Background and Aims: Targeted treatments (TT) have revolutionized the treatment algorithm for advanced biliary tract cancers (BTC) harbouring genomic alterations. However, the clinical relevance of co-occurring MTAs remains unclear. This study evaluates the clinical implications of MTAs in BTC. Methods: In this multicenter observational study, 686 patients diagnosed with BTCs (January 2015-December 2024) with available molecular profiling were enrolled across 11 Italian and Spanish institutions. Participants were divided into 3 different cohorts according to their molecular profiling: patients with MTAs, single TAs (STAs) and no TAs (NTAs). An additional cohort of 697 patients was used to validate key findings.Results: Of 686 patients, 50 (7.3%) harbored MTA, 292 (42.6%) harbored a STAs and the remaining 344 harbored NTAs. Patients with MTAs were more likely to have intrahepatic cholangiocarcinoma. In the overall population, both MTAs (43.2 months vs 23.0 months, HR: 0.53 95% CI 0.33-0.84) and STAs (26.2 months vs 23.0 months, HR:0.82 95% CI 0.66-1.02) were associated with improved overall survival (OS) when compared with NTAs. Of 555 (80.9%) patients diagnosed with advanced diseases, those with MTAs had better OS and progression-free survival (PFS) than those with NTAs, without differences in objective response rate (ORR) according to the number of TAs. Of 82 patients receiving TT, including 14 with MTAs, outcomes did not differ between MTAs and STAs groups.Conclusions: Our findings suggest that the presence of MTAs may be associated with improved prognosis in patients with advanced BTC. These patients may derive a benefit from TT comparable to that observed in patients harboring a STA

BACKGROUND:The treatment landscape for metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) is rapidly evolving, with the development of specific targeted therapies. The bispecific antibody amivantamab is the new standard of care for this population but real-world safety and efficacy data are lacking. METHODS:This is a multicenter, retrospective, observational study conducted on advanced NSCLC patients harboring EGFRex20ins who were included within the ATLAS Italian real-world registry between January and December 2024. Clinical-pathological features, treatment effectiveness, and safety outcomes were retrospectively collected and analyzed. RESULTS:A total of 119 advanced NSCLC patients harboring EGFRex20ins mutations were included. Seventy-six (63.9%) and 24 (20.2%) received first-line platinum-based chemotherapy with or without immunotherapy, respectively. Overall 64 of 119 patients received single agent amivantamab in the subsequent lines. Treatment-related adverse events (TRAEs) of any grade and grade 3-4 were reported in 68.8% and 10.9%, respectively, including skin rash (56%, G3 9.4%), asthenia (9%), peripheral edema (8%), and infusion-related reactions (9.4%, G3 1.5%). Dose interruptions, reductions, and discontinuations due to TRAEs occurred in 20.3%, 12.5%, and 3.1% patients, respectively. The objective response rate was 37.5%, the DCR was 66.2%, the median progression-free survival (mPFS) was 9.6 months, and the median overall survival was 16.9 months under amivantamab. Among the 23 patients with brain metastasis, 13% achieved a partial intracranial (ic) response and 43.5% a stable disease. The ic mPFS was 11.6 months. CONCLUSION:This data confirms the efficacy and safety profile of amivantamab observed in the CHRYSALIS trial, showing a meaningful clinical benefit in a heavily pretreated real-world population.

TPS3647 Background: Circulating tumor DNA (ctDNA) testing has emerged as a transformative tool for detecting molecular residual disease (MRD). Multiple prospective trials have demonstrated the potential of ctDNA in guiding treatment decisions for stage II-III CC pts. Numerous ongoing randomized clinical trials (RCTs) are adjusting adjuvant chemotherapy (ACT) intensity based on MRD status. However, data from ctDNA-guided trials, including PEGASUS (NCT04259944), reveal that intensified ACT is curative in only a small proportion of MRD cases. To address this limitation, the SAGITTARIUS RCT was designed to evaluate whether combining ctDNA detection with targeted agents selected on the basis of tissue-based comprehensive genomic profiling (CGP) can optimize treatment in high risk (i.e. MRD+) pts while sparing low risk (i.e. MRD−) from unnecessary toxicity. Methods: SAGITTARIUS is a Phase III RCT evaluating ctDNA and tissue-guided personalized post-surgical management in resected stage III and high-risk stage II CC pts. Tumor-informed, personalized ctDNA test (Signatera, Natera, Inc.) and CGP (TruSight™ Oncology Comprehensive EU, Illumina, Inc.) are used to determine MRD status and tumor genomic landscape, respectively, including genetic mutation (mut) and amplification (ampl), tumor mutational burden (TMB) and microsatellite instability (MSI) status. Pts are stratified based on post-surgery (3-5 weeks) ctDNA status into two embedded RCTs:Trial-1)ctDNA-positive (ctDNA+) ptsare further stratified based on MSI and RAS/RAF status and randomized 1:1 to standard 6-month ACT (CAPOX/FOLFOX) or personalized treatment (PT) guided by CGP biomarkers with reassessment of ctDNA status to guiding subsequent therapies (chemotherapy regimens in ctDNA+ or maintenance and follow-up in seroconverted; Trial-2) ctDNA-negative (ctDNA−) ptsare randomized 1:1 to a physician-choice strategy or observation with ctDNA reassessed at 2 and 4 months and, in cases of positivity, cross over to Trial-1. PT include 3-month CAPOX followed by FOLFIRI or TEMIRI based on MGMT status (RAS/RAFmut), Ipilimumab + nivolumab (MSI and TMB-high POLEmut), pertuzumab + trastuzumab (HER2ampl), FOLFOX + panitumumab (RAS/RAF/HER2 wild-type). The primary endpoint (EP) is 2-year recurrence-free survival (RFS) in ctDNA+ pts. Secondary EPs include 2-year RFS in ctDNA− pts, 3- and 5-year overall survival, and ctDNA conversion rate. Quality of life and health costs data are collected for cost effectiveness analysis. Biospecimens, including archival tumor tissue, serial blood samples, and buccal swabs, are collected for exploratory analyses. To detect a hazard ratio of 0.6325 for ctDNA-guided PT vs standard ACT, 200 ctDNA+ pts will be randomized in Trial-1. Recruitment began in October 2024 across 26 institutions in Italy, Spain, and Germany. Clinical trial information: NCT06490536 .

Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with a rising global incidence and poor prognosis, largely due to late-stage diagnosis and limited effective treatment options. Standard chemotherapy regimens, including cisplatin and gemcitabine, often fail because of the development of multidrug resistance (MDR), leaving patients with few alternative therapies. Doxycycline, a tetracycline antibiotic, has demonstrated antitumor effects across various cancers, influencing cancer cell viability, apoptosis, and stemness. Based on these properties, we investigated the potential of doxycycline to overcome gemcitabine resistance in iCCA. Methods: We evaluated the efficacy of doxycycline in two MDR iCCA cell lines, MT-CHC01R1.5 and 82.3, assessing cell cycle perturbation, apoptosis induction, and stem cell compartment impairment. We assessed the in vivo efficacy of combining doxycycline and gemcitabine in mouse xenograft models. Results: Treatment with doxycycline in both cell lines resulted in a significant reduction in cell viability (IC50 ~15 µg/mL) and induction of apoptosis. Doxycycline also diminished the cancer stem cell population, as indicated by reduced cholangiosphere formation. In vivo studies showed that while neither doxycycline nor gemcitabine alone significantly reduced tumor growth, their combination led to marked decreases in tumor volume and weight at the study endpoint. Additionally, metabolic analysis revealed that doxycycline reduced glucose uptake in tumors, both as a monotherapy and more effectively in combination with gemcitabine. Conclusions: These findings suggest that doxycycline, especially in combination with gemcitabine, can restore chemotherapy sensitivity in MDR iCCA, providing a promising new strategy for improving outcomes in this challenging disease.

BACKGROUND & AIMS:Extended molecular profiling (EMP) is recommended to tailor targeted treatment for advanced cholangiocarcinoma (CCA). However, neither the impact of EMP nor the availability of targeted therapies has been extensively described in a real-world setting. METHODS:ANITA is an observational (retrospective and prospective) study enrolling 621 patients with CCA from 10 tertiary Italian cancer centers between 2017 and 2023. Current analyses are focused on access to EMP, evolving rates of EMP over time, access to targeted treatments and respective outcomes. Moreover, we explore the prognostic and predictive role of major driver molecular alterations. RESULTS:EMP was performed in 79.9% of patients with advanced CCA. The rate of EMP increased significantly over time (2017-2023: +25.8%). Overall, 139 patients harbored ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) I-III alterations, and 18.7% of these patients received matched targeted therapies. No differences were seen in overall survival (OS) and progression-free survival (PFS) according to EMP availability. Patients receiving targeted therapies had the best OS, which was significantly longer than that of patients who did not receive targeted treatments (hazard ratio 0.49, 95% CI 0.28-0.86) or those without EMP available (hazard ratio 0.34, 95% CI 0.21-0.54). Among ESCAT I-III-positive cases, 42 patients had FGFR2 fusions/rearrangements and 59 had IDH1 mutations. After excluding patients treated with targeted therapies, only FGFR2 fusions/rearrangements retained a prognostic association with OS. CONCLUSIONS:Despite the increasing availability of EMP in advanced CCA, patient access to targeted therapies remains suboptimal. Our findings demonstrate that targeted treatments can markedly improve OS. Therefore, strategies to increase access to - and accelerate the availability of - targeted therapies are warranted. IMPACT AND IMPLICATIONS:ANITA is the largest observational, retrospective and prospective, study exploring the impact of molecular profiling and matched targeted treatment in a large cohort of patients with advanced cholangiocarcinoma. While the availability of molecular profiling has increased in recent years, access to targeted therapy is still limited in routine practice. Administration of targeted treatment has a significant impact on overall survival, highlighting the importance of promoting timely and early access to new agents in this disease. CLINICAL TRIAL NUMBER:ESR-21-21387.

BACKGROUND:Advanced pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal cancers, with >95 % of patients dying from the disease. Chemotherapy is the standard of care in advanced stages, with FOLFIRINOX and Gemcitabine-Nab-Paclitaxel (Gem-NabP) as the main first-line regimens. Both show moderate efficacy and significant toxicity. Except for the PASS-01 trial, no direct comparison exists, though observational studies suggest that specific subgroups may benefit differently. Given the modest outcomes and rapid clinical decline, most patients are ineligible for second-line therapy after progression. The PANThEON study evaluates whether switching from modified FOLFIRINOX (mFOLFIRINOX) to Gem-NabP after three months of induction with mFOLFIRINOX improves outcomes for PDAC. METHODS:PANThEON is a no-profit, phase III, randomized, open-label, multicenter trial. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival (PFS), time to treatment failure (TTF), overall response rate (ORR), and quality of life (QoL). Exploratory analyses will assess tumor profiling, circulating tumor DNA (ctDNA), and radiomics to identify predictive markers. A total of 220 patients will be randomized 1:1 to Gem-NabP (arm B) or continued mFOLFIRINOX (arm A). DISCUSSION:The PANThEON trial addresses two challenges: improving efficacy while reducing toxicity. Switching to Gem-NabP may enhance tolerability without compromising benefit, prolonging survival and refining PDAC treatment strategies. TRIAL REGISTRATION:PANThEON is registered at ClinicalTrials.gov (NCT06897644) and EuCT (2024-515214-41-00).

Thrombocytosis is a clinical condition generally associated with poor prognosis in patients with cancer. Thrombocytosis may be present after lung cancer resection, but the clinical significance of thrombocytosis remains unclear. Herein, we evaluated whether postoperative thrombocytosis was a negative prognostic factor in patients undergoing thoracoscopic lobectomy for lung cancer. It was a retrospective monocentric study including consecutive patients undergoing thoracoscopic lobectomy for lung cancer from January 2020 to January 2023. The outcome of patients with postoperative thrombocytosis (defined as platelet count ≥ 450 × 10^9/L at 24 h after the surgery and confirmed at postoperative day 7) was compared with a control group. Postoperative morbidity, mortality, and survival were compared between the two groups to define whether thrombocytosis negatively affected outcomes. Our study population included 183 patients; of these, 22 (12

Background:Paravertebral block (PVB) is effective in controlling postoperative pain after video-assisted thoracoscopic surgery (VATS) lobectomy but is subject to a high rate of failure because of incorrect site of injection. We compared methylene blue PVB with thoracic epidural anesthesia (TEA) for postoperative pain after VATS lobectomy. Methods:We conducted a prospective randomized trial of patients undergoing VATS lobectomy; 120 patients were randomly assigned to the PVB or TEA group. The end points were postoperative pain at 1 hour, 12 hours, 24 hours, and 48 hours; time to perform TEA and PVB; opioid consumption; and postoperative outcomes. Results:PVB was associated with reduction of local anesthesia time (P < .0001). In 2 cases, methylene blue showed that the block was not well performed; thus, it was repeated. No significant differences were found in postoperative pain, opioid consumption, and postoperative outcomes. Conclusions:PVB with methylene blue is as effective as TEA for controlling postoperative pain. Methylene blue use could help reduce PVB failure.

Introduction Benign tracheobronchial stenosis is a abnormal tracheal lumen narrowing that may incur progressive dyspnea and life-threatening hypoxemia. There is no consensus on which patients should be treated with endoscopic or surgical method. This study investigates the outcomes of bronchoscopic dilatation in the treatment of benign tracheal stenosis using a device equipped with a blade to cut the stenotic lesions with dense fibrosis. Materials and methods The procedure was carried out in an operating room under general anesthesia. All patients were intubated with a Rigid Bronchoscope (RB) placed just above the stenosis. Through Rigid Bronchoscopy combined modalities were used as needed: radial incisions of the mucosal stenosis with blade at the levels of 4, 8 and 12 o’clock, with back and forth movements, then the stenotic area was dilated more easily with a rigid bronchoscope. Dilatation was performed by passing the RB of increasing diameter through stenotic areas and then Balloon dilatation of increasing diameter. There were no complications during the procedure. Result We conducted an observational, retrospective, single-centre study in the Thoracic Surgery Unit of the University of ‘Luigi Vanvitelli’ of Naples from November 2011 to September 2021. We included all consecutive patients with benign tracheal stenosis inoperable. During the study period, 113 patients were referred to our department with benign tracheal stenosis inoperable. 61 patients were treated with the blade. During the follow-up, a recurrence of the stenosis was observed in 8 patients in the first month and in 4 patients in the third month. Instead in the patients treated with the use of laser (52 patients), during the follow-up a recurrence was observed in 16 patients in the first month and in 6 patients in the third month; no patient relapsed after 6 months and after 1 year. Long term successful bronchoscopic management with blade was attained by 99% in simple and 93% in mixed stenosis and in complex type stenosis. Conclusion Our study underlines the importance of the use of the blade in bronchoscopic treatment as a valid conservative approach in the management of patients with inoperable benign tracheal stenosis as an alternative to the use of the laser, reducing the abnormal inflammatory reaction in order to limit recurrences.

Despite a biologically established causative role of viral hepatitis (VH), i.e. HBV and HCV infections, on intrahepatic cholangiocarcinoma (ICC), only few large Western cohorts exploring the association between VH and ICC development are available. The prognostic significance of VH in ICC is debated, and no data are available regarding a predictive role for standard first-line CT (CT1), consisting of gemcitabine +/- platinoids. VH-positivity definition is often clinically incomplete and inconsistent among studies. Five different VH conditions, based on laboratory and anamnestic data, were investigated in a multicentric retrospective cohort of advanced ICC cases. Depending on the specific VH condition considered, 139-194 of 472 ICC cases could be categorized according to the presence of the mentioned VH conditions. VH prevalence ranged from 9.3 to 25.3%. No VH condition showed an impact on survival, although a non-significant worse outcome was observed for some HBV-related conditions. HCV-related conditions were associated to lower pre-CT1 biomarkers of inflammation, markedly higher disease control, and numerically longer time-to-progression with CT1. No benefit on time-to-progression was demonstrated for the addition of platinoids to gemcitabine in VH-positive patients (HR 0.77, CI95% 0.41-1.45), at least in HBV-related cases. These findings are clinically relevant and deserve further investigation.

The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed cell death ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). The present study investigated for the first time the impact on survival of adding durvalumab to cisplatin/gemcitabine compared with cisplatin/gemcitabine in a real-world setting. The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or with cisplatin/gemcitabine alone. The impact of adding durvalumab to chemotherapy in terms of overall survival (OS) and progression free survival (PFS) was investigated with univariate and multivariate analysis. Overall, 563 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 350 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab was found to have an impact on survival, with a median OS of 14.8 months versus 11.2 months [hazard ratio (HR) 0.63, 95

The management of the primary tumor in metastatic colorectal, gastric and pancreatic cancer patients may be challenging. Indeed, primary tumor progression could be associated with severe symptoms, compromising the quality of life and the feasibility of effective systemic therapy, and might result in life-threatening complications. While retrospective series have suggested that surgery on the primary tumor may confer a survival advantage even in asymptomatic patients, randomized trials seem not to definitively support this hypothesis. We discuss the evidence for and against primary tumor resection for patients with metastatic gastrointestinal (colorectal, gastric and pancreatic) cancers treated with systemic therapies and put in context the pros and cons of the onco-surgical approach in the time of precision oncology. We also evaluate current ongoing trials on this topic, anticipating how these will influence both research and everyday practice.

PDF file, 28KB, Statistical analysis of reduction of cell proliferation by saracatinib in BTC cell lines. A statistical significant inhibition was revealed up to 1.25 M in all the cell lines, except for TGBC1, in which no significance was found. In x-axis, doses of Saracatinib. In y-axis, absorbance.

PDF file, 19KB, TUNEL staining of BTC cell lines untreated (NT) and treated (SAR) with Saracatinib at the concentration of 5 M for 24 hours. A statistical significant increase of apoptosis was seen in all the cell lines ( p-value < 0.05) except in HuH28.

PDF file, 11KB, Representative images of p-Src expression in BTC case series. A: Negative control. B-C-D: p-Src expression scored 1+, 2+ and 3+ respectively.

Background: The COVID-19 outbreak had a massive impact on lung cancer patients with the rise in the incidence and mortality of lung cancer. Methods: We evaluated whether a recent COVID-19 infection affected the outcome of patients undergoing thoracoscopic lobectomy for lung cancer using a retrospective observational mono-centric study conducted between January 2020 and August 2022. Postoperative complications and 90-day mortality were reported. We compared lung cancer patients with a recent history of COVID-19 infection prior to thoracoscopic lobectomy to those without recent COVID-19 infection. Univariable and multivariable analyses were performed. Results: One hundred and fifty-three consecutive lung cancer patients were enrolled. Of these 30 (19%), had a history of recent COVID-19 infection prior to surgery. COVID-19 was not associated with a higher complication rate or 90-day mortality. Patients with recent COVID-19 infection had more frequent pleural adhesions (p = 0.006). There were no differences between groups regarding postoperative complications, conversion, drain removal time, total drainage output, and length of hospital stay. Conclusions: COVID-19 infection did not affect the outcomes of thoracoscopic lobectomy for lung cancer. The treatment of these patients should not be delayed in case of recent COVID-19 infection and should not differ from that of the general population.

PDF file, 61KB, Clinical pathological characteristics of BTC patients.