The Hippo signaling pathway is an evolutionarily conserved developmental network vital for the regulation of organ size, tissue homeostasis, repair and regeneration, and cell fate. The Hippo pathway has also been shown to have tumor suppressor properties. Hippo transduction involves a series of kinases and scaffolding proteins that are intricately connected to proteins in developmental cascades and in the tissue microenvironment. This network governs the downstream Hippo transcriptional coactivators YAP and TAZ, which bind to and activate the output of TEADs, as well as other transcription factors responsible for cellular proliferation, self-renewal, differentiation, and survival. Surprisingly, there are few oncogenic mutations within the core components of the Hippo pathway. Instead, dysregulated Hippo signaling is a versatile accomplice to commonly mutated cancer pathways. For example, YAP and TAZ can be activated by oncogenic signaling from other pathways, or serve as coactivators for classical oncogenes. Emerging evidence suggests that Hippo signaling couples cell density and cytoskeletal structural changes to morphogenic signals, and conveys a mesenchymal phenotype. While much of Hippo biology has been described in epithelial cell systems, it is clear that dysregulated Hippo signaling also contributes to malignancies of mesenchymal origin. This review will summarize the known molecular alterations within the Hippo pathway in sarcomas, and highlight how several pharmacologic compounds have shown activity in modulating Hippo components, providing proof-of-principle that Hippo signaling may be harnessed for therapeutic application in sarcomas.

BACKGROUND: A patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO’s ability to predict clinical response to gastrointestinal (GI) cancers. METHODS: We generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma. We compared PDO response with the observed clinical response for donor patients to the same treatments. RESULTS: We report an approximately 80% concordance rate between PDO and donor tumor response. Importantly, we found a profound influence of culture media on PDO phenotype, where we showed a significant difference in response to standard-of-care chemotherapies, distinct morphologies, and transcriptomes between media within the same PDO cultures. CONCLUSION: While we demonstrate a high concordance rate between donor tumor and PDO, these studies also showed the important role of culture media when using PDOs to inform treatment selection and predict response across a spectrum of GI cancers. TRIAL REGISTRATION: Not applicable. FUNDING: The Joan F. & Richard A. Abdoo Family Fund in Colorectal Cancer Research, GI Cancer program of the Mayo Clinic Cancer Center, Mayo Clinic SPORE in Pancreatic Cancer, Center of Individualized Medicine (Mayo Clinic), Department of Laboratory Medicine and Pathology (Mayo Clinic), Incyte Pharmaceuticals and Mayo Clinic Hepatobiliary SPORE, University of Minnesota-Mayo Clinic Partnership, and the Early Therapeutic program (Department of Oncology, Mayo Clinic).

Background: Palliative care has been associated with improved survival and quality of life, with lower rate of end-of-life health care utilization and cost. We examined trends in palliative care utilization in older pancreatic cancer patients. Methods: Pancreatic cancer patients with and without palliative care consults were identified using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database between 2000 and 2009. Trend of palliative care use was studied. Emergency room/intensive care unit (ICU) utilization and costs in the last 30 days of life were compared between both groups using propensity score-matched (PSM) analysis. Results: Of the 54,130 patients, 3,166 (5.8%) received palliative care and 70% received it in the last 30 days of life. The proportion of patients receiving palliative care increased from 1.4% in 2000 to 7.4% in 2009 (P<0.001). Patients with palliative care were more likely to be older, Asian and women. In the unmatched and PSM population, the average visits to the ER in the last 30 days of life were significantly higher for patients who received palliative care, and had a significantly higher cost of care. Similarly, ICU length of stay in the last 30 days of life was higher in patients who did not receive palliative care in both PSM and unmatched patients. Cost of care and number of ICU admissions were not different between palliative and non-palliative care groups in PSM and unmatched patients. Conclusions: In this study of Medicare patients with pancreatic cancer, palliative care use has increased between 2000 and 2009. Palliative care was largely offered close to the end of life and was not associated with reduced health care utilization or cost.

Gastroesophageal cancers are a group of aggressive malignancies that are inherently heterogeneous with poor prognosis. Esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, and gastric adenocarcinoma all have distinct underlying molecular biology, which can impact available targets and treatment response. Multimodality therapy is needed in the localized setting and treatment decisions require multidisciplinary discussions. Systemic therapies for treatment of advanced/metastatic disease should be biomarker-driven, when appropriate. Current FDA approved treatments include HER2-targeted therapy, immunotherapy, and chemotherapy. However, novel therapeutic targets are under development and future treatments will be personalized based on molecular profiling. Herein, we review the current treatment approaches and discuss promising advances in targeted therapies for gastroesophageal cancers.

Purpose: Reducing the length of stay is a high-priority objective for all health care institutions. Delays in chemotherapy initiation for planned preadmissions lead to patient dissatisfaction and prolonged length of stay. Patients and Methods: A multidisciplinary team was formed as part of the ASCO Quality Training Program. We aimed to reduce the time to initiation of chemotherapy from patient arrival at Parkland Hospital from a median of 6.2 hours at baseline to 4 hours over a 6-month period (35% reduction). The team identified inconsistency in blood work requirements, poor communication, and nonstandard patient arrival times as key causes of delay in the process. Plan-Do-Study-Act (PDSA) cycles were implemented based on identified improvement opportunities. The outcome measure was time from arrival to chemotherapy start. Data were obtained from time stamps in the electronic health record. Results: The first PDSA cycle included patient reminders to arrive at specific times, improved communication using a smartphone secure messaging application, and preadmission notes by oncology fellows detailing whether fresh blood work were needed on admission. Baseline data from 36 patients and postimplementation data from 28 patients were analyzed. Median time from admission to chemotherapy initiation preprocess change was 6.2 hours; it was 3.2 hours postchange. A sustained shift in the process was apparent on a control chart. Conclusion: Delays in initiation of chemotherapy can be prevented using classic quality improvement methodology and a multidisciplinary team. We aim to further refine our PDSA cycles and ensure sustainability of change.