The use of angiotensin system inhibitors correlates with longer survival in resected pancreatic adenocarcinoma patients

BackgroundActivities and inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) may affect the survival of resected pancreatic ductal adenocarcinoma (PDAC) patientsMethodA single-institution retrospective analysis of resected PDAC patients between 2010 and 2019. To estimate the effect of angiotensin system inhibitors (ASIs) on patient survival, we performed Kaplan Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse probability weighting (IPW) analysis.Results742 patients were included in the analysis. The average age was 67.0 years, with a median follow-up of 24.1 months. The use of ASI was associated with significantly longer overall survival in univariate (p = 0.004) and multivariable (HR = 0.70 [0.56–0.88],p = 0.003) adjusted analysis. In a propensity score-matched cohort of 400 patients, ASI use was again associated with longer overall survival (p = 0.039). Lastly, inverse probability weighting (IPW) analysis suggested that the use of ASI was associated with an average treatment effect on the treated (ATT) of HR = 0.68 [0.53–0.86],p = 0.002) for overall survival.ConclusionIn this single-institution retrospective study focusing on resected PDAC patients, the use of ASI was associated with longer overall survival in multiple statistical models. Prospective clinical trials are needed before routine clinical implementation of ASI as an adjuvant to existing therapy can be recommended.     

Preoperative evaluation of pancreatic adenocarcinoma

The preoperative evaluation of resectability for pancreatic cancer fails to identify up to 25% of patients who are unfortunately found to be unresectable at surgical exploration. Inoperative findings in this circumstance is usually due to either small volume metastatic disease or regional tumor invasion. While advances in computed tomography (CT) technology has increased accuracy of local tumor extent, occult metastatic disease remains a common problem. Although 2-[¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been demonstrated to be useful in the staging of many malignancies (e.g. esophageal cancer, recurrent colorectal cancer, lung cancer), it has not been found to significantly increase the accuracy of determining resectability preoperatively in pancreatic cancer, especially with regard to detection of small volume metastatic disease. There are a variety of pancreatic cancer-specific antigens which are being developed as a method for targeted molecular imaging; we provide preliminary data targeting the integrin α_vβ₆ to demonstrate the potential feasibility of this approach. Further developments may allow the accurate determination of patients with resectable pancreatic cancer, and more importantly, those with unresectable disease that may forego unnecessary surgery, the associated morbidity, and the subsequent delay of appropriate therapy.     

Pancreatic Cancer UK Grand Challenge: Developments and challenges for effective CAR T cell therapy for pancreatic ductal adenocarcinoma

BackgroundDeath from pancreatic ductal adenocarcinoma (PDAC) is rising across the world and PDAC is predicted to be the second most common cause of cancer death in the USA by 2030. Development of effective biotherapies for PDAC are hampered by late presentation, a low number of differentially expressed molecular targets and a tumor-promoting microenvironment that forms both a physical, collagen-rich barrier and is also immunosuppressive. In 2017 Pancreatic Cancer UK awarded its first Grand Challenge Programme award to tackle this problem. The team plan to combine the use of novel CAR T cells with strategies to overcome the barriers presented by the tumor microenvironment. In advance of publication of those data this review seeks to highlight the key problems in effective CAR T cell therapy of PDAC and to describe pre-clinical and clinical progress in CAR T bio-therapeutics.     

Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma

Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, K_i-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.Pancreatic cancer is among the most lethal malignancies because of its insidious onset and resistance to therapy. The overall 5-y survival rate for this disease is less than 5%, and estimates indicate that pancreatic cancer will be second only to non-small-cell lung cancer as the leading cause of cancer-related mortality in the United States by 2030 (1–2). Surgical resection is the only curative option, with 15% of patients having resectable disease at presentation. Complete resection of all gross and microscopic disease results in a median survival time of 22–23 mo (3, 4). However, nearly 40% of patients with pancreatic cancer have locally advanced, unresectable disease with a median overall survival time of 9.2–13.5 mo (5). Although the true effect of microscopic positive margins is not fully known, patients destined to have the longest survival are those for whom resection with curative intent is feasible (6).The efficacy of chemotherapy for pancreatic cancer is impaired by a unique desmoplastic response (7, 8). Pancreatic tumors have a dense desmoplastic stroma with fibrotic connective tissue that surrounds the tumor and may account for >80% of tumor volume (9). This leads to a microenvironment with low blood perfusion and hypoxia, serving as a barrier to diminish the delivery of anticancer drugs (10, 11). A local drug delivery device capable of overcoming this barrier could provide substantial benefit for patients with locally advanced pancreatic cancer.We have developed an implantable iontophoretic device capable of driving chemotherapies deep into solid tumors. The principle behind iontophoretic drug delivery is the movement of charged species under an applied electric field (12, 13). Iontophoresis has been previously evaluated for oncologic purposes (13–15). An iontophoretic Foley catheter was developed to deliver mitomycin C to bladder tumors. Significant clinical success was achieved using the treatment alone and in combination with Bacillus Calmette-Guérin therapy (15). In addition, Gratieri et al. explored the iontophoretic delivery of 5-fluorouracil and leucovorin in healthy pig buccal tissue for the treatment of head and neck cancer (14).One major benefit of this technology is the ability to deliver highly toxic agents limited by unwanted secondary effects. FOLFIRINOX, a promising mixture of cytotoxic agents including folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin, has limited use in many patients because of its high systemic toxicity (16, 17). Modified FOLFIRINOX regimens have been created to improve tolerability (5, 18). Given the ability of the iontophoretic device to deliver drugs locally with minimal systemic exposure, the iontophoretic delivery of FOLFIRINOX could further enhance the efficacy of this cytotoxic regimen by increasing the local drug concentration and decreasing systemic exposure. The aim of our study was to evaluate the iontophoretic delivery of FOLFIRINOX for the treatment of localized pancreatic cancer. We evaluated this therapy in xenografts derived from patients with pancreatic cancer, which have been shown to reflect recently defined RNA tumor subtypes in patients, mirror patient outcome, and be highly predictive of clinical response to many targeted agents (19, 20). We report the delivery of high levels of the FOLFIRINOX drugs to the tumor, a reduction in systemic exposure of the drugs, and potent tumor regression. This therapy has the potential to improve the resection rates and the outcome for patients with pancreatic cancer.     

Semi-quantitative analysis of telomerase in pancreatic ductal adenocarcinoma

Using a polymerase chain reaction-based amplification assay, we measured telomerase activity in surgically resected pancreatic ductal carcinomas (n=16 cases) and normal ducts (n=6), comparing findings with the telomerase activity of a human pancreatic cancer cell line, MIA PaCa-2, as a standard, i.e., relative telomerase activity was determined. Telomerase activity was expressed as the equivalent telomerase intensity of the number of cells of MIA PaCa-2 per μg protein of tissue samples. The median value for telomerase activity in normal pancreatic ducts was 0.13 and the 25th and 75th percentile were 0.01 and 0.76. The median value for telomerase activity in pancreatic ductal adenocarcinoma was 34.7 (25th percentile, 4.98; and 75th percentile, 296), significantly higher than that of normal ducts (P<0.001). When the cut-off value was set at 1.0 and 3.0, the telomerase positivity rate of pancreatic ductal adenocarcinomas was 100% and 81.3%, respectively. Telomerase may be a specific marker for pancreatic ductal carcinomas.     

Vascular-enteric fistulas associated with radiation therapy in patients with pancreatic adenocarcinoma

BackgroundIrradiation therapy is being evaluated widely as an adjunct to therapy of resectable and unresectable pancreatic exocrine carcinoma. Exsanguinating haemorrhage has been an occasional late complication.Case outlinesTwo patients with unresectable cancer of the pancreas were treated by bypass, chemotherapy and both intra-operative and postoperative irradiation. Both patients died 5–11 months later of gastroduodenal haemorrhage from arterio-enteric fistulas, which were confirmed by autopsy but had been uncontrolled by selective embolisation. A third patient, for whom little other information was available, died of upper abdominal haemorrhage 5 months after a ‘curative’ resection combined with intra-operative and postoperative irradiation.DiscussionJudgement in management is difficult because of the poor prognosis from the underlying disease on the one hand versus the fact that site of bleeding has sometimes been from complicating benign disease. Better endovascular techniques of control of such haemorrhage may be developing.     

The specificity of amylin for the diagnosis of pancreatic adenocarcinoma

Summary Background. Diabetes mellitus or impaired glucose tolerance occurs in up to 80% of patients with pancreatic cancer at the time of cancer diagnosis. It has been reported that plasma amylin (islet amyloid polypeptide [IAPP]) levels are elevated in all patients with pancreatic cancer who are diabetic, and even moderately elevated in pancreatic cancer patients with normal glucose tolerance. Aim. To determine the specificity of elevated amylin levels for pancreatic cancer. Methods. Plasma amylin levels were determined in 168 patients with one or more of the following medical conditions: benign and malignant biliary obstruction, pancreatic cancer, chronic pancreatitis, acute pancreatitis, other gastrointestinal (GI) malignancies, and newly diagnosed type II diabetes. Results. Elevated levels of plasma amylin were detected in several disorders other than pancreatic cancer—particularly chronic pancreatitis, other GI malignancies, and biliary obstruction from benign causes. No statistical differences in amylin levels were detected for any of the tested medical conditions when compared to pancreatic adenocarcinoma. Conclusion. These results suggest that elevated plasma amylin is not specific for pancreatic cancer, thereby limiting its role as a tumor marker. Further studies are needed to determine whether amylin, if used in conjunction with other biological markers, could be useful for the diagnosis of pancreatic cancer.     

Evolving trends in combined modality therapy for pancreatic cancer

Only 5%—15% of patients with pancreatic adenocarcinoma undergo potentially curative resection. Evidence that postoperative adjuvant therapy improves outcome is limited to a single randomized trial utilizing split-course chemoradiation. More aggressive regimens have developed and are associated with, at best, a modest improvement in patient outcome. The potentially significant morbidity associated with pancreaticoduodenectomy, which can compromise the delivery of postoperative chemoradiation, has led to the investigations of preoperative regimens. Although such an approach is feasible, its ultimate impact warrants further evaluation. Among the 4% of patients who present with unresectable or locally advanced disease, combined modality therapy has produced the most promising results. However, only modest improvements in survival have so far been achieved. Combined modality therapy with radioisotope implantation appears to have the greatest potential for improving local control and survival in these patients. Intraoperative radiation therapy (IORT) may be associated with lower morbidity than radioisotope implantation, but its impact may be limited by radiobiological disadvantage associated with single-dose boost therapy. The problem of distant metastasis remains significant. New chemotherapeutic agents have the potential to produce better results than those achieved with 5-fluorouracil. Continued advances in surgery, radiation, and systemic therapy should lead to the increased use of modern combined modality interventions with an associated further improvement in patient outcome.     

Chemoradiation for resected pancreatic adenocarcinoma with or without intraoperative radiation therapy boost: Long-term outcomes

Background/objectivesTo analyze prognostic factors associated with long-term outcomes in patients with pancreatic cancer treated with chemoradiation therapy (CRT) and surgery with or without intraoperative electron beam radiotherapy (IOERT).Patients and methodsFrom January 1995 to December 2012, 60 patients with adenocarcinoma of the pancreas and locoregional disease (clinical stage IB [n = 13; 22%], IIA [n = 16; 27%], IIB [n = 22; 36%], IIIC [n = 9; 15%]) were treated with CRT (45–50.4 Gy before surgery [n = 19; 32%] and after surgery [n = 41; 68%]) and curative resection (R0 [n = 34; 57%], R1 [n = 26, 43%]). Twenty-nine patients (48%) also received a pre-anastomosis IOERT boost (applicator diameter size, 7–10 cm; dose, 10–15 Gy; beam energy, 9–18 MeV).ResultsWith a median follow-up of 15.9 months (range, 1–182), 5-year overall survival (OS), disease-free survival (DFS), and locoregional control were 20%, 13%, and 58%, respectively. Univariate analyses showed that R1 margin resection status (HR, 3.17; p = 0.04), not receiving IOERT (HR, 7.33; p = 0.01), and postoperative CRT (HR, 5.12; p = 0.04) were associated with a higher risk of locoregional recurrence. In the multivariate analysis, only margin resection status (HR, 3.0; p = 0.05) and not receiving IOERT (HR, 6.75; p = 0.01) retained significance with regard to locoregional recurrence. Postoperative mortality and perioperative complications were 3% (n = 2) and 43% (n = 26).ConclusionsAlthough local control is good in the radiation-boosted area, OS remains modest owing to high risk of distant metastases. Intensified locoregional treatment needs to be tested in the context of more efficient systemic therapy.     

Trends in treatment for pancreatic cancer

Although surgical resection is considered to be the only approach that offers a possibility of cure to patients with pancreatic cancer, the prognosis of the disease has not been improved markedly by any surgical procedures in the past 20 years. Large‐scale randomized prospective clinical trials are being conducted in the United States and Italy, comparing standard lymph node dissection with extended lymph node dissection. Although preoperative chemoradiation has various advantages in the treatment of pancreatic cancer, it does not contribute to its downstaging and eventual cure. The combination of leucovorin, 5‐fluorouracil (5‐FU), and extracorporeal irradiation, however, has been proven to improve the patient's quality of life (QOL). Palliative surgery still requires further research in areas such as the examination of morbidity rates and the duration of bypass effects, now that laparoscopic and endoscopic surgery have both been well developed. Recent biological research has revealed the mechanisms of the carcinogenesis and the progression of pancreatic cancer, and, against this background, we assume that more effective trials will be conducted soon. Immunotherapy with dendritic cells, as well as gene therapy with mutant adenovirus, has already been employed clinically. Pancreatic cancer therapy is now facing new prospects.     

Metastatic pancreatic ductal adenocarcinoma: diagnosis and treatment with a view to the future

Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a lethal disease with a poor 5‐year survival. Systemic treatments can be used to control symptoms and prolong life. Cytotoxic chemotherapies are commonly administered, with combination treatments, such as fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) or nab‐paclitaxel and gemcitabine showing the largest clinical benefits. Newer genomic classifications of PDAC may provide a rationale for targeted therapies or immunotherapies, although at present these remain largely experimental. This review discusses the evidence behind the currently used regimens, while introducing the potential future of pancreatic cancer care.     

Meta-analysis of FOLFIRINOX-based neoadjuvant therapy for locally advanced pancreatic cancer

Currently, the combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is the standard therapy for metastatic pancreatic cancer. In recent years, FOLFIRINOX-based neoadjuvant therapy for locally advanced pancreatic cancer (LAPC) has been gaining an increasing amount of attention, owing to its ability to reduce disease stage and transform LAPC to borderline resectable or even resectable pancreatic cancer. Accordingly, we aimed to evaluate the efficacy of first-line FOLFIRINOX chemotherapy in patients with LAPC.We searched PubMed, Embase, and Cochrane Library from the time of establishment till January 1, 2020 and included studies focusing on LAPC patients who received FOLFIRINOX as first-line neoadjuvant treatment. The primary outcomes were: resection rate and radical (R0) resection rate while the secondary outcomes were: objective response rate, overall survival, progression-free survival, and rate of grade 3 to 4 adverse events. The meta package for R 3.6.2 was used for heterogeneity and publication bias testing.Twenty-one studies, including 653 patients with LAPC, were selected. After treatment with FOLFIRINOX, the resection rate was 26% (95% confidence interval [CI] = 20%–32%, I2 = 61%) and R0 resection rate was 88% (95% CI = 78%–95%, I2 = 62%). The response rate was 34% (95% CI = 25%–43%, I2 = 56%). The median overall survival and progression-free survival durations ranged from 10.0 to 32.7 months and 3.0 to 25.3 months, respectively. The observed grade 3 to 4 adverse events were neutropenia (20.0 per 100 patients, 95% CI = 14%–27%, I2 = 75%), febrile neutropenia (7.0 per 100 patients, 95% CI = 5%–9%, I2 = 42%), thrombocytopenia (6.0 per 100 patients, 95% CI = 5%–8%, I2 = 27%), nausea/vomiting (7.0 per 100 patients, 95% CI = 7%–12%, I2 = 76%), diarrhea (10.0 per 100 patients, 95% CI = 8%–12%, I2 = 38%), and fatigue (9.0 per 100 patients, 95% CI = 7%–11%, I2 = 43%).FOLFIRINOX-based neoadjuvant chemotherapy has the potential to improve the rates of resection, R0 resection, and median OS in LAPC. Our results require further validation in large, high-quality randomized controlled trials.     

内镜超声在中晚期胰腺癌诊治中的研究进展

近年来内镜超声（endoscopic ultrasound,EUS）相关新技术被广泛应用于中晚期胰腺癌的诊断和治疗,本文就EUS相关新技术在胰腺癌诊断、治疗以及胰腺癌合并症治疗方面的研究进展进行了综述,以期提高临床医师对EUS相关新技术诊治中晚期胰腺癌的认识。     

Novel directions in neoadjuvant therapy for pancreas adenocarcinoma

Surgical resection of pancreatic carcinoma has long represented the only viable option for a potential cure of pancreas cancer. The use of adjuvant chemotherapy post-resection has been established in treating micro metastases and prolonging disease-free survival. However, studies of neoadjuvant therapy have not come to any definitive conclusion regarding the overall efficacy of such treatment, despite the theoretical benefits. In this review, we examine the historical precedent as well as the current state of affairs regarding neoadjuvant therapy in resectable and borderline resectable pancreatic adenocarcinoma. In addition, we review the definitions for resectable and borderline resectable disease and highlight key areas of clinical investigation in the field and summarize the major ongoing neoadjuvant studies focused on resectable pancreatic adenocarcinoma.     

Overexpression of pancreatitis-associated protein (PAP) in human pancreatic ductal adenocarcinoma

Pancreatitis-associated protein (PAP) is almost absent in normal pancreas, but is strongly induced in acute pancreatitis. PAP mRNA is also expressed in cancer cells, including pancreatic ductal adenocarcinoma. However, the clinicopathological significance of PAP in human pancreatic cancer is not clear. We examined PAP expression in pancreatic tissues from individuals with pancreatic ductal adenocarcinoma using immunohistochemistry. PAP was overexpressed in 79% (30 of 38) of pancreatic ductal adenocarcinoma, 19% (7 of 36) of chronic pancreatitis, and 29% (2 of 7) of mucinous cystadenoma. PAP was found in malignant ductular structures in pancreatic carcinomas as well as in benign proliferating ductules and acinar cells in chronic pancreatitis. It was not expressed in normal pancreas. The incidence of PAP overexpression was significantly higher in pancreatic cancer than in the other pancreatic diseases (P < 0.01). PAP overexpression was significantly correlated with nodal involvement, distant metastasis (P < 0.05), and short survival (P < 0.01) in pancreatic cancer. These results suggest that overexpression of PAP in human pancreatic ductal adenocarcinoma indicates tumor aggressiveness.     

Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma

Pancreatic cancer is one of the most fatal malignancies lacking effective therapies. Notch signaling is a key regulator of cell fate specification and pancreatic cancer development; however, the role of individual Notch receptors and downstream signaling is largely unknown. Here, we show that Notch2 is predominantly expressed in ductal cells and pancreatic intraepithelial neoplasia (PanIN) lesions. Using genetically engineered mice, we demonstrate the effect of conditional Notch receptor ablation in Kras^G12D-driven pancreatic carcinogenesis. Deficiency of Notch2 but not Notch1 stops PanIN progression, prolongs survival, and leads to a phenotypical switch toward anaplastic pancreatic cancer with epithelial–mesenchymal transition. By expression profiling, we identified increased Myc signaling regulated by Notch2 during tumor development, placing Notch2 as a central regulator of PanIN progression and malignant transformation. Our study supports the concept of distinctive roles of individual Notch receptors in cancer development.     

A repeated pancreatectomy in the remnant pancreas 22 months after pylorus-preserving pancreatoduodenectomy for pancreatic adenocarcinoma

We report a case of a repeated curative pancreatic resection in the remnant distal pancreas 22 months after pylorus-preserving pancreatoduodenectomy (PpPD). The patient was a 52-year-old woman with a past history of PpPD for adenocarcinoma of the head of the pancreas 22 months prior to the present operation. The original tumor was histopathologically diagnosed as a papillary adenocarcinoma with clear surgical margin at the surgical cut end of the pancreas (R0, International Union Against Cancer [UICC] classification). Twenty months after the PpPD, a follow-up computed tomography (CT) scan showed multiple low-density lesions in the body and tail of the pancreas without any other distant metastasis. A second operation, curative resection of the remnant pancreas, with splenectomy and distal gastrectomy, was performed. The second tumor was a papillary adenocarcinoma, the same diagnosis as that of the first tumor, and it also showed similar histopathological findings, including immunohistochemical staining of Ki-67 and p53 protein, and the same pattern of K-ras point mutation. The patient is considered to have shown a rare, unique pancreatic cancer with metachronous carcinogenesis in the remnant pancreas.