Dual immune checkpoint blockade in hepatocellular carcinoma: where do we stand?

Hepatocellular carcinoma (HCC) represents the fourth most common cause of cancer-related death. Surgery, local ablative therapies and liver transplantation are the only potentially curative strategies, but the majority of patients present with advanced disease at diagnosis or develop recurrence after surgery. In recent years, immunotherapy for HCC has received growing interest, and one of the most promising strategies is the association of two immune checkpoint inhibitors (ICIs), which has already demonstrated its potential in other solid tumors such as melanoma and renal cell carcinoma. Herein, we discuss the role and the biologic rationale of dual immune checkpoint blockade in HCC patients, focusing on the two ICI combinations: nivolumab plus ipilimumab and durvalumab plus tremelimumab.

Second-Line Chemotherapy in Elderly Patients with Advanced Biliary Tract Cancer: A Multicenter Real-World Study.

Objectives: The ABC-06 and the NIFTY trials recently established the role of second-line chemotherapy (2L) in patients with advanced biliary tract cancer (BTC). Our real-world study aimed to explore 2L in BTC patients aged ≥ 70 years old and to compare their outcomes with younger subjects. Methods: Institutional registries across three academic medical centers were retrospectively reviewed. The Kaplan−Meier methods were used to estimate survival, and the log-rank test was used to make comparisons. Results: A total of 190 BTC patients treated with 2L were identified and included in the analysis. Among them, 52 (27.3%) were aged ≥ 70 years (range 70−87 years). No statistically significant differences in both median overall survival (mOS) and median progression-free survival (mPFS) were recorded between the elderly and younger patients. Absolute lymphocyte count < 1000/mmc (p < 0.001) and albumin level < 3 g/dL (p < 0.001) were independently associated with worse prognoses. Conclusions: The results of this real-world study suggest that for patients aged ≥ 70 years, 2L could be equally effective for younger patients with survival outcomes aligned to those from the ABC-06 and NIFTY trials. The delivery of 2L should be carefully evaluated and monitored in this patient subset.

Fine-Tuning the Interaction and Therapeutic Effect of Cu(II) Carbosilane Metallodendrimers in Cancer Cells: An In Vitro Electron Paramagnetic Resonance Study.

Copper(II) carbosilane metallodendrimers are promising nanosized anticancer metallodrugs. The precise control on their design enables an accurate structure-to-activity study. We hypothesized that different structural features, such as the dendrimer generation and metal counterion, modulate the interaction with tumor cells, and subsequently, the effectivity and selectivity of the therapy. A computer-aided analysis of the electron paramagnetic resonance (EPR) spectra allowed us to obtain dynamical and structural details on the interactions over time between the dendrimers and the cells, the myeloid U937 tumor cells and peripheral blood mononuclear cells (PBMC). The intracellular fate of the metallodendrimers was studied through a complete in vitro evaluation, including cytotoxicity, cytostaticity, and sublethal effects regarding mitochondria function, lysosomal compartments, and autophagic organelle involvement. EPR results confirmed a higher membrane stabilization for chloride dendrimers and low generation complexes, which ultimately influence the metallodrug uptake and intracellular fate. The in vitro evaluation revealed that Cu(II) metallodendrimers are cytostatic and moderate cytotoxic agents for U937 tumor cells, inducing death processes through the mitochondria-lysosome axis as well as autophagic vacuole formation, while barely affecting healthy monocytes. The study provided valuable insight into the mechanism of action of these nanosized metallodrugs and relevant structural parameters affecting the activity.

DOTA Glycodendrimers as Cu(II) Complexing Agents and Their Dynamic Interaction Characteristics toward Liposomes.

Copper (Cu)(II) ions, mainly an excess amount, play a negative role in the course of several diseases, like cancers, neurodegenerative diseases, and the so-called Wilson disease. On the contrary, Cu(II) ions are also capable of improving anticancer drug efficiency. For this reason, it is of great interest to study the interacting ability of Cu(II)-nanodrug and Cu(II)-nanocarrier complexes with cell membranes for their potential use as nanotherapeutics. In this study, the complex interaction between 1,4,7,10-tetraazacyclododecan-N,N',N'',N'''-tetraacetic acid (DOTA)-functionalized poly(propyleneimine) (PPI) glycodendrimers and Cu(II) ions and/or neutral and anionic lipid membrane models using different liposomes is described. These interactions were investigated via dynamic light scattering (DLS), ζ-potential (ZP), electron paramagnetic resonance (EPR), fluorescence anisotropy, and cryogenic transmission electron microscopy (cryo-TEM). Structural and dynamic information about the PPI glycodendrimer and its Cu(II) complexes toward liposomes was obtained via EPR. At the binding site Cu-N2O2 coordination prevails, while at the external interface, this coordination partially weakens due to competitive dendrimer-liposome interactions, with only small liposome structural perturbation. Fluorescence anisotropy was used to evaluate the membrane fluidity of both the hydrophobic and hydrophilic parts of the lipid bilayer, while DLS and ZP allowed us to determine the distribution profile of the nanoparticle (PPI glycodendrimer and liposomes) size and surface charge, respectively. From this multitechnique approach, it is deduced that DOTA-PPI glycodendrimers selectively extract Cu(II) ions from the bioenvironment, while these complexes interact with the liposome surface, preferentially with even more negatively charged liposomes. However, these complexes are not able to cross the cell membrane model and poorly perturb the membrane structure, showing their potential for biomedical use.

Appropriateness of Mini-Invasive Approaches for Nausea and Vomiting Refractory to Medical Therapy in Palliative Care Setting: A Case Report.

Introduction: Nausea and vomiting are frequent multifactorial symptoms in oncological patients. These manifestations, mainly affecting the advanced disease stages, may lead to existential, psychological, and physical suffering, with a negative impact on the quality of life (QoL) of the individual and his family. The medical approach makes use of a wide range of drugs, with different antiemetic potency and various mechanisms of action, taking into account the etiology and the patient's response to the different therapeutic strategies. In recent years, in addition to pharmacological treatments, some endoscopic procedures have been integrated into clinical practice as promising palliative approaches. Case Presentation: Herein, we describe and discuss a case of a 64-year-old female affected by advanced stage pancreatic adenocarcinoma, in which different techniques - both medical and endoscopic - have been used to approach a refractory symptomatology with a negative impact on the patient's QoL. In the context of a multidisciplinary approach in primary palliative care, a tailored intervention encompassing invasive methods for palliative purposes, may be considered adequate and appropriate when the prognostic expectation and the physical functionality indices allow it. Conclusion: Minimally invasive palliative interventions should be offered to patients with advanced cancer when symptoms become refractory to standard medical therapies, as part of the holistic approach in modern treatments. Therefore, the integration of an early palliative approach into the patient's therapeutic path becomes essential for the management of all the individual's needs.

Treatment-related adverse events of first-line immunotherapy versus sorafenib for advanced hepatocellular carcinoma: a meta-analysis.

BACKGROUND: Despite all the improvements achieved over the last decade, the use of immune checkpoint inhibitors (ICIs) has been associated to a wide range of adverse drug events, which are frequently markedly different from those observed with cytotoxic chemotherapy and targeted therapies, such as sorafenib. RESEARCH DESIGN AND METHODS: We performed a meta-analysis with the aim to compare grade 3/4 treatment-related adverse events (TRAEs), grade 5 TRAEs, serious TRAEs, and TRAEs leading to discontinuation in ICIs versus sorafenib across phase III clinical trials of first-line treatment for advanced hepatocellular carcinoma (HCC). RESULTS: Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Patients treated with ICIs showed higher risk of serious TRAEs (OR 1.48, 95% CI = 1.16-1.9) while sorafenib treatment was associated with higher risk of TRAEs leading to discontinuation (OR 0.65, 95% CI = 0.48-0.89). No differences in grade 3/4 TRAEs and grade 5 TRAEs. CONCLUSIONS: Beyond activity and efficacy, careful consideration should be given to toxicity while choosing the appropriate first-line treatment in HCC.

Amphiphilic Dendritic Hydrogels with Carbosilane Nanodomains: Preparation and Characterization as Drug Delivery Systems.

Carbosilane dendrimers are hyperbranched lipophilic scaffolds widely explored in biomedical applications. This work exploits, for the first time, the ability of these scaffolds to generate functional hydrogels with amphiphilic properties. The monodispersity and multivalency enable a precise synthetic control of the network, while the lipophilicity improves the compatibility with poorly soluble cargo. The first family of cleavable carbosilane dendrimers was designed for this purpose, overcoming one of the main drawbacks of these type of dendrimers. Biodegradable dendritic low-swelling hydrogels with aromatic nanodomains were easily prepared using the highly efficient click thiol-ene chemistry. Our studies through electron-paramagnetic resonance, molecular dynamics simulations, and experimental assays confirmed the impact of the carbosilane dendritic nanodomains in both the encapsulation and the release pattern of model drugs such as ibuprofen and curcumin. Curcumin-loaded hydrogels were further tested in in vitro assays against advanced prostate cancer cells. The dendritic hydrogels not only enabled drugs encapsulation; as proof of concept, ibuprofen was efficiently attached via fluoride-promoted esterification and was enzymatically cleaved, achieving a controlled release over time.

Immune-Based Combination Therapies for Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fourth most frequent cause of cancer-related death worldwide. HCC frequently presents as advanced disease at diagnosis, and disease relapse following radical surgery is frequent. In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced HCC, particularly with the introduction of atezolizumab/bevacizumab as the new standard of care for first-line treatment. Recently, dual immune checkpoint blockade with durvalumab plus tremelimumab has also emerged as an effective first-line treatment for advanced HCC and most of the research is currently focused on developing combination treatments based mainly on ICIs. In this review, we will discuss the rationale and ongoing clinical trials of immune-based combination therapies for the treatment of advanced HCC, also focusing on new immunotherapy strategies such as chimeric antigen receptor T cells (CAR-T) and anti-cancer vaccines.

Interactions of Functionalized PAMAM Dendrimers with Model Cell Membranes Studied via Spin-Labeling Technique.

Polyamidoamine (PAMAM) dendrimers are exploited as drug carriers in various biomedical research fields, especially cancer therapy. The present study analyzes the interactions occurring between differently functionalized PAMAM dendrimers, namely, amine, acetamide, and 3-methoxy-carbonyl-5-pyrrolidonyl ("pyrrolidone"), and model membranes, namely, sodium dodecyl sulfate (SDS), sodium hexadecylsulfate (SHS) micelles, and egg-lecithin liposomes. For this purpose, the dendrimers were spin-labeled with the 3-carbamoyl-PROXYL radical. 1H-NMR spectra allowed the verification not only that labeling was successful but also that acetamide and (even more so) pyrrolidone functions shield the proton signals from the influence of the neighboring nitroxide groups. The computer-aided analysis of the electron paramagnetic resonance (EPR) spectra showed that the dendrimers with the acetamide function largely (60%) entered the SDS-micelles interface, while the amino-dendrimer electrostatically interacted with both the SDS and SHS surface forming dendrimer aggregates in solution. The pyrrolidone-dendrimers showed an intermediate behavior between those with the amino and acetamide functions. The acetamide- and pyrrolidone-dendrimers weakly interacted with the lecithin liposome surface, with a synergy between hydrophilic and hydrophobic interactions. Conversely, liposomes/amino-dendrimers interactions were quite strong and led to dendrimer aggregation at the liposome surface in solution. This information showed that acetamide- and pyrrolidone-dendrimers may be used as good alternatives to amino-dendrimers for drug delivery.

Synthesis and biological and physico-chemical characterization of glycodendrimers and oligopeptides for the treatment of systemic lupus erythematosus.

Anti-(ds)-DNA antibodies are the serological hallmark of Systemic Lupus Erythematosus (SLE). They assemble in the bloodstream with (ds)-DNA, forming immunocomplexes, which spread all over the body causing, among the other symptoms, lupic glomerulonephritis. Pathological manifestations of the disease may be reduced by destabilizing or inhibiting the formation of the immunocomplexes. In this respect, glycodendrimers showed peculiar interacting abilities towards this kind of biomolecule. Various generations of open-shell maltose-decorated poly(amidoamine) (PAMAM) and poly(propyleneimine) (PPI) dendrimers and two oligopeptides with different polyethylene glycol units were synthesized and characterized, and then tested for their anti-SLE activity. The activity of glycodendrimers and oligopeptides was evaluated in human plasma from patients with SLE, compared to healthy plasma, by means of an enzyme-linked immunosorbent assay (ELISA), and electron paramagnetic resonance (EPR) characterization using spin-label and spin-probe techniques. Different strategies for the immunocomplex formation were tested. The results show that both kinds of glycodendrimers and oligopeptides inhibited the formation of immunocomplexes. Also, a partial breakdown of preformed immunocomplexes was observed. Both ELISA and EPR analyses indicated a better activity of glycodendrimers compared to oligopeptides, the 3rd generation PPI dendrimer being the most promising against SLE. This study highlights the possibility to develop a new class of dendritic therapeutics for the treatment of Lupus in pre-clinical studies.

Atezolizumab-bevacizumab plus Y-90 TARE for the treatment of hepatocellular carcinoma: preclinical rationale and ongoing clinical trials.

INTRODUCTION: The treatment algorithm of advanced hepatocellular carcinoma (HCC) has evolved since the introduction of immunotherapy. The IMbrave150 trial set atezolizumab-bevacizumab as a new standard-of-care first-line treatment for unresectable HCC patients. However, for patients with intermediate or advanced stage with portal vein thrombosis but without distant metastases, 90Yttrium transarterial radioembolization (90Y-TARE) is considered the treatment of choice. AREAS COVERED: We discuss the main evidence regarding the use of 90Y-TARE in HCC, the recent progress of immunotherapy in this tumor, and the preclinical rationale of combining VEGF blockade with the other two treatment strategies. EXPERT OPINION: HCC has an extremely heterogeneous tumor immune microenvironment. This may explain the inconsistent outcomes obtained with immune-checkpoint inhibitors. The identification of patients who could benefit most from immunotherapy is crucial; however, reliable markers of response are lacking. Radiation therapy and VEGF inhibition have an established synergism with immunotherapy, mainly linked to enhanced antigen presentation and reduced immunosuppressive immune infiltrate. Combining an immune-checkpoint inhibitor with VEGF blockade and 90Y-TARE might hence overcome primary resistances observed when each of these treatments is administerd alone.

Advances in novel systemic therapies for advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents the most frequent type of primary liver tumor. Most HCC patients present with advanced disease at diagnosis and the recurrence rate after surgery remains high. Treatment options for advanced HCC are limited, with sorafenib representing the only systemic agent approved for treatment of advanced HCC in more than a decade. However, in recent years new molecular targeted therapies and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced HCC. In particular, combinations of ICIs with antiangiogenic drugs, or with other ICIs, represent one of the most promising strategies. Herein we provide a comprehensive overview of the main therapeutic advances in the systemic treatment of HCC, focusing on the most relevant ongoing clinical trials.

Targeting tumor microenvironment for cholangiocarcinoma: Opportunities for precision medicine.

Systemic treatments (e.g., chemotherapy and targeted therapies) have limited efficacy for patients with locally advanced - unresectable - and metastatic cholangiocarcinoma (CCA), with an overall survival of less than a year. Tumor microenvironment (TME) represents the ecosystem surrounding the tumor which comprises immune cells, fibroblasts, endothelial cells, and a wide range of soluble factors. CCA TME is characterized by an abundant desmoplastic stroma, exhibits a high heterogeneity and it plays a central role in cancer onset and progression. There is growing evidence suggesting that it is possible to target TME in association with other treatment modalities, such as cytotoxic chemotherapy or targeted therapies, paving the way to possible combination strategies with a synergistic effect. Herein, we describe the components of CCA TME - such as cancer-associated fibroblasts and other cells of pivotal importance - with their most relevant interactions, focusing on the preclinical rationale for the development of effective anticancer treatments.

Molecular Profile and Prognostic Value of BAP1 Mutations in Intrahepatic Cholangiocarcinoma: A Genomic Database Analysis.

BACKGROUND: Recent years have witnessed the advent of molecular profiling for intrahepatic cholangiocarcinoma (iCCA), and new techniques have led to the identification of several molecular alterations. Precision oncology approaches have been widely evaluated and are currently under assessment, as shown by the recent development of a wide range of agents targeting Fibroblast Growth Factor Receptor (FGFR) 2, Isocitrate Dehydrogenase 1 (IDH-1), and BRAF. However, several knowledge gaps persist in the understanding of the genomic landscape of this hepatobiliary malignancy. METHODS: In the current study, we aimed to comprehensively analyze clinicopathological features of BAP1-mutated iCCA patients in public datasets to increase the current knowledge on the molecular and biological profile of iCCA. RESULTS: The current database study, including 772 iCCAs, identified BAP1 mutations in 120 cases (15.7%). According to our analysis, no differences in terms of overall survival and relapse-free survival were observed between BAP1-mutated and BAP1 wild-type patients receiving radical surgery. In addition, IDH1, PBRM1, and ARID1A mutations were the most commonly co-altered genes in BAP1-mutated iCCAs. CONCLUSIONS: The genomic characterization of iCCA is destined to become increasingly important, and more efforts aimed to implement iCCA genomics analysis are warranted.

Intensive Follow-Up Program and Oncological Outcomes of Biliary Tract Cancer Patients after Curative-Intent Surgery: A Twenty-Year Experience in a Single Tertiary Medical Center.

AIM: The aim of this research was to assess the impact of an intensive follow-up program on BTC patients who had received surgery with curative intent at a tertiary referral hospital. METHODS: BTC patients were followed-up every three months during the first two years after their first surgery and every six months from the third to the fifth post-operative year. RESULTS: A total of 278 BTC patients who received R0/R1 surgery were included. A total of 17.7% of patients underwent a second surgery following disease relapse, and none of these patients experienced additional disease relapse. CONCLUSIONS: An intensive follow-up after surgical resection may help in the early identification of disease relapse, leading to early treatment and prolonged survival in selected cases.

Immunotherapy in Pancreatic Cancer: Why Do We Keep Failing? A Focus on Tumor Immune Microenvironment, Predictive Biomarkers and Treatment Outcomes.

The advent of immunotherapy and targeted therapies has dramatically changed the outcomes of patients affected by many malignancies. Pancreatic cancer (PC) remains one the few tumors that is not treated with new generation therapies, as chemotherapy still represents the only effective therapeutic strategy in advanced-stage disease. Agents aiming to reactivate the host immune system against cancer cells, such as those targeting immune checkpoints, failed to demonstrate significant activity, despite the success of these treatments in other tumors. In many cases, the proportion of patients who derived benefits in early-phase trials was too small and unpredictable to justify larger studies. The population of PC patients with high microsatellite instability/mismatch repair deficiency is currently the only population that may benefit from immunotherapy; nevertheless, the prevalence of these alterations is too low to determine a real change in the treatment scenario of this tumor. The reasons for the unsuccess of immunotherapy may lie in the extremely peculiar tumor microenvironment, including distinctive immune composition and cross talk between different cells. These unique features may also explain why the biomarkers commonly used to predict immunotherapy efficacy in other tumors seem to be useless in PC. In the current paper, we provide a comprehensive and up-to-date review of immunotherapy in PC, from the analysis of the tumor immune microenvironment to immune biomarkers and treatment outcomes, with the aim to highlight that simply transferring the knowledge acquired on immunotherapy in other tumors might not be a successful strategy in patients affected by PC.

Elaborated study of Cu(II) carbosilane metallodendrimers bearing substituted iminopyridine moieties as antitumor agents.

Iminopyridine-decorated carbosilane metallodendrimers have recently emerged as a promising strategy in the treatment of cancer diseases. Their unique features such as the nanometric size, the multivalent nature and the structural perfection offer an extraordinary platform to explore structure-to-property relationships. Herein, we showcase the outstanding impact on the antitumor activity of a parameter not explored before: the iminopyridine substituents in meta position. New Cu(II) carbosilane metallodendrimers, bearing methyl or methoxy substituents in the pyridine ring, were synthesized and thoroughly characterized. Electron Paramagnetic Resonance (EPR) was exploited to unveil the properties of the metallodendrimers. This study confirmed the presence of different coordination modes of the Cu(II) ion (Cu-N2O2, Cu-N4 and Cu-O4), whose ratios were determined by the structural features of the dendritic molecules. These metallodendrimers exhibited IC50 values in the low micromolar range (<6 µM) in tumor cell lines such as HeLa and MCF-7. The subsequent in vitro assays on both healthy (PBMC) and tumor (U937) myeloid cells revealed two key facts which improved the cytotoxicity and selectivity of the metallodrug: First, maximizing the Cu-N2O2 coordination mode; second, adequately selecting the pair ring-substituent/metal-counterion. The most promising candidates, G1(-CH3)Cl (8) and G1(-OCH3)NO3(17), exhibited a substantial increase in the antitumor activity in U937 tumor cells, compared to the non-substituted counterparts, probably through two different ROS-production pathways.

Hacking Pancreatic Cancer: Present and Future of Personalized Medicine.

Pancreatic cancer (PC) is a recalcitrant disease characterized by high incidence and poor prognosis. The extremely complex genomic landscape of PC has a deep influence on cultivating a tumor microenvironment, resulting in the promotion of tumor growth, drug resistance, and immune escape mechanisms. Despite outstanding progress in personalized medicine achieved for many types of cancer, chemotherapy still represents the mainstay of treatment for PC. Olaparib was the first agent to demonstrate a significant benefit in a biomarker-selected population, opening the doors for a personalized approach. Despite the failure of a large number of studies testing targeted agents or immunotherapy to demonstrate benefits over standard chemotherapy regimens, some interesting agents, alone or in combination with other drugs, have achieved promising results. A wide spectrum of therapeutic strategies, including immune-checkpoint inhibitors tyrosine kinase inhibitors and agents targeting metabolic pathways or the tumor microenvironment, is currently under investigation. In this review, we aim to provide a comprehensive overview of the current landscape and future directions of personalized medicine for patients affected by PC.

Physical interactions between marine phytoplankton and PET plastics in seawater.

Plastics are the most abundant marine debris globally dispersed in the oceans and its production is rising with documented negative impacts in marine ecosystems. However, the chemical-physical and biological interactions occurring between plastic and planktonic communities of different types of microorganisms are poorly understood. In these respects, it is of paramount importance to understand, on a molecular level on the surface, what happens to plastic fragments when dispersed in the ocean and directly interacting with phytoplankton assemblages. This study presents a computer-aided analysis of electron paramagnetic resonance (EPR) spectra of selected spin probes able to enter the phyoplanktonic cell interface and interact with the plastic surface. Two different marine phytoplankton species were analyzed, such as the diatom Skeletonema marinoi and dinoflagellate Lingulodinium polyedrum, in absence and presence of polyethylene terephthalate (PET) fragments in synthetic seawater (ASPM), in order to in-situ characterize the interactions occurring between the microalgal cells and plastic surfaces. The analysis was performed at increasing incubation times. The cellular growth and adhesion rates of microalgae in batch culture medium and on the plastic fragments were also evaluated. The data agreed with the EPR results, which showed a significant difference in terms of surface properties between the diatom and dinoflagellate species. Low-polar interactions of lipid aggregates with the plastic surface sites were mainly responsible for the cell-plastic adhesion by S. marinoi, which is exponentially growing on the plastic surface over the incubation time.

Long-term survival of two patients with recurrent pancreatic acinar cell carcinoma treated with radiofrequency ablation: A case report.

BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare type of malignant pancreatic cancer that represents approximately 1% of all pancreatic neoplasms. Due to its very low incidence, only a few retrospective studies are available. Although surgery is the first choice for treatment, most patients experience recurrence (mainly in the liver) and there are no clear recommendations for patients with advanced disease. CASE SUMMARY: We report two patients with PACC treated with surgery who experienced tumour recurrence in the liver. Patient 1 carried a germline mutation in the APC gene. Both patients were treated with gemcitabine plus oxaliplatin and gemcitabine plus capecitabine as first- and second-line therapies, respectively. After a favourable response to chemotherapy, the patients underwent radiofrequency ablation of the remaining liver metastases. For patient 1, we documented a relapse in the liver after a disease-free period of 9 mo, and treatment with gemcitabine plus capecitabine was restarted. The patient achieved a complete response, and he remains alive without evidence of disease recurrence after six years. After radiofrequency ablation, patient 2 experienced disease-free survival for 21 mo, when peritoneal relapse was diagnosed and treated with chemotherapy. The patient achieved a stable disease state for nearly two years; nevertheless, further progressive disease was documented, and he died seven years after the first relapse. CONCLUSION: PACC presents different biological behaviours than pancreatic adenocarcinoma. Multidisciplinary treatment involving local ablative therapies may be considered for PACC.