Pancreatic cancer stroma:understanding biology leads to new therapeutic strategies

Pancreatic ductal adenocarcinoma(PDA)is among the deadliest cancers in the United States and in the world.Late diagnosis,early metastasis and lack of effective therapy are among the reasons why only 6%of patients diagnosed with PDA survive past 5 years.Despite development of targeted therapy against other cancers,little progression has been made in the treatment of PDA.Therefore,there is an urgent need for the development of new treatments.However,in order to proceed with treatments,the complicated biology of PDA needs to be understood first.Interestingly,majority of the tumor volume is not made of malignant epithelial cells but of stroma.In recent years,it has become evident that there is an important interaction between the stromal compartment and the less prevalent malignant cells,leading to cancer progression.The stroma not only serves as a growth promoting source of signals but it is also a physical barrier to drug delivery.Understanding the tumor-stroma signaling leading to development of desmoplastic reaction and tumor progression can lead to the development of therapies to decrease stromal activity and improve drug delivery.In this review,we focus on how the current understanding of biology of the pancreatic tumor microenvironment can be translated into the development of targeted therapy.

The crown jewelry of the surgeries for pancreatic cancer

We are very pleased to organize this issue of Chinese Journal of Cancer Research.Authors come from the most distinguished groups of pancreatic cancer surgeons and oncologists in China and in USA.The first two articles make overviews on the historic and contemporary progresses in surgical management of pancreatic cancer.

Differentiating intraductal papillary mucinous neoplasms from other pancreatic cystic lesions

Intraductal papillary mucinous neoplasms(IPMN) can be difficult to distinguish from other cystic lesions of the pancreas.To understand better and discuss the current knowledge on this topic,the literature and the institutional experience at a large pancreatic disease center have been reviewed.A combination of preoperative demographic,historical,radiographic,laboratory data,as well as postoperative pathologic analyses can often distinguish IPMN from other lesions in the differential diagnosis.

Pancreatic cancer surgery: past, present, and future

The history of pancreatic cancer surgery, though fraught with failure and setbacks, is punctuated by periods of incremental progress dependent upon the state of the art and the mettle of the surgeons daring enough to attempt it. Surgical anesthesia and the aseptic techniques developed during the latter half of the 19 th century were instrumental in establishing a viable setting for pancreatic surgery to develop. Together, they allowed for bolder interventions and improved survival through the postoperative period. Surgical management began with palliative procedures to address biliary obstruction in advanced disease. By the turn of the century, surgical pioneers such as Alessandro Codivilla and Walther Kausch were demonstrating the technical feasibility of pancreatic head resections and applying principles learned from palliation to perform complicated anatomical reconstructions. Allen O. Whipple, the namesake of the pancreaticoduodenectomy（PD）, was the first to take a systematic approach to refining the procedure. Perhaps his greatest contribution was sparking a renewed interest in the surgical management of periampullary cancers and engendering a community of surgeons who advanced the field through their collective efforts. Though the work of Whipple and his contemporaries legitimized PD as an accepted surgical option, it was the establishment of high-volume centers of excellence and a multidisciplinary approach in the later decades of the 20^th century that made it a viable surgical option. Today, pancreatic surgeons are experimenting with minimally invasive surgical techniques, expanding indications for resection, and investigating new methods for screening and early detection. In the future, the effective management of pancreatic cancer will depend upon our ability to reliably detect the earliest cancers and precursor lesions to allow for truly curative resections.

Early detection of pancreatic cancer

Pancreatic adenocarcinoma is a low-incident but highly mortal disease. It accounts for only 3% of estimated new cancer cases each year but is currently the fourth common cause of cancer mortality. By 2030, it is expected to be the 2nd leading cause of cancer death. There is a clear need to diagnose and classify pancreatic cancer at earlier stages in order to give patients the best chance at a definitive cure through surgery. Three precursor lesions that distinctly lead to pancreatic adenocarcinoma have been identified, and we have increasing understanding the non-genetic and genetic risk factors for the disease. With increased understanding about the risk factors, the familial patters, and associated accumulation of genetic mutations involved in pancreatic cancer, we know that there are mutations that occur early in the development of pancreatic cancer and that improved genetic risk-based strategies in screening for pancreatic cancer may be possible and successful at saving or prolonging lives. The remaining challenge is that current standards for diagnosing pancreatic cancer remain too invasive and too costly for widespread screening for pancreatic cancer. Furthermore, the promises of noninvasive methods of detection such as blood, saliva, and stool remain underdeveloped or lack robust testing. However, significant progress has been made, and we are drawing closer to a strategy for the screening and early detection of pancreatic cancer.

Surgery for oligometastasis of pancreatic cancer

The incidence of pancreatic adenocarcinoma（PDAC） has steadily increased over the past several decades. The majority of PDAC patients will present with distant metastases, limiting surgical management in this population. Hepatectomy and pulmonary metastasectomy（PM） has been well established for colorectal cancer patients with isolated, resectable hepatic or pulmonary metastatic disease. Recent advancements in effective systemic therapy for PDAC have led to the selection of certain patients where metastectomy may be potentially indicated. However, the indication for resection of oligometastases in PDAC is not well defined. This review will discuss the current literature on the surgical management of metastatic disease for PDAC with a specific focus on surgical resection for isolated hepatic and pulmonary metastases.

Adjuvant and neoadjuvant therapy for pancreatic cancer

Pancreatic cancer still remains a major cause of cancer-related mortality;however,there is a slight but continuous improvement in survival over the past 2 decades.Progress in chemotherapy has contributed to the survival improvement in patients with any stage of pancreatic cancer.In this review,we summarize the currently available evidence regarding adjuvant and neoadjuvant therapy with a focus mainly on randomized controlled trial.The median overall survival in resected pancreatic cancer patients has significantly improved to 22.8 to 54.4 months with the use of adjuvant therapy from 11 to 20.2 months with a strategy of observation only.Recent data from randomized trials support the use of neoadjuvant therapy for patients with resectable or borderline resectable pancreatic cancer.But given a variety of neoadjuvant regimens and different definitions of resectability status,data should be interpreted with caution.Several other trials are ongoing and will provide further evidence.

PD-1 immunotherapy in pancreatic cancer:current status

Pancreatic ductal adenocarcinoma is the known kind of tumor biologically featured as high malignant degree, lack of effective methods for diagnosis and treatment, which reflects its unpleasant prognosis. Recently, with the breakthrough of burgeoning therapeutic methods, the flush of dawn for pancreatic cancer nearly arrives. Nowadays, besides surgery, neoadjuvant chemoradiotherapy, tumor vaccine therapy, and immunotherapy all show their active situation and obtain certain clinical efficacy, but that is still limited to pancreatic cancer. However, the appearance and development of programmed cell death-1 (PD-1) immune checkpoint inhibitor may final improve survival of pancreatic cancer. This article aims to deeply understand the value of PD-1 immune checkpoint inhibitor in pancreatic cancer and validly provide the evidence for treatment by means of performing a systematic review on the current status in the fields of the mechanism and application of anti-PD-1 in pancreatic cancer, associations with surgery, PD- 1-related side effects and prospections.

Advances of pathological complete response after neoadjuvant therapy for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Only 15% to 20% of patients present with a primarily resectable tumor at the time of diagnosis. There has been an increasing interest in the use of neoadjuvant chemotherapy alone or combination with radiotherapy in patients with resectable, borderline resectable, and locally advanced pancreatic cancer. Although the benefit of neoadjuvant therapy on resectable patients remains controversial, around one third of borderline resectable and locally advanced patients could be expected to have resectable tumors following neoadjuvant therapy, with comparable survival as those with primary resectable tumors. A pathological complete response (Pcr) in PDAC is an indicator for significantly better survival although it's rather rare. In this review, we present recent progress of Pcr and the controversies in pancreatic cancer after neoadjuvant therapy.

Circulating tumor cells in pancreatic cancer:a review

Pancreatic cancer remains one of the deadliest types of cancer with little or no recent evidence of significant improvement in survival.This is,in large part,due to the current unavailability of effective screening or even early detection methods.Circulating tumor cells(CTCs),particularly with the rapidly improving methods for isolation,enrichment,and characterization methods,have emerged as the next best hope to overcome these challenges.This paper reviews the current state-of-the-art of CTC technologies with particular focus on the various isolation and enrichment methods based on liquid biopsy,the current limitations of these technologies and,consequently,the areas of further research and improvements in CTC methods that are needed to translate it to the clinical setting of routine diagnosis,treatment,and management of pancreatic cancer.

Pancreatic ductal adenocarcinoma:the role of circulating tumor DNA

Pancreatic ductal adenocarcinoma(PDAC)is one of the most lethal cancers in humans,and utilized treatments over the past decades have shown little evidence of improvement in survival.This lack of progress in PDAC treatment outcomes has largely been attributed to a variety of limitations in all phases of care.These limitations most notably include late diagnosis leading to limited treatment options and consequently poorer response to treatments and eventual outcomes.Clinical implications regarding the emergence of circulating tumor cells and DNA(ctDNA)have shown promise in augmenting each step in the management of PDAC.This paper will review the emergence of ctDNA and its value in detection of common PDAC DNA alterations,potential clinical implications and utility,followed by the current limitations and the next steps that need to be taken to translate its use into a standard of care.