DM2/LMr ≥ 4 and better outcomes. This may suggest the presence of a link between glucose metabolism and lymphocytes activation. Antidiabetic medications could promote the inhibition of Warburg effect in tumor cells, and, consequently, provide a better glucose intake to extracellular microenvironment, and immune cells, including T lymphocytes. This process leads to a higher activity of T-cells and a better treatment response. Further studies are warranted.

Introduction Despite available treatment options, pancreatic ductal adenocarcinoma (PDAC) is frequently lethal. Recent immunotherapy strategies have failed to yield any notable impact. Therefore, research is focussed on unearthing new drug targets and therapeutic strategies to tackle this malignancy and attain more positive outcomes for patients. Areas covered In this perspective article, we evaluate the main resistance mechanisms to immune checkpoint inhibitors (ICIs) and the approaches to circumvent them. We also offer an assessment of concluded and ongoing trials of PDAC immunotherapy. Literature research was performed on Pubmed accessible through keywords such as: 'pancreatic ductal adenocarcinoma,' 'immunotherapy,' 'immunotherapy resistance,' 'immune escape,' 'biomarkers.' Papers published between 2000 and 2021 were selected. Expert opinion The tumour microenvironment is a critical variable of treatment resistance because of its role as a physical barrier and inhibitory immune signalling. Promising therapeutic strategies appear to be a combination of immunotherapeutics with other targeted treatments. Going forward, predictive biomarkers are required to improve patient selection. Biomarker-driven trials could enhance approaches for assessing the role of immunotherapy in PDAC.

This study aimed to clarify the current knowledge on the use of immunotherapy in patients with advanced gastric(G)/gastroesophageal(GEJ) cancers.A meta-analysis was done to evaluate the efficacy of immune checkpoint inhibitors(ICIs) in G/GEJ cancer both in the unselected population and in that stratified for combined positive score (CPS)≥ 1 and ≥ 10 patients.In the unselected population the result showed 21%(P 0.00001), and 29%(P 0.00001) reduction of death and progression risk for patients treated with ICIs compared without ICIs, while in CPS≥ 1 and≥ 10 populations, the result showed a death reduction of 19%(P = 0.001) and 33%(P 0.00001) respectively, and, and 23% (P 0.00001) and 43% (P 0.00001) progression risk reduction respectively, for patients treated with and without ICIs.overall survival(OS) and progression free survival(PFS) data obtained in our meta-analysis, are in favor to use ICIs in association with standard first line chemotherapy for G/GEJ cancer patients regardless to CPS status.

The prognostic relevance of early immune-related adverse events (irAEs) in patients affected by non-small cell lung cancer (NSCLC) upon immunotherapy is not fully understood. The Leading to Treatment Discontinuation cohort included 24 patients experiencing severe irAEs after one of two administrations of single anti-PD-1/PD-L1 in any line setting for metastatic NSCLC between November 2015 and June 2019. The control cohort was composed of 526 patients treated with single anti-PD-1/PD-L1 in any line setting with no severe irAE reported. The primary end points were median progression-free survival, overall survival, objective response rate, risk of progression of disease and risk of death. The correlation of clinic pathological features with early severe irAEs represented the secondary end point. Median PFS was 9.3 and 8.4 months, median OS was 12.0 months and 14.2 months at a median follow-up of 18.1 and 22.6 months in the LTD cohort and in the control cohort, respectively. The ORR was 40% (95% CI 17.2–78.8) in the LTD cohort and 32.7% (95% CI 27.8–38.2) in the control cohort. The risk of disease progression was higher in the LTD cohort (HR 2.52 [95% 1.10–5.78], P = .0288). We found no survival benefit in LTD cohort compared to the control cohort. However, early and severe irAEs might underly an immune anti-tumor activation. We identified a significant association with first-line immune checkpoints inhibitors treatment and good PS. Further studies on risk prediction and management of serious and early irAEs in NSCLC patients are needed.

Background After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. Patients and methods With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. Results The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI, Highlights • This study shows a new prognostic index (LEP index) for patients undergoing systemic therapy for hepatocellular carcinoma. • LEP index is an easy-to-use tool, based on clinical and laboratory features, that identifies three risk groups. • LEP index may be used to stratify hepatocellular carcinoma patients in order to select the most appropriate treatment.

4153 Background: Despite the most recent therapeutic achievements, pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and response to treatments. Among the most investigated prognostic biomarkers, the lymphocyte to monocyte ratio (LMr) is gaining increasing interest in literature, mostly in hematological malignancies, breast cancer, bladder cancer, non-small cell lung cancer, colorectal cancer, and resected pancreatic adenocarcinoma. In these settings, a higher LMr allows identifying a subset of patients with a better prognosis. Our study aimed to evaluate the role of the LMr as a prognostic factor in patients affected by metastatic PDAC and to find a cut-off value able to identify a subset of patients with better prognosis and possibly susceptible to other therapeutic options. Methods: Data from 228 patients were collected retrospectively from 2014 to 2021. 175 from the Department of Medical Oncology of the University Hospital of Cagliari and 53 from the Oncology Clinic - University Hospital of Ospedali Riuniti of Ancona. All patients had metastatic PDAC and blood samples were collected before starting first-line chemotherapy. The cut-off value for LMr was calculated according to the ROC curves at 6, 12, and 18 months. Kaplan-Meier curves were then obtained for the evaluation of survivals. Finally, multivariate analysis was performed, taking into consideration the following prognostic factors: sex, ECOG-PS, NL ratio, metastatic sites, Ca19.9 and LDH. Results: The median age was 68 y.o. (range 39-84 y.o.), 123 (54%) were males. Cut off value obtained for LMR, was 4. 156 (68,4%) patients had an LMr < 4 and 72 (31,6%) patients had an LMR ≥ 4. Patients with a ratio ≥ 4 showed a statistically significant difference in terms of median overall survival compared to patients with a ratio < 4 (23 months versus 11 months, p < 0.0001). First-line median progression-free survival was also different in patients with a value greater than or equal to 4 (11 months versus 6 months, p = 0.005), suggesting a better treatment response in the first group of patients. Finally, multivariate analysis showed that LMR ≥ 4 is an independent prognostic factor for OS ( p = 0.0005). Conclusions: The results of our study show that the lymphocyte to monocyte ratio could be an important prognostic factor in patients with metastatic pancreatic ductal adenocarcinoma, although the limitations of a retrospective study should be considered. Furthermore, these findings suggest the active role of the immune response in limiting disease progression, indicating a group of patients who could benefit most from a target or combined immunotherapy treatment.

e16301 Background: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated. Indeed, DM2 can be both an epiphenomenon of PDAC and a risk factor. However, the data on the influence of DM2 and concomitant drug therapy in the progression of pancreatic neoplasms are conflicting. The present study aimed to investigate the correlation between overall survival (OS) and antidiabetic drugs in patients with metastatic pancreatic ductal adenocarcinoma and DM2. Methods: Data from 232 patients were collected retrospectively from 2014 to 2021. 174 from the Department of Medical Oncology of the University Hospital of Cagliari and 58 from the Department of Medical Oncology, AOU Ospedali Riuniti of Ancona. All patients had stage IV disease and received gemcitabine plus nab-paclitaxel first-line chemotherapy. Statistical analysis was performed with the MedCalc package. We aimed to evaluate the correlation between DM2, anti-diabetic medications (ADMs) and median overall survival (mOS). Survival distribution was assessed by Kaplan-Meier curves. Finally, multivariate analysis was performed, taking into consideration the following prognostic factors: sex, ECOG-PS, LDH, Ca19.9, and metastatic sites. Results: The median age was 69 y.o. (range 40-84 y.o.), 127 (54,7%) were male. All patients received first-line treatment with gemcitabine plus nab-paclitaxel. 138 (59,4%) patients were not affected by DM2, 94/232 (40,6%) were affected by DM2. Among DM2 patients, 57 (%) were insulin-treated and 37 (%) were metformin-treated. DM2 patients showed a statistically significant higher median overall survival (26 versus 11 months, 95% CI, p = 0,0002). Furthermore, among DM2 patients insulin-treated and metformin-treated showed a mOS of 21 months and 33 months, respectively (95% CI, p = 0.0002). Finally, multivariate analysis showed that treated-DM2 is an independent prognostic factor ( p = 0.03). Conclusions: The results of our study showed a correlation between DM2 on treatment (with insulin or metformin) and higher mOSin patients with metastatic PDAC. However, the limitations due to retrospective data collection must be considered. The mechanisms underlying these findings could be explained by maintaining optimal insulin concentration and good glycemic control during treatments, or by the activity of anti-diabetic medication in neoplastic tissues. However, further studies in this setting are needed.

e16068 Background: The FLOT4-AIO phase II/III trial established perioperative FLOT regimen as the new standard in Western countries for patients (pts) with locally advanced resectable gastric (GC) or gastroesophageal junction cancer (GEJC). Microsatellite instability (MSI-H) showed a favorable prognostic role and a concomitant negative predictive impact on the benefit of adjuvant and neoadjuvant 5-fluorouracil-based doublets, but its prognostic and predictive role in pts receiving perioperative FLOT treatment still remains unclear. Our study aims to explore the real-world efficacy of FLOT regimen and to describe histopathological features and clinical outcomes in the MSI-H subgroup population. Methods: This is a retrospective multi-center analysis including pts with GC and GEJC, treated with perioperative FLOT regimen in clinical practice and whose microsatellite status and survival data were available. The association of baseline characteristics, biomolecular and pathological features and overall survival (OS) were firstly assessed in univariate analyses by means of log-rank test, and significantly prognostic variables (p < .05) were included in a multivariable COX proportional hazard model. Results: A total of 250 pts (median age, 62, range 37-81, male 71.6%, ECOG PS 0, 82%) were treated at 11 Italian Oncology Units from January 2017 to June 2021. At a median follow-up time of 22.5 months (mos) (2.3 - 66.7 mos), 123/250 (49.2%) patients relapsed and 77/250 (30.8 %) died. In the global population the median disease-free survival (DFS) was 16,7 mos (95% CI 13,8–21,2) and the median OS 34,9 mos [95% confidence interval (CI) 28–NA]. MSI-H phenotype was found in 26 (10.4%) out of 250 analyzed tumors. Compared to MSS cases, MSI-H were more frequently identified in female (50% vs 25.9%, p = .001), elderly pts (age ≥ 70 years, 76.9% vs 9.4%, p = .003), Laurens’s intestinal type (54% vs 12%, p = .0076) and in pts with primary location tumor in antrum (38.5% vs 13.8%, p = .0004). No relevant differences have been noticed in R0 resections (88% and 96%, p = .06) and pathological complete responses (4.9 % and 3.8%, p = .718), however a statistically significant difference in the rate of pathological negative lymph-nodes between MSS and MSI-H cohort emerged (29.3% vs 65.4%, p = .0004). Compared to MSS tumor population, MSI-H subgroup has a tendency to better DFS (median not reached (NR) vs 15.7, p = .06), metastasis free survival (MFS, median NR vs 17.2 mos, p = .06) and OS (median 41 vs 34 mos, p = .07). Conclusions: These real-world data confirm the efficacy of FLOT perioperative regimen in pts with locally advanced GC/GEJC, maintained also in the MSI-H pts. Our study suggests a better outcome of MSI-H GC and GECJ pts treated with FLOT in comparison to MSS, due to increased rate of nodal status downstaging and despite a poor histological response in the resected tumor tissue of MSI-H pts.

In this work, an analytical formulation for the vibration response of a bridge due to walking pedestrians is proposed to the aim of modelling the human-structure interaction (HSI) in the vertical direction. Bridge and pedestrians are described as mechanical systems having a finite number of degrees of freedom (DOFs). A new single DOF model of a bipedal pedestrian is proposed, that reproduces the alternation of single and double support phases of human gait and the related ground reaction forces. The finite element method is adopted to model the 3D geometry of the bridge. The coupled equations of motion are derived based on the key assumption that contact points between the pedestrians and the bridge deck are massless. However, the structural matrices of the coupled system are time varying due to the pedestrian motion along the bridge. An uncoupled solution strategy is devised to reduce the computational burden, allowing for the separate integration of the bridge and the pedestrian sub-systems. The coupled formulation is uncoupled and associated with an iterative procedure that restores compatibility and equilibrium at contact points. The pedestrian model and the analytical procedure are implemented in a research code where input data are the bridge structural matrices computed with a commercial FE code. The modelling and analysis procedure is applied to a case study, a lively footbridge in Seriate, Italy. A first validation of the code is obtained by comparison with a closed form solution for a 1D beam. For the loading scenarios analyzed here, a maximum of two iterations per step are necessary to achieve convergence within a prescribed tolerance. Loading scenarios encompassing groups of pedestrians in different transverse positions highlight the importance of the 3D bridge modelling. The comparison with a few experimental results clarifies the role of the modelling assumptions. Conclusions discuss novelties, advantages, limits and future developments of the proposed approach.

Targeting tumor-driven angiogenesis is an effective strategy in the management of metastatic colorectal cancer (mCRC); however, the choice of second-line therapy is complicated by the availability of several drugs, the occurrence of resistance and the lack of validated prognostic and predictive biomarkers. This review examines the use of angiogenesis-targeted therapies for the second-line management of mCRC patients. Mechanisms of resistance and anti-placental growth factor agents are discussed, and the role of aflibercept, a recombinant fusion protein consisting of portions of human vascular endothelial growth factor receptor (VEGFR)-1 and VEGFR-2, is highlighted. The novel mechanism of action of aflibercept makes it a useful second-line agent in mCRC patients progressing after oxaliplatin-based chemotherapy, as well as in those with resistance after bevacizumab.

Background Regorafenib is a key agent in metastatic colorectal cancer (mCRC), but no validated factors predicting longer survival are available. Patients and Methods REALITY was a retrospective multicenter trial in regorafenib-treated mCRC patients with overall survival (OS) ≥ 6 months. We aimed to assess the association between clinical parameters and outcome to define a panel identifying long term survivors among regorafenib candidates. Primary and secondary endpoints were OS and progression free survival (PFS), respectively. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; independent role of significant variables at univariate analysis: logistic regression). Results Hundred regorafenib-treated mCRC patients with OS ≥ 6 months were enrolled. Median OS was 11.5 m (95%CI:9.60-12.96); median PFS was 4.2 months (95% CI:3.43-43.03). The absence of liver progression and of dose and/or schedule changes during the first 4 cycles (mainly for good tolerability) were independently correlated at multivariate analysis with OS (Exp(b)1.8869, P= .0277and Exp(b)2.2000, P = .0313) and PFS (Exp(b)2.1583, P = .0065 and Exp(b)2.3036, P= .0169). Patients with neither of these variables had a significantly improved OS (n = 14, 20.8 months; 95% CI:12.967-55.267) versus others (n = 86, 10 months; 95% CI:8.367-12.167; HR = 0.4902, P = .0045) and PFS (11.3 months, 95%CI:4.267-35.8 vs. 3.9 months, 95% CI:3.167-43.033; HR = 0.4648, P = .0086). Conclusion These 2 factors might allow clinicians to better identify patients more likely to benefit from regorafenib. Toxicity management remains crucial.