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Simple Summary: A few types of cancers are currently as challenging and difficult to defeat as pancreatic ductal adenocarcinoma. Several reasons contribute to the complexity of this disease and are extensively studied in the attempt to beat this unassailable condition. Among those factors, the invasion of nerves by cancer cells, or perineural invasion, has been discovered to be a common feature of this cancer helping the tumour in its progression, facilitating relapses and causing considerable pain for patients. For these reasons, more effective therapies directed at inhibiting nerve invasion promoted by pancreatic ductal adenocarcinoma are strongly advocated. This review discusses the current understanding of perineural invasion in pancreatic ductal adenocarcinoma and the state of the art regarding pharmacological progress in this field. Pancreatic ductal adenocarcinoma is one of the most threatening solid malignancies. Molecular and cellular mediators that activate paracrine signalling also regulate the dynamic interaction between pancreatic cancer cells and nerves. This reciprocal interface leads to perineural invasion (PNI), defined as the ability of cancer cells to invade nerves, similar to vascular and lymphatic metastatic cascade. Targeting PNI in pancreatic cancer might help ameliorate prognosis and pain relief. In this review, the modern knowledge of PNI in pancreatic cancer has been analysed and critically presented. We focused on molecular pathways promoting cancer progression, with particular emphasis on neuropathic pain generation, and we reviewed the current knowledge of pharmacological inhibitors of the PNI axis. PNI represents a common hallmark of PDAC and correlates with recurrence, poor prognosis and pain in pancreatic cancer patients. The interaction among pancreatic cancer cells, immune cells and nerves is biologically relevant in each stage of the disease and stimulates great interest, but the real impact of the administration of novel agents in clinical practice is limited. It is still early days for PNI-targeted treatments, and further advanced studies are needed to understand whether they could be effective tools in the clinical setting. [ABSTRACT FROM AUTHOR]

Introduction: Cabozantinib has been approved by the European Medicine Agency (EMA) for hepatocellular carcinoma (HCC) previously treated with sorafenib. Cabozantinib is also being tested in combination with immune checkpoint inhibitors in the frontline setting. Real-life clinical data of cabozantinib for HCC are still lacking. Moreover, the prognostic factors for HCC treated with cabozantinib have not been investigated. Methods: We evaluated clinical data and outcome of HCC patients who received cabozantinib in the legal context of named patient use in Italy. Results: Ninety-six patients from 15 centres received cabozantinib. All patients had preserved liver function (Child-Pugh A), mostly with an advanced HCC (77.1%) in a third-line setting (75.0%). The prevalence of performance status (PS) > 0, macrovascular invasion (MVI), extrahepatic spread, and alpha-fetoprotein (AFP) >400 ng/mL was 50.0, 30.2, 67.7, and 44.8%, respectively. Median overall survival (OS) and progression-free survival were 12.1 (95% confidence interval 9.4–14.8) and 5.1 (3.3–6.9) months, respectively. Most common treatment-related adverse events (AEs) were fatigue (67.7%), diarrhoea (54.2%), anorexia (45.8%), HFSR (43.8%), weight loss (24.0%), and hypertension (24.0%). Most common treatment-related Grade 3–4 AEs were fatigue (6.3%), HFSR (6.3%), and increased aminotransferases (6.3%). MVI, ECOG-PS > 0, and AFP >400 ng/mL predicted a worse OS. Discontinuation for intolerance and no new extrahepatic lesions at the progression were associated with better outcomes. Conclusions: In a real-life Western scenario (mostly in a third-line setting), cabozantinib efficacy and safety data were comparable with those reported in its registration trial. Data regarding the prognostic factors might help in patient selection and design of clinical trials. [ABSTRACT FROM AUTHOR]

The search for systemic therapies for hepatocellular carcinoma has been characterized by difficulties and failures. Despite recent progresses, many issues are still to be settled. In particular, the development of drugs inhibiting different neoplastic pathways remains a priority for patients intolerant or resistant to antiangiogenic drugs. This task may be daunting, as previous failures extensively demonstrated. We aimed to identify the future perspective of postsorafenib trials analyzing the strengths and the critical points of past and currently undergoing studies, in the light of the most recent evidences in the field. We identified various points (including stratification, biomarkers, end points, radiologic criteria of response, treatment beyond radiologic progression) that should be considered by future trials to reduce the risks of failure. [ABSTRACT FROM AUTHOR]

Background. The use of gemcitabine as an adjuvant modality for cholangiocarcinoma (CC) is increasing, but limited data are available on predictive biomarkers of response. Human equilibrative nucleoside transporter 1 (hENT-1) is the major transporter involved in gemcitabine intracellular uptake. This study investigated the putative predictive role of hENT-1 localization in tumor cells of CC patients undergoing treatment with adjuvant gemcitabine. Methods. Seventy-one consecutive patients with resected CC receiving adjuvant gemcitabine at our center were retrospectively analyzed by immunohistochemistry for hENT-1 localization in tumor cells. The main outcome measure was disease-free survival (DFS). Hazard ratios (HRs) of relapse and associated 95% confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score. Results. Twenty-three (32.4%) cases were negative for hENT-1, 22 (31.0%) were positive in the cytoplasm only, and 26 (36.6%) showed concomitant cytoplasm/membrane staining. Patients with membrane hENT-1 had a longer DFS (HR 0.49, 95% CI 0.24-0.99, p = .046) than those who were negative or positive only in the cytoplasm of tumor cells. Notably, the association between DFS and membrane hENT-1 was dependent on the number of gemcitabine cycles (one to two cycles: HR 0.96, 95% CI0.34-2.68; three to four cycles: HR 0.99,95% CI 0.34-2.90; five to six cycles: HR 0.27, 95% CI 0.10-0.77). Conclusion. hENT-1 localization on tumor cell membrane may predict response to adjuvant gemcitabine in CC patients receiving more than four cycles of chemotherapy. Further prospective randomized trials on larger populations are required to confirm these preliminary results, so that optimal gemcitabine-based chemotherapy may be tailored for CC patients in the adjuvant setting. [ABSTRACT FROM AUTHOR]

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest solid tumors and is estimated to become a leading cause of cancer-related death in coming years. Despite advances in surgical approaches and the emergence of new chemotherapy options, its poor prognosis has not improved in the last decades. The current treatment for PDAC is the combination of cytotoxic chemotherapy agents. However, PDAC shows resistance to many antineoplastic therapies with rapid progression. Although PDAC represents a heterogeneous disease, there are common alterations including oncogenic mutations of KRAS, and the frequent inactivation of different cell cycle regulators including the CDKN2A tumor suppressor gene. An emerging field of investigation focuses on inhibiting the function of proteins that suppress the immune checkpoint PD-1/PD-L1, with activation of the endogenous immune response. To date, all conventional immunotherapies have been less successful in patients with PDAC compared to other tumors. The need for new targets, associated with an extended molecular analysis of tumor samples could give new pharmacological options for the treatment of PDAC. It is, therefore, important to push for a broader molecular approach in PDAC research. Here, we provide a selected summary of emerging strategy options for targeting PDAC using CDK4/6 inhibitors, RAS inhibitors, and new drug combinations with immune checkpoint agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the enormous advance in biomarker discovery, many potential biomarkers of drug activity are unable to satisfy the clinical need due to inadequate sensitivity and specificity. The nucleoside transporter hENT-1 has been studied as a potential biomarker to predict the effect of the widely used anticancer drug gemcitabine in pancreatic cancer. However, several studies showed controversial results regarding the predictive value of hENT-1, prompting new analyses with larger cohorts of patients and standardized methodologies. Improved insights on molecular mechanisms underlying hENT-1 expression and activity should also help in the identification of subsets of patients who are more likely to benefit from specific treatments and improve their clinical outcome. The establishment of such biomarker is especially valuable in pancreatic cancer, which is frequently characterized by complex disease biology and high mortality. Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as an upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free status and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. This commentary aims to critically discuss this analysis and lists molecular factors influencing hENT-1 expression. Improved knowledge on these factors should help the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies. [ABSTRACT FROM AUTHOR]