Imaging Modalities for Early Detection of Pancreatic Cancer: Current State and Future Research Opportunities.

Pancreatic cancer, one of the most lethal malignancies, is increasing in incidence. While survival rates for many cancers have improved dramatically over the last 20 years, people with pancreatic cancer have persistently poor outcomes. Potential cure for pancreatic cancer involves surgical resection and adjuvant therapy. However, approximately 85% of patients diagnosed with pancreatic cancer are not suitable for potentially curative therapy due to locally advanced or metastatic disease stage. Because of this stark survival contrast, any improvement in early detection would likely significantly improve survival of patients with pancreatic cancer through earlier intervention. This comprehensive scoping review describes the current evidence on groups at high risk for developing pancreatic cancer, including individuals with inherited predisposition, pancreatic cystic lesions, diabetes, and pancreatitis. We review the current roles of imaging modalities focusing on early detection of pancreatic cancer. Additionally, we propose the use of advanced imaging modalities to identify early, potentially curable pancreatic cancer in high-risk cohorts. We discuss innovative imaging techniques for early detection of pancreatic cancer, but its widespread application requires further investigation and potentially a combination with other non-invasive biomarkers.

Does the Microenvironment Hold the Hidden Key for Functional Precision Medicine in Pancreatic Cancer?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and no significant improvement in patient survival has been seen in the past three decades. Treatment options are limited and selection of chemotherapy in the clinic is usually based on the performance status of a patient rather than the biology of their disease. In recent years, research has attempted to unlock a personalised treatment strategy by identifying actionable molecular targets in tumour cells or using preclinical models to predict the effectiveness of chemotherapy. However, these approaches rely on the biology of PDAC tumour cells only and ignore the importance of the microenvironment and fibrotic stroma. In this review, we highlight the importance of the microenvironment in driving the chemoresistant nature of PDAC and the need for preclinical models to mimic the complex multi-cellular microenvironment of PDAC in the precision medicine pipeline. We discuss the potential for ex vivo whole-tissue culture models to inform precision medicine and their role in developing novel therapeutic strategies that hit both tumour and stromal compartments in PDAC. Thus, we highlight the critical role of the tumour microenvironment that needs to be addressed before a precision medicine program for PDAC can be implemented.

Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition.

Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle gene-silencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. SIGNIFICANCE: This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC.

Ex vivo culture of intact human patient derived pancreatic tumour tissue.

The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is attributed to the highly fibrotic stroma and complex multi-cellular microenvironment that is difficult to fully recapitulate in pre-clinical models. To fast-track translation of therapies and to inform personalised medicine, we aimed to develop a whole-tissue ex vivo explant model that maintains viability, 3D multicellular architecture, and microenvironmental cues of human pancreatic tumours. Patient-derived surgically-resected PDAC tissue was cut into 1-2 mm explants and cultured on gelatin sponges for 12 days. Immunohistochemistry revealed that human PDAC explants were viable for 12 days and maintained their original tumour, stromal and extracellular matrix architecture. As proof-of-principle, human PDAC explants were treated with Abraxane and we observed different levels of response between patients. PDAC explants were also transfected with polymeric nanoparticles + Cy5-siRNA and we observed abundant cytoplasmic distribution of Cy5-siRNA throughout the PDAC explants. Overall, our novel model retains the 3D architecture of human PDAC and has advantages over standard organoids: presence of functional multi-cellular stroma and fibrosis, and no tissue manipulation, digestion, or artificial propagation of organoids. This provides unprecedented opportunity to study PDAC biology including tumour-stromal interactions and rapidly assess therapeutic response to drive personalised treatment.

Diabetes-related outcomes after pancreatic surgery.

BACKGROUND: The development of pancreatogenic diabetes mellitus (PDM) is a common complication post-pancreatectomy; however, its prevalence has not been described in Australia. We aimed to describe the glycaemic status pre- and post-pancreatectomy, compare patients' clinical characteristics, group according to pre- and post-pancreatectomy diabetes mellitus (DM) status and identify predictors of post-operative PDM. METHODS: We retrospectively reviewed the medical records of patients admitted for pancreatic resection at a single institution from 2011 to 2017. Post-operative DM status was determined at the time of discharge or at 30 days post-operation. Longer term DM onset was as documented in medical record subsequent to admission for pancreatic surgery. RESULTS: A total of 137 cases were analysed; 13.3% and 24.8% of patients developed post-operative PDM within 30 days and at median of 1 year (range 1-4 years) follow-up, respectively. All patients with pre-existing DM continued to have DM post-operatively. Patients with pre-existing DM were older (P = 0.004) and had a family history of DM (P = 0.020); 8.3% of patients who had undergone pancreaticoduodenectomy versus 17.1% of patients who had undergone distal pancreatectomy developed PDM (P = 0.318). A lower estimated glomerular filtration rate (P = 0.033) was significantly associated with post-operative PDM development. No independent predictors for post-operative PDM were identified. CONCLUSIONS: The new development of DM within 30 days post-pancreatectomy occurs in approximately one in seven persons. No patients with pre-existing DM demonstrated a remission of DM post-pancreatectomy. These findings suggest that all patients should be screened for DM pre-operatively and followed up post-operatively, particularly those with pre-existing impaired renal function.

The AGITG GAP Study: A Phase II Study of Perioperative Gemcitabine and Nab-Paclitaxel for Resectable Pancreas Cancer.

BACKGROUND: While combination therapy with nab-paclitaxel/gemcitabine (nab-gem) is effective in pancreatic ductal adenocarcinoma (PDAC), its efficacy as perioperative chemotherapy is unknown. The primary objective of this multicenter, prospective, single-arm, phase II study was to determine whether neoadjuvant therapy with nab-gem was associated with higher complete resection rates (R0) in resectable PDAC, while the secondary objectives were to determine the utility of radiological assessment of response to preoperative chemotherapy and the safety and efficacy of nab-gem as perioperative therapy. METHODS: Patients were recruited from eight Australian sites, and 42 patients with radiologically defined resectable PDAC and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled. Participants received two cycles of preoperative nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 (28-day cycle) presurgery, and four cycles postoperatively. Early response to chemotherapy was measured with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scans on day 15. RESULTS: Preoperative nab-gem was completed by 93% of participants, but only 63% postoperatively. Thirty-six patients had surgery: 6 (17%) were unresectable, 15 (52%) had R0 (≥ 1 mm) resections, 14 (48%) had R1 (< 1 mm) resections, and 1 patient did not have PDAC. Median progression-free survival was 12.3 months and median overall survival (OS) was 23.5 months: R0 patients had an OS of 35 months versus 25.6 months for R1 patients after surgery. Seven patients had not progressed after 43 months. CONCLUSIONS: The GAP trial demonstrated that perioperative nab-gem was tolerable. Although the primary endpoint of an 85% R0 rate was not met, the R0 rate was similar to trials using a > 1 mm R0 resection definition, and survival rates were comparable with recent adjuvant studies.

Monitoring quality of care for patients with pancreatic cancer: a modified Delphi consensus.

BACKGROUND: Best practise care optimises survival and quality of life in patients with pancreatic cancer (PC), but there is evidence of variability in management and suboptimal care for some patients. Monitoring practise is necessary to underpin improvement initiatives. We aimed to develop a core set of quality indicators that measure quality of care across the disease trajectory. METHODS: A modified, three-round Delphi survey was performed among experts with wide experience in PC care across three states in Australia. A total of 107 potential quality indicators were identified from the literature and divided into five areas: diagnosis and staging, surgery, other treatment, patient management and outcomes. A further six indicators were added by the panel, increasing potential quality indicators to 113. Rated on a scale of 1-9, indicators with high median importance and feasibility (score 7-9) and low disagreement (<1) were considered in the candidate set. RESULTS: From 113 potential quality indicators, 34 indicators met the inclusion criteria and 27 (7 diagnosis and staging, 5 surgical, 4 other treatment, 5 patient management, 6 outcome) were included in the final set. CONCLUSIONS: The developed indicator set can be applied as a tool for internal quality improvement, comparative quality reporting, public reporting and research in PC care.

Short- and long-term outcomes of elderly patients undergoing liver resection for colorectal liver metastasis.

BACKGROUND: Metastatic colorectal cancer is a disease of advancing age. Increased life expectancy has dramatically increased the number of older patients being assessed for hepatectomy. The objective of the study is to assess the safety and survival of hepatic resection in older patients, with colorectal liver metastases (CLM) and compare that with younger patients. METHODS: All patients undergoing hepatic resection of CLM were included. Patients were divided in groups, less than 75 and 75 and over. Prospectively collected data on patient demographics and post-operative complications were retrospectively analysed. Overall survival was calculated in both groups. RESULTS: Twenty-nine patients over the age of 75 underwent hepatic resection for CLM. A total of 158 patients under the age of 75 underwent resection. Overall, 66% of patients received neoadjuvant chemotherapy and 64% underwent major resection. Ninety-day mortality was 1 out of 29 and 1 out of 158, respectively (P = 0.15). Overall complication rate was low, 4 out of 29 and 26 out of 158 (P = 0.45). Median length of stay was similar in the older population, 8.5 versus 8 days (P = 0.65). Overall 5-year survival was 58% in the over 75 group and 56% in the under 75 group (P = 0.31). CONCLUSION: Hepatic resection for CLM can be achieved safely in patients over the age of 75 and with equivalent short- and long-term outcomes.

Hepatic resection of non-colorectal non-endocrine liver metastases.

BACKGROUND: Hepatic resection is standard treatment for liver metastases from colorectal and neuroendocrine cancers as well as primary biliary and hepatic carcinomas. The role of hepatic resection in patients with non-colorectal non-endocrine liver metastases (NCNELM) is less defined. Overall survival in this group of patients is poor with few patients surviving beyond two years, even with modern chemotherapy. METHODS: A prospective database of all liver resections performed by a single surgeon (KSH) from January 2007 to December 2014 was maintained. Patient demographics, surgical and pathological data were collected prospectively; survival data were updated retrospectively. Patients were grouped according to pathology and analysis was performed using SPSS (version 21). RESULTS: A total of 48 patients underwent hepatic resection for NCNELM, of which 18 were major resections. Pathologies encountered included sarcoma in 8/48, both breast and ovarian in 6/48 each and renal cell carcinoma and melanoma, each representing 5/48. A result of 38/48 patients undertook chemotherapy prior to surgery. R0 margin was achieved in 96%. Seven patients suffered complications from surgery and one peri-operative mortality. Overall survival at 1, 3 and 5 years was 93%, 83% and 61%, respectively. Forty-four percent of patients developed disease recurrence, 29% at distant sites. CONCLUSION: Hepatic resection can be achieved safely for NCNELM. Patient selection is key, along with a standardized surgical and anaesthetic technique. Patients should be rigorously investigated to exclude disseminated disease and multidisciplinary discussion must take place prior to surgery. Patients with NCNELM should not routinely be excluded from liver resection and selected patients may benefit from resection.

Synchronous Nesidioblastosis, Endocrine Microadenoma, and Intraductal Papillary Mucinous Neoplasia in a Man Presenting With Hyperinsulinemic Hypoglycemia.

Herein, we report the first case of concomitant nesidioblastosis, pancreatic neuroendocrine tumor, and intraductal papillary mucinous neoplasia. The combination is significant as each of these pathological entities is independently very rare. The patient was a 33-year-old man who presented with symptomatic hyperinsulinemic hypoglycemia and no risk factors for pancreatic disease. Abdominal imaging showed an isolated 12 mm pancreatic lesion, whilst selective arterial calcium stimulation testing demonstrated multiple territories of insulin excess. He proceeded to subtotal pancreatectomy. Histopathology revealed an endocrine microadenoma, α and ß cell nesidioblastosis, and multifocal intraductal papillary mucinous neoplasia. The endocrine microadenoma and nesidioblastosis stained for insulin, suggesting both likely contributed to hypoglycemia. Glucagon immunohistochemistry was also positive, though there were no clinical features of glucagon excess. Hypoglycemia resolved postoperatively. This case and other evidence from the literature suggest that hyperplasia and neoplasia may occur sequentially in the pancreas, and that endocrine and exocrine tumorigenesis may be linked in some individuals. Further study is required to identify a unifying mechanism, and to elucidate potential ramifications in the management of patients with pancreatic neoplasms.

Surgical complications after intestinal transplantation in infants and children--UK experience.

UNLABELLED: Surgical complications have a significant impact on morbidity and mortality following intestinal transplantation (ITx). Birmingham Children's Hospital commenced intestinal transplantation in 1993 and the following surgical strategies evolved: (a) pretransplant abdominal tissue expanders, 1998; (b) combined en-bloc reduced liver and intestinal transplantation (CRLITx), 1998; (c) staged abdominal closure, 2001; (d) preservation of graft duodenal artery, 2005. AIM: An internal audit was performed to document the surgical complications after ITx and to evaluate strategies in the management and prevention of complications. METHODS: A retrospective analysis of the medical records from January 1993 to June 2007 was conducted to identify surgical complications, evaluate management strategies, and report outcome following ITx. RESULTS: Forty-six children underwent 49 ITx (9 isolated intestinal, 39 combined liver and intestinal [CLITx], and 1 multivisceral transplant). Twenty three children had CRLITx since 1998, although there were none before 1997. The median donor: recipient weight ratio in CLITx was 2.2:1 (range, 0.67:1-6.70:1). Twenty-six children experienced 29 (59%) surgical complications: portacaval shunt thrombosis (n = 2, none alive); graft duodenal stump leakage (n = 3, 2 alive); spontaneous bowel perforation(n = 6, 2 alive); sub-acute bowel obstruction (n = 6, all alive); abdominal compartment syndrome ([ACS], n = 4, 2 alive); pancreatic leak (n = 3, 2 alive); biliary complications (n = 22, 17 alive ) failed staged abdominal closure with wound sepsis requiring skin grafting into the bowel (n = 1, alive), wound dehiscence (n = 1, alive), anastomotic leak (n = 1, alive) and intra-abdominal bleeding (n = 1,alive), primary nonfunction (n = 1, 1 died). Following the complications of ACS in children with primary abdominal closure and graft duodenal stump leaks in 2004, we modified our strategies in 2005 to include staged abdominal closure with recipient to donor weight mismatch, and preservation of the gastroduodenal artery during donor organ procurement in addition to pre transplant abdominal tissue expansion. Fifteen children with recipient and donor weight mismatch subsequently required staged closure of the abdomen and none of them developed ACS. Twelve children had gastroduodenal artery preserved and none developed graft duodenal stump leaks. Twenty-four of the 46 (52%) are alive 6 months to 10 years post transplant. CONCLUSION: Evolving strategies may avoid or reduce surgical complications commonly seen after intestinal transplantation and thus contribute to an improved outcome.

Extending the limits for curative liver resections by portal vein embolization.

The optimal chance of long-term survival for patients with liver metastasis and large hepatocellular carcinoma is curative liver resections. One of the major limiting factors in performing curative liver resections is the necessity of leaving enough functional parenchyma to avoid postoperative liver failure. The preoperative ipsilateral embolization of the portal vein (PVE) was introduced to produce compensatory hypertrophy of the future liver remnant. In this report, we compare the postoperative hepatic function of patients who had preoperative PVE to those with similar resections who did not have preoperative embolization. Also, for the first time, we report the outcome of those patients who were embolized but did not undergo liver resection because of extrahepatic disease identified at laparotomy.

Is a raised CA 19-9 level diagnostic for a cholangiocarcinoma in patients with no history of sclerosing cholangitis ?

BACKGROUND/AIM: A cholangiocarcinoma, the second most common primary hepatic malignancy, can present with diagnostic dilemmas. The aim of this study is to assess the role of CA 19-9 in patients with a cholangiocarcinoma without primary sclerosing cholangitis. METHODS: The prospectively collected information on patients with biopsy-proven cholangiocarcinomas who had the CA 19-9 level measured was obtained (n = 68) from our computer database and medical records. These patients were compared with patients who had benign liver tumours (n = 25) and benign bile duct strictures (n = 13) who also had their CA 19-9 concentration measured. RESULTS: Sensitivity and specificity of CA 19-9 in the diagnosis of a cholangiocarcinoma were 77.9 and 76.3%, respectively, when using a cut-off value of 35 kU/l, while sensitivity and specificity were 67.5 and 86.8%, respectively, when the cut-off value was raised to 100 kU/l. The specificity was found to be higher in patients with peripheral cholangiocarcinomas (96%) using a CA 19-9 cut-off value >100 kU/l. A CA 19-9 value >600 kU/l was associated with non-resectable tumours (p = 0.05). CONCLUSIONS: This study demonstrates that CA 19-9 is a useful adjunct in the diagnosis of cholangiocarcinomas without primary sclerosing cholangitis, especially in the diagnosis of peripheral cholangiocarcinomas. However, it does not provide a reliable guide for the pathological staging of these tumours.

Controlled study of Inline radiofrequency coagulation-assisted partial nephrectomy in sheep.

BACKGROUND: Primary or secondary tumors of kidney often are managed by partial nephrectomy. Intraoperative blood loss can be significant. Laparoscopic partial nephrectomy may be even more challenging. We developed the Inline radiofrequency coagulation (ILRFA) probe for liver surgery. It uses radiofrequency energy to make a linear coagulative plane and considerably reduces bleeding during parenchymal transection. In this stud,y we tested the efficiency of ILRFA in ovine kidney. METHOD: Seven sheep were used in this study. Under general anesthetic, a laparotomy was performed in each sheep. The first two sheep were used as pilot experiments. Five partial nephrectomies were made in the remaining five sheep using ILRFA. As a control, a matching partial nephrectomy was made in each sheep using diathermy and sutures. Blood loss was measured by determining the difference in the weights of dry sponges and blood stained sponges after resection. A paired t test was used to compare the bleeding between the control and the ILRFA technique. RESULTS: The mean blood loss using ILRFA was 33.14 g (SD 17) and 123.43 g (SD 72) in the control group. The bleeding was significantly reduced in the ILRFA group, with a P value of 0.0056. The time taken for applying the ILRFA was 3-4 min. CONCLUSION: We have achieved partial nephrectomy in ovine kidney using radiofrequency energy with significantly reduced blood loss.

In-line radiofrequency ablation to minimize blood loss in hepatic parenchymal transection.

BACKGROUND: Intraoperative blood loss has been shown to be an important factor correlating with morbidity and mortality in liver surgery. A 5-cm long instrument with variably deployable metal electrodes using in-line radiofrequency ablation (ILRFA) energy was used for hepatic transection in an attempt to reduce bleeding. METHODS: Eight patients underwent liver resection. At each resection, half the resection was performed with ILRFA and the other half was performed with an ultrasonic aspirator alone. Blood loss was measured for each mode of resection. RESULTS: The mean blood loss using ILRFA was 6.5 (+/-3.7) mL/cm(2) compared with 20.4 (+/-8.7) mL/cm(2) by using the ultrasonic aspirator (P = .004). CONCLUSIONS: In-line radiofrequency ablation reduced bleeding during hepatic parenchymal transection when compared with the ultrasonic aspirator.

Controlled study of in-line ovine spleen transection assisted by radiofrequency ablation.

BACKGROUND: Trauma to the spleen or tumors of the spleen often require total splenectomy for control of hemorrhage. Partial splenectomy is the preferred technique because of the short- and long-term sepsis problems in asplenic patients. Multiple techniques for partial splenectomy have been tried in the past with limited success. The authors designed the in-line radiofrequency ablation (ILRFA) probe for liver surgery. It uses radiofrequency energy to make a linear coagulative plane that allows the parenchyma of solid vascular organs to be divided. In this study, for the first time, the efficiency of ILRFA was tested with the ovine spleen. METHODS: Seven sheep were used for this study. With the sheep under general anesthesia, a laparotomy was performed. The first sheep was used for a pilot study. Eight partial splenectomies were made in the remaining six sheep using ILRFA. For a control, a matching partial splenectomy was made in each sheep using diathermy and sutures. Blood loss was measured by determining the difference in the weights of dry sponges and blood-stained sponges after resection. A paired t test was used to compare the bleeding between the control and the ILRFA techniques. RESULTS: The mean blood loss was 33.14 +/- 17 g using ILRFA and 123.43 +/- 72 g in the control group. The bleeding was significantly reduced in the ILRFA group (p = 0.0056). The time required to apply ILRFA was 12 minutes. CONCLUSION: Partial splenectomy was achieved in the ovine spleen using radiofrequency energy with minimal blood loss.

Effect of vessel diameter on the creation of ovine lung radiofrequency lesions in vivo: preliminary results.

OBJECTIVE: We sought to evaluate the effect of radiofrequency ablation (RFA) on pulmonary vessels with respect to potential of injury of these structures, to assess perfusion-mediated "heat sink" effect, and to consider acute and chronic complications. MATERIAL AND METHODS: RFAs targeted to perihilar, middle third, and peripheral lung regions were created in vivo in the lung of 10 crossbred sheep. The RITA generator and the Starburst XLi electrode with deployable hooks were used. The approach was open, performed under general anesthesia. Lesions 4 cm in diameter at a target temperature of 80 degrees C were created. Acute (immediate postinterventional euthanasia), subacute (96 h), and chronic (28 days) lesions were evaluated macroscopically, and histologic analysis of the vessels was performed. Patency of the vessels, both arteries and veins, was macroscopically assessed by presence or absence of thrombus and the degree of vascular injury and the viability of perivascular pneumocytes as well as endobronchial injury were histologically assessed. RESULTS: In the acute, subacute, and chronic setting, heat sink effect, indicated by invagination of the tissue between vessel and ablated region, was only observed in vessels greater than 3 mm in diameter. Thrombus was seen in 20% of the vessels smaller than 3 mm. On histopathology, vessels smaller than 3 mm showed at least partial vessel wall injury, characterized by endothelial cell necrosis and luminal thrombus. In the vessels greater than 3 mm the extent of vessel wall injury decreased with increasing vessel diameter. No acute complications were noted. For the chronic complications a bronchopleural fistula and a lung abscess were found. CONCLUSION: There seems to be a narrow transition zone for pulmonary vessels around 3 mm, beyond which the heat sink effect was seen consistently and substantial vascular injury was rare.