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BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by dense desmoplastic stroma that limits the delivery of anticancer agents. VCN-01 is an oncolytic adenovirus designed to replicate in cancer cells with a dysfunctional RB1 pathway and express hyaluronidase. Here, we evaluated the mechanism of action of VCN-01 in preclinical models and in patients with pancreatic cancer.MethodsVCN-01 replication and antitumor efficacy were evaluated alone and in combination with standard chemotherapy in immunodeficient and immunocompetent preclinical models using intravenous or intratumoral administration. Hyaluronidase activity was evaluated by histochemical staining and by measuring drug delivery into tumors. In a proof-of-concept clinical trial, VCN-01 was administered intratumorally to patients with PDAC at doses up to 1×1011 viral particles in combination with chemotherapy. Hyaluronidase expression was measured in serum by an ELISA and its activity within tumors by endoscopic ultrasound elastography.ResultsVCN-01 replicated in PDAC models and exerted antitumor effects which were improved when combined with chemotherapy. Hyaluronidase expression by VCN-01 degraded tumor stroma and facilitated delivery of a variety of therapeutic agents such as chemotherapy and therapeutic antibodies. Clinically, treatment was generally well-tolerated and resulted in disease stabilization of injected lesions. VCN-01 was detected in blood as secondary peaks and in post-treatment tumor biopsies, indicating virus replication. Patients had increasing levels of hyaluronidase in sera over time and decreased tumor stiffness, suggesting stromal disruption.ConclusionsVCN-01 is an oncolytic adenovirus with direct antitumor effects and stromal disruption capabilities, representing a new therapeutic agent for cancers with dense stroma.Trial registration numberEudraCT number: 2012-005556-42 and NCT02045589.

Pancreatic cancer is one of the most lethal malignancies with poor outcomes. The incidence of pancreatic adenocarcinoma is rising in the developed world and modifiable lifestyle factors may play an important role in this setting. Pancreatic cancer in the early stages typically causes vague non-specific symptoms. These symptoms may include abdominal/back pain, weight loss and jaundice because the tumor mass most commonly arises from the head of the pancreas and disrupts the natural deposition of bile fluid in the small bowel. Clinical jaundice occurs when bilirubin level is >2 mg/dl. High level of bilirubin impedes the initiation of chemotherapy treatment and indicates poor prognosis and high postoperative morbidity in resectable pancreatic adenocarcinoma. A multidisciplinary assessment is needed to determine the best method to achieve adequate levels and initiate oncologic treatment. Such situations that are not possible to lower bilirubin level require individualization chemotherapy in order to achieve a clinical benefit without development of too much toxicity. There is not much clinical evidence for the recommendation of use of chemotherapy in this setting. This chapter summarizes the diagnosis and management of patients with significant hyperbilirubinaemia.

Background and aims: stereotactic body radiation therapy (SBRT) for pancreatic malignancies requires the placement of fiducials to guide treatment delivery. The aim of this study was to assess the safety and feasibility of endoscopic ultrasound (EUS) guided fiducial placement using a 22-gauge needle, in patients with pancreatic cancer undergoing SBRT. Methods: this single-center retrospective study included 47 patients with biopsy-proven advanced pancreatic cancer who underwent EUS-guided fiducial placement between February 2014 and February 2018. Primary outcome measurements included technical success, fiducial migration rate and procedural complications. Results: all 47 patients received a sufficient number of fiducials and could therefore undergo a successful SBRT. The mean number of fiducials inserted per case was 2 ± 1 (range 1-3) and no fiducial migration was noted. The adverse event rate was 4.2%, as one patient developed mild pancreatitis and another patient required one week of hospitalization one month after fiducial placement due to a duodenal abscess. Conclusions: EUS-guided fiducial placement is a safe and technically feasible procedure in centers with endosonographers that are well trained in EUS with FNA. https://www.reed.es/endoscopic-ultrasound-guided-fiducial-placement-in-pancreatic-tumors-safety-and-technical-feasibility3613

Background Dense stroma is a hallmark of hard-to-treat cancers such as pancreatic adenocarcinoma. VCN-01 oncolytic adenovirus is designed to replicate in cancer cells with dysfunctional RB1 pathway, improve tumor targeting and express hyaluronidase to enhance virus intratumor spreading and facilitate drug extravasation into the tumor. Methods The mechanisms of action of VCN-01 were tested in pancreatic xenograft models after both intravenous and intratumor administration. In a proof of concept phase I clinical trial study (8 patients), VCN-01 was escalated up to 1E+11vp per Endoscopic Ultrasound (EUS)-guided intratumor injection (3x) combined with the standard of care, SoC (gemcitabine or nab-paclitaxel/gemcitabine) in patients with advanced pancreatic adenocarcinoma. Results VCN-01 alone showed antitumor efficacy in preclinical models and further increased its efficacy when combined with SoC chemotherapy. VCN-01 replicated within injected tumors regardless of chemotherapy. Hyaluronidase expression by VCN-01 facilitated tumor extravasation and increased uptake of chemotherapy agents and antibodies. Data obtained from a phase 1 clinical trial of VCN-01 administered by repeated intratumor injection showed that the combination treatment was generally well-tolerated although dose limiting toxicity was found at highest dose. When combined with chemotherapy, VCN-01 stabilized the injected lesion in all patients, with a patient showing long progression free survival of 134 weeks. VCN-01 was detected as secondary peaks in blood several days after injection and in tumors at day 20-28, indicating virus replication. Hyaluronidase PH20 presence in sera was confirmed for all patients injected at 1E+11vp. Elastography of VCN-01-treated tumors evidenced reduction in tumor stiffness regardless of nab-paclitaxel co-administration. Conclusions VCN-01 replicates and expresses hyaluronidase after intratumor injection both in preclinical models and in patients with pancreatic cancer. Enhanced chemotherapy access and reduction of tumor stiffness favours local control of pancreatic tumours treated with VCN-01 + standard of care. Clinical trial identification EudraCT: 2012-005556-42. Legal entity responsible for the study VCN Biosciences. Funding VCN Biosciences. Disclosure M. Hidalgo: Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): EMD; Speaker Bureau / Expert testimony: Ipsem; Speaker Bureau / Expert testimony: Shire; Advisory / Consultancy: SOBI; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Champions Oncology; Advisory / Consultancy: Agenus; Advisory / Consultancy: Erytech; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Pharmacyte; Advisory / Consultancy: Bioline; Advisory / Consultancy, Shareholder / Stockholder / Stock options: BioOncotech; Advisory / Consultancy, Research grant / Funding (institution): Oncomatrix; Advisory / Consultancy: VCN Biosciences; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Nelum; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Eng T Cells. M. Bazan-Peregrino: Full / Part-time employment: VCN Biosciences. B. Laquente: Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: Servier; Research grant / Funding (institution): Mylan. R. Alvarez Gallego: Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution): Shire. A. Mato-Berciano: Full / Part-time employment: VCN Biosciences. M. Gimenez-Alejandre: Full / Part-time employment: VCN Biosciences. V. Maliandi: Full / Part-time employment: VCN Biosciences. M.C. Riesco Martinez: Speaker Bureau / Expert testimony: Merck. M. Perez-Carreras: Advisory / Consultancy: Intercept; Research grant / Funding (institution): GENFIT. G. Capella: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: VCN Biosciences. R. Alemany: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: VCN Biosciences; Research grant / Funding (institution): Lokon Pharma; Research grant / Funding (institution): Mologen. R. Salazar: Advisory / Consultancy, Research grant / Funding (institution): VCN Biosciences; Advisory / Consultancy: Agendia; Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Roche Diagnostics; Advisory / Consultancy: Ferrer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Roche Farma; Advisory / Consultancy: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: AZD; Speaker Bureau / Expert testimony: Celgene; Leadership role, Shareholder / Stockholder / Stock options: Sace MedHealth; Research grant / Funding (institution): PsiOxus; Research grant / Funding (institution): Mologen. E. Blasi: Full / Part-time employment: VCN Biosciences. C. Blasco: Full / Part-time employment: VCN Biosciences. M. Cascallo: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: VCN Biosciences. R. Garcia-Carbonero: Advisory / Consultancy: AAA; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: PharmaMar; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Servier; Research grant / Funding (institution): ARMO; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): VCN Biosciences. All other authors have declared no conflicts of interest.

Development of hyperbilirubinaemia is common in patients with advanced pancreatic adenocarcinoma, both at diagnosis as well throughout disease evolution. For this reason, hyperbilirubinaemia determines chemotherapy treatment selection, and therefore it should be considered one of the most relevant conditions. There is very little evidence for the use of chemotherapy in this setting. This article summarises the main causes of hyperbilirubinaemia, how to treat them as well as their differential diagnosis. The current clinical evidence of the available drugs as well as the recommendations of use different combinations in the context of hyperbilirubinaemia are also reviewed.

Background and Aims TC-325 (Hemospray, Cook Medical, Winston-Salem, NC) is an inorganic hemostatic powder recently approved by the U.S. Food and Drug Administration. This study aimed to examine the effectiveness, safety, and predictors of TC-325 failure in a large real-life cohort. Methods This was a retrospective study conducted at 21 Spanish centers. All patients treated with TC-325 until September 2018 were included. The primary outcome was treatment failure, defined as failed intraprocedural hemostasis or recurrent bleeding within the first 30 postprocedural days. Secondary outcomes included safety and survival. Risk and predictors of failure were assessed via competing-risk models. Results The cohort comprised 261 patients, of whom 219 (83.9%) presented with upper gastrointestinal bleeding (GIB). The most common causes were peptic ulcer (28%), malignancy (18.4%), and therapeutic endoscopy-related GIB (17.6%). TC-325 was used as rescue therapy in 191 (73.2%) patients. The rate of intraprocedural hemostasis was 93.5% (95% confidence interval [CI], 90%-96%). Risks of TC-325 failure at postprocedural days 3, 7, and 30 were 21.1%, 24.6%, and 27.4%, respectively. On multivariate analysis, spurting bleeding (P = .004), use of vasoactive drugs (P = .02), and hypotension (P = .008) were independent predictors of failure. Overall 30-day survival was 81.9% (95% CI, 76%-86%) and intraprocedural hemostasis was associated with a better prognosis (adjusted hazard ratio, 0.29; P = .006). Two severe adverse events were noted. Conclusion TC-325 was safe and effective for intraprocedural hemostasis in more than 90% of patients, regardless of the cause or site of bleeding and its use as rescue therapy. In this high-risk cohort treated with TC-325, the 30-day failure rate exceeded 25% and was highest with spurting bleeding or hemodynamic instability.

Background: Nab-paclitaxel and gemcitabine have demonstrated a survival benefit over gemcitabine alone in advanced pancreatic cancer (PDA). This study aimed to investigate the clinical, biological, and imaging effects of the regimen in patients with operable PDA. Methods: Patients with operable PDA received two cycles of nab-paclitaxel and gemcitabine before surgical resection. FDG-PET and CA19.9 tumour marker levels were used to measure clinical activity. Effects on tumour stroma were determined by endoscopic ultrasound (EUS) elastography. The collagen content and architecture as well as density of cancer-associated fibroblasts (CAFs) were determined in the resected surgical specimen and compared with a group of untreated and treated with conventional chemoradiation therapy controls. A co-clinical study in a mouse model of PDA was conducted to differentiate between the effects of nab-paclitaxel and gemcitabine. Results: A total of 16 patients were enrolled. Treatment resulted in significant antitumour effects with 50% of patients achieving a >75% decrease in circulating CA19.9 tumour marker and a response by FDG-PET. There was also a significant decrement in tumour stiffness as measured by EUS elastography. Seven of 12 patients who completed treatment and were operated had major pathological regressions. Analysis of residual tumours showed a marked disorganised collagen with a very low density of CAF, which was not observed in the untreated or conventionally treated control groups. The preclinical co-clinical study showed that these effects were specific of nab-paclitaxel and not gemcitabine. Conclusion: These data suggest that nab-paclitaxel and gemcitabine decreases CAF content inducing a marked alteration in cancer stroma that results in tumour softening. This regimen should be studied in patients with operable PDA.

Purpose To investigate the feasibility of personalizing chemotherapy in patients with rectal cancer. Methods Patients with cT3 or cN1 and cM0 rectal cancer were eligible. A set of 6 molecular markers including KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), ERCC-1, and thymidylate synthase (TS) using immunohistochemistry were performed in a tumor biopsy. All patients were treated with capecitabine 625 to 825 mg/m/12 h M-F in combination with either irinotecan or oxaliplatin based on Topo-1 and ERCC-1 expression plus either bevacizumab or cetuximab based on the mutation status. All patients received intensity-modulated radiation therapy. A surgery was performed 6 to 8 weeks after the treatment. Results Fifteen patients (94%) had T3 tumor and 10 (62%) N+ disease of 16 patients enrolled. In all patients, the full set of markers was analyzed within 10 days. Seven patients had K-ras mutation, and 4, 5, and 10 expressed Topo-1, ERRC-1 and TS, respectively. All patients had wild-type BRAF and PI3K tumors. The median time from obtaining informed consent to the treatment period was 18 days and all patients completed the chemoradiation treatment. Fifty percent achieved a complete pathologic response to treatment. Four patients (25%) developed grade 3 proctitis or diarrhea. There were no relevant surgical complications. Sixty-nine percent of the patients received adjuvant XELOX. Conclusions The individualization of neoadjuvant chemotherapy in patients with rectal cancer is feasible and leads to a high rate of pathologic response.

Sir, In response to Boeck et al We read with interest the comments made by Boeck et al (2014) about our study. We appreciate their attention to the units used to report CA19.9 levels, which indeed should have been U ml−1 and not U dl−1 as stated. We certainly agree that a high level of CA19.9 at diagnosis may be an indication of advanced disease and that this should be considered in the selection criteria in preoperative studies. Indeed in our study, with small sample size, one patient with very high CA19.9 level who actually progressed during chemotherapy skewed that average level of CA19.9. This patient was not operated and therefore does not affect the tissue results. As Boeck et al mention, levels of CA19.9 should be either a selection criteria or a stratification factor in outcome-oriented preoperative studies that should also include better imaging methods to determine responses and histological, rather than cytological, diagnosis. In our study, however, as the goals were to determine the effects of Nab-paclitaxel in tumour tissue, this criterion was not part of the eligibility criteria. We agree, however, that future controlled studies to confirm our observations should exclude patients with elevated CA19.9 and plan to do so. In clinical practice, however, one of the goals of preoperative treatment is to identify patients with more advanced or resistant disease who can be spared from surgery, as surgery would not be beneficial for those patients. Thus, for patients with resectable or borderline resectable disease by CT scan and high (>180 U ml−1) CA19.9, we usually administer chemotherapy upfront and explore surgically those patients who do not progress after two cycles of treatment provided laparoscopic assessment of peritoneal disease is negative as well. In response to Ramirez et al We read with great interest the comments made by Ramirez et al (2014) in which they highlight the importance of tumour stroma in pancreatic cancer (PDAC) and the role of ‘pancreatic stellate cells' in the development of tumour stroma. The current data, while with still some inconsistencies, show that in preclinical models of PDAC, the combination of gemcitabine and Nab-paclitaxel (PTX) increases the delivery of gemcitabine to the tumour. Mechanistically, this has been explained by a decrease in the expression of the gemcitabine catabolism enzyme cytidine deaminase and hence increasing the intracellular retention time of the active gemcitabine metabolites or by elimination of the PDAC stroma (Von Hoff et al, 2011; Frese et al, 2012). In the only clinical study available so far, we have shown that Nab-PTX markedly alters the PDAC stroma and decreases the number of CAF (Alvarez et al, 2013). The precise mechanisms underlying these observations remain obscure. Selective binding of albumin-coated Nab-PTX to SPARC-positive cells or uptake of nutrient-rich drug by cancer cells by pynocitosis have been proposed and are the subject of specific studies. The role of SPARC has been studied in the MPACT randomised clinical trial and we hope to have these results available in the near future (Von Hoff et al, 2013). As these authors propose, the effects of Nab-PTX on cancer stroma could be a consequence of the direct elimination of cancer cells and interruption of the cancer cell–stroma interactions. Certainly, additional preclinical and translational clinical studies are needed to determine the precise mechanism of action of this, otherwise, clinically effective regimen.

The BioEnterics® Intragastric Balloon (BIB®) is a well-established device for temporary treatment in morbidly obese patients. The aim of this study is the evaluation, in a population of 714 consecutive outpatient setting cases, BIB® results in terms of weight loss and comorbidity change.BIB® was positioned in all cases after diagnostic endoscopy. The device was inflated under direct endoscopic vision with saline solution (600-700 ml) and methylene blue (10 ml). Intubation was carried out in patients with body mass index (BMI) 40 kg/m(2) affected by sleep apnea or chronic obstructive pulmonary disease. After 6 months, balloon removal was carried out, and patients were discharged with drug therapy and 1,000 kcal diet. More than 100 patients underwent a second consecutive balloon positioning. One month from the removal of the first BIB, patients were given a second BIB. Patients were followed up weekly. Mortality, complications and their treatment, postplacement symptoms, comorbidities, BMI, percentage of excess BMI loss (%EBL), and percentage of excess weight loss (%EWL) were considered. Data are expressed as mean ± standard deviation.From June 1, 2005, to May 31, 2007, 714 patients underwent BIB® placement (143 males/571 females; mean age, 38.4 ± 16.1; mean BMI, 37.6 ± 5.7 kg/m(2); mean EW, 56.3 ± 27.1 kg). After 6 months, mean BMI was 31.1 ± 7.2, mean %EWL was 41.6 ± 21.8, mean BMI loss was 6.5 ± 12.7, and mean %EBL was 44.5 ± 22.6. Of 714 patients, 112 underwent a second BIB placement. At the time of the second balloon placement, mean BMI was 32.9 ± 6.7 kg/m(2); range was 31-51. After the second balloon removal, mean BMI was 30.3 ± 7.2.BIB® treatment is a safe and effective procedure for weight reduction, without mortality and with very low morbidity rates even in nonhospitalized patients. A second balloon can also be positioned without difficulties, achieving good results after 12 months of treatment.

TPS3112 Background: To date convincing clinical success with oncolytic viruses tends to be associated with intra-tumoral (IT) administration and evidence for successful systemic delivery of viruses...