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.

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.

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.

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.

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.

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.

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.