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Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the second leading cause of cancer-related mortality. HCC typically arises within a cirrhotic liver, but in about 20% of cases occurs in absence of cirrhosis. Among non-cirrhotic risk factors, non-alcoholic fatty liver disease (NAFLD) currently represents the most important emerging cause of HCC in developed countries. It has been estimated that annual incidence of HCC among patients with non-cirrhotic NAFLD is approximately 0.1–1.3 per 1000 patients/year and ranges from 0.5% to 2.6% among patients with non-alcoholic steatohepatitis (NASH) cirrhosis. However, only a few clinical trials enrolling HCC patients actually distinguished NAFLD/NASH-related cases from other non-cirrhotic causes and therefore evidence is still lacking in this subset of patients. This review aims to describe the biology underpinning NAFLD development, to investigate the main molecular pathways involved in its progression to NASH and HCC and to describe how different pathogenetic mechanisms underlying the onset of HCC can have an impact in clinical practice. We hereby also provide an overview of current HCC treatment options, with a particular focus on the available data on NAFLD-related cases in practice-changing clinical trials.

Historically, metastatic melanoma was considered a highly lethal disease. However, recent advances in drug development have allowed a significative improvement in prognosis. In particular, BRAF/MEK inhibitors and anti-PD1 antibodies have completely revolutionized the management of this disease. Nonetheless, not all patients derive a benefit or a durable benefit from these therapies. To overtake this challenges, new clinically active compounds are being tested in the context of clinical trials. CDK4/6 inhibitors are drugs already available in clinical practice and preliminary evidence showed a promising activity also in melanoma. Herein we review the available literature to depict a comprehensive landscape about CDK4/6 inhibitors in melanoma. We present the molecular and genetic background that might justify the usage of these drugs, the preclinical evidence, the clinical available data, and the most promising ongoing clinical trials.

Background Endocrine therapy (ET) plus cyclin-dependent-kinases 4/6 inhibitors (CDK4/6i) represents the standard treatment for luminal-metastatic breast cancer (MBC). However, prospective head-to-head comparisons are still lacking for 1st line (L) options, and it is still crucial to define the best strategy between 1st and 2nd L. Materials and methods 717 consecutive luminal-MBC pts treated between 2008 and 2020 were analyzed at the Oncology Department of Aviano and Udine, Italy. Differences about survival outcomes (OS, PFS and PPS) were tested by log-rank test. The attrition rate (AR) between 1st and 2ndL was calculated. Results At 1stL, pts were treated with ET (49%), chemotherapy (CT) (31%) and ET-CDKi (20%) while, at 2ndL, 33% received ET, 33% CT and 8% ET-CDKi. Overall AR was 10%, 7% for CT, 8% for ET and 17% for ET-CDKi. By multivariate analysis, 1stL ET-CDK4/6i showed a better mPFS1 and OS. Moreover, 2ndL ET-CDK4/6i demonstrated better mPFS2 compared to ET and CT. Notably, 1stL ET-CDKi resulted in higher mPFS than 2ndL ET-CDKi. Intriguingly, 1stL ET-CDK4/6i was associated with worse mPPS compared to CT and ET. Secondarily, 1stL ET-CDK4/6i followed by CT had worse OS compared to 1stL ET-CDK4/6i followed by ET. Notably, none of baseline characteristics at 2ndL influenced 2ndL treatment choice (ET vs. CT) after ET-CDKi. Conclusion Our real-world data demonstrated that ET-CDKi represents the best option for 1stL luminal-MBC compared to ET and CT. Also, the present study pointed out that 2ndL ET, potentially combined with other molecules, could be a feasible option after CDK4/6i failure, postponing CT on later lines., Highlights • To define the best treatment strategy for 1st and 2nd L is crucial for luminal mBC. • 1st L CDK4/6i-based therapies represent the standard treatment in luminal mBC. • This study confirmed the key role of 1st L CDK4/6i on a real-world cohort. • This study suggested a preeminent role for ET after first-line CDK4/6i. • The 2nd line ET with other molecules could allow to further postpone CT.

e13008 Background: Liquid biopsy-based biomarkers, including circulating tumor DNA (ctDNA), are increasingly important for the characterization of metastatic breast cancer (MBC). Currently, CA15.3 is the most commonly used serum marker for monitoring disease burden. To date, no liquid biopsy-based biomarkers have been proposed for this scope in clinical practice. Methods: The CRO-2018-56 multicenter study prospectively enrolled 83 patients (pts) with luminal-like MBC treated with first line endocrine therapy (ET) and CDK4/6 inhibitors. All pts were characterized for ctDNA through droplet digital PCR (ddPCR) in from 2018 to 2021. Clinicopathological and laboratory characteristics at baseline were tested for associations with tumor markers, ACTB fragments lengths, methylation status of ESR1 main promoters (expressed as promA and promB ratio, i.e., met_ratio) and ESR1/PIK3CA mutational status through Kruskal-Wallis test and Chi-square test. Prognosis was tested in terms of Progression Free Survival (PFS) and Overall Survival (OS) through log-rank test. Results: At baseline, in 26 (31%) pts disease was diagnosed as de novo metastatic, 66 (80%) pts had < 3 of metastatic sites, and 41 (49%) pts had < 5 of metastatic lesions. Bone metastases were detected in 53 (64%) pts, liver metastases in 21 (25%) pts, and lung lesions in 30 (36%) pts. A ctDNA-detected ESR1 mutation and a PIK3CA mutation were found in 15% of pts and in 34% pts, respectively. Met_ratio was > 1.5 in 35 (42%) of pts. Median CA15.3 was 48.2 U/mL and median CEA was 3.8 U/mL. Number of liver metastases and number of metastatic sites were significantly higher in pts with ESR1 mutation (respectively, P = 0.0055 and P = 0.0208). CA15.3 and ctDNA yield were significantly higher in pts with number of metastatic sites ≥ 3, (respectively, P = 0.0164, and P = 0.0239), while number of metastatic sites ≥ 3 and number of metastatic lesions ≥ 5 were significantly associated with CEA > 3.8 U/mL (respectively, P = 0.039, and P = 0.029). Presence of bone metastases was significantly associated with PIK3CA mutation (P = 0.040), while number of metastatic sites ≥ 3 was significantly associated with ESR1 mutation (P = 0.022). No association with tumor burden was observed for different ACTB DNA fragments lengths. Met_ratio > 1.5 was significantly associated with lower number of metastatic lesions (P = 0.031). Number of metastatic sites ≥ 3, high ctDNA yield and CEA were associated with worse OS (respectively P = 0.0465, P = 0.0250 and P = 0.0474), while only CEA impacted on PFS (P = 0.0097). Conclusions: In pts with luminal-like MBC, some liquid biopsy-based biomarkers (i.e., ctDNA-detected ESR1 and PIK3CA mutations, ctDNA yield) were significantly associated with the burden of disease. The potential clinical validity and utility of these results deserve to be tested in an expansion cohort.

1027 Background: The combination of ET and CDK4/6i is the current standard of care for hormone receptor (HR)-positive/HER2-negative MBC (luminal MBC), with neutropenia being the main dose limiting toxicity. We previously observed the potential association between leucocyte count (WBC) and different fractions of cell free circulating DNA (cfDNA) (Bortot et al 2020). The present study aimed to evaluate the feasibility of a cfDNA-based workflow as a new tool to assess the risk of treatment induced neutropenia. Methods: The study analyzed a prospective cohort 83 luminal MBC patients (pts) treated with first line ET and CDK4/6i in the CRO-2018-56 multicenter study from 2018 to 2021. cfDNA was characterized through droplet digital PCR (ddPCR) based on different ACTB DNA fragments lengths: short (s), medium (m) and long (l). Blood samples were collected before treatment start (BL) and at the first clinical evaluation after 3 months (E1). Associations between clinical characteristics, neutropenia and cfDNA were explored through Kruskal Wallis, time to G3 neutropenia (NG3) (TTN) was analyzed through log-rank and Cox regression. Results: Neutropenia was G3 in 44 out of 83 pts (53%) and G4 in 2 pts (2%). Median TTN was 1.8 months, 60% of NG3 occurred within 3.7 months. Overall, 74 pts (89%) resolved toxicity within 7 days, 10 pts (12%) reduced CDK4/6i dose after NG3. BL neutrophils count (Neu) and WBC were significantly lower in pts that developed NG3 (P = 0.0013 and P = 0.0020 respectively). De novo metastatic pts had numerically higher Neu (median 4825 vs 3895), but only a numerically lower risk of NG3 was observed (HR 0.53 P = 0.064). Although bone involvement was not associated with risk of developing NG3, the total number of metastatic lesions was associated with higher NG3 (P = 0.0016). In particular, > 5 metastatic lesions were associated with higher NG3 risk (p = 0.013). E1 ACTB_m was significantly lower with respect to BL in pts that experienced NG3 (median 100% vs 16%, P = 0.0136 in NG3 no vs yes) with a consistent impact on the risk of NG3 (HR: 2.81, P = 0.025). No associations were observed for the other ACTB fragment length fractions. BL Neu and ACTB_m dichotomized at the median were then combined to describe 4 distinct TTN risk groups (P = 0.0006). Interestingly, pts with low BL Neu and low E1 ACTB_m had a median TTN of 0.9 months, while pts with high BL Neu and high E1 ACTB_m have not experienced NG3 after a median follow-up of 16.1 months. Conclusions: The present study proofed the concept of using cfDNA to provide clinically meaningful data not only about tumor biology, but also for a comprehensive patient assessment. Based on these results, a prospective study focused on a multiparametric neutropenia risk assessment will be started.

279 Background: In the last years, the introduction of immune checkpoint inhibitors (ICI) in clinical practice translated into major changes in oncology workload. We conducted a study aimed to estimate the shift in workload generated, within 1 year of first consultation, by any new metastatic cancer patient receiving ICI at the Oncology Department of the Academic Hospital of Udine, Italy. Methods: We collected from our electronic accountability system data all new cases of metastatic cancer between 01.01.2017 and 31.12.2018, leading to at least a second clinical episode (treatment sessions, unplanned presentations, hospitalizations, re-evaluations, follow-up, and inpatient oncology advices) during the following year. Patients (pts) were divided into those receiving ICI (anti-CTLA4/PD1/PDL1) versus pts receiving other treatments. Mean number per patient and standard deviation were calculated for clinical episodes, and the mean numbers in each group were compared using Student’s t-test (significance p

Case report A 38-year-old female patient with bilateral papilledema who presented with loss of vision in her left eye. The Magnetic Resonance Imagining (MRI) showed thickening of the dura mater, and the intracranial pressure was elevated. A cancer, infectious origin, and autoimmune origin were ruled out. Discussion The initial response to high doses of corticoids was satisfactory, with disappearance of the optic disk enema, with visual acuity and an improvement in the MRI. However, after one year without treatment she had a new outbreak of the disease. Despite renewed treatment with corticoids and azathioprine, the patient developed a left optic neuropathy and irreversible visual loss.

Case report An alcoholic patient with loss of vision in his right eye and a peripapillar hemorrhage, who then presented with a venous thrombosis. Blood analysis revealed hyperhomocysteinemia with coagulation parameters within the normal range. In the follow-up he developed a bilateral optic neuropathy. Discussion An increase in homocysteine levels is common in alcoholics, and it has been considered a vascular risk factor. Folic acid and vitamins B 6 and B 12 deficiency may lead to hyperhomocysteinemia, as they participate in its metabolism. Conclusions When presented with a retinal occlusive disease or ischemic optic neuropathy in young patients, coagulation disorders and elevated levels of homocysteine should be ruled out.

Background Cancer multidisciplinary team meetings (MDMs) are commonly acknowledged as a good clinical practice. One of the roles of MDMs is to identify the best diagnostic and therapeutic strategies for patients (pts) with new diagnosis of early breast cancer (EBC). In this setting, the purpose of the study was to define whether there was agreement between the planned program (i.e. MDMs-based decision) and that actually applied (i.e. actual therapeutic choice, ATC). In addition, the study explored factors associated with discordance. Methods We conducted a monocentric retrospective study of a consecutive series of 291 pts with new diagnosis of EBC, discussed at MDMs at the University Hospital of Udine (Italy), from January 2017 to June 2018. Results Median age was 62 years (range 27-88 years). Among invasive EBC patients, the most frequent phenotype was luminal-A (38%), followed by luminal-B (33%), HER2-positive (12%) and triple negative (5%). Thirty-four pts (12%) had diagnosis of in situ carcinoma (DCIS). Median time from MDMs discussion to first oncological examination was two weeks. Rate of discordance between MDMs-based decision and final choice, during face to face consultation with the oncologist, was 15.8% (46/291). Among cases with discordance, 19 pts (41.3%) had age > 70 years; 8 pts (17%) had a diagnosis of DCIS, 13 pts (28%) luminal-B carcinoma, 12 pts (26%) luminal-A, 9 pts (20%) HER2-positive and 4 pts (9%) triple negative EBC. The most frequent reason for changing the MDMs-based program was clinical decision by the oncologist at the first evaluation (87%). Follow-up was preferred to the chemotherapy proposed within the MDMs by 15% of pts, and to the endocrine therapy in 39% cases (among these, 44.5% had diagnosis of DCIS). In our study 16/46 pts (35%) had a therapeutic change from chemotherapy to endocrine therapy: among these pts, 7/16 had a luminal-B and 6/16 had a HER2-positive disease. Further analysis aiming at evaluating variables which could predict discordance between MDMs proposal and face to face oncological consultation are ongoing. Conclusions The results of our study could be useful for enhance the role of MTD and identify unmet needs in decision making process in EBC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background High BMI is associated with better survival in metastatic melanoma patients (MM pts), while sarcopenia is linked to poorer outcome in pts with stage III. The aim of this study was to examine the prognostic impact of body-mass index (BMI), baseline sarcopenia, loss of skeletal muscle mass (LSMM) on overall survival (OS) in MM pts who received immunotherapy (IT). Methods The retrospective series included 42 consecutive MM pts (Jan 2011-Dec 2018) treated with IT in a single referral center. Sarcopenia was defined according to Prado’s criteria. Skeletal muscle index (SMI) was calculated as cross-sectional-area of muscle (cm2), using CT-scan, at the L3 level divided by the square of the height (m2). Early LSMM, during IT, was defined as a decrease in SMI > =10% from baseline at first evaluation. BMI was calculated as weight (kg) divided by the square of height (m2) and categorized according to standard WHO definitions. Weight loss was analyzed as continuous variable. Results At baseline, 27 pts (64,3%) were male, 26 pts (61.9%) were =25. Out of 42 pts, 30 (71.4%) had a CT-scan at first evaluation, and 30% of them had an early LSMM. Median OS was 11.38 months. Both in univariate and multivariate analysis, ECOG PS > =1, and early LSMM > =10% were significantly associated with worse OS. Conversely, pts with weight loss had better OS (Table). Table . 1367P OS univariate analysis OS multivariate analysis Factors HR p 95% Confidence Interval HR p 95% Confidence Interval PS ECOG³1 3.02 0.01 (1.29-7.08) 3.99 0.043 (1.04-15.31) Weight loss 0.88 0.03 (0.78-0.98) 0.85 0.02 (0.74-0.97) Early LSMM > =10% 4.24 0.006 (1.50-11.97) 3.09 0.04 (1.04-9.22) Conclusions Early LSMM > =10% and ECOG PS > =1 may negatively influence the outcome of MM pts treated with IT. Further prospective studies are needed to confirm these data. Legal entity responsible for the study Maria Grazia Vitale. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Patients (pts) with melanoma brain metastases (BM) have a historically poor prognosis, with a reported median overall survival (mOS) of 4-6 months. Aim of this study is to evaluate predictive factors of survival in pts with melanoma BM. Secondly, a multivariate model was used to define groups with distinct prognosis. Methods Consecutive pts with melanoma BM treated in two Italian cancer centers were included in this 10-year retrospective cohort study (2008-2018). Baseline clinicopathological factors, systemic and loco-regional treatments were registered. The Kaplan-Meier method and the Cox model were used to analyze the association of prognostic factors and OS. Results 150 pts with melanoma BM were enrolled in this study: 42% with a single BM, 51.3% with ≥ 3 extracranial metastatic sites and 38% with an ECOG performance status (PS) of 0. About 50.7% of pts had a BRAF mutation. Notably, 56% of pts were asymptomatic at BM diagnosis, and 40% presented high LDH levels at baseline. Overall, mOS after BM diagnosis was 5.78 months (95% CI 4.80-6.67), and median intracranial progression-free survival was 4.63 months (95% CI 3.81-5.12). According to treatment modality, stereotactic radiosurgery/neurosurgery plus systemic therapy showed the best outcome (mOS 12.32 months, 95% CI 7.92-25.30). A multivariate model was used to identify baseline prognostic factors independently associated with OS (Table). Conversely, sex and symptomatic BM did not significantly impact on OS. Predicted survival functions defined 3 distinct prognostic groups (P Table . 1363P Covariates HR 95% CI P Points BRAF wild type 1.95 1.22-3.12 1 BM > 1 2.20 1.35-3.59 1 LDH ≥ 2 x upper normal limit 1.83 1.07-3.11 0.026 1 ECOG PS > 0 2.68 1.62-4.43 0.0001 1 Extracranial metastatic sites ≥ 3 1.91 1.17-3.1 1 Age ≥ 65 1.86 1.15-3.02 0.012 1 Conclusions This score can be useful for stratifying prognosis in pts with melanoma BM. Prospective studies are needed to validate this score and to explore how it may guide treatment strategy. Legal entity responsible for the study Dipartimento di Oncologia, Azienda Sanitaria Universitaria Integrata di Udine. Funding Has not received any funding. Disclosure F. Puglisi: Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eisai; Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Research grant / Funding (self): Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self): Pierre Fabre; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Takeda; Research grant / Funding (self): Astrazeneca. All other authors have declared no conflicts of interest.

Case report An 80 year old woman operated on by trabeculectomy for primary open-angle glaucoma due to increased pressure, who started treatment with latanoprost. Monitoring of blood pressure (BP) showed a statistically significant increase in both systolic and diastolic BP, coinciding with the use of topical hypotensive, which resolved by voluntarily suspending treatment, thus increasing again to reintroduce the prostaglandin. Discussion Prostaglandin analogues reduce intraocular pressure to produce vasodilation of the episcleral and ciliary arteries, increasing the outflow of aqueous humour. Cardiovascular effects are rare, but have been described by the vasoconstrictor effect that can trigger the reversible increase in BP, as in this case.