NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial

Gemcitabine; Metastatic pancreatic ductal adenocarcinomaGemcitabina; Adenocarcinoma ductal de pàncrees metastàticGemcitabina; Adenocarcinoma ductal de páncreas metastásicoBackground Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies, with few treatment options. NAPOLI 3 aimed to compare the efficacy and safety of NALIRIFOX versus nab-paclitaxel and gemcitabine as first-line therapy for metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods NAPOLI 3 was a randomised, open-label, phase 3 study conducted at 187 community and academic sites in 18 countries worldwide across Europe, North America, South America, Asia, and Australia. Patients with mPDAC and Eastern Cooperative Oncology Group performance status score 0 or 1 were randomly assigned (1:1) to receive NALIRIFOX (liposomal irinotecan 50 mg/m2, oxaliplatin 60 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2, administered sequentially as a continuous intravenous infusion over 46 h) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2, administered intravenously, on days 1, 8, and 15 of a 28-day cycle. Balanced block randomisation was stratified by geographical region, performance status, and liver metastases, managed through an interactive web response system. The primary endpoint was overall survival in the intention-to-treat population, evaluated when at least 543 events were observed across the two treatment groups. Safety was evaluated in all patients who received at least one dose of study treatment. This completed trial is registered with ClinicalTrials.gov, NCT04083235. Findings Between Feb 19, 2020 and Aug 17, 2021, 770 patients were randomly assigned (NALIRIFOX, 383; nab-paclitaxel–gemcitabine, 387; median follow-up 16·1 months [IQR 13·4–19·1]). Median overall survival was 11·1 months (95% CI 10·0–12·1) with NALIRIFOX versus 9·2 months (8·3–10·6) with nab-paclitaxel–gemcitabine (hazard ratio 0·83; 95% CI 0·70–0·99; p=0·036). Grade 3 or higher treatment-emergent adverse events occurred in 322 (87%) of 370 patients receiving NALIRIFOX and 326 (86%) of 379 patients receiving nab-paclitaxel–gemcitabine; treatment-related deaths occurred in six (2%) patients in the NALIRIFOX group and eight (2%) patients in the nab-paclitaxel–gemcitabine group. Interpretation Our findings support use of the NALIRIFOX regimen as a possible reference regimen for first-line treatment of mPDAC.Ipsen

Isolation of exosomes from whole blood by a new microfluidic device: proof of concept application in the diagnosis and monitoring of pancreatic cancer

Background: Exosomes are endocytic-extracellular vesicles with a diameter around 100 nm that play an essential role on the communication between cells. In fact, they have been proposed as candidates for the diagnosis and the monitoring of different pathologies (such as Parkinson, Alzheimer, diabetes, cardiac damage, infection diseases or cancer). Results: In this study, magnetic nanoparticles (Fe3O4NPs) were successfully functionalized with an exosome-binding antibody (anti-CD9) to mediate the magnetic capture in a microdevice. This was carried out under flow in a 1.6 mm (outer diameter) microchannel whose wall was in contact with a set of NdFeB permanent magnets, giving a high magnetic field across the channel diameter that allowed exosome separation with a high yield. To show the usefulness of the method, the direct capture of exosomes from whole blood of patients with pancreatic cancer (PC) was performed, as a proof of concept. The captured exosomes were then subjected to analysis of CA19-9, a protein often used to monitor PC patients. Conclusions: Here, we describe a new microfluidic device and the procedure for the isolation of exosomes from whole blood, without any need of previous isolation steps, thereby facilitating translation to the clinic. The results show that, for the cases analyzed, the evaluation of CA19-9 in exosomes was highly sensitive, compared to serum samples

Gene expression profiling and its use in adenocarcinomas of unknown primary origin: A case report

Carcinomas of unknown primary origin account for 3-5% of all malignancies. The current literature suggests that metastatic dissemination is able to occur in the absence of primary tumor growth. In metastatic disease that is difficult to diagnose, the origin usually remains unknown even after an exhaustive evaluation of immunohistochemistry (IHC) markers. In the current study, a 49-year-old male presented with lymph nodes metastases of unknown origin. The exci- sional biopsy of an inguinal node revealed an adenocarcinoma growth pattern, but the IHC could not determine the primary origin. A gene profiling test was performed to complete the diagnosis and a salivary gland adenocarcinoma was diagnosed with 90% probability. Subsequently, the patient underwent appropriate chemotherapy for salivary gland adenocarcinoma, and exhibited an improved partial response. The present case study highlights the importance of an accurate diagnosis of the primary tumor and the use of all the current tools available in order to provide patients with the best treatment possibl

SEOM clinical guideline on unknown primary cancer (2017)

Cancer of unknown primary site is a histologically confirmed cancer that manifests in advanced stage, with no identifiable primary site following standard diagnostic procedures. Patients are initially categorized based on the findings of the initial biopsy: adenocarcinoma, squamous-cell carcinoma, neuroendocrine carcinoma, and poorly differentiated carcinoma. Appropriate patient management requires understanding several clinical and pathological features that aid in identifying several subsets of patients with more responsive tumors

SEOM clinical guidelines for pancreatic and biliary tract cancer (2020)

Pancreatic cancer (PC) and biliary tract cancer (BTC) are both aggressive and highly fatal malignancies. Nowadays we have a profound knowledge about the molecular landscape of these neoplasms and this has allowed new therapeutic options. Surgery is the only potentially curative therapy in both cancers, but disease recurrence is frequent. In PC, adjuvant treatment with mFOLFIRINOX has improved overall survival (OS) and in BTC adjuvant treatment with capecitabine seems to improve OS and relapse-free survival. Concomitant radio-chemotherapy could also be considered following R1 surgery in both neoplasms. Neoadjuvant treatment represents the best option for achieving an R0 resection in borderline PC. Upfront systemic chemotherapy is the treatment of choice in unresectable locally advanced PC and BTC; then locoregional therapy could be considered after an initial period of at least 3-4 months of systemic chemotherapy. In metastatic PC, FOLFIRINOX or Gemcitabine plus nab-paclitaxel have improved OS compared with gemcitabine alone. In metastatic BTC, cisplatin plus gemcitabine constitute the standard treatment. Progress in the knowledge of molecular biology has enabled the identification of new targets for therapy with encouraging results that could in the future improve the survival and quality of life of patients with PC and BTC

Adoptive NK cell transfer as a treatment in colorectal cancer patients: analyses of tumour cell determinants correlating with efficacy in vitro and in vivo

6 figures.-- Supplementary material available.Background: Colorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC.Methods: NK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed in vitro and in vivo and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity.Results: HLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression. In vivo experiments confirmed the efficacy of the therapy against both HLA+ and HLA− CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control.Conclusions: Our results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy.Work in the JP laboratory is funded by ASPANOA, CIBER (CB 2021; Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación and Union Europea.NextGenerationEU), Fundacion Inocente, Carrera de la Mujer Monzón, FEDER/Gobierno de Aragón (Group B29_17R), and Ministerio de Ciencia, Innovación e Universidades (MCNU), Agencia Estatal de Investigación (SAF2017‐83120‐C2‐1‐R and PID2020-113963RB-I00). Predoctoral grants/contracts from Gobierno de Aragon (IU-M and JP) are supported by ARAID Foundation. EG is funded by Ministerio de Ciencia, Innovación y Universidades (MCNU), and Agencia Estatal de Investigación (PID2020-113963RB-I00). MA and LS are funded by Postdoctoral Juan de la Cierva Contract. SR, LC, SH, and IU-M are funded by predoctoral contracts from Aragon Government. PL is funded by FPU predoctoral grants from Ministerio de Ciencia, Innovación e Universidades. Work at the Catalan Institute of Oncology is funded by the entity, the Instituto de Salud Carlos III and Ministerio de Economia y Competitividad, and co-funded by FEDER funds—a way to build Europe (PI20/00767), CIBERESP (grant CB07/02/2005), H2020 grant MoTriColor, and the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723. This work is supported by COST Action CA17118.Peer reviewe