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Early activation of palliative care for patients with advanced cancer is central in the treatment trajectory. At the Veneto Institute of Oncology, a simultaneous-care outpatient clinic (SCOC) has been active since 2014, where patients are evaluated by an oncologist together with a palliative care team. Recently, we reported on consecutive patients admitted at SCOC from 2018 to 2021 in terms of appropriateness, process, and outcome indicators. Here, we report further analysis in the same group of 753 patients, evaluating other parameters and the correlation between symptom intensity, gender, age, and survival.SCOC data were retrieved from a prospectively maintained database.Among the patients, 42.2% were women, and the median age was 68 years, with 46.7% of patients aged ≥70 years. The most prevalent disease type was gastrointestinal cancer (75.2%), and 90.9% of the patients had metastatic disease. The median score for the distress thermometer was 4; the vast majority of the patients (98.6%) reported physical problems, and 69.4% presented emotional issues. Younger women demonstrated a significantly greater median distress than other patients (p=0.0018). Almost all symptoms had a higher prevalence on the 0-3 Edmonton Symptom Assessment Scale (ESAS) score, except for fatigue. About 43.8% of the patients received systemic anticancer treatment (SAT) in the last 60 days of life, 15.0% of whom received SAT in the last month and 3.1% in the last 2 weeks. For some symptoms, women frequently had more ESAS3. Pain and nausea were significantly less reported by older patients compared with younger adults. Men had a lower risk of having MUST score ≥ 2 (p=0.0311). Men and older patients showed a lower prognosis awareness (p=0.0011 and p=0.0049, respectively). Older patients received less SAT within the last 30 days of life (p=0.0006) and had death risk decreased by 20.0%.Our study identified two subgroups of patients with advanced cancer who require special attention and support due to important symptoms' burden detected by Patient Reported Outcome Measures tests: women and younger adults. These categories of patients require special attention and should be provided early access at SCOC. The role of an oncologist remains crucial to intercept all patients in need of early palliative care and balancing trade-offs of anticancer treatment in advanced metastatic disease.

Immune checkpoint inhibitors (ICIs) yielded unprecedented efficacy in patients with microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC). Since the Pan-Immune-Inflammation Value (PIV) is a blood-based biomarker with prognostic usefulness in mCRC, it might predict clinical outcomes and primary resistance to ICIs.We retrospectively analysed the association of PIV and its early modulation at 3/4 weeks after treatment initiation with the outcomes of MSI-high mCRC patients receiving anti-programmed death-(ligand)1 (PD-[L]1) +/- anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) agents. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. PIV cut-offs were determined using the maximally selected rank statistics.A total of 163 patients were included. In the multivariable models for overall survival (OS) and progression-free survival (PFS), both high (492) baseline PIV (OS: adjusted [a] HR, 3.00; 95% CI, 1.49-6.04, p = 0.002; PFS: aHR, 1.91; 95% CI, 1.06-3.44, p = 0.031) and early PIV increase ≥+30% (OS: aHR, 3.21; 95% CI, 1.65-6.23, p 0.001; PFS: aHR, 2.25; 95% CI, 1.30-3.89, p = 0.003) confirmed an independent prognostic impact. After stratifying patients according to baseline PIV and ICI regimen, OS and PFS were significantly worse in subjects with high PIV receiving anti-PD-1/PD-L1 monotherapy. Early PIV increase was an independent predictor of clinical benefit (aOR, 0.23; 95% CI, 0.08-0.66; p = 0.007), whereas a trend was observed for baseline PIV (aOR, 0.33; 95% CI, 0.10-1.07; p = 0.065).PIV is a strong predictor of outcomes in MSI-high mCRC patients receiving ICIs. Prospective validation of these results is required to establish its role as a stratification factor for personalised combination strategies.

218 Background: Immune checkpoint inhibitors (ICI) showed high efficacy in both first and subsequent lines in metastatic colorectal cancer with mismatch repair deficiency (dMMR-mCRC); however, they still fail in a minority of patients (pts). In non-preplanned analyses from previous studies, RAS mutations ( RASm) have been related to limited activity of ICI monotherapy (ICIm) as compared to ICI doublets (ICId) in dMMR-mCRC. Emerging data suggest different immunological features in presence of RASm, resulting in lower immunogenicity. Methods: NERDY is a retrospective, monocentric study designed to investigate the effect of ICIm and ICId on dMMR-mCRC basing on RASm. Pts with dMMR-mCRC treated with ICIm/ICId at our Institute were included. Clinical-pathological features for each patient were collected. On primary tumor specimens, proinflammatory pathways and CMS subgroup will be assessed by Nanostring and RNA-Seq respectively. The study is exploratory and no formal hypothesis has been postulated. Both PFS and OS were calculated with Kaplan-Meier. Cox proportional hazard model was adopted in the interaction tests. Primary objective was to assess OS and PFS according to RAS in dMMR-mCRC pts treated with ICIm or ICId. Secondary objectives were to describe the inflammatory infiltrate and TMB in dMMR-mCRC according to RAS status. Results: From June 2015 to January 2022, a total of 126 consecutive dMMR-mCRC pts treated with ICI were included, 33 RASm/93 RASwt. RASm pts were more frequently males (p=0.015) and younger (median age 47 vs 65). An imbalance was observed in sidedness (more right-CRC in RASwt than in RASm as BRAF effect, p=0.001) and timing of ICI (administered in later lines in RASm, p=0.013). No differences in ECOG-PS, histotype, disease burden, stage at diagnosis, treatment with ICIm vs ICId and best response. At a median follow up of 53.5 months (95%CI 34.7-56.9), a trend toward longer PFS in pts treated with ICId over ICIm was found in the overall population (HR 0.62; 95%CI 0.36-1.05; p=0.055), being significantly longer in RASm-only pts (HR 0.41; 95%CI 0.13-1.28; p=0.047) but not in RASwt-only pts (HR 0.64; 95%CI 0.34-1.20; p=0.139). No difference was observed in OS between ICId and ICIm in the overall population (HR 0.64; 95%CI 0.36-1.16; p=0.121), in RASwt (HR 0.59; 95%CI 0.29-1.20; p=0.132) nor in RASm pts (HR 0.59; 95%CI 0.19-1.78; p=0.275). Interaction test for RAS and ICI treatment type was not significant for PFS (HR 0.63; 95%CI 0.21-1.94; p=0.423) nor for OS (HR=1.00; 95%CI 0.29-3.41; p=0.999). Conclusions: Preliminary clinical results of the NERDY study suggest enhanced activity of ICId compared to ICIm in pts with RASm dMMR-mCRC. Further data are expected from pending translational analyses and a pre-planned adjunctive cohort from two other Italian centers will be used for external validation.

BackgroundThe aim of this study is to evaluate the correlation between body mass index (BMI) and body fat composition (measured with radiological fat parameters (RFP)) and pathological response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer patients. The secondary aim of the study was to assess the role of BMI and RFP on major surgical complications, overall survival (OS), and disease-free survival (DFS).MethodsAll patients who underwent surgical resection following nCRT between 2005 and 2017 for mid-low rectal cancer were retrospectively collected. Visceral fat area (VFA), superficial fat area (SFA), visceral/superficial fat area ratio (V/S), perinephric fat thickness (PNF), and waist circumference (WC) were estimated by baseline CT scan. Predictors of pathologic response and postoperative complications were investigated using logistic regression analysis. The correlations between BMI and radiologic fat parameters and survival were investigated using the Kaplan–Meier method and log-rank test.ResultsOut of 144 patients included, a complete (TRG1) and major (TRG1+2) pathologic response was reported in 32 (22%) and 60 (45.5%) cases, respectively. A statistically significant correlation between BMI and all the RFP was found. At a median follow-up of 60 (35–103) months, no differences in terms of OS and DFS were found considering BMI and radiologic fat parameters. At univariable analysis, neither BMI nor radiologic fat parameters were predictors of complete or major pathologic response; nevertheless, VFA, V/S>1, and BMI were predictors of postoperative major complications.ConclusionsWe found no associations between BMI and body fat composition and pathological response to nCRT, although VFA, V/S, and BMI were predictors of major complications. BMI and RFP are not related to worse long-term OS and DFS.

PARP inhibitors are largely recognized as active drugs in BRCA-mutated breast and ovarian malignancies. In pancreatic ductal adenocarcinoma, the PARP inhibitor olaparib has recently been approved as maintenance treatment in patients with germline BRCA mutations reaching disease control after a platinum-based first line chemotherapy, proving significant benefit on progression free survival. On the other hand, little evidence is available regarding olaparib as single agent after progression with standard treatment in BRCA-mutated pancreatic ductal adenocarcinoma. A 61-year-old female patient harboring germline BRCA2 mutation was treated at our institution for a pancreatic ductal adenocarcinoma with lung and liver metastases. The patient received three previous lines of treatment with standard therapies, as follows: after the third line treatment failure, we started a further line of treatment with olaparib in off-label prescription. After the first two cycles, a CT scan documented partial response, with complete regression of lung metastases. The response was maintained after four cycles, with further response and clinical benefit. The radiologic and clinical response was maintained for 6 months. This case highlights the potential of olaparib as single agent after progression with standard treatment in BRCA-mutated pancreatic cancer.

Background V600EBRAF mutated metastatic colorectal cancer (mCRC) is a subtype (10%) with overall poor prognosis, but the clinical experience suggests a great heterogeneity in survival. It is still unexplored the real distribution of traditional and innovative biomarkers among V600EBRAF mutated mCRC and which is their role in the improvement of clinical prediction of survival outcomes. Methods Data and tissue specimens from 155 V600EBRAF mutated mCRC patients treated at eight Italian Units of Oncology were collected. Specimens were analysed by means of immunohistochemistry profiling performed on tissue microarrays. Primary endpoint was overall survival (OS). Results CDX2 loss conferred worse OS (HR = 1.72, 95%CI 1.03–2.86, p = 0.036), as well as high CK7 expression (HR = 2.17, 95%CI 1.10–4.29, p = 0.026). According to Consensus Molecular Subtypes (CMS), CMS1 patients had better OS compared to CMS2-3/CMS4 (HR = 0.37, 95%CI 0.19–0.71, p = 0.003). Samples showing less TILs had worse OS (HR = 1.72, 95%CI 1.16–2.56, p = 0.007). Progression-free survival analyses led to similar results. At multivariate analysis, CK7 and CMS subgrouping retained their significant correlation with OS. Conclusion The present study provides new evidence on how several well-established biomarkers perform in a homogenousV600EBRAF mutated mCRC population, with important and independent information added to standard clinical prognosticators. These data could be useful to inform further translational research, for patients’ stratification in clinical trials and in routine clinical practice to better estimate patients’ prognosis.

Andrea Casadei-Gardini,1 Francesco Montagnani,2 Chiara Casadei,1 Francesca Arcadipane,3 Kalliopi Andrikou,4 Deborah Aloi,5 Alessandra Anna Prete,6,7 Maria Giulia Zampino,8 Antonella Argentiero,9 Giuseppe Pugliese,4 Stefania Martini,10 Giuseppe Carlo Iorio,10 Mario Scartozzi,11 Massimiliano Mistrangelo,12 Lorenzo Fornaro,13 Paola Cassoni,14 Giorgia Marisi,15 Veronica Dell’Acqua,16 Paola Simona Ravenda,8 Sara Lonardi,6 Nicola Silvestris,7 Berardino De Bari,5 Umberto Ricardi,3 Stefano Cascinu,4 Pierfrancesco Franco91Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; 2Oncology Department, SOC Oncology, ASL (Health Local Authority), Biella, Italy; 3Department of Oncology, Radiation Oncology, AOU Città della Salute e della Scienza, Turin, Italy; 4Department of Hematology and Oncology, University of Modena and Reggio Emilia, Modena, Italy; 5Radiation Oncology Department, Centre Hospitalier Régional Universitaire “Jean Minjoz”, Besançon Cedex, France; 6Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy; 7Department of Radiological, Oncological and Pathological Sciences, Policlinico Umberto I University Hospital, Rome, Italy; 8Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy; 9Medical Oncology Unit, Cancer Institute Giovanni Paolo II, Bari, Italy; 10Department of Oncology, Radiation Oncology, University of Turin, Turin, Italy; 11Department of Medical Oncology, University of Cagliari, Cagliari, Italy; 12Department of Surgical Sciences, University of Turin, Turin, Italy; 13Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana University, Pisa, Italy; 14Department of Medical Sciences, Pathology Unit, University of Turin, Turin, Italy; 15Biosciences Laboratory, Istituto Scientifico Romagnolo per Lo Studio e La Cura Dei Tumori (IRST) IRCCS, Meldola, Italy; 16Department of Radiotherapy, IRCCS, European Institute of Oncology, Milan, ItalyBackground: In anal cancer, there are no markers nor other laboratory indexes that can predict prognosis and guide clinical practice for patients treated with concurrent chemoradiation. In this study, we retrospectively investigated the influence of immune inflammation indicators on treatment outcome of anal cancer patients undergoing concurrent chemoradiotherapy.Methods: All patients had a histologically proven diagnosis of squamous cell carcinoma of the anal canal/margin treated with chemoradiotherapy according to the Nigro’s regimen. Impact on prognosis of pre-treatment systemic index of inflammation (SII) (platelet x neutrophil/lymphocyte), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were analyzed.Results: A total of 161 consecutive patients were available for the analysis. Response to treatment was the single most important factor for progression-free survival (PFS) and overall survival (OS). At univariate analysis, higher SII level was significantly correlated to lower PFS (p

Background Adenoid cystic carcinoma of the trachea is a rare tumor, characterized by slow growth and low rate of local and distant metastasis. When achievable, complete surgical resection represents the optimal treatment approach, with the highest results in terms of overall survival. Radiation therapy is a reasonable alternative in cases of inoperable disease. Case presentation We report a case of an 82-year-old white man affected by primary adenoid cystic carcinoma of the trachea, treated with debulking surgery and radiotherapy on the residual disease. A three-dimensional conformal radiation therapy was conducted. The total dose amounted to 70 Gy, administered in 35 fractions of 2 Gy. The medium doses given to the esophagus and lungs were 23 Gy and 4.2 Gy respectively. The maximum dose delivered to the spinal cord was 31 Gy with satisfactory results in terms of local control of the disease. Conclusion A combined approach of surgical resection followed by radiotherapy on the residual disease provided an excellent result in terms of disease control, quality of life, and overall survival in a patient with locally advanced tracheal adenoid cystic carcinoma.

Purpose To investigate the prevalence, incidence and characteristics of bacterial infections and their impact on outcome in critically ill patients infected with COVID-19. Methods We conducted a prospective observational study in eight Italian ICUs from February to May 2020; data were collected through an interactive electronic database. Kaplan–Meier analysis (limit product method) was used to identify the occurrence of infections and risk of acquisition. Results During the study period 248 patients were recruited in the eight participating ICUs. Ninety (36.3%) patients developed at least one episode of secondary infection. An ICU length of stay between 7 and 14 days was characterized by a higher occurrence of infectious complications, with ventilator-associated pneumonia being the most frequent. At least one course of antibiotic therapy was given to 161 (64.9%) patients. Overall ICU and hospital mortality were 33.9% and 42.9%, respectively. Patients developing bacteremia had a higher risk of ICU mortality [45.9% vs. 31.6%, odds ratio 1.8 (95% CI 0.9–3.7), p = 0.069] and hospital mortality [56.8% vs. 40.3%, odds ratio 1.9 (95% CI 1.1–3.9), p = 0.04]. Conclusion In critically ill patients infected with COVID-19 the incidence of bacterial infections is high and associated with worse outcomes. Regular microbiological surveillance and strict infection control measures are mandated. Supplementary Information The online version contains supplementary material available at 10.1007/s15010-021-01661-2.

5 Background: Advanced squamous cell anal cancer (aSCAC) is a rare and aggressive disease, accounting for poor prognosis and high morbidity. No targeted therapies are currently available and, after the first line, no standard treatments are approved. Immune checkpoint inhibitors (ICI) showed signs of activity in previous phase I/II trials, but predictive and prognostic biomarkers are lacking. Anti-EGFR have been tested given the rarity of KRAS mutations in aSCAC, with encouraging results. Earlier preclinical evidence suggests possible synergism between cetuximab (cet) and ICI. Methods: In the phase II randomized trial CARACAS (NCT03944252), we tested avelumab (ave) alone (Arm A) or with cet (Arm B) in pretreated aSCAC; overall response rate (ORR) was the primary endpoint. With one-sided a error set at 0.05 and power of 80%, at least 4 responses out of 27 patients (pts) per arm had to be observed to declare the study positive. On pre-treatment tumor tissue samples, we assessed HPV status, PD-L1 expression, microsatellite status, tumor mutational burden (TMB) and performed next generation sequencing (NGS) via FoundationOne CDx. Primary objective was to describe the clinical outcomes of ICI in SCAC in the CARACAS trial population according to molecular analyses. Secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular characteristics to individuate new prognostic biomarkers in SCAC. Cox regression was used to investigate the effect of the main variables analysed on survival. Translational analyses were performed on the 100% of the study population since all the pts received ICI. Results: In the clinical trial, the Arm B reached the primary endpoint (ORR 17%, 95% CI 5·6-34·7). High TMB (≥10 mutations per megabase) was related with longer OS (HR=0.09; 95% CI 0.01-0.68; p=0.019), showing the same trend in PFS (HR=0.44; 95%CI=0.15-1.27; p=0.129). As well, tumors with high expression of PD-L1 (>40 measured with combined positive score, CPS) showed significantly longer OS (HR=2.19; 95% CI=0.92-5.19; p=0.075) and PFS (HR=2.35; 95%CI=1.09-5.1; p=0.03). High TILs (>1.2) did not affect significantly OS (HR=0.77; 95% CI=0.42-1.4; p=0.39) nor PFS (HR=1.19; 95%CI=0.57-2.48; p=0.645). When combined together and with high TILs, high TMB and PD-L1identified pts with significantly better prognosis in OS (HR=0.43; 95% CI=0.21-0.87; p=0.019) and PFS (HR=0.48; 95%CI=0.23-1.00; p=0.051). Remarkable responses were also observed in pts with high PD-L1 expression and TMB. Conclusions: TranslaCARACAS study documented prognostic role of high TMB and PD-L1 in mSCAC treated with ICI with or without anti-EGFR. Stratifying per high TMB, PD-L1 and TILs, a subgroup of pts with particularly favorable prognosis and deep responses were detected. Further investigation in larger cohorts is warranted to confirm our findings.

Background The impact of free triiodothyronine (FT3)/free thyroxine (FT4) ratio on survival in hospitalized geriatric patients was recently described. Up today, there are no data regarding the prognostic role of FT3/FT4 ratio in patients with advanced cancer. We evaluated the impact of FT3/FT4 ratio on survival in patients with refractory colorectal cancer (CRC) treated with regorafenib. Methods Patients with metastatic CRC treated with regorafenib with available clinical data and baseline measurement of FT3, FT4, and thyroid-stimulating hormone (TSH) were considered eligible. Exploratory analyses included subjects treated at Istituto Oncologico Veneto. A confirmatory analysis was planned based on FT3/FT4 ratio tertile results, and a validation cohort was built on data retrieved from University of Cagliari. Results In an exploratory cohort, the median overall survival in patients with low, intermediate, and high FT3/FT4 ratios, according to tertiles' value, was 4.8, 5.0, and 7.6 months, respectively (P = .003). The differences were significant in the multivariate model (hazard ratio, 0.43; 95% confidence interval, 0.28-0.68; P = .0003). Confirmatory results were obtained in a validation cohort, both in univariate (P = .0002) and in multivariate (hazard ratio, 0.56; 95% confidence interval, 0.36-0.88; P = .0118) models. Conclusions High baseline FT3/FT4 ratio is strongly associated to better outcome in patients with progressive metastatic CRC treated with regorafenib. Further investigations are ongoing to draw definitive conclusions regarding a potential predictive effect.

In small-cell lung cancer (SCLC), the role of chemotherapy and radiotherapy is well established. Large-cell neuroendocrine carcinoma (LCNEC) shares several clinicopathological features with SCLC, but its optimal therapy is not defined. We evaluated clinical response and survival outcomes of advanced LCNEC treated in first-line therapy compared with SCLC. 72 patients with stage III–IV LCNEC (n=28) and extensive-stage SCLC (ES-SCLC) (n=44) received cisplatin–etoposide with/without thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI). Comparing LCNEC with SCLC, we observed similar response rates (64.2% versus 59.1%), disease control rates (82.1% versus 88.6%), progression-free survival (mPFS) (7.4 versus 6.1 months) and overall survival (mOS) (10.4 versus 10.9 months). TRT and PCI in both histologies showed a benefit in mOS (34 versus 7.8 months and 34 versus 8.6 months, both p=0.0001). LCNEC patients receiving TRT showed an improvement in mPFS and mOS (12.5 versus 5 months, p=0.02 and 28.3 versus 5 months, p=0.004), similarly to ES-SCLC. PCI in LCNEC showed an increase in mPFS (20.5 versus 6.4 months, p=0.09) and mOS (33.4 versus 8.6 months, p=0.05), as in ES-SCLC. Advanced LCNEC treated with SCLC first-line therapy has a similar clinical response and survival outcomes to ES-SCLC., Cisplatin–etoposide is an efficient treatment for large-cell neuroendocrine carcinoma. RT and PCI improve survival. http://ow.ly/sBJo309HG8s

Background Immunotherapy with immune checkpoint inhibitors (ICIs) is highly effective in microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC); however, specific predictive biomarkers are lacking. Patients and Methods Data and samples from 85 patients with MSI-H mCRC treated with ICIs were gathered. Tumor infiltrating lymphocytes (TILs) and tumor mutational burden (TMB) were analyzed in an exploratory cohort of “super” responders and “clearly” refractory patients; TILs were then evaluated in the whole cohort of patients. Primary objectives were the correlation between the number of TILs and TMB and their role as biomarkers of ICI efficacy. Main endpoints included response rate (RR), progression-free survival (PFS), and overall survival (OS). Results In the exploratory cohort, an increasing number of TILs correlated to higher TMB (Pearson's test, p = .0429). In the whole cohort, median number of TILs was 3.6 in responders compared with 1.8 in nonresponders (Mann-Whitney test, p = .0448). RR was 70.6% in patients with high number of TILs (TILs-H) compared with 42.9% in patients with low number of TILs (odds ratio = 3.20, p = .0291). Survival outcomes differed significantly in favor of TILs-H (PFS: hazard ratio [HR] = 0.42, p = .0278; OS: HR = 0.41, p = .0463). Conclusion A significant correlation between higher TMB and increased number of TILs was shown. A significantly higher activity and better PFS and OS with ICI in MSI-H mCRC were reported in cases with high number of TILs, thus supporting further studies of TIL count as predictive biomarker of ICI efficacy. Implications for Practice Microsatellite instability is the result of mismatch repair protein deficiency, caused by germline mutations or somatic modifications in mismatch repair genes. In metastatic colorectal cancer (mCRC), immunotherapy (with immune checkpoint inhibitors [ICIs]) demonstrated remarkable clinical benefit in microsatellite instability–high (MSI-H) patients. ICI primary resistance has been observed in approximately 25% of patients with MSI-H mCRC, underlining the need for predictive biomarkers. In this study, tumor mutational burden (TMB) and tumor infiltrating lymphocyte (TIL) analyses were performed in an exploratory cohort of patients with MSI-H mCRC treated with ICIs, demonstrating a significant correlation between higher TMB and increased number of TILs. Results also demonstrated a significant correlation between high number of TILs and clinical responses and survival benefit in a large data set of patients with MSI-H mCRC treated with ICI. TMB and TILs could represent predictive biomarkers of ICI efficacy in MSI-H mCRC and should be incorporated in future trials testing checkpoint inhibitors in colorectal cancer.

Despite the well-known negative prognostic value of theTwo large retrospective series ofA total of 395These scoring systems are based on easy-to-collect data and defined specific subgroups with relevant differences in their life expectancy. These tools could be useful in clinical practice, would allow better stratification of patients in clinical trials and may be adopted for proper adjustments in exploratory translational analyses.

Angiogenesis is an essential process for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown significant results in a plethora of tumors. Anti-angiogenic agents are currently part of many standard-of-care options for several metastatic gastrointestinal cancers. Bevacizumab, aflibercept, ramucirumab, and regorafenib have significantly improved both progression-free and overall survival in different lines of treatment in metastatic colorectal cancer. Second-line ramucirumab and third-line apatinib are effective anti-angiogenic treatments for patients with metastatic gastric cancer. Unfortunately, the anti-angiogenic strategy has major practical limitations: resistance inevitably develops through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions. Anti-angiogenic agents may be more effective in combination therapies, with not only cytotoxics but also other emerging compounds in the anti-angiogenic class or in the separate class of the so-called vascular-disrupting agents. This review aims to provide an overview of the approved and under development anti-angiogenic compounds as well as the vascular-disrupting agents in the treatment of gastrointestinal cancers, focusing on the actual body of knowledge available on therapy challenges, pharmacodynamic and pharmacokinetic mechanisms, safety profiles, promising predictive biomarkers, and future perspectives.

The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy.

Background Despite the well-known negative prognostic value of the V600EBRAF mutation in patients with metastatic colorectal cancer (mCRC), its outcome is quite heterogeneous, and the basis for this prognostic heterogeneity should be better defined. Methods Two large retrospective series of V600EBRAF-mutated mCRC from 22 institutions served as an exploratory and validation set to develop a prognostic score. The model was internally and externally validated. Results A total of 395 V600EBRAF-mutated mCRCs were included in the exploratory set. Performance status, CA19.9, lactate dehydrogenase, neutrophil/lymphocyte ratio, grading and liver, lung and nodal involvement emerged as independent prognostic factors for overall survival (OS). Two different scoring systems were built: a ‘complete’ score (0–16) including all significant covariates and a ‘simplified’ score (0–9), based only on clinicopathological covariates, and excluding laboratory values. Adopting the complete score, proportions of patients with a low (0–4), intermediate (5–8) and high (9–16) score were 44.7%, 42.6% and 12.6%, respectively. The median OS was 29.6, 15.5 (hazard ratio [HR] for intermediate vs low risk: 2.16, 95% confidence interval [CI]: 1.44–3.22, p Conclusions These scoring systems are based on easy-to-collect data and defined specific subgroups with relevant differences in their life expectancy. These tools could be useful in clinical practice, would allow better stratification of patients in clinical trials and may be adopted for proper adjustments in exploratory translational analyses.

87 Background: Anti-PD-(L)1-based therapy yielded unprecedented efficacy in patients with MSI-high mCRC. A relevant proportion of subjects may achieve long-term disease control when receiving ICIs, particularly anti-PD-1 plus anti-CTLA-4 combo. However, some patients still experience treatment refractoriness or short-term clinical benefit. Methods: We analyzed data of 163 patients with MSI-high mCRC treated with anti-PD-1 +/- anti-CTLA-4 agents. The endpoint was progression-free survival (PFS); multivariable analyses were performed using a cure model (Othus et al, CCR 2012), which allows to test which factors, including ICI type, could identify patients achieving long-term disease control. To account for biases consistent with non-random ICI assignment, we estimated a propensity score (covariates: ECOG PS, age, sex, primary tumor location, its resection, adjuvant treatment, synchronous presentation of mets, mucinous histotype, RAS/BRAF status, n. prior treatment lines, previous chemo, n. metastatic sites, presence of peritoneal, lung, liver, bone, brain, nodal mets), and then in the cure model we applied an inverse-probability-of-treatment-weight (IPTW) based on propensity score. A beforehand variable selection was operated using a random survival forest (RSF) model (RSF covariates: all the propensity score covariates plus ICI line and ICI type, platelets count (PLT), NLR, LDH), where we introduced a weight system in order to adjust variable selection net of ICI type. Results: RFS selected 5 variables: ICI type, ECOG PS, NLR, PLT and N. prior lines, the combination of which allowed to estimate the cure probability: the higher the probability the greater the chance of achieving long-term disease control. The Table shows the odds ratio estimates, defining the chance of being “cured” according to the values of the selected variables. ICI type was significantly associated with long-term disease control: patients treated with anti CTLA-4-combo achieved the highest chance of being cured, 3.41 times greater than the chance of patients treated with anti PD-1 mono. The median cure probability was as higher as 70.1% (IQR: 51.9-81.0%) with CTLA-4-combo vs 34.8% (IQR: 18.4-51.9%) with anti-PD-1 mono; the probability within treatment groups was varying according to ECOG PS, NLR, PLT and n. prior lines. Conclusions: Based on 5 variables including the ICI treatment type, a nomogram was built in order to estimate the cure probability in patients with MSI-high mCRC and potentially assist clinicians in their clinical practice. [Table: see text]

4051 Background: Advanced squamous cell anal carcinoma (advSCAC) is a rare disease with poor prognosis. No standard therapies beyond first line are currently available, yet a promising activity was documented for the anti-EGFR cetuximab (CET) and for anti-PD-1 agents in previous retrospective case series and phase I-II studies, respectively. In experimental models combination of EGFR and PD-L1 blockade was synergistic as PD-L1 blockade led to NK cells activation enhancing cetuximab ADCC. In this trial we aimed to evaluate safety and activity of the anti-PD-L1 avelumab (AVE) alone or in combination with CET in pretreated advSCAC. Methods: This was an open-label, prospective, multicenter randomized phase 2 trial (NCT03944252). Patients (pts) with advSCAC progressed after at least 1 line of treatment were randomized 1:1 to receive either AVE 10 mg/kg (arm A) or AVE + CET 500 mg/sqm (arm B) as bi-weekly regimens. A Simon’s two-stage Mini-Max design was used. The null hypothesis of a true response rate 5% was tested against the one-sided alternative of a true response rate 20% in each arm. Setting type I error at 0.05 and power at 80%, 30 pts per arm had to be randomized. No formal comparison between the two arms was planned. Primary endpoint was overall response rate (ORR); secondary endpoints were Progression-Free Survival (PFS), Overall Survival (OS) and safety. Results: Sixty pts were enrolled, 30 in each arm. All baseline characteristics were well balanced between the two arms. Median age was 63 years; M/F was 19/41; 12 out of 30 pts in each arm had distant metastases; 7 in arm A and 10 in arm B received > 1 previous lines of treatment. At a median follow up of 8.7 months, 3 out of 30 pts in each arm obtained PR (ORR 10%); SD was observed in 12 pts in arm A (40%) and 14 in arm B (47%). Disease control rate was thus 50% in arm A and 57% in arm B. Duration of disease control was 6.1 (95%CI 3.7–11.0) and 6.1 (95%CI 4.1–9.6) months in arm A and B, respectively. Median PFS was 2.1 (95%CI 1.8–4.0) in arm A and 3.9 months (95%CI 2.1–5.6) in arm B. Grade 3-4 adverse events were 13.3% in arm A and 33.3% in arm B: anemia 10% vs 13.3%, fatigue 0 vs 6.7%, skin toxicity 0 vs 6.7%. Treatment interruption due to AE occurred in 3 pts, 1 in arm A and 2 in arm B. Translational analyses will be performed on tissue and blood samples for exploratory purpose. Conclusions: The CARACAS trial was the first clinical study to test dual EGFR and PD-L1 blockade in advSCAC. Both AVE monotherapy and AVE-CET showed promising activity with manageable safety profile. Clinical trial information: NCT03944252 .

Background FOLFOXIRI + bev is regarded as a valuable option in the first-line tx of mCRC pts. A possible concern for the adoption is the feasibility and efficacy of tx after progression, and especially the reintroduction of the same agents used upfront. The aim of the study was to evaluate the efficacy of tx after progression among pts treated with first-line FOLFOXIRI + bev in the phase III TRIBE (NCT00719797) and TRIBE2 (NCT02339116) studies. The impact of the oxaliplatin and irinotecan free interval (OIFI), defined as the time from the last administration of oxaliplatin and irinotecan to disease progression, on the efficacy of tx after progression was also investigated. Methods Data about tx received after progression including 2ndPFS (i.e. the time from 2nd line tx start to disease progression or death) were collected. The efficacy of tx after progression according to the duration of the OIFI was explored. A cut-off value of 4 months was adopted. Results Out of 586 pts treated with upfront FOLFOXIRI + bev, 520 progressed. Among 409 (79%) pts who received a tx after progression, 168 (41%) received FOLFOXIRI ± bev (Group A) and 241 (59%) received other tx (Group B), including FOLFOX or FOLFIRI ± bev or other agents not used in first line in 124 and 117 cases, respectively. Anti-EGFR moAbs were administered in 68 cases. Pts in Group A experienced significantly longer 2nd PFS than pts in Group B (median 2nd PFS: 6.1 vs 4.2, HR 0.76, 95%CI 0.62-0.94; p = 0.012). Pts with an OIFI ≥ 4 mos (n = 279) had longer 2nd PFS than those with an OIFI Conclusions Tx after progression to first-line FOLFOXIRI + bev were feasible. Pts with longer OIFI showed better 2nd PFS and seemed to derive more benefit from the reintroduction of the triplet. Clinical trial identification TRIBE NCT00719797 TRIBE2 NCT02339116. Legal entity responsible for the study G.O.N.O.: Gruppo Oncologico Nord Ovest. Funding Has not received any funding. Disclosure S. Lonardi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Servier. D. Santini: Advisory / Consultancy: Amgen; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Eisai; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Janssen; Advisory / Consultancy: Merck. A. Falcone: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy: Lilly; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Servier. C. Cremolini: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Amgen; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Servier. All other authors have declared no conflicts of interest.

Casadei-Gardini A, Montagnani F, Casadei C, et al. Cancer Manag Res. 2019;11:3631–3642. The authors have advised that the affiliations are not correct in the published paper (page 3631). They have provided revised author and affiliations lists, as follows, and confirm that the modifications do not alter their conflicts of interest status in regard to this work. Andrea Casadei-Gardini,1,2 Francesco Montagnani,3 Chiara Casadei,1 Francesca Arcadipane,4 Kalliopi Andrikou,2 Deborah Aloi,5 Alessandra Anna Prete,6 Maria Giulia Zampino,7 Antonella Argentiero,8 Giuseppe Pugliese,2 Stefania Martini,4 Giuseppe Carlo Iorio,4 Mario Scartozzi,9 Massimiliano Mistrangelo,10 Lorenzo Fornaro,11 Paola Cassoni,12 Giorgia Marisi,13 Veronica Dell’Acqua,14 Paola Simona Ravenda,7 Sara Lonardi,6 Nicola Silvestris,8 Berardino De Bari,5 Umberto Ricardi,4 Stefano Cascinu,2 Pierfrancesco Franco4 1Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; 2Department of Hematology and Oncology, University of Modena and Reggio Emilia, Modena, Italy; 3Oncology Department, SOC Oncology, ASL (Health Local Authority), Biella, Italy; 4Department of Oncology, Radiation Oncology, University of Turin, Turin, Italy; 5Radiation Oncology Department, Centre Hospitalier Régional Universitaire “Jean Minjoz”, Besançon Cedex, France; 6Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy; 7Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy; 8Medical Oncology Unit, Cancer Institute Giovanni Paolo II, Bari, Italy; 9Department of Medical Oncology, University of Cagliari, Cagliari, Italy; 10Department of Surgical Sciences, University of Turin, Turin, Italy; 11Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana University, Pisa, Italy; 12Department of Medical Sciences, Pathology Unit, University of Turin, Turin, Italy; 13Biosciences Laboratory, Istituto Scientifico Romagnolo per Lo Studio e La Cura Dei Tumori (IRST) IRCCS, Meldola, Italy; 14Department of Radiotherapy, IRCCS, European Institute of Oncology, Milan, ItalyRead the original article

Background and objective In the past 2 decades, in developed countries, spine procedures (surgical and percutaneous) had the highest absolute increase in case volume trend. The optimal approach to prevent and treat postoperative pain is continuously evolving. This systematic literature review presents evidence on safety and efficacy of pharmacological and nonpharmacological therapies to prevent and treat postoperative pain after lumbar spine procedures. Databases and data treatment Publications listed in PUBMED and EMBASE were considered to identify randomized clinical trials suitable for inclusion in this systematic review. Key words for literature search were selected, with authors' agreement, using the PICOS approach (participants, interventions, comparisons, outcomes, and study design). Results Fifty-nine randomized clinical trials (involving a total of 4,238 patients, with ages ranging from 18 to 86 years) published between January 2012 and September 2017 were retrieved. Data are presented according to the timing of therapy administration. Conclusion and recommendations Clinical evidence on perioperative pain management in patients undergoing spine procedures have significantly evolved after the review published in 2012. The aim of this systematic review was to report the latest evidence published. These include the preoperative use of dexamethasone, which was shown to be able to reduce pain at mobilization but not to reduce pain at rest or total morphine consumption; the use of gabapentinoids as part of a multimodal analgesic approach; and the safety and effectiveness of the intraoperative use of ketamine, dexketoprofen, and tramadol. Finally, electrical nerve stimulation is gaining interest and is potentially suitable for clinical needs.

Summary Objectives The present pilot study was performed to evaluate the HPA axis and ANS activity by measuring salivary cortisol and α-amylase diurnal trajectory and production, respectively, in mild or moderate-to-severe (MS) OSA-affected, but otherwise healthy, children. Moreover, a correlative analysis was performed between the salivary biomarker concentrations and the PSG variables characterizing the OSA severity. Methods We studied 27 consecutive OSA patients (13 mild OSA; 14 MS OSA) and seven healthy children who were enrolled as controls by collecting salivary samples and measuring cortisol and α-amylase levels using enzyme-linked bioassays. Results Compared with controls, both mild and MS OSA children showed: (1) increased salivary cortisol diurnal production, (2) maintenance of the physiological circadian activity of the HPA axis, and (3) no changes in α-amylase diurnal trajectory and production. In addition, morning salivary cortisol concentrations was negatively associated with the disease severity in the MS OSA group. Conclusions OSA is associated with dysregulation of the HPA axis activity in children, the latter potentially underlying some of the adverse consequences of the disease. Pediatr Pulmonol. 2014; 49:1145–1152. © 2014 Wiley Periodicals, Inc.

Controversial results on the predictive value of programmed death ligand 1 (PD-L1) status in lung tumor tissue for response to immune checkpoint inhibitors do not allow for any conclusive consideration. Liquid biopsy might allow real-time sampling of patients for PD-L1 through the course of the disease. Twenty-four stage IV NSCLC patients included in the Expanded Access Program with Nivolumab were enrolled. Circulating tumor cells (CTCs) were analyzed by CellSearch with anti-human B7-H1/PD-L1 PE-conjugated antibody. PD-L1 expressing CTCs were assessed at baseline, at 3 and 6 months after starting therapy, and correlated with outcome. At baseline and at 3 months of treatment, the presence of CTCs and the expression of PD-L1 on their surface were found associated to poor patients outcome. Nevertheless, the high frequency of PD-L1 expressing CTCs hampered to discriminate the role of PD-L1 in defining prognosis. Conversely although CTCs were found in all patients 6 months after treatment, at this time patients could be dichotomized into two groups based PD-L1 expression on CTCs. Patients with PD-L1 negative CTCs all obtained a clinical benefit, while patients with PD-L1 (+) CTCs all experienced progressive disease. This suggests that the persistence of PD-L1(+) CTCs might mirror a mechanism of therapy escape.

Female infertility is a widespread problem in Western countries. During past years, an association between ovarian stimulation in unfertile women and breast cancer risk has been hypothesized.Purpose of the present investigation was to comment the most updated studies about an eventual relationship between fertility drugs and breast cancer risk.The authors performed a review of the current literature regarding the possible association between the use of fertility drugs and the enhanced risk of breast cancer. They searched digital databases including Pubmed, EMBASE, and the Cochrane Library. The literature search was performed using various combinations of keywords. They carefully analyzed only the full versions of all relevant studies.Using various combination of keywords, the authors examined 930 papers. They considered only papers written in English. With these criteria they selected the studies that had been discussed in detail on the text.None of the works commented provides an indisputable evidence about a link between ovarian stimulation and breast cancer risk. On the contrary, most of them actually suggest a lack of interaction between them or even a protective role of ovarian stimulation.

Objective: This study will investigate the reproducibility and influencing factors of exhaled breath temperature measured with the tidal breathing technique in asthmatic patients and healthy children. Methods: Exhaled breath temperature, fractional exhaled nitric oxide, and spirometry were assessed in 124 children (63 healthy and 61 asthmatic), aged 11.2 +/- 2.5 year, M/F 73/51. A modified version of the American Thoracic Society questionnaire on the child's present and past respiratory history was obtained from parents. Parents were also asked to provide detailed information on their child's medication use during the previous 4 weeks. Ear temperature, ambient temperature, and relative-ambient humidity were also recorded. Results: Exhaled breath temperature measurements were highly reproducible; the second measurement was higher than the first measurement, consistent with a test-retest situation. In 13 subjects, between-session within-day reproducibility of exhaled breath temperature was still high. Exhaled breath temperature increased with age and relative-ambient humidity. Exhaled breath temperature was comparable in healthy and asthmatic children; when adjusted for potential confounders (i.e. ambient conditions and subject characteristics), thermal values of asthmatic patients exceeded those of the healthy children by 1.1 degrees C. Normalized exhaled breath temperature, by subtracting ambient temperature, was lower in asthmatic patients treated with inhaled corticosteroids than in those who were corticosteroid-naive. Conclusion: Measurements of exhaled breath temperature are highly reproducible, yet influenced by several factors. Corrected values, i.e. normalized exhaled breath temperature, could help us to assess the effect of therapy with inhaled corticosteroids. More studies are needed to improve the usefulness of the exhaled breath temperature measured with the tidal breathing technique in children.

Several adverse effects have been related to infertility treatments, such as cancer development. In particular, the relationship between infertility, reproductive strategies, and risk of gynecological cancers has aroused much interest in recent years. The evaluation of cancer risk among women treated for infertility is very complex, mainly because of many factors that can contribute to occurrence of cancer in these patients (including parity status). This article addresses the possible association between the use of fertility treatments and the risk of ovarian cancer, through a scrupulous search of the literature published thus far in this field. Our principal objective was to give more conclusive answers on the question whether the use of fertility drug significantly increases ovarian cancer risk. Our analysis focused on the different types of drugs and different treatment schedules used. This study provides additional insights regarding the long-term relationships between fertility drugs and risk of ovarian cancer.

e12000 Background: Transitory or definitive amenorrhea (A) is a related side effect, specifically affecting young women diagnosed with breast cancer and treated with adjuvant chemotherapy (CT). Pre...

Though a relatively rare disease, botulism can be a serious problem of public health, particularly when connected with the consumption of industrial canned food; moreover, in the last years the shortage of botulism antitoxin has caused some concern in the Public Health Authorities. This work presents the results of a five-year surveillance of botulism in Italy, with the distribution of the cases by Regions (first level administrative units which, in Italy, have administrative and legislative competencies in the sanitary field) and by vehicle of transmission. All the relevant and confirmed botulism outbreaks that occurred in the period under consideration are described.

The present pilot study was performed to evaluate the HPA axis and ANS activity by measuring salivary cortisol and α-amylase diurnal trajectory and production, respectively, in mild or moderate-to-severe (MS) OSA-affected, but otherwise healthy, children. Moreover, a correlative analysis was performed between the salivary biomarker concentrations and the PSG variables characterizing the OSA severity.We studied 27 consecutive OSA patients (13 mild OSA; 14 MS OSA) and seven healthy children who were enrolled as controls by collecting salivary samples and measuring cortisol and α-amylase levels using enzyme-linked bioassays.Compared with controls, both mild and MS OSA children showed: (1) increased salivary cortisol diurnal production, (2) maintenance of the physiological circadian activity of the HPA axis, and (3) no changes in α-amylase diurnal trajectory and production. In addition, morning salivary cortisol concentrations was negatively associated with the disease severity in the MS OSA group.OSA is associated with dysregulation of the HPA axis activity in children, the latter potentially underlying some of the adverse consequences of the disease.

e12005 Background: Neutropenia (N) is a common chemotherapy (CT) related adverse event and febrile N (FN) often requires hospitalization, being associated with morbidity and mortality. Primary prop...

Management of metastatic colorectal cancer requires a multimodal approach and must be performed by an experienced, multidisciplinary expert team. The optimal choice of the individual treatment modality, according to disease localization and extent, tumor biology, and patient clinical characteristics, will be one that can maintain quality of life and long-term survival, and even cure selected patients. This review is an overview of the different therapeutic approaches available in metastatic colorectal cancer, for the purpose of defining personalized therapeutic algorithms according to tumor biology and patient clinical features.

Background After failure of a second or third line therapy with TKI, many clinicians offer to their advanced NSCLC pts a new line of cht, even if there are no perspective trials that support this choice. We report our experience about cytotoxic treatment administered after a target therapy with Erlotinb or Gefitinib in pts with unknown EGFR mutational status or EGFR wild type. Patients and methods Since January 2003 to December 2011, 84 pts received TKI in second or third line and after progression 34 of them were treated with at least one subsequent line of cht. We collected response data, analyzed overall survival (OS) and progression free survival (PFS) of cht beyond TKI with Kaplan-Meier method and correlated them with Disease Control (DC) and PFS of first line cht and TKI using log-rank test. Results 29 out of 34 pts received cht as third and 5 pts as forth line treatment. 67,6 % of pts received a monotherapy, while 32,4% a combination treatment, platinum based in 7 cases. A response rate (RR) of 20,5% and a DC rate of 52,9% were registered. Median OS post-TKI and PFS were 13 (95% C.I. 6,36-19,63) and 3 months (mos) (95% C.I 0,5-5,5) respectively. OS of pts who obtained DC during TKI was 18,2 mos compared to 5,7 mos of pts not responder to target treatment (p = 0,019). At univariate analysis good PS(≤1) after TKI (p = 0,022), DC (p = 0,025) and PFS > 6 mos with first line cht(p = 0,002) were found to be the only predictive factors of a better PFS with post-TKI cht. At multivariate analysis only the PFS > 6 mos with first line cht was confirmed as an independent predictive factor of better PFS in post-TKI setting (p = 0,05). Age more or less than 65 years (p = 0,7) use of combination (p = 0,84) and platinum-based therapy (p = 0,75) seems not to improve survival outcome and DC of cht beyond TKI. Conclusions DC with TKI identify a good prognostic group of pts. Good and prolonged response (> 6 mos) to the first line cht and a PS ≤1 are useful predictive factors to select pts who could benefit from receiving a cytotoxic treatment after target agents failure. Aggressive cht strategies do not seem to produce a real advantage in this setting. Disclosure All authors have declared no conflicts of interest.

48 Background: First-line decision making is the key to the successful management of mCRC patients (pts). RAS/BRAF status is essential to choose the best targeted agent. In hub centers, a not negligible proportion of pts referred from elsewhere may not have standard tissue-based (STB) molecular results available at the time of first oncologic visit (T0). LB may help circumvent these hurdles. Methods: A monoinstitutional prospective head-to-head comparison of LB versus (vs) STB testing was conducted in a real-world setting. Selection criteria included: mCRC with unknown RAS/BRAF status at T0, tissue from primary or metastases archived in external centers, no previous anti- EGFR agents. At T0, pts underwent plasma sampling for LB testing and procedure for tissue recovery. RAS/BRAF genotyping was carried out by droplet digital PCR on circulating-free (cf) DNA. Primary endpoint was the comparison of time to LB (T1) vs STB (T2) results. Secondary endpoints were the overall percent agreement (OPA), specificity, sensitivity, positive and negative predictive value (PPV and NPV) of LB. Urinary (u) cfDNA testing was also explored. Results: A total of 33 pts were included. Mean T1 was 7 (2-12) days (d) as compared to 22 (7-65) d mean T2. T2 included a mean time for tissue recovery of 17 d. The OPA between LB and STB analysis was 83%. Compared to STB testing, LB specificity and sensitivity were 90% and 80%, respectively, with a PPV of 94% and NPV of 69%. In detail, at STB and LB testing, RAS mutation was found in 50% and 43% of pts; BRAF mutation in 17% and 13%, respectively. LB results included 1 false positive and 4 false negative (FN). FN showed a significantly lower tumor burden (i.e. total tumor volume) at basal CT scan. Concordance between STB and ucfDNA testing was 89%, with a sensitivity of 83% and specificity of 100% recorded for ucfDNA analysis. Conclusions: Faster turnaround time, high concordance and accuracy are 3 key-points supporting the adoption of LB in routinary mCRC care, in particular when decision on first-line is urgent and tissue recovery from external centers may require a long time. Results should be interpreted with caution in LB wild-type cases with low tumor burden.

Introduction Lymphoepithelioma is a very rare form of malignant tumor originating from epithelial line cells. Its occurrence has potential clinical, therapeutic and prognostic implications. In the present report we describe an unusual case of bladder cancer with two different histological varieties: transition cell carcinoma and lymphoepithelioma-like carcinoma. Lymphoepithelioma-like carcinoma of the bladder has only been rarely reported in the literature to date. Case presentation We present the case of a 68-year-old Caucasian man who, after occurrence of hematuria, underwent transurethral resection of a bladder tumor. The results of a histological examination confirmed a high-grade non-muscle-invasive pT1 lymphoepithelioma-like carcinoma of the urinary bladder, associated with a concurrent high-grade transition cell carcinoma. After analyzing the histological features, our patient was subjected to treatment with intra-vesical instillations of bacillus Calmette-Guérin. Our work stresses that diagnosis and therapeutic approaches can be difficult and controversial, especially in the early stages of this rare carcinoma. Conclusions This report emphasizes the importance of extending our knowledge and experiences regarding this uncommon carcinoma. Further studies are needed to better understand this rare disease and define more accurate diagnostic and therapeutic strategies.