Laleh G. Melstrom

The pancreatic cancer microenvironment: A true double agent

The tumor microenvironment in pancreatic cancer is a complex balance of pro‐ and anti‐tumor components. The dense desmoplasia consists of immune cells, extracellular matrix, growth factors, cytokines, and cancer associated fibroblasts (CAF) or pancreatic stellate cells (PSC). There are a multitude of targets including hyaluronan, angiogenesis, focal adhesion kinase (FAK), connective tissue growth factor (CTGF), CD40, chemokine (C‐X‐C motif) receptor 4 (CXCR‐4), immunotherapy, and Vitamin D. The developing clinical therapeutics will be reviewed.

Development and Validation of a Prognostic Score for Intrahepatic Cholangiocarcinoma

Importance In patients with intrahepatic cholangiocarcinoma (ICC), the oncologic benefit of surgery and perioperative outcomes for large multifocal tumors or tumors with contiguous organ involvement remain to be defined. Objectives To develop and externally validate a simplified prognostic score for ICC and to determine perioperative outcomes for large multifocal ICCs or tumors with contiguous organ involvement. Design, Setting, and Participants This study of a contemporary cohort merged data from the California Cancer Registry (January 1, 2004, through December 31, 2011) and the Office of Statewide Health Planning and Development inpatient database. Clinicopathologic variables were compared between tumors that were intrahepatic, small (<7 cm), and solitary (ISS) and those that had extrahepatic extension and were large (≥7 cm) and multifocal (ELM). External validation of the prognostic model was performed using an independent data set from the National Cancer Institute’s Surveillance, Epidemiology, and End Results database from January 1, 2004, through December 31, 2013. Main Outcomes and Measures Patient overall survival after hepatectomy. Results A total of 275 patients (123 men [44.7%] and 152 women [55.3%]; median [interquartile range] age, 65 [55-72] years) met the inclusion criteria. No significant differences in overall complication rate (ISS, 48 [34.5%]; ELM, 37 [27.2%]; P = .19) and mortality rate (ISS, 10 [7.2%]; ELM, 6 [4.4%]; P = .32) were found. A multivariate Cox proportional hazards model demonstrated that multifocality, extrahepatic extension, grade, node positivity, and age greater than 60 years are independently associated with worse overall survival. These variables were used to develop the MEGNA prognostic score. The prognostic separation/discrimination index was improved with the MEGNA prognostic score (0.21; 95% CI, 0.11-0.33) compared with the staging systems of the American Joint Committee on Cancer sixth (0.17; 95% CI, 0.09-0.29) and seventh (0.18; 95% CI, 0.08-0.30) editions. Conclusions and Relevance The MEGNA prognostic score allows more accurate and superior estimation of patient survival after hepatectomy compared with current staging systems.

Wireless Monitoring Program of Patient-Centered Outcomes and Recovery Before and After Major Abdominal Cancer Surgery

Importance A combined subjective and objective wireless monitoring program of patient-centered outcomes can be carried out in patients before and after major abdominal cancer surgery. Objective To conduct a proof-of-concept pilot study of a wireless, patient-centered outcomes monitoring program before and after major abdominal cancer surgery. Design, Setting, and Participants In this proof-of-concept pilot study, patients wore wristband pedometers and completed online patient-reported outcome surveys (symptoms and quality of life) 3 to 7 days before surgery, during hospitalization, and up to 2 weeks after discharge. Reminders via email were generated for all moderate to severe scores for symptoms and quality of life. Surgery-related data were collected via electronic medical records, and complications were calculated using the Clavien-Dindo classification. The study was carried out in the inpatient and outpatient surgical oncology unit of one National Cancer Institute–designated comprehensive cancer center. Eligible patients were scheduled to undergo curative resection for hepatobiliary and gastrointestinal cancers, were English speaking, and were 18 years or older. Twenty participants were enrolled over 4 months. The study dates were April 1, 2015, to July 31, 2016. Main Outcomes and Measures Outcomes included adherence to wearing the pedometer, adherence to completing the surveys (MD Anderson Symptom Inventory and EuroQol 5-dimensional descriptive system), and satisfaction with the monitoring program. Results This study included a final sample of 20 patients (median age, 55.5 years [range, 22-74 years]; 15 [75%] female) with evaluable data. Pedometer adherence (88% [17 of 20] before surgery vs 83% [16 of 20] after discharge) was higher than survey adherence (65% to 75% [13 of 20 and 15 of 20] completed). The median number of daily steps at day 7 was 1689 (19% of daily steps at baseline), which correlated with the Comprehensive Complication Index, for which the median was 15 of 100 (r = −0.64, P < .05). Postdischarge overall symptom severity (2.3 of 10) and symptom interference with activities (3.5 of 10) were mild. Pain (4.4 of 10), fatigue (4.7 of 10), and appetite loss (4.0 of 10) were moderate after surgery. Quality-of-life scores were lowest at discharge (66.6 of 100) but improved at week 2 (73.9 of 100). While patient-reported outcomes returned to baseline at 2 weeks, the number of daily steps was only one-third of preoperative baseline. Conclusions and Relevance Wireless monitoring of combined subjective and objective patient-centered outcomes can be carried out in the surgical oncology setting. Preoperative and postoperative patient-centered outcomes have the potential of identifying high-risk populations who may need additional interventions to support postoperative functional and symptom recovery.

Hypothermia Is Associated with Surgical Site Infection in Cytoreductive Surgery with Hyperthermic Intra-Peritoneal Chemotherapy

BACKGROUND Maintenance of peri-operative normothermia remains a global quality metric for hospitals. Hypothermia is associated with surgical site infections (SSIs) in colorectal surgery. Patients undergoing cytoreductive surgery (CRS) with hyperthermic intra-peritoneal chemotherapy (HIPEC) can experience multiple complications post-operatively. We sought to investigate the association of peri-operative hypothermia with SSIs in patients undergoing CRS/HIPEC at our institution. PATIENTS AND METHODS Patients undergoing CRS/HIPEC from 2009-2017 were identified retrospectively from a prospectively collected institutional database. Hypothermia defined as less than 36.0°C in accordance with the Agency for Healthcare Research and Quality metric. Regression analyses were performed with SSIs diagnosed within 30 days post-operatively as the primary outcome. RESULTS A total of 170 patients were identified, 14 (8.2%) of whom developed an SSI. Patients who developed an SSI experienced lower median temperatures (p = 0.027) and a greater percentage of operative time in hypothermia (p = 0.008). On a multivariable analysis adjusting for known risk factors for SSI, the percentage of operative time in hypothermia (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.01-1.07, p = 0.008) was the only parameter associated with SSI within 30 days post-operatively. CONCLUSION Hypothermia is associated with the development of SSIs in patients undergoing CRS/HIPEC. Our findings suggest that minimizing peri-operative temperatures to less than 36.0°C may decrease peri-operative SSI in this patient population.

Primary liver sarcomas in the modern era: Resection or transplantation?

Primary liver sarcomas (PLS) are rare. Published series are limited by small numbers of patients.

Enhanced Recovery after Surgery for Gastric Cancer Patients Improves Clinical Outcomes at a US Cancer Center

Purpose Enhanced recovery after surgery (ERAS) protocols for gastric cancer patients have shown improved outcomes in Asia. However, data on gastric cancer ERAS (GC-ERAS) programs in the United States are sparse. The purpose of this study was to compare perioperative outcomes before and after implementation of an GC-ERAS protocol at a National Comprehensive Cancer Center in the United States. Materials and Methods We reviewed medical records of patients surgically treated for gastric cancer with curative intent from January 2012 to October 2016 and compared the GC-ERAS group (November 1, 2015–October 1, 2016) with the historical control (HC) group (January 1, 2012–October 31, 2015). Propensity score matching was used to adjust for age, sex, number of comorbidities, body mass index, stage of disease, and distal versus total gastrectomy. Results Of a total of 95 identified patients, matching analysis resulted in 20 and 40 patients in the GC-ERAS and HC groups, respectively. Lower rates of nasogastric tube (35% vs. 100%, P<0.001) and intraabdominal drain placement (25% vs. 85%, P<0.001), faster advancement of diet (P<0.001), and shorter length of hospital stay (5.5 vs. 7.8 days, P=0.01) were observed in the GC-ERAS group than in the HC group. The GC-ERAS group showed a trend toward increased use of minimally invasive surgery (P=0.06). There were similar complication and 30-day readmission rates between the two groups (P=0.57 and P=0.66, respectively). Conclusions The implementation of a GC-ERAS protocol significantly improved perioperative outcomes in a western cancer center. This finding warrants further prospective investigation.

Pancreatic Emergencies in the Cancer Patient

Pancreatic malignancy without treatment presents a grim prognosis. Yet, modalities involved in the treatment of this disease are not without potential complications. Complications, particularly postsurgical, are well reported in the literature. Pancreatic emergencies are a dangerous subset of complications related to this disease, frequently requiring expeditious decision making and management. In this chapter, we review the diagnostic workup, treatment, and sequelae of pancreatic emergencies.

Accelerating Progress in the Fight Against Pancreatic Cancer Proceedings of the 2017 Leo and Anne Albert Symposium for Pancreatic Cancer Research

About 56,000 new cases of pancreas adenocarcinoma are diagnosed annually in the United States and 43,090 deaths are expected in 2017. Nearly 85% of patients present with advanced disease and are not candidates for curative resection. Of those 15–20% who undergo resection, 90% are at risk of recurrence in 2 years’ time and for these patients, the prognosis is quite poor. Overall, only approximately 8% of patients diagnosed with pancreatic adenocarcinoma are five year survivors, and few are cured. A coupling of early local and systemic spread with the inherent biologic resistance of this cancer to conventional chemotherapy and radiation has resulted in the poor overall outcome. It is clear that single agent or single modality treatments are unlikely to result in major survival improvement in this disease. That is why the hundreds of thousands of promising compounds studied in the laboratory resulting in hundreds of clinical trials has only yielded two approved chemotherapies for the treatment of pancreatic cancer. Furthermore, the prolongation of median survival by either of these agents is only months. The lack of progress has not been because of a lack of funding. Between 2007 and 2014 the NCI funded 4,141 grants for pancreatic research, with a total spent of over 750 million dollars. Many philanthropic foundations, including the American Cancer Society, the Pancreatic Cancer Network, the Lustgarten Foundation, The Hirshberg Foundation for Pancreatic Cancer Research, and the National Pancreas Foundation have all contributed greatly to funding research to defeat this deadly cancer. The hundreds of millions of philanthropic dollars that have funded research in this area are beginning to result in exciting emerging data. Many of the biologic reasons for such a dismal outcome are being uncovered by exciting recent research, and include the drivers for spread of pancreatic cancer along nerves, lymphatics, and blood vessels. Most pancreatic tumors also have local environments that result in poor delivery of systemic therapies. These include a high proportion of stroma to cellular elements, poor central vascularity, and highly hypoxic environments. The progress in cancer knowledge has also translated recently into many agents entering human clinical trials. It is clear that defeating this cancer will require a multi-agent and multi-pronged strategy. It may require combining agents that dissolve the cancer-protecting stroma, with small molecules, and antibodies targeting cancer growth and metastasis pathways. It may require adding molecules, viruses, and cells active in cancer killing through stimulation of the immune system, or vaccines to prevent recurrence. The goal of the 2017 Leo and Anne Albert Symposium for Novel Trials in Pancreatic Cancer is to bring together scientists and clinicians with diverse and novel approaches in targeting pancreatic cancer to share important discoveries in each field. The symposium gathered in San Francisco in January of 2017 with the presentation of some of the most exciting trials in pancreatic cancer and was hosted by the City of Hope Medical Center. This symposium is meant to enhance collaborations, to increase the likelihood of combination therapies, to allow sharing of tissues and other clinical resources for study, and to accelerate progress in improving cure in this disease. The proceedings to this symposium are in the following issue of the Journal of Surgical Oncology (JSO). This conference and these proceedings are possible due to the generosity of The Leo and Anne Albert Charitable Trust, the legacy of two Florida philanthropists (cover of this journal). This Charitable Trust has funded many grants to study pancreatic cancer. After serving in the Marines in WWII, Leo Albert joined Prentice Hall publishers as a stock boy in 1946. He retired nearly four decades later, in 1985, as chairman of Prentice Hall International Publishers. He also served as chair of the prestigious Association of American Book Publishers. The Alberts moved to Palm Beach, FL, in 1992, where together they quickly earned a reputation for their support of causes both local and global in scope. Their lives were impacted by cancer, and both died of cancer. “These grants are an effort by the Albert Charitable Trust to help conquer a deadly form of cancer,” says trustee Gene M. Pranzo. “Leo and Anne Albert would be pleased to know they are supporting discoveries that will help people the world over.” We thank Mr. Pranzo and the Albert Charitable Trust for funding ongoing research in pancreatic cancer, and for funding this symposium.We thank Editor Stephen Sener for allowing us to guest edit this issue of JSO. Most of all, we thank our many patients with pancreatic cancer, whose struggle against this disease, and whose participation in studies and trials have paved the way for progress in fighting this deadly cancer.

Minimally Invasive Surgery of the Liver

Operations on the liver have been undertaken for centuries for numerous indications including trauma, infections, and even for malignancy, but it was not until the past few decades that rates dramatically increased. This expanse in liver operations is due to a multitude of factors, including broader indications as well as improved safety. Our understanding of metastatic disease to the liver, especially colorectal cancer metastases, has vastly amplified the number of patients who would be candidates for hepatic resections and liver-directed therapies. We will focus our discussion here on planned minimally invasive operations for benign and malignant tumors as the majority of the literature relates to this setting.