Small bowel adenocarcinoma (SBA) is a rare tumor with an unfavorable prognosis, and due to its rarity, few studies on its treatment are available. Chemotherapy remains the standard of treatment in advanced disease. Recently immunotherapy has demonstrated to be a valid therapeutic option for many solid tumors. We reviewed the data published in literature to understand the impact of immunotherapy in this cancer.

Supplementary table 1. HOMA indexes at baseline among patients according to glucose tolerance Supplementary table 2. Cox proportional hazard models of the predictors of mortality and disease progression by univariate and multivariate analysis Supplementary figure 1. PFS and OS after stratification for baseline glucose, insulin and insulin sensitivity.

Background: Anal squamous cell carcinoma (ASCC) is a relatively rare malignancy ac-counting for about 2-3% of all the gastrointestinal tumors. The standard of treatment for localized disease is chemoradiotherapy. Several studies reported a sex disparity in ASCC prognosis showing a better survival for female compared to men. Methods: We examined 1,380 patients with ASCC who received comprehensive genomic profiling as part of routine clinical care and present key differences in mutational patterns based on sex and human papilloma virus status. Results: HPV-16 is identified more frequently in female patients, whereas HPV-6 incidence was higher in male patients. Male patients had higher rates of alterations for TERT, TP53, and CDKN2A, while alterations in CBFB were nearly exclusively found in female HPV(+) patients. Approximately 30% of patients have alteration of PIK3CA. Over 70% of the population was positive for PD-L1 (1%+), with nearly 20% exhibiting a high PDL-1 expression (50%+). Additionally, ~18% of patients had a high tumor mutational burden (TMB>=10 mutations/Mb).Conclusions: High rates of PI3K gene alteration and favorable immunological profiles observed in our study suggest possible therapeutic opportunities in which ASCC patients may benefit from newfound precision treatments and immunotherapy in addition to, or in lieu of, standard-of-care chemoradiotherapy.

TPS590 Background: Radical cystectomy (RC) without neoadjuvant chemotherapy is standard-of-care for cisplatin (cis)-ineligible pts (and those refusing cisplatin) with MIBC. Checkpoint inhibitors (CPIs) are being actively explored in the perioperative setting. CPIs documented a 42% pathologic complete response-rate (ypT0N0) in our previous trial (PURE-01, NCT02736266). In this trial, programmed cell-death ligand-1 (PD-L1) expression was associated with ypT0N0 response ( Necchi A, et al. Eur Urol. 2019), and a cohort of PD-L1+ pts who refused RC are still alive at long-term follow-up ( Bandini, Ann Oncol 2020). Initial data from trials aimed at delivering a systemic therapy while sparing any local therapy on the bladder tumor in highly-selected pts are promising ( Galsky, 2021, Geynisman, 2021). Sasanlimab (SASI) is a humanized, hinge region–stabilized (21) IgG4 mAb directed against human PD-1. Sasanlimab is currently being tested subcutaneously (SQ) in a phase III study in non-MIBC. Our hypothesis is that SASI can be offered in PD-L1+ pts as an exclusive therapeutic option instead of any additional treatment, after a clinical complete response (cCR) with an induction phase. Methods: This is a Phase 2, open-label, non-randomized, single-cohort study in pts with MIBC who are ineligible or unwilling to receive cisplatin-based neoadjuvant chemotherapy. The study will include pts with a PD-L1 CPS≥10% in tumor biopsy.Other key inclusion criteria: UC histology, an ECOG PS 0−1. Cis-ineligibility is defined as one of the following: glomerular filtration rate ≥30 but < 60 mL/min, or CTCAE v5 ≥grade 2 hearing loss or peripheral neuropathy. Key exclusion criteria: clinical evidence of ≥N1 or metastatic disease or UC in upper urinary tract; prior systemic therapy, radiation therapy, or prior RC. Pts will undergo a transurethral resection of the bladder (TURBT), a CT scan, and a 18FDG-PET/CT scan. SASI will be administered SQ at the recommended dose of 300mg for a total of 3 cycles every 4 weeks prior to redo-TURBT. Pts who will achieve a cCR (i.e., no evidence of residual viable tumor at re-TURBT sample, urinary cytology and imaging tests) will receive additional SASI treatment for a total period of 12 months, every 4 weeks. Pts with non-CR will be excluded from the study and start treatment according to guidelines or investigator preference. Primary endpoint: event-free survival (EFS). Secondary endpoint: proportion of cCR. According to Simon's 2-stage MinMax design, a total of 55 pts will be included, and we anticipate the need for enrolling 110 pts for the neoadjuvant phase of the study. This assumption will correspond to the need for screening approximatively 220 pts onto this trial. Exploratory analyses will include: artificial intelligence through multiparametric bladder MRI/PET, and ctDNA analyses pre-post neoadjuvant period. Clinical trial information: 2021-001649-10.

Properly selecting the configuration of a database management system (DBMS) is essential to increase performance and reduce costs. However, the task is astonishingly tricky due to a large number of tunable configuration parameters and their inter-dependencies. Also, the optimal configuration depends upon the workload to which the DBMS is exposed. To extract the full potential of a DBMS, we must also consider the entire IT stack on which the DBMS is running, comprising layers like the Java virtual machine, the operating system and the physical machine. Each layer offers a multitude of parameters that we should take into account. The available parameters vary as new software versions are released, making it impractical to rely on historical knowledge bases. We present a novel tuning approach for the DBMS configuration auto-tuning that quickly finds a well-performing configuration of an IT stack and adapts it to workload variations, without having to rely on a knowledge base. We evaluate the proposed approach using the Cassandra and MongoDB DBMSs, showing that it adjusts the suggested configuration to the observed workload and is portable across different IT applications. We try to minimise the memory consumption without increasing the response time, showing that the proposed approach reduces the response time and increases the memory requirements only under heavy-load conditions, reducing it again when the load decreases.

Properly selecting the configuration of a database management system (DBMS) is essential to increase performance and reduce costs. However, the task is astonishingly tricky due to a large number of tunable configuration parameters and their inter-dependencies. Also, the optimal configuration depends upon the workload to which the DBMS is exposed. To extract the full potential of a DBMS, we must also consider the entire IT stack on which the DBMS is running, comprising layers like the Java virtual machine, the operating system and the physical machine. Each layer offers a multitude of parameters that we should take into account. The available parameters vary as new software versions are released, making it impractical to rely on historical knowledge bases. We present a novel tuning approach for the DBMS configuration auto-tuning that quickly finds a well-performing configuration of an IT stack and adapts it to workload variations, without having to rely on a knowledge base. We evaluate the proposed approach using the Cassandra and MongoDB DBMSs, showing that it adjusts the suggested configuration to the observed workload and is portable across different IT applications. We try to minimise the memory consumption without increasing the response time, showing that the proposed approach reduces the response time and increases the memory requirements only under heavy-load conditions, reducing it again when the load decreases.

Selecting the right compiler optimisations has a severe impact on programs' performance. Still, the available optimisations keep increasing, and their effect depends on the specific program, making the task human intractable. Researchers proposed several techniques to search in the space of compiler optimisations. Some approaches focus on finding better search algorithms, while others try to speed up the search by leveraging previously collected knowledge. The possibility to effectively reuse previous compilation results inspired us toward the investigation of techniques derived from the Recommender Systems field. The proposed approach exploits previously collected knowledge and improves its characterisation over time. Differently from current state-of-the-art solutions, our approach is not based on performance counters but relies on Reaction Matching, an algorithm able to characterise programs looking at how they react to different optimisation sets. The proposed approach has been validated using two widely used benchmark suites, cBench and PolyBench, including 54 different programs. Our solution, on average, extracted 90% of the available performance improvement 10 iterations before current state-of-the-art solutions,which corresponds to 40% fewer compilations and performance tests to perform.

As of today, most movie recommendation services base their recommendations on collaborative filtering (CF) and/or content-based filtering (CBF) models that use metadata (e.g., genre or cast). In most video-on-demand and streaming services, however, new movies and TV series are continuously added. CF models are unable to make predictions in such a scenario, since the newly added videos lack interactions—a problem technically known as new item cold start (CS). Currently, the most common approach to this problem is to switch to a purely CBF method, usually by exploiting textual metadata. This approach is known to have lower accuracy than CF because it ignores useful collaborative information and relies on human-generated textual metadata, which are expensive to collect and often prone to errors. User-generated content, such as tags, can also be rare or absent in CS situations. In this paper, we introduce a new movie recommender system that addresses the new item problem in the movie domain by (i) integrating state-of-the-art audio and visual descriptors, which can be automatically extracted from video content and constitute what we call the movie genome; (ii) exploiting an effective data fusion method named canonical correlation analysis, which was successfully tested in our previous works Deldjoo et al. (in: International Conference on Electronic Commerce and Web Technologies. Springer, Berlin, pp 34–45, 2016b; Proceedings of the Twelfth ACM Conference on Recommender Systems. ACM, 2018b), to better exploit complementary information between different modalities; (iii) proposing a two-step hybrid approach which trains a CF model on warm items (items with interactions) and leverages the learned model on the movie genome to recommend cold items (items without interactions). Experimental validation is carried out using a system-centric study on a large-scale, real-world movie recommendation dataset both in an absolute cold start and in a cold to warm transition; and a user-centric online experiment measuring different subjective aspects, such as satisfaction and diversity. Results show the benefits of this approach compared to existing approaches.

The association of anti-EGFR to gemcitabine and oxaliplatin (GEMOX) chemotherapy did not improve survival in biliary tract carcinoma (BTC) patients. Multiple mechanisms might be involved in the resistance to anti-EGFR. Here, we explored the mutation profile of EGFR extracellular domain (ECD), of tyrosine kinase domain (TKD), and its amplification status. EGFR mutational status of exons 12, 18-21 was analyzed in 57 tumors by Sanger sequencing. EGFR amplification was evaluated in 37 tumors by Fluorescent In Situ Hybridization (FISH). Kaplan-Meier curves were calculated using the log-rank test. Six patients had mutations in exon 12 of EGFR ECD and 7 in EGFR TKD. Neither EGFR ECD nor TKD mutations affected progression free survival (PFS) or overall survival (OS) in the entire population. In the panitumumab plus GEMOX (P-GEMOX) arm, ECD mutated patients had a worse OS, while EGFR TKD mutated patients had a trend towards shorter PFS and OS. Overall, the presence of mutations in EGFR or in its transducers did not affect PFS or OS, while the extrahepatic cholangiocarcinoma (ECC) mutated patients had a worse prognosis compared to WT. Nineteen out of 37 tumors were EGFR amplified, but the amplification did not correlate with survival. ECC EGFR amplified patients had improved OS, whereas the amplification significantly correlated with poor PFS (p = 0.03) in gallbladder carcinoma patients. The high molecular heterogeneity is a predominant feature of BTC: the alterations found in this work seem to have a prognostic impact rather than a predictive role towards anti-EGFR therapy.

In the last years, there has been much attention given to the semantic gap problem in multimedia retrieval systems. Much effort has been devoted to bridge this gap by building tools for the extraction of high-level, semantics-based features from multimedia content, as low-level features are not considered useful because they deal primarily with representing the perceived content rather than the semantics of it. In this paper, we explore a different point of view by leveraging the gap between low-level and high-level features. We experiment with a recent approach for movie recommendation that extract low-level Mise-en-Scene features from multimedia content and combine it with high-level features provided by the wisdom of the crowd. To this end, we first performed an offline performance assessment by implementing a pure content-based recommender system with three different versions of the same algorithm, respectively based on (i) conventional movie attributes, (ii) mise-en-scene features, and (iii) a hybrid method that interleaves recommendations based on movie attributes and mise-en-scene features. In a second study, we designed an empirical study involving 100 subjects and collected data regarding the quality perceived by the users. Results from both studies show that the introduction of mise-en-scene features in conjunction with traditional movie attributes improves both offline and online quality of recommendations.

In item cold-start, collaborative filtering techniques cannot be used directly since newly added items have no interactions with users. Hence, content-based filtering is usually the only viable option left. In this paper we propose a feature-based machine learning model that addresses the item cold-start problem by jointly exploiting item content features, past user preferences and interactions of similar users. The proposed solution learns a relevance of each content feature referring to a community of similar users. In our experiments, the proposed approach outperforms classical content-based filtering on an enriched version of the Netflix dataset.

Item-based recommender systems suggest products based on the similarities between items computed either from past user preferences (collaborative filtering) or from item content features (content-based filtering). Collaborative filtering has been proven to outperform content-based filtering in a variety of scenarios. However, in item cold-start, collaborative filtering cannot be used directly since past user interactions are not available for the newly added items. Hence, content-based filtering is usually the only viable option left.

1MASSIMO VENTURINI, MD, 1CLAUDIO SALLEMI, MD, 1GIULIA AGOSTINI, MD, 1PAOLO MARRA, MD, 2STEFANO CEREDA, MD, 2MICHELE RENI, MD, 3LUCA ALDRIGHETTI, MD, 1,4FRANCESCO DE COBELLI, MD and 1,4ALESSANDRO DEL MASCHIO, MD Department of di Radiology, San Raffaele Scientific Institute, Milan, Italy Department of Oncology, San Raffaele Scientific Institute, Milan, Italy Department of Hepatobiliary Surgery, San Raffaele Scientific Institute, Milan, Italy Vita-Salute University, San Raffaele Hospital, Milan, Italy

OBJECTIVE The aim of our preliminary study was to compare the efficacy of drug-eluting beads preloaded with irinotecan (DEBIRI) vs drug-eluting beads preloaded with doxorubicin (DEBDOX) as second-line treatment of unresectable liver metastases from cholangiocarcinoma (CCA). METHODS In 2013, 10 patients affected by multiple liver metastases from CCA, resistant to the first-line chemotherapy regimen, were enrolled: 5 patients were submitted to lobar/segmental transarterial chemoembolization (TACE) with DEBIRI (100-mg irinotecan/1 vial) and 5 patients with DEBDOX (50-mg doxorubicin/1 vial), performed every 3 weeks. Patients treated with DEBIRI received antipain premedication consisting of 30-mg of morphine and 3-4 ml of intra-arterial lidocaine. Complications and efficacy were assessed (response evaluation criteria in solid tumour 1.1). RESULTS A total of 32 TACE were performed (mean: 3.2 TACE/patient), all well tolerated, with only 1 case of asymptomatic cholecystitis spontaneously recovered. Response rates of patients treated with DEBDOX and DEBIRI were: 4/5 progressive disease and 1/5 partial response vs 2/5 partial response, 2/5 stable disease and 1/5 progressive disease, respectively, with the appearance of variable necrosis percentage. Progression-free survival from the first procedure and progressive disease were 12.67 weeks for DEBIRI and 15.78 weeks for DEBDOX, respectively. Overall survival from time of primary diagnosis was 176 weeks for DEBIRI and 125 weeks for DEBDOX, respectively. CONCLUSION In our preliminary experience, DEBIRI was more effective than DEBDOX as a second-line treatment for hepatic metastases from CCA. Antipain drug administration and the use of the microcatheter led to a good treatment tolerability and a low complication rate. Advances in knowledge: In our preliminary experience, DEBIRI was more effective than DEBDOX as a second-line treatment of hepatic metastases from CCA; further studies involving a larger cohort of patients are needed.

Abstract Purpose: We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action. Experimental Design: We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population. Results: Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n = 31) or without metformin (n = 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33–69] in the control group and 42% (95% CI, 24–59) in the metformin group (P = 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin. Conclusions: Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy. Clin Cancer Res; 22(5); 1076–85. ©2015 AACR. See related commentary by Yang and Rustgi, p. 1031

281 Background: Biliary tract cancer (BTC) is a rare and lethal disease with very few therapeutic options. Preclinical data suggest that Epithelial Growth Factor Receptor (EGFR) pathway activation could be involved in BTC pathogenesis, envisaging a potential role of anti-EGFR monoclonal antibodies. Methods: Patients (pts) with metastatic or unresectable BTC, harboring wild-type KRAS status, with ECOG performance status 0-2, without prior systemic therapy, were randomized to GEMOX (gemcitabine, 1000 mg/m² and oxaliplatin, 100 mg/m²) therapy with (arm A) or without (arm B) panitumumab (6 mg/kg), q2w for up to 12 cycles. Maintenance therapy with panitumumab alone was allowed in arm A in case of clinical benefit after 12 cycles. The primary endpoint was the progression-free survival (PFS). The target hazard ratio was 0.60 requiring 88 pts for 74 PFS events (80% 1-β power, α = 0.10, log-rank test 1-sided). Secondary endpoints were objective response rate (RR) (RECIST vers.1.1), overall survival (OS), and safety. Results: From 06/2010 to 09/2013, 89 pts were enrolled (median age 64 years; metastatic 78%; gallbladder 32%, extra-hepatic 21%, intra-hepatic 47%). After a median follow-up of 8.6 months (mo), with six pts (two progression-free) in arm A, and eight pts (none progression-free) in arm B still in follow-up, median PFS was 7.7 mo in arm A (95% CI 4.7–10.6) and 5.5 mo (95% CI 3.2–7.8) in arm B (p=0.10). RR was 25.0% in arm A and 18.2% in arm B. No differences in survival were seen, being median OS 9.5 mo (95% CI 5.7-13.3) in arm A and 9.9 mo in arm B (95% CI 5.1-14.6), p= 0.49. The most common all grade toxicities were skin toxicity (71%), nausea (67%), and fatigue (53%) in arm A; nausea (64%), neurotoxicity (57%), and fatigue (52%) in arm B. The most common grade 3 or 4 toxicities were: hepatic toxicity (20%), diarrhea (13%), and nausea (13%) in arm A; cholestasis (14%), dyspnea (9%), and diarrhea (9%) in arm B. Conclusions: Although the results are not fully mature, the combination of GEMOX and panitumumab showed a trend towards better PFS and RR in KRAS wild-type BTC pts as compared to GEMOX alone. No impact on OS seems evident. Clinical trial information: NCT01389414.

BACKGROUND:After progression to a standard first-line platinum and gemcitabine combination (GP), there is no established second-line therapy for patients with advanced biliary tract cancers (aBTC). Indeed, literature data suggest limited activity of most second-line agents evaluated so far.METHODS:We collected a large retrospective series of aBTC patients treated with second-line chemotherapy after progression to a first-line GP regimen at different Italian institutions. We then pooled the data with those reported in previous studies, which were identified with a Medline search and the on-line abstract datasets of major international oncology meetings.RESULTS:A total of 174 patients were included in the multicenter survey: response rate (RR) with second-line chemotherapy was low (3.4 %), with median PFS and OS of 3.0 months and 6.6 months, respectively. At multivariate analysis, preserved performance status, low CA19.9 levels and absence of distant metastases were favorable prognostic factors. Data from other five presented or published series were identified, for a total of 499 patients included in the pooled analysis. The results confirmed marginal activity of second-line chemotherapy (RR: 10.2 %), with limited efficacy in unselected patient populations (median PFS: 3.1 months; median OS: 6.3 months).CONCLUSIONS:The current analysis highlights the limited value of second-line chemotherapy after a first-line GP combination in aBTC. While waiting for effective biologic agents in this setting, ongoing randomized trials will identify the optimal second-line chemotherapy regimen and validate prognostic factors for individual patient management.

BACKGROUNDBiliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the epidermal growth factor receptor (EGFR) pathway could be involved in its progression.METHODSThis open‐label, randomized phase 2 trial recruited chemotherapy‐naive patients with advanced BTC displaying a wild‐type (WT) KRAS status. Patients were randomized to gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) with (arm A) or without (arm B) panitumumab (6 mg/kg) for up to 12 cycles. The primary endpoint was progression‐free survival (PFS) analyzed in an intention‐to‐treat fashion.RESULTSEighty‐nine patients (45 in arm A and 44 in arm B) were enrolled between June 2010 and September 2013. After a median follow‐up of 10.1 months, the median PFS was 5.3 months (95% confidence interval, 3.3‐7.2 months) in arm A and 4.4 months (95% confidence interval, 2.6‐6.2 months) in arm B (P = .27). No survival differences were observed: the median overall survival was 9.9 months in arm A and 10.2 months in arm B (P = .42). In a subgroup analysis, no differences in PFS according to the site of the primary tumor were observed; patients with intrahepatic cholangiocarcinoma treated with panitumumab may have had a survival benefit in comparison with the control group (15.1 vs 11.8 months, P = .13). As for safety, skin toxicity was the main adverse event in arm A (80% of the patients). A higher incidence of diarrhea (55.5% vs 31.8%), mucositis (22.2% vs 13.6%), and constipation (24.4% vs 15.9%) was seen in arm A.CONCLUSIONSThese results confirm the marginal role of anti‐EGFR therapy even for WT KRAS–selected BTC. Cancer 2016;122:574–581. © 2015 American Cancer Society.

Background and purpose: Hypofractionated radiotherapy (RT) of pancreatic adenocarcinoma is limited by the tolerance of adjacent normal tissues. A better understanding of the influence of dosimetric variables on the rate of toxicity after RT must be considered an important goal.Methods and materials: Sixty-one patients with histologically proven locally advanced disease (LAPD) were analyzed. The therapeutic strategy consisted of induction chemotherapy (ChT) followed by concurrent chemoradiotherapy (CRT). In 39 out of 61 patients the target volume was based on a four-dimensional CT (4D-CT) procedure. Delivered dose was 44.25 Gy in 15 fractions to PTV2, which consisted of pancreatic tumor and regional lymph nodes considered radiologically involved; 23 out of 61 patients received a simultaneous integrated boost (SIB) to a tumor sub-volume infiltrating the great abdominal vessels (PTV1) with dose in the range of 48-58 Gy. RT was delivered with Helical Tomotherapy. Dose-volume histograms (DVHs) of target volumes and organs at risk (OARS) were collected for analysis. The predictive value of clinical/dosimetric parameters was tested by univariate/multivariate analyses.Results: The crude incidence of acute gastrointestinal (GI) grade 2 toxicity was 33%. The 12-month actuarial rate of "anatomical" (gastro-duodenal mucosa damage) toxicity was 13% (95% CI: 4-22%). On univariate analysis, several stomach and duodenum DVH endpoints are predictive of toxicity after moderately hypofractionated radiotherapy. Multivariate analysis confirmed that baseline performance status and the stomach V-20[%] were strong independent predictors of acute GI grade >= 2 toxicity. The high-dose region of duodenum DVH (V-45[%]; V-40[%]) was strongly correlated with grade >= 2 "anatomical" toxicity; the best V-40[%] and V-45[%] cut-off values were 16% and 2.6% respectively.Conclusion: Regarding dosimetric indices, stomach V-20[%] correlates with a higher rate of acute toxicity; more severe acute and late anatomical toxicities are related to the high dose region of duodenum DVH. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Biliary tract cancer is a rare malignant tumor. Accordingly, to perform prospective and randomized trials is difficult and the knowledge of its natural history and optimal management remains limited. Chemotherapy is commonly used to improve the outcome and to delay tumor progression in advanced disease. Only recently, cisplatin-gemcitabine combination was identified as the new standard first-line therapy. Despite the outcome improvement, disease progression is a constant and approximately half of patients failing upfront treatment maintain a good performance status and are willing to undergo further treatment. No standard salvage chemotherapy regimen has been identified yet. Experiences of salvage therapy in advanced biliary tract cancer are sparse and yielded disappointing results. Well designed multi-institutional randomized trials are warranted to clarify the role and the activity of a second-line therapy.