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Lipid metabolism impacts immune cell differentiation, activation, and functions, modulating inflammatory mediators, energy homeostasis, and cell membrane composition. Despite preclinical evidence, data in humans lack concerning tumors and immunotherapy (IO). We aimed at investigating the correlations between circulating lipids and the outcome of non-small cell lung cancer (NSCLC) patients treated with IO.We identified all patients with advanced NSCLC treated with IO at our Institution with available baseline plasma samples. Fatty acids (FAs) were analyzed through gas chromatography. Survival curves were estimated by the Kaplan-Meier method. Cox multivariate models were constructed through a stepwise procedure, with entry and exit P value set at .2.We identified 112 patients, mostly with performance status 1 (65.2%) and PD-L1≥1% (75.3%). Median progression-free survival (PFS) and overall survival (OS) were 2.8 and 11.0 months, respectively. Multivariable model for survival identified a positive association of circulating free (FFA) C16:0 (P .005) and esterified (EFA) C16:1 (P .030) with PFS, and a positive association of EFA C16:1 (P .001) and EFA C18:0 (P .020) with OS. EFA C16:0 was negatively associated with PFS (P .008).FFA C16:0 and FAs derived from its unsaturation (EFA C16:1) and elongation (EFA C18:0) are associated with a better outcome in NSCLC patients treated with IO. It is conceivable that the ratio among those FAs may modify membrane fluidity and receptor activity, influencing IO efficacy. These data pave the way for the investigation of lipid-modulating strategies in association with IO in NSCLC.

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.

Introduction The study investigates the emotional discomfort of cancer patients and their caregivers, who need to access the oncology day hospital to receive treatment during the COVID-19 pandemic in Italy. Methods This is a single-institution, prospective, cross-sectional study. From May to June 2020, the points of view of both patients and caregivers were compared through 2 different multiple-choice questionnaires, enquiring demographic characteristics, changes in emotional status, interpersonal relationships with health professionals (HCPs) and self-perception of treatment outcomes. Results Six hundred twenty-five patients and 254 caregivers were enrolled. Females were prevalent and patients were generally older than caregivers. Forty percent of patients and 25.6% of caregivers thought they were at a greater risk of contagion because lived together with a cancer patient or accessed the hospital. Both patients (86.3%) and caregivers (85.4%) considered containment measures a valid support to avoid the spread of infection. People with a lower education level were less worried about being infected with SARS-COV-2. Waiting and performing visits/treatments without caregivers had no impact on the emotional status of patients (64.4%), but generated in caregivers greater anxiety (58.8%) and fear (19.8%) of not properly managing patients at home. The majority of patients (54%) and caregivers (39.4%) thought the pandemic does not influence treatment outcomes. The relationship with HCPs was not negatively impacted for majority of patients and caregivers. Conclusions Starting from these data, we can better understand the current psychological distress of patients and their families in order to develop potential strategies to support them in this strenuous period of crisis. Supplementary Information The online version contains supplementary material available at 10.1007/s00520-021-06489-y.

IntroductionUp to one-fifth of patients with colorectal cancer will develop peritoneal metastases, frequently without other districts’ involvement. Despite the recent unsuccesses of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer peritoneal metastases treatment, the rationale in the prophylactic setting remains strong. Several clinical and pharmacokinetic data suggest that the efficacy of intraperitoneal chemotherapy is highest when the disease is microscopic. However, robust evidence demonstrating whether the addition of HIPEC for high-risk colorectal cancers offers better control of local recurrence is lacking.Methods and analysisThis is a multicentre randomised phase 3 trial comparing prophylactic surgery plus HIPEC CO2 with mitomycin, over standard surgical excision in patients with colorectal cancer at high risk of peritoneal carcinomatosis; 388 patients will be included in this study. The primary objective is to compare the efficacy of prophylactic surgery (radical colorectal resection, omentectomy, appendectomy, round ligament of the liver resection and bilateral adnexectomy) plus HIPEC CO2 with mitomycin and standard surgery in terms of local recurrence-free survival. The main secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. The primary endpoint will be described with a cumulative incidence function and will be analysed with Grey test to take account of the competing risks. DFS and OS will be described with the Kaplan-Meier method.Ethics and disseminationThis trial has been evaluated by the Italian Medicines Agency, local ethics committees and will be submitted to the Ministry of Health to notify the start of the trial according to the regulation of trials on devices with CE mark/certification.The results will be submitted for presentation at academic meetings and for publication in a peer-reviewed journal, whatever the findings.Trial registration numberNCT03914820.

Previous studies on the immunogenicity of SARS-CoV-2 mRNA vaccines showed a reduced seroconversion in cancer patients. The aim of our study is to evaluate the immunogenicity of two doses of mRNA vaccines in solid cancer patients with or without a previous exposure to the virus. This is a single-institution, prospective, nonrandomized study. Patients in active treatment and a control cohort of healthy people received two doses of BNT162b2 (Comirnaty, BioNTech/Pfizer, The United States) or mRNA-1273 (Spikevax, Moderna). Vaccine was administered before starting anticancer therapy or on the first day of the treatment cycle. SARS-CoV-2 antibody levels against S1, RBD (to evaluate vaccine response) and N proteins (to evaluate previous infection) were measured in plasma before the first dose and 30 days after the second one. From January to June 2021, 195 consecutive cancer patients and 20 healthy controls were enrolled. Thirty-one cancer patients had a previous exposure to SARS-CoV-2. Cancer patients previously exposed to the virus had significantly higher median levels of anti-S1 and anti-RBD IgG, compared to healthy controls (P = .0349) and to cancer patients without a previous infection (P .001). Vaccine type (anti-S1: P .0001; anti-RBD: P = .0045), comorbidities (anti-S1: P = .0274; anti-RBD: P = .0048) and the use of G-CSF (anti-S1: P = .0151) negatively affected the antibody response. Conversely, previous exposure to SARS-CoV-2 significantly enhanced the response to vaccination (anti-S1: P .0001; anti-RBD: P = .0026). Vaccine immunogenicity in cancer patients with a previous exposure to SARS-CoV-2 seems comparable to that of healthy subjects. On the other hand, clinical variables of immune frailty negatively affect humoral immune response to vaccination.

Introduction At the time of diagnosis, 15–20% of gastric carcinomas are in stage T4 or T4b. Furthermore, 5–20% of patients undergoing potentially curative surgery suffer from synchronous or metachronous peritoneal metastases. To date, neither surgery nor systemic chemotherapy successfully controls peritoneal dissemination, offering a limited impact on survival. Peritoneal metastases are in fact responsible for death in around 60% of gastric cancer patients. Several Eastern studies in the past have focused on hyperthermic intraperitoneal chemotherapy (HIPEC) as a prophylactic measure in patients with serosal extension, nodal involvement, and positive peritoneal fluid cytology. Therefore, a new multimodal therapeutic strategy based on aggressive surgery plus new locoregional treatment may prolong survival in this particular clinical scenario. Methods This study compares the efficacy of prophylactic surgery (radical gastric resection, appendectomy, resection of the round ligament of the liver, and bilateral adnexectomy) plus hybrid CO2 HIPEC system versus standard surgery in patients with T3-T4 N0-N + gastric adenocarcinoma. Patients will be randomly assigned (1:1 ratio) to the experimental arm or standard surgery. The primary endpoint is to establish the difference in disease-free survival between the groups. The secondary objective is to compare the safety and tolerability of prophylactic surgery plus HIPEC CO2 versus standard surgery. Discussion Considering the poor prognosis of patients with peritoneal dissemination from gastric cancer, a prophylactic strategy to prevent peritoneal metastases may be beneficial. In patients with gastric cancer at high risk of peritoneal carcinomatosis, we propose aggressive surgical treatment with radical gastrectomy, removal of organs at risk of harbouring tumour cells, and HIPEC. Trial registration ClinicalTrials.gov NCT03917173. Registered on 16 April 2019. Protocol version: v1, March 27, 2019. Protocol number: IRFMN-GCC-7813. EudraCT number: 2019–001478-27.

Background Sentinel lymph node biopsy (SNB) still remains a key procedure to appropriately stage melanoma patients and to select those who are candidate to novel treatments with immunotherapy and targeted therapy in the adjuvant setting. The impact of timing of SNB on disease-free survival (DFS) and overall survival (OS) is still unclear. Material and methods The study was conducted at 6 Italian Melanoma Intergroup (IMI) centres and included 8953 consecutive clinical stage I-II melanoma patients who were diagnosed, treated, and followed up between November 1997 and March 2018. All patients were prospectively included in dedicated IMI database. Multivariable Cox regression analyses were performed to investigate how baseline characteristics and time interval until SNB are related to DFS and OS. Results Considering the whole population, at multivariable analysis, after adjusting for age, gender, Breslow thickness, site, ulceration, and the SNB status, a delay in the timing of SNB was associated with a better DFS (adjusted hazard ratio [aHR, delayed versus early SNB] 0.98, 95% confidence interval [CI] 0.97–0.99, p, Highlights • Sentinel lymph node biopsy (SNB) is a key procedure to stage melanoma patients (MPs). • In our series, the time interval of SNB is irrelevant in MPs with positive sentinel lymph node. • A delayed SNB biopsy is not detrimental in clinically stage I-II MPs.

Precis Central corneal thickness (CCT) may increase over time in children affected by primary congenital glaucoma and treated with latanoprost for at least 30 months. Purpose The purpose of this study was to investigate CCT modification over time in a population of primary pediatric glaucoma (PPG) patients prescribed a monotherapy of latanoprost. Materials and methods The present paper reports the results of a post hoc analysis on patients enrolled in the Glaucoma Italian Pediatric Study (GIPSy). Children affected by PPG, with a postsurgical intraocular pressure between 22 and 26 mm Hg and treated with latanoprost monotherapy for at least 30 months were eligible for the analysis. CCT variation from baseline was investigated over the follow-up using univariable and multivariable longitudinal linear mixed models. The impact of age, sex, and intraocular pressure on CCT variation were evaluated taking into account the interaction of each variable with time. Results Twenty-seven eyes (20 patients) were included in the analysis. Mean duration of latanoprost treatment was 36.6 months (SD 2.5) and mean CCT at baseline was 551 μm (SD 37.7). A significant increase of CCT over time was revealed by multivariable analysis, taking into account the impact of age at baseline and its interaction with time (P=0.03). The interaction between age and time was significant (P=0.04), indicating that older age at baseline was associated with lower increase of CCT over time. No variation of CCT was found in univariable analysis (P=0.28). Conclusion In this population of PPG patients treated with latanoprost for at least 30 months, CCT significantly increased over time, when the impact of age and its interaction with time were considered.

BACKGROUND: Metastatic breast cancer (MBC) is an incurable disease and its treatment focuses mainly on prolonging patients (pts) survival and improving their quality of life. As a consequence, management of treatment related adverse events (AE) is very important. Eribulin (E) is a microtubule inhibitor that has shown to increase overall survival in pre-treated MBC pts. Its most common AEs are asthenia, neutropenia and peripheral neuropathy (N). PATIENTS AND METHODS: PAINTER (Clinical trial registration: NCT 0286403) is a multicenter, interventional, single-arm, phase IV study, aimed at surveying the tolerability of E (dose 1.4 mg/m2 day 1, 8 every 21 days) in an unselected MBC pts population pre-treated with taxanes and antracyclines. The secondary objective was to investigate the relationship between specific polymorphisms and incidence and severity of peripheral N. Toxicity (T) was reported according to the NCI CTCAE v4.0. Genomic DNA was isolated from whole blood samples (Maxwell whole blood DNA kit-Promega). 15 SNPs (Single Nucleotide Polymorphisms) were genotyped by Taqman specific assays. For SNPs analysis, we selected pts with available genomic data and who started E treatment N was evaluated by medical examination. RESULTS: From May 2014 to June 2018, 180 pts were enrolled from 20 Italian centres and 170 were evaluable. Pts and tumors characteristics were as follows: median age 60 years, ductal carcinoma 76.3%, visceral disease 68.8%, luminal type 64.7%, Her2 positive 18.3%, triple negative 17%, median previous treatment lines for MBC 5, median years from first diagnosis 6.1. Pts received E for 4.5 median cycles (Q1-Q3: 3.0-7.0; min-max: 1-23); 48.8% of pts experienced dose reduction, due to neutropenia (23.9%) and liver injury (12%) and 5.2% of pts discontinued E for T or for pts refusal. Previous neuropathy was reported in 15.9% of pts. Table 1 shows the incidence of expected AEs. N (all grades) during E treatment was reported in 33.9% of patients (G2-G3-G4: 15%). The risk of N occurrence in the first 5 cycles was 32.5% (for any grade N) and 13.2% (for severe N). Other G1-G4 toxicities were: dermatological in 8.6% pts, liver injury in 13.6%, pulmonary in 13.6%. Interestingly, 40.7% of pts reported pain, especially osteo-muscular, abdominal and at tumor site. Ten serious AEs were reported and only two were E related. 159 pts were evaluable for the analysis of polymorphism. Among the selected SNPs, the allelic variant T of the polymorphism rs2233335 in NDRG1 gene (Fisher test p CONCLUSIONS: PAINTER study offers a wide spectrum of information about E tolerability. Asthenia, neuropathy and neutropenia were the most common T, but few pts experienced severe AEs. Schedule and dosage modifications were common, as expected in pre-treated pts, but T rarely led to treatment discontinuation. Importantly, we found for first time that the SNPs rs2233335 (G/T and T/T) in NDRG1 gene and rs7214723 (CC and CT) in CAMKK1 gene were associated with E induced N. These data on pharmacogenetic testing, if validated, could allow a tailored treatment with E. Table 1. Incidence of expected AEsAEsG1G2G3G4Severe T (G3+G4) N=170n (%)n (%)n (%)n (%)% [%95%CI]Neuropathy 31 (18.2)20 (11.8)5 (2.9)0 (0.0)14.7 [9.75 - 20.9] #Neutropenia 15 (8.8)11 (6.5)16 (9.4)10 (5.9)15.3 [10.2 - 21.6]Constipation 16 (9.4)8 (4.7)1 (0.6)0 (0.0)0.6 [0.02 - 3.23]Alopecia 25 (14.7)13 (7.6)N.A.*N.A.*7.6 [4.13 - 12.7]Asthenia 38 (22.4)38 (22.4)10 (5.9)0 (0.0)5.9 [2.86 - 10.6]Nausea 19 (11.2)6 (3.5)0 (0.0)0 (0.0)0.0#: G2 for neuropathy and alopecia were considered as severe T *N.A.: Not applicable Citation Format: Nicla La Verde, Giovanna Damia, Ornella Garrone, Loretta D'Onofrio, Alessandra Fabi, Mariangela Ciccarese, Daniele Generali, Martina Nunzi, Elena Poletto, Paolo Pedrazzoli, Elisabetta Cretella, Giuseppa Scandurra, Icro Meattini, Alessandro S Bertolini, Luigi Cavanna, Emanuela Romagnoli, Lorenzo Legramandi, Federica Guffanti, Eliana Rulli, Anna Moretti, Barbara Bocci, Gabriella Farina. Eribulin tolerability and correlation between neuropathy and a set of polymorphisms in metastatic breast cancer patients. Results from the PAINTER (Polymorphism And Incidence of Toxicity in ERibulin treatment) study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-01.

Background Although American Society of Clinical Oncology and European Society for Medical Oncology guidelines have identified the negative prognostic factors that clinicians have to consider when treating their patients with stage II colon cancer (CC), the role of histological subtype is controversial. Subjects, Materials, and Methods The randomized, multicenter, phase III TOSCA trial compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy in 3,759 patients with high-risk stage II or stage III CC. The objective of this substudy was to evaluate the influence of histological subtypes on the impact of the treatment duration of adjuvant chemotherapy in terms of relapse-free survival (RFS) and overall survival (OS) in 85 mucinous adenocarcinoma (MUC) and 389 nonmucinous adenocarcinoma (NMUC) patients with high-risk stage II, grade 3 CC. Results A significant interaction between treatment duration and histology was observed in both RFS (p = .027) and OS (p = .017). In the subgroup of patients with MUC, worse RFS (adjusted hazard ratio [HR], 3.95; 95% confidence interval [CI], 1.03–15.17; p = .045) and OS (HR, 9.56; 95% CI, 1.14–79.98; p = .037) were detected for patients treated in the 3-month arm. No statistically significant differences were found in the subgroup of patients with NMUC. Conclusion Patients with MUC, grade 3, stage II CC require special attention and may need 6 months of oxaliplatin-based chemotherapy. Larger studies are required to assess the combined use of histology and other prognostic/predictive factors to define the administration of chemotherapy in patients with stage II CC and to improve their prognosis. Implications for Practice Although ASCO and ESMO guidelines define the prognostic factors for patients with stage II colon cancer to establish the use of adjuvant chemotherapy, the influence of histological subtypes is controversial in this population. This study underscores that patients with grade 3 mucinous adenocarcinomas may need adjuvant chemotherapy with oxaliplatin and fluoropyrimidines for a duration of 6 months rather than 3 months.

Background: Previous findings showed that cediranib-olaparib increased PFS in women with recurrent platinum-sensitive ovarian cancer compared to olaparib alone. Methods: BAROCCO trial randomized 123 patients: 80 mg/m2 paclitaxel weekly up to 24 weeks (control), olaparib 300 mg tablets twice daily together with 20 mg cediranib daily (continuous schedule) or with 20 mg cediranib 5 days/week (intermittent schedule) until progression. The primary objective was the PFS comparison between each experimental arm and the control (alpha one-sided 5%; power 80%; HR 0.5). Results: The median platinum-free interval was 1.9 months, 60% of patients had been pretreated with 3 or more chemotherapy lines. Median PFS for paclitaxel, the continuous, and the intermittent schedules were 3.1, 5.6, and 3.8 months. The HR for PFS in the continuous arm vs control was 0.76 (90% CI: 0.50–1.14, p = 0.265). The HR for PFS in the intermittent arm vs control was 1.03 (90% CI: 0.68–1.55, p = 0.904). Treatment was discontinued due to adverse events in 15%, 20%, and 5% of patients in the control, continuous and intermittent arms. Grade ≥ 3 anemia and diarrhea and hypertension of any grade occurred only in the experimental arms, and peripheral neuropathies and alopecia only in the control arm. Five serious adverse drug reactions occurred and two were fatal: one in the control and one in the continuous arm. Conclusions: The combination of cediranib-olaparib was not superior to chemotherapy in terms of PFS in heavily pretreated platinum-resistant ovarian cancer patients. However, this oral doublet, is active and may offer a non-chemotherapy option in this difficult to treat population. Clinical trial identification: IRFMN-OVA-7289, EudraCT: 2016–003964-38, NCT03314740.

Background: The search for biomarkers to evaluate ovarian cancer (OC) homologous recombination (HR) function and predict the response to therapy is an urgent clinical need to improve the selection of patients who could benefit from platinum- and olaparib (poly-ADP ribose polymerase inhibitors, PARPi)-based therapies. Methods: We used a large collection of OC patient-derived xenografts (PDXs) (n = 47) and evaluated their HR status based on BRCA1/2 mutations, BRCA1 promoter methylation and the HRDetect score. RAD51 foci were quantified in formalin-fixed, paraffin-embedded untreated tumour specimens by immunofluorescence and the messenger RNA expression of 21 DNA repair genes by real-time PCR. Results: Tumour HR deficiency predicted both platinum and olaparib responses. The basal level of RAD51 foci evaluated in geminin-positive/replicating cells strongly inversely correlated with olaparib response (p = 0.011); in particular, the lower the foci score, the greater the sensitivity to olaparib, while low RAD51 foci score seems to associate with platinum activity. Conclusions: The basal RAD51 foci score is a candidate predictive biomarker of olaparib response in OC patients as it can be easily translatable in a clinical setting. Moreover, the findings corroborate the importance of OC-PDXs as a reliable tool to identify and validate biomarkers of response to therapy. [Figure not available: see fulltext.].

Studies assessing whether heart failure (HF) is associated with cancer and cancer-related mortality have yielded conflicting results.This study assessed cancer incidence and mortality according to pre-existing HF in a community-based cohort.Among individuals ≥50 years of age from the Puglia region in Italy with administrative health data from 2002 to 2018, no cancer within 3 years before the baseline evaluation, and ≥5-year follow-up, the study matched 104,020 subjects with HF at baseline with 104,020 control subjects according to age, sex, drug-derived complexity index, Charlson comorbidity index, and follow-up duration. Cancer incidence and mortality were defined based on International Classification of Diseases-Ninth Revision codes in hospitalization records or death certificates.The incidence rate of cancer in HF patients and control subjects was 21.36 (95% CI: 20.98-21.74) and 12.42 (95% CI: 12.14-12.72) per 1000 person-years, respectively, with the HR being 1.76 (95% CI: 1.71-1.81). Cancer mortality was also higher in HF patients than control subjects (HR: 4.11; 95% CI: 3.86-4.38), especially in those 70 years of age (HR: 7.54; 95% CI: 6.33-8.98 vs HR: 3.80; 95% CI: 3.44-4.19 for 70-79 years of age; and HR: 3.10; 95% CI: 2.81-3.43 for ≥80 years of age). The association between HF and cancer mortality was confirmed in a competing risk analysis (subdistribution HR: 3.48; 95% CI: 3.27-3.72). The HF-related excess risk applied to the majority of cancer types. Among HF patients, prescription of high-dose loop diuretic was associated with higher cancer incidence (HR: 1.11; 95% CI: 1.03-1.21) and mortality (HR: 1.35; 95% CI: 1.19-1.53).HF is associated with an increased risk of cancer and cancer-related mortality, which may be heightened in decompensated states.

Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/−), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.

9033 Background: In advanced NSCLC (aNSCLC) with PD-L1 < 50% chemo-immunotherapy is the standard of care. Although the activity of single agent pembrolizumab was reported, no biomarkers have been identified able to select patients who mostly benefit. The trial aimed to identify immune biomarkers associated with PFS in aNSCLC patients with PD-L1 levels < 50% treated with first-line pembrolizumab. Here we reported for the first time the clinical outcomes of the trial and circulating immune profiling (CIP) biomarkers correlated to PFS. Methods: This phase II trial was conducted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan. Eligible patients were previously untreated stage IIIB-IV NSCLC, EGFR and ALK wild type with PD-L1 < 50%, PS 0-2. PD-L1 was assessed with 22-C3 antibody (Dako). Patients received pembrolizumab 200 mg every 3 weeks until 35 cycles, disease progression or unacceptable toxicity. The primary endpoint was the association of immune biomarkers with PFS. OS, ORR, DCR, DoR and safety were secondary endpoints. CIP was performed by determination of absolute cell counts for 36 innate and adaptive immunity subsets through multiparametric flow cytometry on freshly isolated whole blood samples at baseline. An orthoblique principal components-based clustering approach and multivariable Cox regression model adjusted for clinical variables were used to analyse CIP variables and their correlation with clinical endpoints. Results: From May 2018 to October 2020, of 87 screened, 65 patients were enrolled. The median age was 70.9 years, most patients were male (67.7%), smoker (87.7%), non-squamous (83.1%), PDL1 + (70.8%). 12 patients (18.5%) had PS 2. During a median follow-up of 26.4 months (mo), 51 radiological progressions, 46 deaths and 60 PFS events were observed. The median PFS was 2.9 mo (95%CI 1.8 - 5.6) and the median OS was 12.1 mo (95%CI 8.7 - 17.1). The ORR was 24.1% (2 complete and 12 partial responses), DCR was 53.4% and median DoR was 14.5 mo (95%CI 6.4 - 24.9). Drug related G3-G4 adverse events were: 2 hyponatremia, 2 lipase increased, 1 pneumonitis. Out of 7 CIP clusters identified, 2 were statistically significant at multivariable analysis on 57 patients. Higher baseline counts of 8 subsets within these two clusters were associated with better PFS (HR values range: 0.88-0.98; p values range: 0.001- 0.016). The significant subsets included lymphocytes (cells expressing CD3, or CD19 or CD56, but lacking granulocyte and monocyte markers) and main NK subsets (including CD56dim CD16+, CD56dim CD16- and HLA-DR+ NK cells). Conclusions: This trial confirmed that pembrolizumab as first-line single agent is safe and active also in a subgroup of aNSCLC patients with PD-L1 < 50%. CIP biomarkers can be useful to identify patients with a favourable outcome, thus avoiding the adding toxicity of chemotherapy. Clinical trial information: NTC03447678.

11575 Background: To further explore the activity of T as second/further line treatment in retroperitoneal leiomyosarcoma (LMS) and well differentiated/dedifferentiated liposarcoma (LPS). The primary endpoint of the study was the growth modulation rate (GMR) defined as the ratio between the time to progression under T (TTP) and during previous chemotherapy treatment (TTP-1). The secondary end-points were objective response rate as per RECIST and PFS. Methods: This was a multicenter, single-arm Phase 2 study, conducted in 20 Italian centers. Patients with locally relapsed or metastatic disease, already treated with one or more previous systemic treatments with anthracyclines and/or ifosfamide, were enrolled. T was administered at a dose of 1.3-1.5 mg/mq with a top dose of 2.6 mg per cycle. T was administered as a 24h continuous infusion until progressive disease, major toxicity, patient’s intolerance or medical decision. As per protocol, patients were considered responders if the GMR was > 1.33, non-responders if < 0.75 and neither if 0.76-1.32. Eighty evaluable patients were needed to detect an odds of trabectedin response ≥ 2.5, corresponding to 71.4% of patients with a GMR > 1.33 (80% power, one-sided alpha 2.5%). Results: From August 2014 to February 2019, 104 patients were registered and 91 were evaluable for the primary endpoint (32 pts with LMS and 59 with LPS). Overall, the median number of cycles received was 6.0 (q1-q3 3.0-12.0), the main reason for treatment discontinuation was disease progression in 72% of patients, followed by medical decision (8%). The median TTP was 6.0 months (6.2 and 6.0 for LMS and LPS), while the median TTP-1 was 7.5 months (8.1 and 6.4 for LMS and LPS). Thirty three patients (52% 95%CI: 36-58, p = 0.674, odds of response = 1.1) had a GMR > 1.33 (LMS: 46%, 95%CI 26-67,odds = 0.85; LPS 56%, 95%CI 40-72, odds = 1.3).Overall, response rate (CR+PR) was 16% (24% for LMS and 12% for LPS). Overall, in LPS we observed 15/47 patients with GMR < 0.5 and 15/47 with GMR > 2. Among LMS patients, 9/26 had a GMR < 0.5 and 10/26 > 2. Between LPS six patients had a GMR > 5. Previous treatment had been based on anthracyclines and/or ifosfamide in 85% of patients (91% in LPS population). Conclusions: While the primary end point of the study was not met, we noticed a subgroup of patients with a markedly discrepant TTP with T in comparison to previous therapy (GMR < 0.5 or > 2, the latter including some pts with a long TTP with T). Efforts are ongoing to assess the pathologic counterparts of such discrepancies. T seems to be selectively active in poorly understood subgroups, with a pattern of activity distinct from other available agents. Clinical trial information: 2012-005428-14.

Background: the prognostic significance of tumor infiltrating lymphocytes (TILs) in intermediate/thick primary cutaneous melanoma (PCM) remains controversial, partially because conventional evaluation is not reliable, due to inter-observer variability and diverse scoring methods. We aimed to assess the prognostic impact of the density and spatial distribution of immune cells in early stage intermediate/thick PCM. Materials and Methods: digital image acquisition and quantitative analysis of tissue immune biomarkers (CD3, CD4, CD8, CD68, PD-L1, CD163, FOX-P3, and PD-1) was carried out in a training cohort, which included patients with primary PCM ³ 2 mm diagnosed, treated, and followed-up prospectively in three Italian centers. Results were validated in an independent Italian cohort. Results: in the training cohort, 100 Stage II–III melanoma patients were valuable. At multivariable analysis, a longer disease free survival (DFS) was statistically associated with higher levels of CD4+ intratumoral T-cells (aHR [100 cell/mm2 increase] 0.98, 95%CI 0.95–1.00, p = 0.041) and CD163+ inner peritumoral (aHR [high vs. low] 0.56, 95%CI 0.32–0.99, p = 0.047). A statistically significant longer DFS (aHR [high-high vs. low-low] 0.52, 95%CI 0.28–0.99, p = 0.047) and overall survival (OS) (aHR [high-high vs. low-low] 0.39, 95%CI 0.18–0.85, p = 0.018) was found in patients with a high density of both intratumoral CD8+ T-cells and CD68+ macrophages as compared to those with low density of both intratumoral CD8+ T-cells and CD68+ macrophages. Consistently, in the validation cohort, patients with high density of both intratumoral CD8+ and CD3+ T-cells were associated to a statistically better DFS (aHR[high-high vs. low-low] 0.24, 95%CI 0.10–0.56, p &lt, 0.001) and those with high density of both intratumoral CD8+ and CD68+ were associated to a statistically longer OS (aHR[high-high vs. low-low] 0.28, 95%CI 0.09–0.86, p = 0.025). Conclusion: our findings suggest that a specific preexisting profile of T cells and macrophages distribution in melanomas may predict the risk of recurrence and death with potential implications for the stratification of stage II–III melanoma patients.

Background: High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. Aim of this study was to assess safety and efficacy of high-dose ivermectin in reducing viral load in individuals with initial SARS-CoV-2 infection. Methods: Randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial performed in outpatients in Italy. Participants: adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection, providing informed consent. Exclusion criteria: pregnant or lactating women; CNS diseases; participants under dialysis; severe medical condition with prognosis < 6 months; warfarin treatment; antiviral/chloroquine phosphate/hydroxychloroquine treatment. Participants were assigned according to a randomized permuted block procedure to one of the following arms with allocation ratio 1:1:1: placebo (arm A); single dose ivermectin 600 μg/kg plus placebo for 5 days (arm B); single dose ivermectin 1200 μg/kg for 5 days (arm C). The pharmacist prepared the treatment according to the randomization list and on the basis of the participant’s weight. Primary outcomes: serious adverse drug reactions (SADR) and change of viral load at Day 7. The protocol was registered with ClinicalTrials.gov , NCT04438850. Findings. From 31th July, 2020 to 26th May, 2021, 32 participants were randomized to arm A, 29 to arm B and 32 to arm C. The recruitment was stopped on 10th June, because of a dramatic drop of cases. Eighty-nine participants were included in the safety analysis set, the change in viral load was calculated on 87 participants. No SADR were registered. The mean log10 viral load reduction was 2.9 in arm C (SD 1.6), 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (p=0.099 and 0.122 for C versus A and B versus A, respectively). Interpretation: High- dose ivermectin demonstrated safe, but did not prove efficacy to reduce viral load. Trial Registration: The protocol was registered with ClinicalTrials.gov , NCT04438850. Funding: The trial was partly funded by the Italian Ministry of Health. Declaration of Interest: None to declare. Ethical Approval: This study was approved by the national Ethics Committee of INMI – Spallanzani in Rome that is competent for all COVID-19 trials in Italy (resolution 139/2020 of 28th May, 2020), and by the Italian drug agency AIFA (resolution 136BIS/2020 of 18th May, 2020).

AimsAmeloblastoma is a rare odontogenic tumour with an aggressive local behaviour. Mutations in the mitogen-activated protein kinase pathway, namely BRAF V600E mutations, are a common finding. To date, there is no clear correlation between BRAF V600 mutation and clinical outcome.MethodsWe retrospectively reviewed the medical records of patients who underwent surgery for ameloblastoma between May 1998 and June 2018, at 11 participating Italian centres. BRAF mutational status was evaluated by quantitative PCR/pyrosequencing. The primary end points were to determine BRAF mutational status in primitive and recurrent ameloblastoma, and to assess the relapse-free interval (RFI); the secondary end point was to investigate the correlation of BRAF mutational status with the clinical features of the tumour and survival outcomes.ResultsOverall, 74 patients were included: 33 (44.5%) were BRAF wild type and 41 (55.4%) BRAF V600 mutated. BRAF V600 mutated ameloblastomas occurred more frequently in younger patients (p=0.0031), were located at the mandible (p=0.0009) and presented with unicystic variant. After a median follow-up of 60 months, 21 (28.3%) patients relapsed (30.3% and 26.8% in the BRAF wild type and BRAF mutated group, respectively). At univariable Cox models, none of the investigated variables, including microscopic margin involvement, was associated with RFI.ConclusionsLocal recurrence occurs in 30% of patients with ameloblastoma. BRAFV600 mutation is associated with younger age, mandibular localisation and with unicystic ameloblastoma. Neither BRAF mutation nor microscopically positive surgical margins were associated with RFI. Further studies are needed to elucidate outcomes of this rare disease according to clinical, histopathological and comprehensive molecular features.

Background Oxaliplatin-based adjuvant chemotherapy is the standard treatment of high-risk colon cancer (CC). A shorter duration (3 months) can achieve a similar outcome [in terms of relapse-free survival (RFS)] to a longer duration. This study reports the overall survival (OS) analysis of the three or six colon adjuvant (TOSCA) phase III study. It assessed different adjuvant chemotherapy durations in patients with resected high-risk stage II and stage III CC. Material and methods TOSCA was an open-label, phase III, multicentre, non-inferiority trial conducted in 130 Italian centres. Patients were randomly assigned, in a 1 : 1 ratio, to receive 3 months of standard doses of FOLFOX/CAPOX, or 6 months of FOLFOX/CAPOX. Patients with histologically confirmed high-risk stage II and III CC were included, with RFS being the primary end point. OS was a secondary end point. Results From June 2007 to March 2013, 3759 patients were accrued. At a median follow-up of 7 years, the hazard ratio (HR) for RFS of the 3-month versus 6-month arms was 1.13; 95% confidence interval (CI) 0.99-1.29, P for non-inferiority = 0.380, P for superiority = 0.068, crossing the non-inferiority limit of 1.20. This result did not allow us to reject the null hypothesis of the inferiority of the 3-month arm. The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). At the last follow-up analysis, the absolute OS difference between arms was Conclusions The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. The extra benefit provided by the longer treatment should be balanced against the extra toxicity of more prolonged therapy. The trial is registered with ClinicalTrials.gov , registration number: NCT0064660.

Clinical data suggest that only a subgroup of non-small cell lung cancer (NSCLC) patients has long-term benefits after front-line platinum-based therapy. We prospectively investigate whether KRAS status and DNA polymerase &beta, expression could help identify patients responding to platinum compounds. Prospectively enrolled, advanced NSCLC patients treated with a first-line regimen containing platinum were genotyped for KRAS and centrally evaluated for DNA polymerase &beta, expression. Overall survival (OS), progression-free survival (PFS), and the objective response rate (ORR) were recorded. Patients with KRAS mutations had worse OS (hazard ratio (HR): 1.37, 95% confidence interval (95% CI): 0.70&ndash, 2.27). Negative DNA polymerase &beta, staining identified a subgroup with worse OS than patients expressing the protein (HR: 1.43, 95% CI: 0.57&ndash, 3.57). The addition of KRAS to the analyses further worsened the prognosis of patients with negative DNA polymerase &beta, staining (HR: 1.67, 95% CI: 0.52&ndash, 5.56). DNA polymerase &beta, did not influence PFS and ORR. KRAS may have a negative role in platinum-based therapy responses in NSCLC, but its impact is limited. DNA polymerase &beta, when not expressed, might indicate a group of patients with poor outcomes. KRAS mutations in tumors not expressing DNA polymerase &beta, further worsens survival. Therefore, these two biomarkers together might well identify patients for whom alternatives to platinum-based chemotherapy should be used.

Introduction Preclinical models recently unveiled the vulnerability of LKB1/KRAS comutated NSCLC to metabolic stress-based treatments. Because miR-17 is a potential epigenetic regulator of LKB1, we hypothesized that wild-type LKB1 (LKB1WT) NSCLC with high miR-17 expression may be sensitive to an energetic stress condition, and eligible for metabolic frailties-based therapeutic intervention. Methods We took advantage of NSCLC cell lines with different combinations of KRAS mutation and LKB1 deletion and of patient-derived xenografts (PDXs) with high (LKB1WT/miR-17 high) or low (LKB1WT/miR-17 low) miR-17 expression. We evaluated LKB1 pathway impairment and apoptotic response to metformin. We retrospectively evaluated LKB1 and miR-17 expression levels in tissue specimens of patients with NSCLC and PDXs. In addition, a lung cancer series from The Cancer Genome Atlas data set was analyzed for miR-17 expression and potential correlation with clinical features. Results We identified miR-17 as an epigenetic regulator of LKB1 in NSCLC and confirmed targeting of miR-17 to LKB1 3′ untranslated region by luciferase reporter assay. We found that miR-17 overexpression functionally impairs the LKB1/AMPK pathway. Metformin treatment prompted apoptosis on miR-17 overexpression only in LKB1WT cell lines, and in LKB1WT/miR-17 high PDXs. A retrospective analysis in patients with NSCLC revealed an inverse correlation between miR-17 and LKB1 expression and highlighted a prognostic role of miR-17 expression in LKB1WT patients, which was further confirmed by The Cancer Genome Atlas data analysis. Conclusions We identified miR-17 as a mediator of LKB1 expression in NSCLC tumors. This study proposes a miR-17 expression score potentially exploitable to discriminate LKB1WT patients with NSCLC with impaired LKB1 expression and poor outcome, eligible for energy-stress-based treatments.

Clinical data suggest that only a subgroup of non-small cell lung cancer (NSCLC) patients has long-term benefits after front-line platinum-based therapy. We prospectively investigate whether KRAS status and DNA polymerase β expression could help identify patients responding to platinum compounds. Prospectively enrolled, advanced NSCLC patients treated with a first-line regimen containing platinum were genotyped for KRAS and centrally evaluated for DNA polymerase β expression. Overall survival (OS), progression-free survival (PFS), and the objective response rate (ORR) were recorded. Patients with KRAS mutations had worse OS (hazard ratio (HR): 1.37, 95% confidence interval (95% CI): 0.70–2.27). Negative DNA polymerase β staining identified a subgroup with worse OS than patients expressing the protein (HR: 1.43, 95% CI: 0.57–3.57). The addition of KRAS to the analyses further worsened the prognosis of patients with negative DNA polymerase β staining (HR: 1.67, 95% CI: 0.52–5.56). DNA polymerase β did not influence PFS and ORR. KRAS may have a negative role in platinum-based therapy responses in NSCLC, but its impact is limited. DNA polymerase β, when not expressed, might indicate a group of patients with poor outcomes. KRAS mutations in tumors not expressing DNA polymerase β further worsens survival. Therefore, these two biomarkers together might well identify patients for whom alternatives to platinum-based chemotherapy should be used.

Background Although elderly patients (≥70 years) represent 30% of new diagnoses of soft tissue sarcoma (STS), they are underrepresented in clinical trials and are often unfit to receive standard anthracycline-based chemotherapy. Trabectedin is registered as a second-line treatment for advanced STS and is characterized by a favorable safety profile. Methods The aim of this single-arm, phase 2 study was to investigate trabectedin (scheduled dose, 1.3-1.5 mg/m2 ) as a first-line treatment in elderly patients with advanced stage STS who are inoperable and are unfit to receive standard anthracycline-based chemotherapy. The coprimary endpoints were progression-free survival at 3 months (PFS3) and the rate of clinically limiting toxicities (CLTs). We also conducted an ancillary study on pharmacokinetics. Results Twenty-four patients (12 men and 12 women) with a median age of 79 years (interquartile range [IQR], 74-83 years) were enrolled. The histological subtype was leiomyosarcoma in 46%, liposarcoma in 33%, and other histotypes in 21%. The median number of trabectedin courses was 4 (IQR, 3-6), with 7 patients (29%) receiving ≥6 cycles. Eight patients (33%) required dose reductions. The most frequent grade 3/4 adverse events were neutropenia in 9 patients (38%), fatigue in 5 patients (21%), and aminotransferase elevation in 5 patients (21%). PFS3, median PFS, and overall survival were 71% (80% CI, 57%-81%), 4 months, and 12 months, respectively. Ten patients (42% [80% CI, 28%-57%]) experienced CLTs. Trabectedin Cmax , half-life, clearance, and distribution volume were 1.28 ng/mL (standard deviation [SD], 0.58 ng/mL), 26.70 hours (SD, 9.09 hours), 39.98 L/h/m2 (SD, 14.08 L/h/m2 ), and 1460 L/m2 (SD, 561 L/m2 ), respectively. Conclusion Trabectedin can be administered safely to elderly patients with STS who are unfit to receive anthracyclines. Pharmacokinetics in the elderly population was superimposable to historical data.

Importance The addition of oxaliplatin to the standard 6-month fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer has been reported to reduce the risk of relapse although it does not increase survival. The Three or Six Colon Adjuvant (TOSCA) trial compared 3 months with 6 months of adjuvant fluoropyrimidine and oxaliplatin-based chemotherapy in patients with stage III colon cancer. The utility remains unknown. Objective To assess the noninferiority and toxic effects of 3 vs 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin) adjunct chemotherapy among patients with high-risk stage II resected colorectal cancer enrolled in the TOSCA trial. Design, Setting, and Participants The TOSCA study was a noninferiority phase 3 randomized clinical trial conducted from June 2007 to March 2013 in 130 Italian centers. Included patients had resected colorectal cancer located 12 cm from the anal verge by endoscopy or above the peritoneal reflection at surgery. In this preplanned study assessing the per-protocol population, 5-year relapse-free survival was evaluated in 1254 patients with high-risk stage II resected colorectal cancer who had received adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Interventions Patients were originally randomized (1:1) in the TOSCA trial to receive 3 months (experimental group) or 6 months (control) of standard doses of FOLFOX or CAPOX at the discretion of the treating physician. Main Outcome and Measures A hazard ratio of at least 1.2 between the 3-month and 6-month chemotherapy groups was set to reject the null hypothesis of noninferiority. Results Overall, 1254 patients (mean [SD] age, 62.4 [9.8] years; 565 women [45.1%]) with clinical high-risk stage II resected colorectal cancer were analyzed at a median follow-up of 62 months (interquartile range, 53-71) months. Of them, 301 patients (24.0%) had pT4N0M0 tumors, and the remaining 953 patients (76.0%) had high-risk pT3N0M0 tumors; 776 patients (61.9%) received FOLFOX and 478 (38.1%) received CAPOX. The 5-year relapse-free survival was 82.2% for the 3-month arm and 88.2% for the 6-month arm, with an estimated hazard ratio of 1.41 (95% CI, 1.05-1.89;P = .86 for noninferiority). For CAPOX, the 5-year relapse-free survival was similar in the 2 arms (difference, 0.76% favoring the 6-month arm; 95% CI, −6.28% to 7.80%), whereas for FOLFOX, the difference was pronounced: 8.56% in favor of the longer-duration arm (95% CI, 3.45%-13.67%). Nevertheless, the test for an interaction between duration and regimen was not statistically significant. Neurotoxicity was approximately 5 times lower in the shorter duration arm than in the longer duration arm. Conclusions and Relevance In the 3-month arm, the treatment was significantly less toxic than in the 6-month arm. Noninferiority was not shown for 5-year relapse-free survival. However, a possible regimen effect was observed, suggesting that either 3 months of CAPOX or 6 months of FOLFOX therapy can be used whenever an oxaliplatin doublet is indicated for treatment of patients with stage II colorectal cancer. Trial Registration ClinicalTrials.gov Identifier:NCT0064660

Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/-), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.

Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80hiCD115hiC3aRhiCD88hi), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1-CSF1R-C3aR axis. Inhibition of F4/80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1+ myeloid subgroup as a new antimetastatic target and prognostic blood marker.

BackgroundObesity is a risk factor for malignancy; however, its prognostic role in patients with metastatic melanoma is controversial. We aim to investigate the prognostic role of body mass index (BMI) in patients with metastatic melanoma receiving mitogen-activated pathway kinase inhibitors (MAPKi), immune checkpoint inhibitors (ICIs) alone or their sequence.MethodsData on patients with metastatic melanoma receiving ≥1 line of systemic treatment were retrieved from prospectively collected databases. Progression-free survival (PFS) and overall survival (OS) were analyzed by means of multivariable stratified Cox regression models; disease control rate (DCR) was analyzed by multivariable stratified logistic regression models. Subgroup analyzes according to the type of treatments received, and in BRAF-mutated patients were pre-planned. All multivariable models included BMI, age, gender, American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment sequencing strategy as covariates.ResultsBetween November 2010 and November 2018, 688 patients from three Italian and two Polish centers were enrolled. 379 (57%) patients had M1c/d disease, 273 (41%) were female and the mean BMI was 27.1 (SD=4.9). Considering first-line treatment, 446 patients (66.8%) received ICIs and 222 MAPKi. No impact of BMI on OS was detected either considering the first line of ICIs, or ICIs sequencing (HR=1.02, 95% CI: 0.99 to 1.05, p=0.202, and HR=1.02, 95% CI: 0.99 to 1.04, p=0.237, respectively). A late effect of BMI on OS was found in patients treated with MAPKi: for five units increment, a 51% of risk reduction at 18 months and a 76% of risk reduction at 30 months were observed. No significant effect of BMI on PFS and DCR was found in any of the subgroup analyzes.ConclusionIn patients with metastatic melanoma receiving ICIs, there is no impact of BMI on DCR, PFS and OS. The late prognostic effect of BMI in patients treated with MAPKi should be considered hypothesis generating and needs to be further investigated.

Purpose In patients with advanced lung adenocarcinoma, the impact of LKB1 mutations on cytotoxic chemotherapy efficacy remains poorly explored. Here, we aimed at investigating the potential impact of LKB1 mutational status on chemotherapy efficacy in advanced non-small-cell lung cancer (NSCLC) patients enrolled in the TArceva Italian Lung Optimisation tRial (TAILOR) trial. Methods The multicenter TAILOR trial randomised patients with EGFR-wild type (wt) advanced NSCLC progressing on/after previous platinum-based chemotherapy to receive docetaxel or erlotinib. Here, we evaluated the impact of LKB1 mutational status on progression-free survival (PFS) and overall survival (OS) in patients treated with second-line docetaxel/erlotinib or during prior platinum-based chemotherapy. Results Out of 222 patients randomised in the TAILOR trial, left-over tumour tissues were available for 188 patients, and 120 patients with evaluable LKB1 status were included. Of them, 17 (14.17%) patients had LKB1-mutated tumours, while 103 (85.83%) had LKB1-wt disease. During second-line treatment, PFS and OS were not statistically significantly different in patients with LKB1-mutated when compared with LKB1-wt NSCLC (adjusted HR (aHR)=1.29, 95% CI 0.75 to 2.21; p=0.364 and aHR=1.41, 95% CI 0.82 to 2.44; p=0.218, respectively). Similarly, we found no significant association between LKB1 mutations and patient PFS or OS during prior first-line platinum-based chemotherapy (aHR=1.04, 95% CI 0.55 to 1.97; p=0.910 and aHR=0.83, 95% CI 0.42 to 1.65; p=0.602, respectively). Conclusion Among advanced NSCLC patients receiving two lines of systemic therapy, LKB1 mutations were not associated with PFS or OS during second-line docetaxel or prior first-line platinum-based chemotherapy. While larger prospective trials are needed to confirm our findings, cytotoxic chemotherapy remains the backbone of investigational combination strategies in this patient population.

Background: The evaluation of the proportional hazards (PH) assumption in survival analysis is an important issue when Hazard Ratio (HR) is chosen as summary measure. The aim is to assess the appropriateness of statistical methods based on the PH assumption in oncological trials. Methods: We selected 58 randomised controlled trials comparing at least two pharmacological treatments with a time-to-event as primary endpoint in advanced non-small-cell lung cancer. Data from Kaplan–Meier curves were used to calculate the relative hazard at each time point and the Restricted Mean Survival Time (RMST). The PH assumption was assessed with a fixed-effect meta-regression. Results: In 19% of the trials, there was evidence of non-PH. Comparison of treatments with different mechanisms of action was associated (P = 0.006) with violation of the PH assumption. In all the superiority trials where non-PH was detected, the conclusions using the RMST corresponded to that based on the Cox model, although the magnitude of the effect given by the HR was systematically greater than the one from the RMST ratio. Conclusion: As drugs with new mechanisms of action are being increasingly employed, particular attention should be paid on the statistical methods used to compare different types of agents.

Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy.

Metastatic melanoma carrying BRAF mutations represent a still unmet medical need as success of BRAF inhibitors is limited by development of resistance. Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme in NAD biosynthesis. An extracellular form (eNAMPT) possesses cytokine-like functions and is up-regulated in inflammatory disorders, including cancer. Here we show that eNAMPT is actively released in culture supernatants of melanoma cell lines. Furthermore, cells that become resistant to BRAF inhibitors (BiR) show a significant increase of eNAMPT levels. Plasma from mice xenografted with BiR cell lines contain higher eNAMPT levels compared to tumor-free animals. Consistently, eNAMPT levels are elevated in 113 patients with BRAF-mutated metastatic melanoma compared to 50 with localized disease or to 38 healthy donors, showing a direct correlation with markers of tumor burden, such as LDH, or aggressive disease (such as PD-L1). eNAMPT concentrations decrease in response to therapy with BRAF/MEK inhibitors, but increase again at progression, as inferred from the serial analysis of 50 patients. Lastly, high eNAMPT levels correlate with a significantly shorter overall survival. Our findings suggest that eNAMPT is a novel marker of tumor burden and response to therapy in patients with metastatic melanoma carrying BRAF mutations.

Background Several electrocardiographic (ECG) abnormalities have been described in patients with acute pulmonary embolism (PE), with discordant reportings about their prognostic value. Methods Consecutive patients with echocardiography performed within 48 h from admission and ECG at presentation, were included in this analysis. The primary study outcome was in-hospital death for high-risk patients and in-hospital death or clinical deterioration for intermediate-risk patients. As secondary outcomes, the associations among ECG abnormalities and both right ventricular dysfunction at echocardiography and baseline troponin elevation were considered. Results 1194 patients were included in this analysis: 13.8% of patients were at high risk of early death, 61.7% were at intermediate risk and 24.5% were at low risk. ECG signs of RV strain showed a continuously decreasing prevalence from high-risk to intermediate-risk and low-risk patients. Differently, the prevalence of T- wave inversion was similar in high and intermediate-risk patients. In high-risk-patients, Qr pattern in lead V1 was the only ECG abnormality associated with in-hospital mortality, but this sign was detected in only 15.9% of this risk category; the presence of at least one ECG abnormality was not associated with the risk of in-hospital death. In not high-risk patients, the presence of at least one ECG abnormality was significantly associated with RVD and this association was confirmed for each individual ECG abnormality. Similar results were obtained as regards the baseline troponin elevation in 816 patients. Conclusions Among the electrocardiographic signs of RV strain/ischemia, Qr pattern in lead V1 was the only ECG abnormality associated with in-hospital mortality in high-risk patients. In not high-risk patients the demonstrated association among baseline ECG signs of RV strain/ischemia and RV dysfunction at echocardiography or troponin elevation highlights the need for early further investigations in patients with such ECG abnormalities.

To assess intraocular pressure (IOP), systolic, diastolic, and mean arterial blood pressure (SBP, DBP, MAP) changes in the sitting, supine, and 20° head-down (Trendelenburg) position in treated (tPOAG) and untreated (uPOAG) primary open-angle glaucoma patients and healthy controls.All participants underwent IOP and systemic BP measurements in the sitting, supine, and Trendelenburg positions during office hours. IOP and BP readings in the sitting, supine, and Trendelenburg positions were analyzed.Twenty-one tPOAG patients, 17 uPOAG patients, and 21 controls were enrolled in the study. Compared to controls, eyes in the tPOAG and uPOAG groups had significantly larger posture-induced IOP elevation upon changing from the sitting to the supine position (P = 0.020 and P = 0.032, respectively). Compared to controls, the IOP elevation in the Trendelenburg position was statistically higher for the tPOAG (P = 0.003), but not the uPOAG group (P = 0.840). All 3 groups had a similar pattern of SBP, DBP, and MAP changes.Compared to controls, posture-induced IOP changes are more pronounced in treated and untreated POAG patients.

Background: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of fluoropyrimidine-related severe toxicity. Methods: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. Results: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR