Plasma neurofilament light chain levels in chemotherapy-induced peripheral neurotoxicity according to type of anticancer drug.

BACKGROUND AND PURPOSE: A real-time biomarker in chemotherapy-induced peripheral neurotoxicity (CIPN) would be useful for clinical decision-making during treatment. Neurofilament light chain (NfL) can be detected in blood in the case of neuroaxonal damage. The aim of the study was to compare the levels of plasma NfL (pNfL) according to the type of chemotherapeutic agent and the severity of CIPN. METHODS: This single-center prospective observational longitudinal study included patients treated with paclitaxel (TX; n = 34), brentuximab vedotin (BV; n = 29), or oxaliplatin (PT; n = 19). All patients were assessed using the Total Neuropathy Score-clinical version and Common Terminology Criteria for Adverse Events before, during, and up to 6-12 months after the end of treatment. Nerve conduction studies (NCS) were performed before and after chemotherapy discontinuation. Consecutive plasma samples were analyzed for NfL levels using a Simoa® analyzer. Changes in pNfL were compared between groups and were eventually correlated with clinical and NCS data. Clinically relevant (CR) CIPN was considered to be grade ≥ 2. RESULTS: Eighty-two patients, mostly women (59.8%), were included. One third of the patients who received TX (29.4%), BV (31%), or PT (36.8%) developed CR-CIPN, respectively, without differences among them (p = 0.854). Although pNfL significantly increased during treatment and decreased throughout the recovery period in all three groups, patients receiving TX showed significantly greater and earlier changes in pNfL levels compared to the other agents (p < 0.001). CONCLUSIONS: A variable change in pNfL is observed depending on the type of agent and mechanism of neurotoxicity with comparable CIPN severity, strongly implying the need to identify different cutoff values for each agent.

Metagenomic Study Reveals Phage-Bacterial Interactome Dynamics in Gut and Oral Microbiota in Pancreatic Diseases.

Individuals with pancreatic-related health conditions usually show lower diversity and different composition of bacterial and viral species between the gut and oral microbiomes compared to healthy individuals. We performed a thorough microbiome analysis, using deep shotgun sequencing of stool and saliva samples obtained from patients with chronic pancreatitis (CP), pancreatic ductal adenocarcinoma (PDAC), and healthy controls (HCs).We observed similar microbiota composition at the species level in both the gut and oral samples in PDAC patients compared to HCs, among which the most distinctive finding was that the abundance of oral-originated Fusobacterium nucleatum species did not differ between the oral and the gut samples. Moreover, comparing PDAC patients with HCs, Klebsiella oxytoca was significantly more abundant in the stool samples of PDAC patients, while Streptococcus spp. showed higher abundance in both the oral and stool samples of PDAC patients. Finally, the most important finding was the distinctive gut phage-bacterial interactome pattern among PDAC patients. CrAssphages, particularly Blohavirus, showed mutual exclusion with K. oxytoca species, while Burzaovirus showed co-occurrence with Enterobacteriaceae spp., which have been shown to be capable of inducing DNA damage in human pancreatic cells ex vivo. The interactome findings warrant further mechanistic studies, as our findings may provide new insights into developing microbiota-based diagnostic and therapeutic methods for pancreatic diseases.

Prognostic risk factors in 113 patients undergoing cephalic duodenopancreatectomy for distal cholangiocarcinoma. / Factores de mal pronóstico en 113 pacientes sometidos a duodenopancreatectomía cefálica por colangiocarcinoma distal.

INTRODUCTION: Distal cholangiocarcinoma is a malignant epithelial neoplasia that affects the extrahepatic bile ducts, below the cystic duct. No relevant relationship between perioperative factors and worse long-term outcome has been proved. OBJECTIVE: To analyze the risk factors for mortality and long-term recurrence of distal cholangiocarcinoma in resected patients. MATERIALS AND METHODS: A single-center prospective database of patients operated on for distal cholangiocarcinoma between 1990 and 2021 was analyzed in order to investigate mortality and recurrence factors. RESULTS: One hundred and thirteen patients have undergone surgery, with mean actuarial survival of 100.2 (76-124) months after resection. The bivariate study did not show differences between patients depending on age or preoperative variables studied. When multivariate analysis was performed, the presence of affected adenopathy was a risk factor for long-term mortality. The presence of affected lymph nodes, tumor recurrence, and biliary fistula during the postoperative period implied worse actuarial survival when comparing the Kaplan-Meier curves. CONCLUSIONS: The presence of affected lymph nodes influence the prognosis of the disease. The occurrence of biliary fistula during postoperative cholangiocarcinoma distal could aggravate long-term outcomes, a finding that should be reaffirmed in future studies.

Is a coaxial plastic stent within a lumen-apposing metal stent useful for the management of distal malignant biliary obstruction?

BACKGROUND: There are uncertainties concerning the possible benefits derived from the insertion of double-pigtail plastic stents (DPS) within lumen-apposing metal stents (LAMS) in EUS-guided choledochoduodenostomy (CDS). The aim of this study was to determine whether a DPS within a biliary LAMS offers a potential benefit in EUS-guided CDS for the palliative management of malignant biliary obstruction. METHODS: This was a multicentre retrospective study at three tertiary institutions. PERIOD: May 2015 to August 2020. Two interventional strategies (LAMS alone and LAMS plus DPS) were compared. The choice was the endoscopist's discretion. Inclusion: unresectable/inoperable biliopancreatic tumours with previous failed ERCP. Clinical success: bilirubin decrease > 30% at 4 weeks. RESULTS: Forty-one consecutive cases of EUS-CDS using biliary LAMS were treated (22 women; mean age, 72.3 years) during the study period. The procedure was technically successful in 39 (95.1%), who were managed using the two strategies (22 LAMS alone; 17 LAMS plus DPS). No differences between the groups, in terms of clinical success (77.3 vs 87.5%, p = 0.67), adverse events (AEs, 13.6 vs 11.8%, p = 0.99), recurrent biliary obstruction (RBO, 13.6 vs 23.5%, p = 0.67), or survival rate (p = 0.67) were encountered. The LAMS alone group had a shorter length of procedure (50 min vs 66 min, p = 0.102). No risk factors related to clinical success, AEs, RBO, or survival were detected. CONCLUSIONS: The technical variant of adding a coaxial DPS within LAMS in EUS-CDS seems not to be enough to prevent biliary morbidities, and it is a time-consuming strategy. Although prospective studies are needed, these results do not support its routine use.

Tumor-Associated Microbiome: Where Do We Stand?

The study of the human microbiome in oncology is a growing and rapidly evolving field. In the past few years, there has been an exponential increase in the number of studies investigating associations of microbiome and cancer, from oncogenesis and cancer progression to resistance or sensitivity to specific anticancer therapies. The gut microbiome is now known to play a significant role in antitumor immune responses and in predicting the efficacy of immune-checkpoint inhibitors in cancer patients. Beyond the gut, the tumor-associated microbiome-microbe communities located either in the tumor or within its body compartment-seems to interact with the local microenvironment and the tumor immune contexture, ultimately impacting cancer progression and treatment outcome. However, pre-clinical research focusing on causality and mechanistic pathways as well as proof-of-concept studies are still needed to fully understand the potential clinical utility of microbiome in cancer patients. Moreover, there is a need for the standardization of methodology and the implementation of quality control across microbiome studies to allow for a better interpretation and greater comparability of the results reported between them. This review summarizes the accumulating evidence in the field and discusses the current and upcoming challenges of microbiome studies.

Quality of life of patients with metastatic pancreatic adenocarcinoma initiating first-line chemotherapy in routine practice.

BACKGROUND: Despite advances in surgery, radiotherapy, and chemotherapy, pancreatic adenocarcinoma often progresses rapidly and causes death. The physical decline of these patients is expected to impact their quality of life (QoL). Therefore, in addition to objective measures of effectiveness, the evaluation of health-related QoL should be considered a matter of major concern when assessing therapy outcomes. METHODS: Observational, prospective, multicenter study including patients with metastatic pancreatic adenocarcinoma who started first-line chemotherapy in 12 Spanish centers. Treatment and clinical characteristics were recorded at baseline. Patients' health-related quality of life, ECOG, and Karnofsky index were measured at baseline, at Days 15 and 30, and every four weeks up to 6 months of chemotherapy. Health-related quality of life was measured using the EORTC-QLQ-C30 and EQ-5D questionnaires. Other endpoints included overall survival and progression-free survival. RESULTS: The study sample included 116 patients (median age of 65 years). Mean (SD) scores for the QLQ-C30 global health status scale showed a significant increasing trend throughout the treatment (p = 0.005). Patients with either a Karnofsky index of 70-80 or ECOG 2 showed greater improvement in the QLQ-C30 global health status score than the corresponding groups with better performance status (p ≤ 0.010). Pain, appetite, sleep disturbance, nausea, and constipation significantly improved throughout the treatment (p < 0.005). Patients with QLQ-C30 global health status scores ≥50 at baseline had significantly greater overall survival and progression-free survival (p = 0.005 and p = 0.021, respectively). No significant associations were observed regarding the EQ-5D score. CONCLUSIONS: Most metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy showed an increase in health-related quality of life scores throughout the treatment. Patients with lower performance status and health-related quality of life at baseline tended to greater improvement. The EORTC QLQ-C30 scale allowed us to measure the health-related quality of life of metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy.

Endoscopic biliary drainage in unresectable biliary obstruction: the role of endoscopic ultrasound-guidance in a cohort study.

BACKGROUND AND STUDY AIMS: the use of endoscopic ultrasound-guided biliary drainage (EUS-BD) has increased in cases of failed endoscopic retrograde cholangiopancreatography (ERCP) and there are some concerns. The main aim of the study was to determine the role of EUS-BD in a palliative case cohort. The secondary aim was to compare the efficacy, safety and survival of EUS-BD and ERCP procedures. PATIENTS AND METHODS: this was an observational study at a single tertiary institution, with a consecutive inclusion from January 2015 to December 2016. The inclusion criteria were unresectable tumors of the biliopancreatic region with an indication of BD. Statistical comparison analysis was performed between the ERCP and EUS-BD groups. The incidence between groups was compared using the Chi-square and Fisher exact tests. The log rank test was used to compare the risk of death. RESULTS: fifty-two cases with an indication of palliative BD were included in the study. Transpapillary drainage via ERCP was possible in 44 procedures and EUS-BD was required in eight cases; 15.4% of the cohort and seven using lumen apposing metal stent (LAMS). The technical and clinical success of global endoscopic BD was 100% and 88.5% (ERCP: 84.6% and 78.9%; EUS-BD: 100% and 62.5%, respectively). Pancreatitis was the most frequent adverse event (AE) in the ERCP group (9.62%) and bleeding in the EUS-BD (25%). There were fatal AEs in ERCP (1.9%) and EUS-BD (25%) cases. Patient survival was higher with ERCP transpapillary stents compared to EUS-guided stents, which was statistically significant (p = 0.007). CONCLUSIONS: the requirement of EUS-BD in palliative biliopancreatic pathology is not marginal. EUS-BD is associated with a lower survival rate and a higher rate of fatal AE, which argues against its use as a first choice procedure.

Pain in pancreatic ductal adenocarcinoma: A multidisciplinary, International guideline for optimized management.

Abdominal pain is an important symptom in most patients with pancreatic ductal adenocarcinoma (PDAC). Adequate control of pain is often unsatisfactory due to limited treatment options and significant variation in local practice, emphasizing the need for a multidisciplinary approach. This review contends that improvement in the management of PDAC pain will result from a synthesis of best practice and evidence around the world in a multidisciplinary way. To improve clinical utility and evaluation, the evidence was rated according to the GRADE guidelines by a group of international experts. An algorithm is presented, which brings together all currently available treatment options. Pain is best treated early on with analgesics with most patients requiring opioids, but neurolytic procedures are often required later in the disease course. Celiac plexus neurolysis offers medium term relief in a substantial number of patients, but other procedures such as splanchnicectomy are also available. Palliative chemotherapy also provides pain relief as a collateral benefit. It is stressed that the assessment of pain must take into account the broader context of other physical and psychological symptoms. Adjunctive treatments for pain, depression and anxiety as well as radiotherapy, endoscopic therapy and neuromodulation may be required in selected patients. There are few comparative studies to help define which combination and order of these treatment options should be applied. New pain therapies are emerging and could for example target neural transmitters. However, until better methods are available, management of pain should be individualized in a multidisciplinary setting to ensure optimal care.

A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients.

BACKGROUND: The aim of this study was to determine whether checkpoint kinase 1 inihibitor (CHK1), LY2603618, and gemcitabine prolong overall survival (OS) compared to gemcitabine alone in patients with unresectable pancreatic cancer. METHODS: Patients with Stage II-IV locally advanced or metastatic pancreatic cancer were randomized (2:1) to either 230 mg of LY2603618/1000 mg/m2 gemcitabine combined or 1000 mg/m2 gemcitabine alone. OS was assessed using both a Bayesian augment control model and traditional frequentist analysis for inference. Progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics (PK), and safety (Common Terminology Criteria for Adverse Events [AEs] v 3.0) were also evaluated. RESULTS: Ninety-nine patients (n = 65, LY2603618/gemcitabine; n = 34, gemcitabine) were randomized (intent-to-treat population). The median OS (months) was 7.8 (range, 0.3-18.9) with LY2603618/gemcitabine and 8.3 (range, 0.8-19.1+) with gemcitabine. Similarly, in a Bayesian analysis, the study was not positive since the posterior probability that LY2603618/gemcitabine was superior to gemcitabine in improving OS was 0.3, which did not exceed the prespecified threshold of 0.8. No significant improvements in PFS, ORR, or duration of response were observed. Drug-related treatment-emergent AEs in both arms included nausea, thrombocytopenia, fatigue, and neutropenia. The severity of AEs with LY2603618/gemcitabine was comparable to gemcitabine. The LY2603618 exposure targets (AUC(0-∞) ≥21,000 ng∙hr/mL and Cmax ≥2000 ng/mL) predicted for maximum pharmacodynamic response were achieved after 230 mg of LY2603618. CONCLUSIONS: LY2603618/gemcitabine was not superior to gemcitabine for the treatment of patients with pancreatic cancer. TRIAL REGISTRATION: NCT00839332 . Clinicaltrials.gov. Date of registration: 6 February 2009.

Initial Experience in the Treatment of "Borderline Resectable" Pancreatic Adenocarcinoma. / Experiencia inicial en el tratamiento del adenocarcinoma de páncreas borderline resectable.

INTRODUCTION: A borderline resectable group (APBR) has recently been defined in adenocarcinoma of the pancreas. The objective of the study is to evaluate the results in the surgical treatment after neoadjuvancy of the APBR. METHOD: Between 2010 and 2014, we included patients with APBR in a neoadjuvant and surgery protocol, staged by multidetector computed tomography (MDCT). Treatment with chemotherapy was based on gemcitabine and oxaliplatin. Subsequently, MDCT was performed to rule out progression, and 5-FU infusion and concomitant radiotherapy were given. MDCT and resection were performed in absence of progression. A descriptive statistical study was performed, dividing the series into: surgery group (GR group) and progression group (PROG group). RESULTS: We indicated neoadjuvant treatment to 22 patients, 11 of them were operated, 9 pancreatoduodenectomies, and 2 distal pancreatectomies. Of the 11 patients, 7 required some type of vascular resection; 5 venous resections, one arterial and one both. No postoperative mortality was recorded, 7 (63%) had any complications, and 4 were reoperated. The median postoperative stay was 17 (7-75) days. The pathological study showed complete response (ypT0) in 27%, and free microscopic margins (R0) in 63%. At study clossure, all patients had died, with a median actuarial survival of 13 months (9,6-16,3). The median actuarial survival of the GR group was higher than the PROG group (25 vs. 9 months; p < 0.0001). CONCLUSION: The neoadjuvant treatment of APBR allows us to select a group of patients in whom resection achieves a longer survival to the group in which progression is observed. Post-adjuvant pancreatic resection requires vascular resection in most cases.

A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features.

BACKGROUND: Perioperatory chemoradiotherapy (CRT) improves local control and survival in patients with locally advanced rectal cancer (LARC). The objective of the current study was to evaluate the addition of bevacizumab (BEV) to preoperative capecitabine (CAP)-based CRT in LARC, and to explore biomarkers for downstaging. METHODS: Patients (pts) were randomized to receive 5 weeks of radiotherapy 45 Gy/25 fractions with concurrent CAP 825 mg/m(2) twice daily 5 days per week and BEV 5 mg/kg once every 2 weeks (3 doses) (arm A), or the same schedule without BEV (arm B). The primary end point was pathologic complete response (ypCR: ypT0N0). RESULTS: Ninety pts were included in arm A (44) or arm B (46). Grade 3-4 treatment-related toxicity rates were 16% and 13%, respectively. All patients but one (arm A) proceeded to surgery. The ypCR rate was 16% in arm A and 11% in arm B (p =0.54). Fifty-nine percent vs 39% of pts achieved T-downstaging (arm A vs arm B; p =0.04). Serial samples for biomarker analyses were obtained for 50 out of 90 randomized pts (arm A/B: 22/28). Plasma angiopoietin-2 (Ang-2) levels decreased in arm A and increased in arm B (p <0.05 at all time points). Decrease in Ang-2 levels from baseline to day 57 was significantly associated with tumor downstaging (p =0.02). CONCLUSIONS: The addition of BEV to CAP-based preoperative CRT has shown to be feasible in LARC. The association between decreasing Ang-2 levels and tumor downstaging should be further validated in customized studies. TRIAL REGISTRY: Clinicaltrials.gov identifier NCT01043484. Trial registration date: 12/30/2009.

The involvement of the hepatic artery is a risk factor for unresectability after neoadjuvant treatment in borderline pancreatic adenocarcinoma.

INTRODUCTION: Borderline Resectable Pancreatic Ductal Adenocarcinoma (BR-PDAC) benefits from neoadjuvant treatment (NAT) with the intent of surgical salvage in the absence of disease progression during chemotherapy (CT) or chemoradiotherapy (CRT). Scarce literature exists about prognostic factors of resectability at the time of diagnosis or during neoadjuvant treatment, especially regarding vascular relationships. MATERIALS: We reviewed our prospective BR-PDAC cohort to determine resectability predictors. We collected data about clinical baseline characteristics, vessels' involvement, type of NAT, CA19-9 evolution, and radiological outcome. We performed a descriptive analysis and a logistic regression model to define resectability predictors; we finally compared overall survival (OS) and progression-free survival (PFS) for those predictors. RESULTS: One hundred patients started NAT, with a resection rate of 44 % (40 pancreaticoduodenectomies, 4 distal pancreatectomies). The most frequent vessel relationship was the abutment of the superior mesenteric artery (44 %), and 26 patients had ≥2 vessels involved. Prognostic factors of resectability were CA19-9 response >10 % (OR 3.07, p = 0.016) and Hepatic Artery involvement (OR 0.21, p = 0.026). Median overall survival was better for CA19-9 responders than for non-responders (20.9 months and 11.8 months respectively, p < 0.001), and similar to normalized CA19-9 (25.0 months, p = 0.48). There were no differences in terms of OS or PFS with the involvement of the HA (17.7 vs 17.1 months, p = 0.367; and 8.7 vs 12.0 months, p = 0.267). CONCLUSION: The involvement of the Hepatic Artery seems to confer a worse prognosis regarding resectability. A decrease of only >10 % of CA19-9 is a predictive factor for resectability and better overall and progression-free survival.

Endoscopic ultrasound-guided biliary rendezvous after failed cannulation, and comparison between benign vs malignant biliopancreatic disorders: outcomes at a single tertiary-care centre.

BACKGROUND: Endoscopic ultrasound (EUS)-guided biliary rendezvous (RV) is an EUS-assisted technique described as a rescue method in cases of failed biliary cannulation via endoscopic retrograde cholangiography (ERC). Current literature remains unclear regarding its current role. The study aim was to evaluate the effectiveness for biliary EUS-RV, and comparison between benign vs malignant biliopancreatic disorders. METHODS: Retrospective observational study with prospective consecutive inclusion in a specific database from a tertiary-center. All patients with biliopancreatic diseases that underwent a EUS-assisted ERC between October-2010 and November-2022 for failed ERC were included. Main outcomes were technical/overall success. Secondary outcomes were safety, potential factors related to failure/success or safety; and a comparative analysis between EUS-RV and EUS-guided transmural drainage (TMD) in malignant cases. RESULTS: A total of 69 patients who underwent EUS-RV procedures, with benign and malignant pathologies (n = 40 vs n = 29), were included. Technical / overall success and related-adverse events (AEs) were 79.7% (95%CI, 68.3-88.4) / 74% (95%CI, 61-83.7) and 24% (95%CI, 15.1-36.5), respectively. Failed cases were mainly related with guidewire manipulation. Seven failed RV were successfully rescued by EUS-TMD. On multivariable analysis, EUS-RV and malignant pathology was associated with a greater failure rate (technical success: OR,0.21; 95%CI,0.05-0.72; p = 0.017), and higher AEs rate (OR,3.46; 95%CI,1.13-11.5; p = 0.034). Also, the EUS-TMD group had greater technical success (OR,16.96; 95%CI,4.69-81.62; p < 0.001) and overall success (OR, 3.09; 95%CI,1.18-8-16; p < 0.026) with a lower AEs rate (OR,0.30; 95%CI,0.11-0.78; p = 0.014) than EUS-RV in malignant disorders. CONCLUSIONS: EUS-RV is a demanding technique with better outcomes in benign than in malignant biliopancreatic diseases. Comparison of the EUS-TMD group on malignant disorders showed worse outcomes with EUS-RV. Given these findings, maybe EUS-RV is not the best option for malignant biliopancreatic disorders.

Last international guidelines suggest Endoscopic Ultrasound (EUS)-guided assisted bile duct access (or biliary rendezvous) after a second failed Endoscopic Retrograde Cholangiography (ERC) in benign biliary disease, in high volume centers, but its current role in malignant disease is unclear.This study provides a larger number of EUS-guided biliary rendezvous cases than reported in previous studies, and offers new and relevant information, not available in the last clinical guidelines or systematic reviewsThe EUS-guided biliary rendezvous associates better effectiveness in benign than in malignant biliopancreatic disorders. When comparing EUS-guided rendezvous with EUS-biliary transmural drainage in malignant diseases, rendezvous has a lower success, and higher adverse events. Therefore, maybe EUS-guided rendezvous is not the best option for malignant disorders and might be reserved for benign cases.

Exploring the Associations of Inflammatory and Oxidative Stress Biomarkers with Pancreatic Diseases: An Observational and Mendelian Randomisation Study.

Identifying biomarkers linked to pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP) is crucial for early detection, treatment, and prevention. Methods: Association analyses of 10 serological biomarkers involved in cell signalling (IFN-γ, IL-6, IL-8, IL-10), oxidative stress (superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities, total glutathione (GSH), malondialdehyde (MDA) levels), and intestinal permeability proteins (zonulin, I-FABP2) were conducted across PDAC (n = 12), CP (n = 21) and control subjects (n = 23). A Mendelian randomisation (MR) approach was used to assess causality of the identified significant associations in two large genetic cohorts (FinnGen and UK Biobank). Results: Observational results showed a downregulation of SOD and GPx antioxidant enzyme activities in PDAC and CP patients, respectively, and higher MDA levels in CP patients. Logistic regression models revealed significant associations between CP and SOD activity (OR = 0.21, 95% CI [0.05, 0.89], per SD), GPx activity (OR = 0.28, 95% CI [0.10, 0.79], per SD), and MDA levels (OR = 2.05, 95% CI [1.36, 3.08], per SD). MR analyses, however, did not support causality. Conclusions: These findings would not support oxidative stress-related biomarkers as potential targets for pancreatic diseases prevention. Yet, further research is encouraged to assess their viability as non-invasive tools for early diagnosis, particularly in pre-diagnostic CP populations.

Metronomic chemotherapy following the maximum tolerated dose is an effective anti-tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells.

In this article, the effectiveness of a multi-targeted chemo-switch (C-S) schedule that combines metronomic chemotherapy (MET) after treatment with the maximum tolerated dose (MTD) is reported. This schedule was tested with gemcitabine in two distinct human pancreatic adenocarcinoma orthotopic models and with cyclophosphamide in an orthotopic ovarian cancer model. In both models, the C-S schedule had the most favourable effect, achieving at least 80% tumour growth inhibition without increased toxicity. Moreover, in the pancreatic cancer model, although peritoneal metastases were observed in control and MTD groups, no dissemination was observed in the MET and C-S groups. C-S treatment caused a decrease in angiogenesis, and its effect on tumour growth was similar to that produced by the MTD followed by anti-angiogenic DC101 treatment. C-S treatment combined an increase in thrombospondin-1 expression with a decrease in the number of CD133+ cancer cells and triple-positive CD133+/CD44+/CD24+ cancer stem cells (CSCs). These findings confirm that the C-S schedule is a challenging clinical strategy with demonstrable inhibitory effects on tumour dissemination, angiogenesis and CSCs.

Predictive factors for resection and survival in type A borderline resectable pancreatic ductal adenocarcinoma patients after neoadjuvant therapy: A retrospective cohort study.

INTRODUCTION: Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, and surgical resection with radical intent remains the only potentially curative treatment option today. However, borderline resectable pancreatic ductal adenocarcinomas (BR-PDAC) stand in the gray area between the resectable and unresectable disease since they are technically resectable but have a high probability of incomplete exeresis. Neoadjuvant treatment (NAT) plays an important role in ensuring resection success.Different survival prognostic factors for BR-PDAC have been well described, but evidence on the predictive factors associated with resection after NAT is scarce. This study aims to study if CA 19-9 plasmatic levels and the tumor anatomical relationship with neighboring vascular structures are prognostic factors for resection and survival (both Overall Survival and Progression-Free Survival) in patients with type A BR-PDAC. METHODS: This will be a retrospective cohort study using data from type A BR-PDAC patients who received NAT in the Bellvitge University Hospital. The observation period is from January 2010 until December 2019; patients must have a minimum 12-month follow-up. Patients will be classified according to the MD Anderson Cancer Center criteria for BR-PDAC. DISCUSSION: Patients with BR-PDAC have a high risk for a margin-positive resection. Serum Carbohydrate Antigen 19-9 plasmatic levels and vascular involvement stand out as disease-related prognostic factors.This study will provide valuable information on the prognostic factors associated with resection. We will exclude locally advanced tumors and expect this approach to provide more realistic resection rates without selecting those patients that undergo surgical exploration. However, focusing on an anatomical definition may limit the results' generalizability.

Multicenter study of lumen-apposing metal stents with or without pigtail in endoscopic ultrasound-guided biliary drainage for malignant obstruction-BAMPI TRIAL: an open-label, randomized controlled trial protocol.

BACKGROUND: It is unclear whether the insertion of an axis-orienting double-pigtail plastic stent (DPS) through biliary lumen-apposing meal stent (LAMS) in EUS-guided choledochoduodenostomy (CDS) improves the stent patency. The aim of this study is to determine whether this technical variant offers a clinical benefit in EUS-guided biliary drainage (BD) for the management of distal malignant biliary obstruction. METHODS/DESIGN: This is a multicenter open-label, randomized controlled trial with two parallel groups. Eighty-four patients with malignant biliary obstruction will undergo EUS-BD (CDS type) using LAMS in 7 tertiary hospitals in Spain and will be randomized to the LAMS and LAMS plus DPS groups. The primary endpoint is the rate of recurrent biliary obstruction, as a stent dysfunction parameter, detected during follow-up. Secondary endpoints: technical and clinical success (reduction in bilirubin > 50% within 14 days of stent placement), safety, and others (number of reinterventions, time to biliary obstruction, prognostic factors, survival rate). DISCUSSION: The BAMPI trial has been designed to determine whether the addition of a coaxial axis-orienting DPS through LAMS is superior to LAMS alone to prevent stent dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov NCT04595058 . Registered on October 14, 2020.

VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects.

BACKGROUND: Pancreatic 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. METHODS: VCN-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. RESULTS: VCN-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. CONCLUSIONS: VCN-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 NUMBER: EudraCT number: 2012-005556-42 and NCT02045589.