Advanced Pancreatic Tumors Research Articles

Refractory hypercalcaemia in advanced metastatic pancreatic neuroendocrine tumour controlled on weekly denosumab

Refractory hypercalcaemia in advanced metastatic pancreatic neuroendocrine tumour controlled on weekly denosumab

ASO Author Reflections: Ampulla of Vater Carcinoma with Advanced Pancreatic Invasion Imply Advanced Tumor Progression to Systemic Disease.

ASO Author Reflections: Ampulla of Vater Carcinoma with Advanced Pancreatic Invasion Imply Advanced Tumor Progression to Systemic Disease.

Evolution and improved outcomes in the era of multimodality treatment for extended pancreatectomy.

The evolution and outcomes of extended pancreatectomies at a single institute over 15 years are presented in this study. A retrospective analysis of the institutional database was performed from 2015 to 2022 (period B). Patients undergoing extended pancreatic resections, as defined by the International Study Group for Pancreatic Surgery, were included. Perioperative and survival outcomes were compared with data from 2007-2015 (period A). Regression analyses were used to identify factors affecting postoperative and long-term survival outcomes. A total of 197 (16.1%) patients underwent an extended resection in period B compared to 63 (9.2%) in period A. Higher proportions of borderline resectable (5 (18.5%) versus 51 (47.7%), P = 0.011) and locally advanced tumours (1 (3.7%) versus 24 (22.4%), P < 0.001) were resected in period B with more frequent use of neoadjuvant therapy (6 (22.2%) versus 79 (73.8%), P < 0.001). Perioperative mortality (4 (6.0%) versus 12 (6.1%), P = 0.81) and morbidity (23 (36.5%) versus 83 (42.1%), P = 0.57) rates were comparable. The overall survival for patients with pancreatic adenocarcinoma was similar in both periods (17.5 (95% c.i. 6.77 to 28.22) versus 18.3 (95% c.i. 7.91 to 28.68) months, P = 0.958). Resectable, node-positive tumours had a longer disease-free survival (DFS) in period B (5.81 (95% c.i. 1.73 to 9.89) versus 14.03 (95% c.i. 5.7 to 22.35) months, P = 0.018). Increasingly complex pancreatic resections were performed with consistent perioperative outcomes and improved DFS compared to the earlier period. A graduated approach to escalating surgical complexity, multimodality treatment, and judicious patient selection enables the resection of advanced pancreatic tumours.

Endoscopic ultrasonography-guided biliary drainage in a patient with a locally advanced pancreatic tumor with obstructive jaundice. (Case report)

Endoscopic ultrasonography-guided biliary drainage in a patient with a locally advanced pancreatic tumor with obstructive jaundice. (Case report)

Pancreatic Cancer Outcome: Local Treatment with Radiation Using MRI-Linac

Stereotactic MR-guided on-table adaptive radiotherapy (SMART) is a surging modality in radiotherapy, delivering high dose radiation to the tumor in great proximity to susceptible organs. The aim of this study is to evaluate the clinical outcome in locally advanced or recurrent pancreatic tumors with or without prior irradiation. All consecutive patients were treated in our center for pancreatic cancer (PC) using SMART technology to a prescription of 50Gy (BED10 100 Gy1o) in 5 fractions, with daily on-table adaptation of treatment plan. Endpoints for this retrospective, single center, IRB approved study were local control, overall survival, local disease-free period, acute and late toxicities. Fifty-four PC patients were treated between 8.2019-9.2022, with median follow-up of 8.9 months from SMART (0.8-34 months). Forty patients had upfront inoperable PC (45% were metastatic at RT, five treated to liver metastatic lesions concomitantly) and fourteen patients had local recurrence following prior pancreatectomy, six of them had prior adjuvant RT. 87% received at least one round of chemotherapy (Oxaliplatin based- 72%), 25% received ≥2 regimens. Mean age was 68.9 (45-86) years. There was no significant difference in baseline parameters between prior pancreatectomy and inoperable groups. On-table adaptive replanning was performed for 100% of all (269) fractions (one patient received 4 fractions). No patient reported grade ≥2 acute GI toxicity. Six patients reported fatigue at the end of RT, four of them had prior radiation. Forty-eight patients were available for evaluation. Complete local control was achieved in 21.7% (10 patients) for median of 9 months (2.8-28.8 months), three had later local progression. Eight patients had regional or marginal recurrence following treatment. 6-months and 12-months OS was 75% and 52%, respectively. There was no significant difference in toxicity and outcome between post-pancreatectomy and inoperable groups. Pancreatic cancer local ablative SMART is safe, with minimal treatment-related toxicity, even in previously irradiated patients. Local control with complete response was achieved by 20% of patients. Further studies are needed to evaluate long-term outcome and late toxicity.

Two Stage Resection of a Bilateral Pheochromocytoma and Locally Advanced Pancreatic Tumor in a 26 Years Old Pregnant Women: Case Report

Synchronous occurrence of pheochromocytoma and pancreatic tumors is rare and considered as part of Von Hippel Lindau Syndrome. We herein report a such case that was managed by a two staged resection of the pancreatic tumor along with excision of bilateral pheochromocytomas and also discuss in detail our review of literature about this condition.

CTNI-03. A PHASE I/IIA, OPEN-LABEL STUDY OF THE BRAIN-PENETRANT PARP1-SELECTIVE INHIBITOR AZD9574 AS MONOTHERAPY AND IN COMBINATION IN PATIENTS WITH ADVANCED SOLID MALIGNANCIES (CERTIS1)

Abstract BACKGROUND Currently approved Poly ADP-Ribose Polymerase (PARP) inhibitors (PARPi) selectively inhibit and trap both PARP1 and PARP2 (PARP1/2) at sites of single strand (ss) deoxyribonucleic acid (DNA) (ssDNA) damage, preventing ssDNA repair and leading to replication-dependent DNA double strand breaks. Recent data suggest that only inhibition of PARP1 is required for anti-proliferative effects, while PARP2 functions in the survival of haematopoietic stem and progenitor cells. These observations suggest that the inhibition and trapping of PARP 2 is not needed for anti-cancer effects, and may be a major driver of haematological toxicity observed. AZD9574 is a novel brain-penetrant PARPi that potently and selectively inhibits and traps PARP1, with the goal of delivering efficacious, less toxic, and more combinable PARPi. Furthermore, owing to its central nervous system penetration capability, AZD9574 may provide a new treatment option for patients with CNS malignancies or patients with brain metastases characterized by homologous recombination deficiency (HRD). METHODS This is a first-in-human modular study primarily designed to evaluate the safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents at increasing dose levels in patients with advanced solid malignancies, followed by expansion cohorts in specific indications. The study will also characterize the pharmacokinetics of AZD9574 and explore potential biological activity by assessing pharmacodynamic and exploratory biomarkers and anti-tumour activity. Module 1 will enrol patients with advanced breast, ovarian, pancreatic or prostate tumours harbouring homologous recombination deficiencies. Module 2 will enrol patients with isocitrate dehydrogenase (IDH)1/2 mutated glioma.

Brachytherapy via a depot of biopolymer-bound 131I synergizes with nanoparticle paclitaxel in therapy-resistant pancreatic tumours.

Locally advanced pancreatic tumours are highly resistant to conventional radiochemotherapy. Here we show that such resistance can be surmounted by an injectable depot of thermally responsive elastin-like polypeptide (ELP) conjugated with iodine-131 radionuclides (131I-ELP) when combined with systemically delivered nanoparticle albumin-bound paclitaxel. This combination therapy induced complete tumour regressions in diverse subcutaneous and orthotopic mouse models of locoregional pancreatic tumours. 131I-ELP brachytherapy was effective independently of the paclitaxel formulation and dose, but external beam radiotherapy (EBRT) only achieved tumour-growth inhibition when co-administered with nanoparticle paclitaxel. Histological analyses revealed that 131I-ELP brachytherapy led to changes in the expression of intercellular collagen and junctional proteins within the tumour microenvironment. These changes, which differed from those of EBRT-treated tumours, correlated with the improved delivery and accumulation of paclitaxel nanoparticles within the tumour. Our findings support the further translational development of 131I-ELP depots for the synergistic treatment of localized pancreatic cancer.

The correlation between the embryological development of the pancreas and the local extent of the pancreatic tumors

Progression reported so far in the field of hepato-bilio-pancreatic surgery leaded to a significant increase of the number of cases diagnosed with borderline or locally advanced pancreatic tumors which are successfully submitted to radical surgery. However, it has been observed that local invasion of the vascular structures respects the embryological and anatomical development of the pancreatic parenchyma. The aim of the current paper is to analyze the correlation ship between the embryological development of the pancreas, location, extent and possible therapeutic strategies in borderline or locally advanced pancreatic head cancer.

Autologous grafts for vascular resections after extended resections for locally advanced or borderline resectable pancreatic tumors

Once the surgical techniques improved, vascular resections have been proposed in order to increase the radicality in borderline or locally advanced pancreatic cancer. Traditionally, vascular reconstructions in such cases have been performed by using synthetic grafts; however, these prostheses have been associated with significant complications such as infection, thrombosis or leaks, leading to a very difficult postoperative recovery. Therefore, attention was focused on replacing these artificial materials with biological ones such as cadaveric grafts, autologous grafts or even animal grafts. These grafts proved to be more efficient when it comes to the rates of perioperative complications, thrombosis, infection or leakage being more rarely reported. The aim of the current paper is to discuss about the most frequently used biological grafts.

Robotic modified Appleby: Case report, technical aspects and video

Introduction and importancePancreatic body and tail adenocarcinoma is a tumor of silent evolution, showing up as advanced disease at diagnosis in the majority cases.Case presentationA 60-year-old man, presenting a solid expansive lesion (3.1 × 2.8 cm) in the body of the pancreas, by imaging exams. There was 50% involvement of the celiac trunk at the level of the it's bifurcation and suspected peripancreatic lymph nodes. Clinical staging was cT4N1M0. After neoadjuvant chemotherapy (NQT), there was a small reduction of the tumor to 3.0 × 2.6 cm, an important decreasing of the celiac trunk involvement (25%), and also a reduction in the levels of C19–9 from 650 U/mL to 358 U/mL. Further on, the patient underwent a Robotic Modified Appleby procedure, without intra and postoperative complications.Clinical discussionLocally advanced pancreatic tumors should be referred to NQT, and those with good response might benefit to radical surgery. The modified Appleby technique - distal pancreatectomy with splenectomy and celiac trunk resection – is the procedure of choice when there is involvement of celiac trunk, but concern must be given to the liver vascularization. The use of robotic system on pancreatic surgery is emerging, but still, there is lower data regarding its safety in major pancreatic procedures.ConclusionThe use of neoadjuvant therapy is recommended to assess the in vivo response, improve oncological results and increase negative margins. Pre-operative imaging is mandatory for surgical planning. The robotic modified Appleby procedure is feasible and safe, with reduced of intraoperative blood loss and transfusion rate, corroborating the literature.

Venous segmental resection in locally advanced pancreatic tumors.

e16243 Background: Surgical treatment is considered the main treatment for pancreatic cancer improving the patient survival. The most common obstacle to surgery with R0 resection is the involvement of the great vessels. Recently, venous resections have been increasingly performed for this type of tumors. Our purpose was to evaluate radicality of surgical treatment and postoperative morbidity in patients with locally advanced pancreatic cancer. Methods: The study included patients with locally advanced pancreatic cancer (T3 N0-1 M0) with damage to the venous segment (portal vein system) confirmed by CT angiography. Results: Over a 5-year period, 73 (18.9%) of 386 operated-on patients with pancreatic cancer underwent surgeries for pancreatic ductal adenocarcinoma with venous resection. The frequency of wedge venous resection was 24.7% (18), segmental resection with end-to-end anastomosis - 46.6% (34), prosthetics - 26% (19), prosthetics with replantation of the splenic vein - 2.7% (2). The postoperative morbidity rate was 30.1%. Within 30 days after surgery, the mortality rate reached 5.5% (4 patients). The main causes were bleeding and thrombosis of the reconstruction area. Only patients with venous segment replacement developed thrombotic complications. Microscopically complete resection was performed in 87.7% of cases (64 patients). During the follow-up period, the 1-year survival rate reached 90%, and the recurrence-free rate was 93%. Conclusions: Surgical treatment for locally advanced pancreatic tumors with damage to the portal vein system shows an acceptable rate of postoperative complications due to the vascular stage, and a high rate of reaching a negative resection margin. Initial assessment of the need for venous resection is required in patients with pancreatic tumors, as well as expanding the extent of surgical intervention due to venous resection to achieve R0 resections.

An open, single-center, exploratory clinical trial to evaluate the safety and efficacy of RNA CAR-mesothelin T cells in patients with advanced refractory pancreatic cancer.

TPS628 Background: Pancreatic cancer is an aggressive gastrointestinal cancer characterized by late diagnosis initially, prone to distant metastasis and poor prognosis. The current treatment of pancreatic cancer is very limited, resulting in its 5-year survival rate of less than 10%. It is necessary to seek new treatment methods and treatments. Chimeric antigen receptor T (CART) cell therapy has made a breakthrough in hematological malignancies. Therefore, the goal of this clinical trial is to study the safety, efficacy and pharmacokinetics of mRNA-engineered anti-Mesothelin Chimeric Antigen Receptor T-Cell (anti-MESO CAR-T cells) therapy in patients with mesothelin expression-positive, advanced pancreatic tumors that have failed at least first-line or second-line therapy. Methods: The study will adopt the "3+3" dose escalation design exploring two doses of 1×109 and 3×109. The administration is planned to infuse 3 times a week for 2 consecutive weeks. The subjects will receive a total dose of 1x109 RNA transduced anti-MESO CAR-T cells in the first week, following lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days by intravenous infusion. If there is no obvious dose-limiting toxicity (DLT) after the first week of infusion, three times consecutive infusions of 1x109 anti-MESO CAR-T cells each time is planned in the second week. Each subject needs to be observed for at least 2 weeks (14 days) after completing the last infusion. Lymphodepleting chemotherapy will not be repeated prior to additional infusions of anti-MESO CAR-T cells. Clinical trial information: 04981691.

Palliative Surgery in Pancreatic Head Cancer at the University Hospital of Bouaké

<i>Introduction</i>: Cancer of the head of the pancreas is increasing in incidence. It represents 3% of all cancers and 20% of digestive cancers. Diagnosis is most often late. Indeed, 80% of these cancers are discovered at an advanced stage. In this case, the treatment is essentially palliative. The reference treatment is chemotherapy associated with endoscopic treatment if there is obstruction of the bile duct. Palliative surgery is only indicated in the case of intraoperative discovery of a contraindication to a curative surgical procedure. However, this palliative surgery is still in the forefront in low-income countries with limited technical facilities. The aim of this work was to determine the frequency and modalities of palliative surgery in unresectable pancreatic head cancer and to evaluate the results. <i>Methods</i>: Retrospective and descriptive study of the files of patients who underwent palliative surgery for a malignant tumour of the head of the pancreas; operated at the University Hospital of Bouake from January 2011 to December 2020. <i>Results</i>: Palliative surgery was performed in 71 patients, or 80.6% of patients with locally advanced pancreatic head tumour. We performed a double biliary and digestive bypass systematically. The digestive bypass was a gastrojejunal anastomosis in all cases. For the biliary-digestive diversion, different modalities were performed, notably a choledocho-jejunal anastomosis in 53.6% (n=38), a cholecysto-jejunal anastomosis in 38.0% (n=27) and a choledochodenal anastomosis in 8.4% (n=6). The overall morbidity was 22.5% (n=16). Morbidity related to the surgical procedure was 18.3% (n=13). These were biliary leakage (n=6; 8.4%) and parietal bleeding (n=4; 5.6%). Three patients died immediately postoperatively, giving an operative mortality of 4.2%. The mean survival of the patients was 5.8±2.2 months. <i>Conclusion</i>: Palliative surgery occupies a privileged place in our practice, allowing an improvement in the quality of life of the patients without apparent influence on the long-term prognosis which remains appalling. The hope of improving the prognosis lies in early diagnosis and strengthening the technical platform.

Intraoperative HIFU Ablation of the Pancreas Using a Toroidal Transducer in a Porcine Model. The First Step towards a Clinical Treatment of Locally Advanced Pancreatic Cancer.

Simple SummaryRegardless of treatment, the overall 5-year survival rate for patients with pancreatic adenocarcinoma is less than 5%. The aim of this preclinical study was to evaluate the feasibility of intraoperative focused ultrasound ablation of the pancreas under Doppler guidance to treat the pancreatic parenchyma and tissues surrounding the superior mesenteric vessels in vivo in a pig model. Large and homogeneous destruction of the pancreatic parenchyma and tissues around the peripancreatic artery without spasm or occlusion by focused ultrasound during an open procedure was feasible without organ penetration. Ultrasound guidance allows for the objective evaluation of the actual treated region. This method could aid in the treatment of locally advanced pancreatic adenocarcinoma that is inaccessible by other known therapeutic methods. The device presented herein is simple to use, reliable and adaptable to local conditions. Such a treatment may also be used in conjunction with resection.Apart from palliative chemotherapy, no other therapy has been proven effective for the treatment of locally advanced pancreatic tumors. In this study, an intraoperative high-intensity focused ultrasound (HIFU) device was tested in vivo to demonstrate the feasibility of treating the pancreatic parenchyma and tissues surrounding the superior mesenteric vessels prior to clinical translation of this technique. Twenty pigs were included and treated using a HIFU device equipped with a toroidal transducer and an integrated ultrasound imaging probe. Treatments were performed with energy escalation (from 30 kJ to 52 kJ). All treatments resulted in visible (macroscopically and in ultrasound images) homogeneous thermal damage, which was confirmed by histology. The dimensions of thermal lesions measured in ultrasound images and those measured macroscopically were correlated (r = 0.82, p < 0.05). No arterial spasms or occlusion were observed at the lowest energy setting. Temporary spasm of the peripancreatic artery was observed when using an energy setting greater than 30 kJ. The possibility of treating the pancreas and tissues around mesenteric vessels without vascular thrombosis holds great promise for the treatment of locally advanced pancreatic cancers. If clinically successful, chemotherapy followed by HIFU treatment could rapidly become a novel treatment option for locally advanced pancreatic cancer.

Auto-intestine transplantation for pancreatic tumors with mesenteric root involvement: a systematic review and survival-based analysis

Abstract To analyze a long-term survival outcome of an auto-intestine transplantation (aINTx) for the patients with locally advanced pancreatic tumor and identify the potential prognostic factors, databases were carefully searched for the studies reporting the patients with a locally advanced pancreatic tumor which typically underwent aINTx. We performed a database search using PubMed, the Cochrane Library, EMBASE, and MEDLINE to identify multiple case series of the patients who had pancreatic tumors with mesenteric root involvement and underwent aINTx, to evaluate the treatment outcomes, and calculated the patient survival using the Kaplan–Meier method and Cox proportional hazard regression analysis to properly identify an independent predictor of the survival. A total of 9 retrospective studies with a total of 29 patients were included in our study. The calculated 1-, 2-, and 3-year survival rates for the patients with pancreatic cancer and benign or low grade pancreatic tumors were 49.64%, 22.06%, and 0% versus 100%, 100%, and 80%, respectively. The corresponding median survival time was 13.4 months and 84 months, respectively. Moreover, when stratifying the pancreatic cancer patients undergoing aINTx on the basis of neoadjuvant chemotherapy (aINTx + neoadjuvant vs aINTx - neoadjuvant) there was a significant difference in the survival (P = .01). The 1- and 2-year survival rates were 75% and 75% versus 34.1% and 0%, respectively. Corresponding median survival times were 24 months and 10 months, respectively. Our analysis shows the long-term survival benefit with acceptable morbidity and mortality of pancreatoduodenectomy and aINTx for the pancreatic tumors with the mesenteric root involvement that are otherwise unresectable by the conventional surgical techniques. However, from an oncological point of view, a larger study with the control group is required to determine its safety compared to less aggressive surgical treatment.

Clinical challenges and dilemmas in the management of advanced pancreatic neuroendocrine tumour - the first manifestation of von Hippel-Lindau disease in a young patient.

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Risk factors for early morbidity and mortality following pancreatoduodenectomy with concomitant vascular reconstruction

BackgroundLocally advanced pancreatic tumors may require vascular reconstruction for complete resection. However, pancreatoduodenectomy with vascular resection (PDVR) remains a subject of debate due to increased complications. MethodsPatients were identified using the ACS NSQIP Participant User Data Files from 2014 to 2019. ResultsThe 30-day mortality rate was 2.7%; major complications occurred in 32.2%. There is an increasing trend of PDVR in patients requiring pancreatectomy. There were no significant differences in mortality between PDVR with vein, artery, or venous and arterial resections. High BMI and postoperative biliary stent were risk factors for early complications. High BMI and COPD increased risk of early mortality. Chemotherapy and chemoradiotherapy were negative predictors for early morbidities and mortality, respectively. ConclusionThis study identifies the predictors of early morbidity and mortality in PDVR. The results of this study may assist decision making in perioperative management to optimize overall survival and guide additional research.

Robot-assisted Distal Pancreatectomy with En Bloc Celiac Axis Resection (Modified Appleby Procedure) after Neoadjuvant Therapy

Pancreatic carcinoma in the body and on the left side of the mesentericoportal axis is often only detected in late stages owing to unspecific or even missing clinical symptoms. In approximately 20% of the cases, there is already infiltration of the tumour into the surrounding arteries or veins. Despite locally advanced growth, 30% of patients do not have distant metastases and would potentially qualify for local resection. Arterial resections and vascular reconstruction are associated with an almost 9-fold increase in postoperative mortality compared with resections without vascular reconstruction. The Appleby procedure is a complex surgical technique originally developed for advanced gastric cancer. The technique has been further developed for patients with advanced pancreatic body and tail tumours with infiltration of the coeliac trunk (modified Appleby procedure). The advantage of the procedure is that technically, no reconstruction of the resected arteries is required. This is because a natural internal anastomosis in the pancreatic head between the A.mesenterica superior and the A.hepatica via branches of the A.gastroduodenalis is used to maintain liver perfusion and gastric blood flow. However, the surgical procedure is also associated with high morbidity and mortality, with comparably poor oncological results (R0 rates of approximately 60%). Therefore, the procedure was not recommended until a few years ago, and patients were considered inoperable. With developments in neoadjuvant therapy for pancreatic carcinoma, the Appleby procedure is being performed more frequently, with the goal of improving oncological outcomes in the context of multimodal treatment. With developments in robotics in visceral surgery, the previous limitations of minimally invasive pancreatic surgery can be overcome, and significantly more patients may benefit from the advantages of this minimally invasive surgery, such as faster convalescence. The use of robotic surgical techniques allows the extension of minimally invasive techniques into the field of complex vessel resection and reconstruction. In this video contribution, we describe a robot-assisted modified Appleby procedure using the Da Vinci Xi Surgical System in a patient with advanced pancreatic carcinoma of the pancreatic body, after neoadjuvant therapy.

Pancreaticoduodenectomy with vascular divestment for locally advanced pancreatic neuroendocrine tumour.

Pancreaticoduodenectomy with vascular divestment for locally advanced pancreatic neuroendocrine tumour.