Facilitation of Surgical Innovation: Is It Possible to Speed the Introduction of New Technology While Simultaneously Improving Patient Safety?

OBJECTIVE: To review efficiency metrics and patient safety data before and after implementation of a structured review process for surgical innovations. SUMMARY BACKGROUND DATA: Surgical innovation ranges from minor incremental improvement to radical experimentation. Although innovation paradigms have been described, these are not widely adopted or enforced in the surgical community. METHODS: A Continuous Quality Improvement Team (CQIT) of surgical quality officers and perioperative nurses was organized to perform structured reviews of proposed new surgical devices and procedures at a large quaternary cancer care center. The CQIT process was placed to precede an established Value Analysis Team business evaluation. Pre- and post-CQIT implementation metrics of approval process efficiency and patient safety data were compared. Seven novel procedures were also vetted by the CQIT. RESULTS: Forty-six product requests were evaluated after CQIT implementation. Compared with 34 products evaluated prior to CQIT establishment, the total mean evaluation time decreased from 124 to 51 days (P= 0.007). For new devices requiring intraoperative trial, the time between product proposal and trial decreased from a mean of 260 to 99 days (P= 0.014). The rate of device-related complications in the pre-CQIT group was 10% compared with 0% post-CQIT. Two devices, which administratively bypassed CQIT review, had both minor and major complications, including a mortality. Five novel procedures approved by CQIT with simulation were performed without complications. CONCLUSIONS: Using novel algorithms, the addition of a dedicated team of surgical quality officers to the surgical innovation evaluation process improved both the efficiency and the safety associated with introducing new devices and procedures into practice.

Severe Preoperative Symptoms Delay Readiness to Return to Intended Oncologic Therapy (RIOT) After Liver Resection.

BACKGROUND: Symptom burden, as measured by patient-reported outcome (PRO) metrics, may have prognostic value in various cancer populations, but remains underreported. The aim of this project was to determine the predictive impact of preoperative patient-reported symptom burden on readiness to return to intended oncologic therapy (RIOT) after oncologic liver resection. METHODS: Preoperative factors, including anthropometric analysis of sarcopenia, were collected for patients undergoing oncologic liver resection from 2015 to 2018. All patients reported their preoperative symptom burden using the MD Anderson Symptom Inventory, Gastrointestinal version (MDASI-GI). Time to RIOT readiness was compared using standard statistics. RESULTS: Preoperative symptom burden was measured in 107 consecutive patients; 52% had at least one moderate symptom score and 21% reported at least one severe score. Highest rated symptoms were fatigue, disturbed sleep, and distress. For patients reporting a severe preoperative symptom burden, the median time to RIOT readiness was 35 days (interquartile range [IQR] 28-42), compared with 21 days (IQR 21-28) for those without severe symptoms (p < 0.001). On multivariable analysis, severe preoperative symptom burden was independently associated with longer time to RIOT readiness (estimate +7.5 days, 95% confidence interval 2.6-12.3; p = 0.002). CONCLUSIONS: Preoperative symptom burden has a substantial impact on time to RIOT readiness, leading to, on average, a 7-day delay in RIOT readiness compared with patients without severe preoperative symptoms. Identifying and targeting severe preoperative symptoms may hasten recovery and improve time to necessary adjuvant therapies.

Determining the Safety and Efficacy of Enhanced Recovery Protocols in Major Oncologic Surgery: An Institutional NSQIP Analysis.

BACKGROUND: Enhanced-recovery (ER) protocols are increasingly being utilized in surgical practice. Outside of colorectal surgery, however, their feasibility, safety, and efficacy in major oncologic surgery have not been proven. This study compared patient outcomes before and after multispecialty implementation of ER protocols at a large, comprehensive cancer center. METHODS: Surgical cases performed from 2011 to 2016 and captured by an institutional NSQIP database were reviewed. Following exclusion of outpatient and emergent surgeries, 2747 cases were included in the analyses. Cases were stratified by presence or absence of ER compliance, defined by preoperative patient education and electronic medical record order set-driven opioid-sparing analgesia, goal-directed fluid therapy, and early postoperative diet advancement and ambulation. RESULTS: Approximately half of patients were treated on ER protocols (46%) and the remaining on traditional postoperative (TP) protocols (54%). Treatment on an ER protocol was associated with decreased overall complication rates (20% vs. 33%, p < 0.0001), severe complication rates (7.4% vs. 10%, p = 0.010), and median hospital length of stay (4 vs. 5 days, p < 0.0001). There was no change in readmission rates (ER vs. TP, 8.6% vs. 9.0%, p = 0.701). Subanalyses of high magnitude cases and specialty-specific outcomes consistently demonstrated improved outcomes with ER protocol adherence, including decreased opioid use. CONCLUSIONS: This assessment of a large-scale ER implementation in multispecialty major oncologic surgery indicates its feasibility, safety, and efficacy. Future efforts should be directed toward defining the long-term oncologic benefits of these protocols.

Genetics and Genomics in Clinical Practice: The Views of Wisconsin Physicians.

INTRODUCTION: Decreasing costs and increased availability of genetic testing and genome sequencing mean many physicians will consider using these services over the next few years. Despite this promising future, some argue the present roadmap for translating genetics and genomics into routine clinical practice is unclear. OBJECTIVE: We conducted a pilot study to explore Wisconsin physicians' views, practices and educational desires regarding genetic and genomic testing. METHODS: Our study consists of an Internet survey (n=155) conducted in August and September 2015 and follow-up phone interviews with a portion of survey participants. Physicians of all specialties were invited to participate. Variables measured include physicians' general knowledge and experience regarding genetic and genomic testing, attitudes and perceptions toward these tests, testing intentions, and educational desires. Sociodemographic variables included gender, age, and medical specialty. RESULTS: In our exploratory survey of Wisconsin physicians, adult primary care providers (PCPs) lagged behind other providers in terms of familiarity and experience with genetic and genomic testing. PCPs in our sample were less likely than other physicians to feel their training in genetics and genomics is adequate. Physicians younger than 50 were more likely than older colleagues to feel their training is adequate. CONCLUSIONS: Our exploratory study suggests a gap in physician education and understanding regarding genomic testing, which is fast becoming part of personalized medical care. Future studies with larger samples should examine ways for physicians to close this gap, with special focus on the needs of PCPs.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: a systematic review and meta-analysis.

BACKGROUND: Due to the increased adoption of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), patients with malignant peritoneal mesothelioma (MPM) have seen improved outcomes. We aimed to evaluate and synthesize the recent published literature. METHODS: The review was conducted according to the recommendation of the Meta-Analysis of Observational Studies in Epidemiology group with prespecified inclusion and exclusion criteria. The DEALE method was used to combine mortality rates, and imputation techniques were used to calculate standard errors. Meta-regression techniques were used to synthesize data. Publication bias was assessed using funnel plots. RESULTS: Of 6,528 citations collected, 20 articles reporting on 1,047 patients were included in the analysis. The median age was 51 years (interquartile range 49-55), with 59 % (54-67) female. The median peritoneal carcinomatosis index score was 19 (16-23). Complete cytoreduction (CC0, 1) was performed in 67 % (46-93 %) of patients. Pooled estimates of survival yielded a 1-, 3- and 5-year survival of 84, 59, and 42 %, respectively. Patients receiving early postoperative intraperitoneal chemotherapy [EPIC] (44 %) and those receiving cisplatin intraperitoneal chemotherapy alone (48 %) or in combination (44 %) had an improved 5-year survival. CONCLUSIONS: While CRS + HIPEC has led to an improved survival for patients with MPM compared to historic data, heterogeneity of studies precludes generalizable inferences. EPIC chemotherapy and cisplatin chemoperfusion may infer survival benefit.

Exploring the Genomic Landscape of Hepatobiliary Cancers to Establish a Novel Molecular Classification System.

Taxonomy of hepatobiliary cancer (HBC) categorizes tumors by location or histopathology (tissue of origin, TO). Tumors originating from different TOs can also be grouped by overlapping genomic alterations (GA) into molecular subtypes (MS). The aim of this study was to create novel HBC MSs. Next-generation sequencing (NGS) data from the AACR-GENIE database were used to examine the genomic landscape of HBCs. Machine learning and gene enrichment analysis identified MSs and their oncogenomic pathways. Descriptive statistics were used to compare subtypes and their associations with clinical and molecular variables. Integrative analyses generated three MSs with different oncogenomic pathways independent of TO (n = 324; p < 0.05). HC-1 "hyper-mutated-proliferative state" MS had rapidly dividing cells susceptible to chemotherapy; HC-2 "adaptive stem cell-cellular senescence" MS had epigenomic alterations to evade immune system and treatment-resistant mechanisms; HC-3 "metabolic-stress pathway" MS had metabolic alterations. The discovery of HBC MSs is the initial step in cancer taxonomy evolution and the incorporation of genomic profiling into the TNM system. The goal is the development of a precision oncology machine learning algorithm to guide treatment planning and improve HBC outcomes. Future studies should validate findings of this study, incorporate clinical outcomes, and compare the MS classification to the AJCC 8th staging system.

Human embryonic stem cells differentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity.

Natural killer (NK) cells serve as important effectors for antitumor immunity, and CD56+CD45+ NK cells can be routinely derived from human embryonic stem cells (hESCs). However, little is know about the ability of hESC-derived NK cells to mediate an effective in vivo antitumor response. Using bioluminescent imaging, we now demonstrate that H9 line hESC-derived NK cells mediate effective clearance of human tumor cells in vivo. In addition to increased in vitro killing of diverse tumor targets, the in vivo tumor clearance by H9 hESC-derived NK cells was more effective compared with NK cells derived from umbilical cord blood (UCB). Phenotypic analysis demonstrates the hESC-derived NK cells are uniformly CD94+CD117(low/-), an NK-cell population characterized by potent cytolytic activity and thus more competent to mediate tumor clearance. These studies demonstrate that hESCs provide an important model to study human lymphocyte development and may serve as a novel source for antitumor immunotherapy.

Detours on the Road to Recovery: What Factors Delay Readiness to Return to Intended Oncologic Therapy (RIOT) After Liver Resection for Malignancy?

BACKGROUND: Poor recovery after oncologic hepatic resection delays Return to Intended Oncologic Therapy (RIOT) and shortens survival. In order to identify at-risk patients, this study was designed to determine which psychosocial and perioperative factors are associated with delayed RIOT readiness. METHODS: A prospectively maintained database was queried to identify consecutive patients undergoing hepatectomy for malignancy from 2015 to 2017. Perioperative factors were compared between patients with early (≤ 28 postoperative days) vs. delayed (> 28 postoperative days) clearance to RIOT. Univariate analysis and multivariable logistic regression were performed. RESULTS: Of 114 patients, 76 patients (67%) had an open surgical approach, 32 (28%) had a major hepatectomy, and 6 (5%) had a major complication, with no mortalities. Eighty-two patients (72%) had early and 32 patients (28%) had delayed RIOT readiness. Patients with high preoperative symptom burden were more likely to have delayed RIOT readiness (OR 3.1, 95% CI 1.1-8.4, p = 0.024). On multivariable analysis, open surgical approach (OR 6.9, 95% CI 1.4-34.7, p = 0.018), length of stay > 5 days (OR 3.6, 95% CI 1.4-9.4, p = 0.010), and any complication (OR 3.4, 95% CI 1.1-10.7, p = 0.033) were associated with delayed RIOT readiness. Postoperative factors associated with delayed RIOT readiness included nutritional and wound-healing parameters. CONCLUSIONS: This study highlights the previously under-described importance of preoperative patient symptom burden on delayed postoperative recovery. As a cancer patient's return to oncologic therapy after hepatectomy has a substantial impact on survival, it is critical to adhere to enhanced recovery principles and address all other modifiable factors that delay recovery.

Enhanced recovery in liver surgery decreases postoperative outpatient use of opioids.

BACKGROUND: Pathways of enhanced recovery in liver surgery decrease inpatient opioid use; however, little data exist regarding their effect on discharge prescriptions and post-discharge opioid intake. METHODS: For consecutive patients undergoing liver resection from 2011-2018, clinicopathologic factors were compared between patients exposed to enhanced recovery vs. traditional care pathways. Multivariable analysis was used to determine factors predictive for traditional opioid use at the first postoperative follow-up. The enhanced recovery in liver surgery protocol included opioid-sparing analgesia, goal-directed fluid therapy, early postoperative feeding, and early ambulation. RESULTS: Of 244 cases, 147 enhanced recovery patients were compared with 97 traditional pathway patients. Enhanced recovery patients were older (median 57 years vs 52 years, P = .031) and more frequently had minimally invasive operations (37% vs 16%, P < .001), with fewer major complications (2% vs 9%, P = .011). Enhanced recovery patients were less likely to be discharged with a prescription for traditional opioids (26% vs 79%, P < .001) and less likely to require opioids at their first postoperative visit (19% vs 61%, P < .001) despite similarly low patient-reported pain scores (median 2/10 both groups, P = .500). On multivariable analysis, the traditional recovery pathway was independently associated with traditional opioid use at the first follow-up (odds ratio 6.4, 95% confidence interval 3.5-12.1; P < .001). CONCLUSION: The implementation of an enhanced recovery in liver surgery pathway with opioid-sparing techniques was associated with decreased postoperative discharge prescriptions for opioids and outpatient opioid use after oncologic liver surgery, while achieving the same level of pain control. For this and other populations at risk of persistent opioid use, enhanced recovery strategies can eliminate excess availability of opioids.

Challenges to clinical utilization of hereditary cancer gene panel testing: perspectives from the front lines.

Next generation sequencing (NGS) technology is rapidly being implemented into clinical practice. Qualitative research was performed to gain an improved understanding of the landscape surrounding the use of NGS in cancer genetics. A focus group was conducted at the Wisconsin Cancer Risk Programs Network biannual meeting. Free flowing discussion with occasional open-ended questions provided insights into the use of NGS. 19 genetic counselors and medical professionals participated. Three major themes were identified with respect to NGS and its use in cancer genetics: knowledge gaps, the evolving clinician role, and uncertain utility. Several corresponding subthemes were identified. With respect to knowledge gaps, participants expressed concern regarding unexpected results and variants of unknown significance, lack of data about NGS findings, absence of standardization regarding use of NGS and guidelines for interpretation, and discomfort with new technology. Regarding the evolving clinician role, necessary changes to the roles of genetic counselors and physicians were noted, as was the resultant impact on care received by patients and their families. Finally, the clinical and economic utility of NGS was questioned. While a shift from traditional Sanger sequencing to NGS is occurring in molecular genetic testing for disease susceptibility, there are several obstacles that need to be overcome before widespread adoption of this technology can occur. Furthermore, key aspects of NGS and it utility remain unexplored. Continued investigation into these subjects is necessary before this technology will consistently be of benefit to patients and their families.

Wnt signaling promotes hematoendothelial cell development from human embryonic stem cells.

Human embryonic stem cells (hESCs) provide an important means to effectively study soluble and cell-bound mediators that regulate development of early blood and endothelial cells in a human model system. Here, several complementary methods are used to demonstrate canonical Wnt signaling is important for development of hESC-derived cells with both hematopoietic and endothelial potential. Analyses using both standard flow cy-tometry, as well the more detailed high-throughput image scanning flow cytometry, characterizes sequential development of distinct early developing CD34(bright)CD31(+)Flk1(+) cells and a later population of CD34(dim)CD45(+) cells. While the CD34(bright)CD31(+)Flk1(+) have a more complex morphology and can develop into both endothelial cells and hematopoietic cells, the CD34(dim)CD45(+) cells have a simpler morphology and give rise to only hematopoietic cells. Treatment with dickkopf1 to inhibit Wnt signaling results in a dramatic decrease in development of cells with hematoendothelial potential. In addition, activation of the canonical Wnt signaling pathway in hESCs by coculture with stromal cells that express Wnt1, but not use of noncanonical Wnt5-expressing stromal cells, results in an accelerated differentiation and higher percentage of CD34(bright)CD31(+)Flk1(+) cells at earlier stages of differentiation. These studies effectively demonstrate the importance of canonical Wnt signaling to mediate development of early hematoendothelial progenitors during human development.