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Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10−10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10–6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10-9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.

Purpose: We aimed to explore the role of drugs re-challenge at thedisease progression after a chemotherapy-free interval for pancreatic adenocarcinoma (PDAC) patients. Methods: We retrospectively analyzed the outcome of re-treatments at theprogression in two cohorts of advanced PDAC patients who had disease control (DC) and a treatment holiday ≥ 3months after upfront chemotherapy. Results: Between 2015 and 2019, 66 advanced PDAC patients (cohort A) had DC with nab-paclitaxel-based chemotherapy (i.e. AG or PAXG = cisplatin, nab-paclitaxel, gemcitabine, capecitabine). At the time of progressive disease (PD), 34 patients were re-treated with AG (A1) and 32 were treated with other regimens (A2). The median (m) duration of chemotherapy holiday was 6.1 and 5.9monthsin A1 and A2, respectively. Partial response (PR) and stable disease (SD) were found in 14 (41%) and 12 (35%) ofpatients in A1 and in 8 (25%) and 6 (19%) patients in A2. CA19-9 response was recorded in 23/33 evaluable patients (70%) in A1 and in 5/20 (25%) in A2. mPFS2 and mOS2, defined as the time between the second line of treatment start and the disease progression or death, were 4.8 and 12.2months in A1 and 3.9 and 8.4months in A2, respectively. Similarly, between 2006 and 2013, 64 patients (cohort B) had DC with upfront PEFG/PEXG/PDXG regimens (epirubicin or docetaxel, cisplatin, gemcitabine, capecitabine or 5-fluorouracil) and were re-treated at PD with either 4-drug (B1; N = 30) or other regimens (B2; N = 34), yielding a mOS2 of 10.9 and 7.2months, respectively. Conclusion: Our data endorse the strategy of resuming prior drugs after a chemotherapy holiday ≥ 3months in advanced PDAC patients who achieved a durable disease control after upfront treatments.

The development of curvilinear-array EUS and EUS-guided fine-needle aspiration (EUS-FNA) has led these approaches to become interventional procedures rather than purely diagnostic, as a minimally invasive antitumor therapeutic alternative to radiological and surgical treatments. The possibility to accurately position needle devices and to reach a deep target like the pancreas gland under real-time imaging guidance has expanded the use of EUS to ablate tumors. Currently, a variety of probes specifically designed for EUS ablation are available, including radiofrequency, hybrid cryothermal ablation (combining radiofrequency with cryotechnology), photodynamic therapy, and laser ablation. To date, several studies have demonstrated the safety and feasibility of these ablation techniques in the pancreatic setting, but only a few small series on pancreatic thermal ablation under EUS guidance are available. EUS-guided thermal ablation is primarily used for pancreatic cancer. It is well suited to this disease because of its superior anatomical access compared with other imaging modalities and the dismal prognosis despite improvements in chemoradiotherapy and surgery in the management of pancreatic cancer. Other targets are pancreatic neuroendocrine tumors and pancreatic cystic neoplasms, which are curable by surgical resection, but some patients are poor surgical candidates or prefer conservative management. This is a literature review of previously published clinical studies on EUS-guided thermal ablative therapies. Data on the long-term efficacy of EUS-guided antitumor thermal ablation therapy and large prospective randomized studies are still needed to confirm the real clinical benefits of these techniques for the management of pancreatic neoplasms.

Transcriptome analyses allow the distinguishing of pancreatic ductal adenocarcinoma (PDAC) subtypes, exhibiting different prognoses and chemotherapy responses. However, RNA extraction from pancreatic tissue is cumbersome and has been performed mainly from surgical samples, which are representative of &lt, 20% of cases. The majority of PDAC patients undergo endoscopic ultrasound (EUS)-guided tissue acquisition (EUS-TA), but RNA has been rarely extracted from EUS-TA with scanty results. Herein, we aimed to determine the best conditions for RNA extraction and analysis from PDAC EUS-TA samples in order to carry out molecular analyses. PDAC cases underwent diagnostic EUS-TA, with needles being a 25G fine needle aspiration (FNA) in all patients and then either a 20G lateral core-trap fine needle biopsy (FNB) or a 25G Franseen FNB, the conservation methods were either snap freezing, RNALater or Trizol. RNA concentration and quality (RNA integrity index, RIN) were analyzed and a panel of genes was investigated for tissue contamination and markers of molecular subtype and aggressivity through qRT-PCR. Seventy-four samples from 37 patients were collected. The median RNA concentration was significantly higher in Trizol samples (10.33 ng/uL) compared with snap frozen (0.64 ng/uL, p &lt, 0.0001) and RNALater (0.19 ng/uL, 0.0001). The RIN was similar between Trizol (5.15) and snap frozen samples (5.85), while for both methods it was higher compared with RNALater (2.7). Among the needles, no substantial difference was seen in terms of RNA concentration and quality. qRT-PCR analyses revealed that samples from all needles were suitable for the detection of PDAC subtype markers (GATA6 and ZEB1) and splice variants associated with mutational status (GAP17) as well as for the detection of contaminating tissue around PDAC cells. This is the first study that specifically investigates the best methodology for RNA extraction from EUS-TA. A higher amount of good quality RNA is obtainable with conservation in Trizol with a clear superiority of neither FNA nor FNB needles. RNA samples from EUS-TA are suitable for transcriptome analysis including the investigation of molecular subtype and splice variants expression.

With recent advances in molecular pathology and the development of new chemotherapy regimens, the knowledge of the molecular alterations of pancreatic ductal adenocarcinoma (PDAC) is becoming appealing for stratifying patients for prognosis and response to a defined treatment. Archival formalin-fixed, paraffinembedded samples are a useful source of genomic deoxyribonucleic acid; nevertheless, most studies employed formalin-fixed, paraffin-embedded samples deriving from surgical specimens, which are therefore representative of