Susanne G. Warner

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.

Viroimmunotherapy for Colorectal Cancer: Clinical Studies

Colorectal cancer is a leading cause of cancer incidence and death. Therapies for those with unresectable or recurrent disease are not considered curative at present. More effective and less toxic therapies are desperately needed. Historically, the immune system was thought to be an enemy to oncolytic viral therapy. Thinking that oncolysis would be the only mechanism for cell death, oncolytic virologists theorized that immune clearance was a detriment to oncolysis. Recent advances in our understanding of the tumor microenvironment, and the interplay of tumor survival and a patient’s immune system have called into question our understanding of both arenas. It remains unclear what combination of restrictions or enhancements of innate and/or cell-mediated immunity can yield the highest likelihood of viral efficacy. This article reviews the variety of mechanisms explored for viruses such as immunotherapy for colorectal cancer.

Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells

Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection.

Early recovery pathway for hepatectomy: data-driven liver resection care and recovery

In recent years, great progress has been made toward safer hepatobiliary surgical interventions. This has resulted in more widely available treatments for patients who in the past were ineligible for curative resection of primary liver tumors, liver metastases, and advanced biliary tumors. However, the rise in procedures has seen increasingly heterogeneous perioperative management, yielding strikingly disparate outcomes. A number of groups have attempted to standardize perioperative care in an effort to create enhanced recovery pathways (ERPs) and provide clinicians with a dependable roadmap to success following hepatectomy. In the future, each aspect of perioperative care could be pre-ordained with emphasis on nutrition, anesthesia, prophylaxis, use of surgical drains, post-operative fluid and electrolyte management, and contact with physician extenders following discharge. This article reviews the data behind ERPs preceding and following hepatectomy. It includes primary data justifying practices in post-hepatectomy support. It also touches on the benefits of minimally invasive hepatectomy and offers future directions for research in peri-hepatectomy ERPs. Overall, this article seeks to formulate a pathway for practice based on data, with enough details to allow creation of rational order sets for efficient and superior practice.

Disparities in managing emotions when facing a diagnosis of breast cancer: Results of screening program of couples distress

Introduction: Distress screening is now required for cancer center accreditation. Understanding patient and caregiver stress is critical to successful cancer care. This study examines the perceived emotional impact of breast cancer on both patients and partners. Methods: From March 2011‐February 2016, patients and partners undertook an electronic, 48‐point distress screen during their first visit at a surgical breast clinic. Distress was measured via self‐reported concerns on a five point Likert scale. Respondents were also asked about preferred interventions. The ability of the patient and partner to manage emotions was assessed in relation to education, ethnicity, fatigue, anxiety, and depression using ordered logistic regression. Results: Of the 665 individuals screened, 51.7%(n = 344) were patients, while 48.3%(n = 321) were partners. Patients were more distressed than partners regarding fatigue, anxiety, depression, and worrying about the future (p < 0.005). Only 19.7% of partners requested information with regards to “managing emotions” compared to 46.3% of patients. In the univariate analysis, being a partner was protective (OR 0.49 (95%CI 0.34–0.70, p < 0.000) as was holding an advanced educational degree (OR 0.36 (95%CI 0.14–0.93) p = 0.035). In the multivariate regression, having more education remained protective, while being a partner was no longer protective (OR 0.93(95%CI 0.62–1.39, p = 0.789). Financial concerns, anxiety, depression, and worrying about the future remained statistically significant. Partners asked for help less than patients (OR 0.28 (95%CI 0.17–0.48), p < 0.000). Conclusion: While partners have similar concerns as patients, they do not seek information or help in managing emotions as often as do patients. Both patient and partners with less education and increased financial distress were likely to report difficulty in managing emotions. This study identifies groups who would benefit from supportive measures even in the absence of a request for help.

Novel oncolytic chimeric orthopoxvirus causes regression of pancreatic cancer xenografts and exhibits abscopal effect at a single low dose

BackgroundPancreatic ductal adenocarcinoma (PDAC) has been increasing by 0.5% per year in the United States. PDAC portends a dismal prognosis and novel therapies are needed. This study describes the generation and characterization of a novel oncolytic chimeric orthopoxvirus for the treatment of pancreatic cancer.MethodsAfter chimerization and high-throughput screening, CF33 was chosen from 100 new chimeric orthopoxvirus isolates for its ability to kill pancreatic cancer cells. In vitro cytotoxicity was assayed in six pancreatic cancer cell lines. In vivo efficacy and toxicity were evaluated in PANC-1 and MIA PaCa-2 xenograft models.ResultsCF33 caused rapid killing of six pancreatic cancer cells lines in vitro, releasing damage-associated molecular patterns, and regression of PANC-1 injected and non-injected distant xenografts in vivo after a single low intratumoral dose of 103 plaque-forming units. Using luciferase imaging, CF33 was noted to preferentially replicate in tumors which corresponds to the low viral titers found in solid organs.ConclusionThe low dose of CF33 required to treat pancreatic cancer in this preclinical study may ease the manufacturing and dosing challenges currently facing oncolytic viral therapy.

Therapeutic oncolytic viruses: clinical advances and future directions

Purpose of review The present review will highlight recent advances in the clinical application of oncolytic viral therapy. Recent findings Until recently, oncolytic viral researchers saw the immune system as an enemy that would clear the virus from the bloodstream. However, researchers now understand that sustained responses are seen in those patients with more robust antitumor immune responses. Much of the current focus in oncolytic viral research is trained on manipulation of the immune system to affect cancer cell killing in the tumor microenvironment and to facilitate durable systemic antitumor immunity. Many investigators have demonstrated synergistic effects of checkpoint inhibition and other immune therapies with viral administration. At the same time, insertion of various markers enables noninvasive deep tissue imaging. Finally, following regulatory approval in the United States and Europe, unbridled clinical use of T-VEC for patients with metastatic melanoma is also generating large volumes of patient data that will help elucidate strengths and weaknesses of oncolytic viral therapy. Perhaps the most telling sign of the fields future is a seismic shift in clinical trials with more investigators combining virus and immunotherapies. Summary This article reviews the current state of therapeutic oncolytic viruses in clinical use, and explores future directions of the field.

A Novel Oncolytic Chimeric Orthopoxvirus Encoding Luciferase Enables Real-Time View of Colorectal Cancer Cell Infection

This study hypothesizes that a novel oncolytic chimeric orthopoxvirus CF33-Fluc is imageable and targets colorectal cancer cells (CRCs). A novel chimeric orthopoxvirus (CF33) was constructed. The thymidine kinase locus was replaced with firefly luciferase (Fluc) to yield a recombinant virus—CF33-Fluc. In vitro cytotoxicity and viral replication assays were performed. In vivo CRC flank xenografts received single doses of intratumoral or intravenous CF33-Fluc. Viral biodistribution was analyzed via luciferase imaging and organ titers. CF33-Fluc infects, replicates in, and kills CRCs in vitro in a dose-dependent manner. CF33 has superior secretion of extracellular-enveloped virus versus all but one parental strain. Rapid tumor regression or stabilization occurred in vivo at a low dose over a short time period, regardless of the viral delivery method in the HCT-116 colorectal tumor xenograft model. Rapid luciferase expression in virus-infected tumor cells was associated with treatment response. CRC death occurs via necroptotic pathways. CF33-Fluc replicates in and kills colorectal cancer cells in vitro and in vivo regardless of delivery method. Expression of luciferase enables real-time tracking of viral replication. Despite the chimerism, CRC death occurs via standard poxvirus-induced mechanisms. Further studies are warranted in immunocompetent models.

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.

The Art of Innovation: an Interview with Yuman Fong, MD

Dr. Yuman Fong is the Sangiocomo Family Chair in Surgery and Chairman of the Department of Surgery at City of Hope in Los Angeles. There, he is also a professor of Experimental Therapeutics and the director of International Medicine. He received a Bachelor of Arts in medieval literature from Brown University in 1981, and his medical doctorate from Cornell University Medical College in 1984. He completed his residency at Cornell under the mentorship of Dr. G. Thomas Shires along with a research fellowship under Dr. Stephen Lowry. He then completed a fellowship in surgical oncology with Dr. Murray F. Brennan at the Memorial Sloan-Kettering Cancer Center (MSKCC). At MSKCC, he served for over twenty years as an attending surgeon ultimately becoming the Murray F. Brennan Chair in Surgery. There, he mentored countless trainees on the wards, in the OR, and in the lab, many of whom are now prominent leaders in American surgery and abroad. He is a true renaissance man who loves his family and nurtures broad interests ranging from expert rifle shooting to camping on beaches. He is also a technically gifted liver surgeon, viral gene therapist, innovator, disruptor, and visionary. His work has set the standard in many ways for liver surgery as we know it today. He has navigated regulatory hurdles to bring many different ideas to fruition in arenas including medical devices, surgical techniques, and viral gene therapy among others. Dr. Fong was kind enough to share some of his wisdom during a filmed interview with his junior faculty mentee, Dr. Susanne Warner, which was published on the SSAT Resident’s Corner website as a BMentor of the Month^ video. The following questions and answers are paraphrased for ease of reading. The full interview can be found at ssat. com/residents in the mentor of the month archives section.