Implementation of a surgical site infection prevention bundle in gynecologic oncology patients: An enhanced recovery after surgery initiative.

OBJECTIVE: To evaluate the clinical outcomes pre- and post-implementation of an evidence-informed surgical site infection prevention bundle (SSIPB) in gynecologic oncology patients within an Enhanced Recovery After Surgery (ERAS) care pathway. METHODS: Patients undergoing laparotomy for a gynecologic oncology surgery between January-June 2017 (pre-SSIPB) and between January 2018-December 2020 (post-SSIPB) were compared using t-tests and chi-square. Patient characteristics, surgical factors, and ERAS process measures and outcomes were abstracted from the ERAS® Interactive Audit System (EIAS). The primary outcomes were incidence of surgical site infections (SSI) during post-operative hospital admission and at 30-days post-surgery. Secondary outcomes included total postoperative infections, length of stay, and any surgical complications. Multivariate models were used to adjust for potential confounding factors. RESULTS: Patient and surgical characteristics were similar in the pre- and post-implementation periods. Evaluation of implementation suggested that preoperative and intraoperative components of the intervention were most consistently used. Infectious complications within 30 days of surgery decreased from 42.1% to 24.4% after implementation of the SSIPB (p < 0.001), including reductions in wound infections (17.0% to 10.8%, p = 0.02), urinary tract infections (UTI) (12.7% to 4.5%, p < 0.001), and intra-abdominal abscesses (5.4% to 2.5%, p = 0.05). These reductions were associated with a decrease in median length of stay from 3 to 2 days (p = 0.001). In multivariate analysis, these SSI reductions remained statistically significant after adjustment for potential confounders. CONCLUSION: Implementation of SSIPB was associated with a reduction in SSIs and infectious complications, as well as a shorter length of stay in gynecologic oncology patients.

Molecular Surrogate Subtypes of Ovarian and Peritoneal Low-grade Serous Carcinoma.

Low-grade serous carcinoma (LGSC) is an uncommon histotype of ovarian carcinoma, accounting for ~3% of cases. There is evidence that survival of peritoneal LGSC (pLGSC) is longer than that of ovarian LGSC (oLGSC). Key molecular alterations of LGSC have been established, including loss of CDKN2A and PR expression, MAPK pathway alterations, and loss of USP9X expression. We hypothesized that LGSC could be subclassified into clinically applicable molecular subtypes by a few surrogate tests similar to endometrioid carcinomas using a hierarchical decision tree based on the strength of the prognostic associations of the individual alterations. Our study included 71 LGSCs. Immunohistochemistry for CDKN2A, ER, PR, NF1, and USP9X and sequencing for KRAS , NRAS , and BRAF were performed. Our data showed the co-occurrence of key molecular alterations, and despite suggestive trends, hierarchical molecular subtyping did not provide significantly different stratification of patients according to survival in this cohort. We confirmed that patients diagnosed with pLGSC have a longer survival than high-stage oLGSC, with the intriguing observation that normal CDKN2A and PR status were associated with excellent survival in pLGSC. Therefore, CDKN2A and PR status might aid in the classification of indeterminate implants, where abnormal findings favor pLGSC over noninvasive implants. Molecular subtypes should be further evaluated in larger cohorts for their prognostic and potentially predictive value.

Universal Testing to Identify Lynch Syndrome Among Women With Newly Diagnosed Endometrial Carcinoma.

BACKGROUND: Lynch syndrome (LS) is an autosomal dominant cancer syndrome caused by a germline mutation in the mismatch repair (MMR) genes. Protocols based on immunohistochemical expression of MMR proteins in cancer are used to identify patients with LS. METHODS: The universal LS screening protocol of the Tom Baker Cancer Centre (Calgary, AB) of all patients diagnosed between April 1, 2013 and April 1, 2015 with endometrioid carcinoma of the endometrium was audited through a retrospective chart review. LS status and frequency of protocol compliance at each of the key steps were calculated (Canadian Task Force Classification II-2). RESULTS: The cohort consisted of 375 patients. MMR immunohistochemical testing was requested for 321 (85.6%). Expression of at least one protein was lost in 86 (26.8%). Twenty-one (6.5%) patients were eligible for genetic counselling because PMS2, MSH2, or MSH6 protein expression was lost in 19, and two patients had a family history of LS. Eleven (91.7%) of 12 (57.1%) who attended had germline testing, and six (54.5%) showed a mutation diagnostic of LS. LS status among the cohort of 375 patients was positive in six (1.6%), negative in 294 (78.4%), and unknown in 75 (20%) because of protocol non-compliance. LS was confirmed in six (2%) of the 321 women who completed the protocol. CONCLUSION: This is the first audit of a Canadian-based universal LS screening protocol of patients with endometrial cancer. The success of the protocol is endorsed by the 80% compliance and by the 2% prevalence of LS, which is within the published range.

Impact of transversus abdominis plane blocks versus non-steroidal anti-inflammatory on post-operative opioid use in ERAS ovarian cancer surgery.

BACKGROUND: Treatment of ovarian cancer often requires extensive surgical resection. The transversus abdominis plane (TAP) block has been utilized in benign gynecologic surgery to decrease post-operative pain and opioid use. We hypothesized that TAP blocks would decrease total opioid use in the first 24 hours and decrease length of stay following staging and cytoreductive surgery for ovarian cancer compared with either no local anesthetic or local wound infiltration alone. METHODS: All patients undergoing surgery for ovarian cancer from November 2016 to June 2017 were included in this retrospective cohort study. Median opioid use at 24, 48, and 72 hours post-operatively, as well as length of stay, were assessed. Multivariate median regression analysis was performed to adjust for potential confounders: post-operative non-steroidal anti-inflammatory drug (NSAID) usage, pre-operative opioid consumption, and extent of cytoreductive surgery. Length of stay was compared using Cox regression analysis. RESULTS: One-hundred-and-twenty patients were included in the analysis. Eighty-two patients had a TAP block, while 38 did not. After adjusting for potential confounders there was no difference in median 24 hours opioid consumption (p=0.29) or length of stay (HR 0.95, p=0.78) between patients receiving TAP block compared with those without. After adjusting for potential confounders, patients receiving scheduled NSAIDs had a 2.6-fold greater likelihood of being discharged (p<0.0005) and a significant reduction in median opioid use at 24 hours (23.5 vs 14.5 mg) (p=0.017) compared with those patients without NSAIDs. DISCUSSION: Post-operative administration of NSAIDs, but not TAP block, was associated with a decrease in post-operative opioid use and length of stay following surgery for ovarian cancer. Further investigation into alternative regional anesthetics for Enhanced Recovery after Surgery (ERAS) protocols is warranted.

Treatment related outcomes in high-risk endometrial carcinoma: Canadian high risk endometrial cancer consortium (CHREC).

OBJECTIVE: The lack of randomized clinical data pertaining to optimal surgery and adjuvant treatment in women with high-risk histotypes of endometrial cancer has resulted in selective management based on institutional policies. The objective of this study was to assess differences in treatment strategies and their outcomes among various institutions. METHOD: High-risk endometrial cancer cases (2000-2012) with corresponding clinicopathologic data were collected from 7 academic cancer centers. Histotypes included grade 3 endometrioid (EC3), serous (ESC), clear cell (CCC) and carcinosarcoma (CS). Associations with overall survival were performed using Cox proportional hazard regression. RESULTS: 1260 patients treated between 2000 and 2012 were included in the study: 398 EC3, 449 ESC, 91 CCC, 236 CS and 83 'other'. The use of adjuvant chemotherapy, adjuvant radiation, and extent of surgical staging were statistically different among the 7 centers (P<0.001). Histotype was independently associated with overall survival (OS) in patients with stage 1 and 2 disease who underwent surgical staging (P=0.0324). Adjuvant radiation was associated with improved OS for EC3 and CCC and adjuvant chemotherapy was associated with improved OS for ESC and CS. There was a high rate of recurrence (17.8% and 21.4%) in completely staged, stage 1A patients with ESC and CS respectively. CONCLUSION: There exists a wide variation in practice and outcomes for high-risk histotypes of endometrial cancer. The relative impact of adjuvant therapy appears to be histotype dependent and prospective studies examining adjuvant treatment in high-risk histotypes should use caution combining them together.

Canadian high risk endometrial cancer (CHREC) consortium: analyzing the clinical behavior of high risk endometrial cancers.

OBJECTIVES: The objective of this study is to analyze the clinical behavior of endometrial carcinomas by high risk(HR) histotype, including stage, overall survival, recurrence free survival and patterns of failure. METHODS: This is a retrospective multi-institutional cohort study performed at 7 tertiary care centers across Canada between 2000 and 2012 and included: grade 3 endometrioid (EC3), endometrial serous cancer (ESC), clear cell carcinomas (CCC) and carcinosarcoma (CS). Clinicopathological and outcome data was collected. RESULTS: 1260 women with endometrial carcinoma with 1013 having staging procedures were identified; 398 EC3, 449 ESC, 236 CS and 91 CCC. 51.8% had lymphovascular space invasion (LVSI) and 18.5% had omental involvement with a statistically significant difference between tumor types (p=0.0005 and 0.0047 respectively); ESC had a significantly greater rate of omental involvement compared to EC3 (22% to 9%, p=0.0005). Within the entire cohort 49.3% were stage 1, 10.6% were stage 2, 27.4% were stage 3 and 12.7% were stage 4. Overall survival and recurrence free survival were significantly different between histotypes (p<0.0001) with CS having the worst outcome. Overall 31.5% of patients recurred. CS and ESC had a higher distant recurrence rate compared to EC3 (29.6%, 31.0% compared to 16.4%, p=0.0002 and p<0.001). CONCLUSION: This study is one of the largest clinical cohorts of HR endometrial cancers. We have further clarified the impact of histotype and stage on recurrence and survival, and the high likelihood of distant recurrence. However, the differences are modest and risk prediction models will require additional molecular markers.

Impact of hydrogel biophysical properties on tumor spheroid growth and drug response.

The extracellular matrix (ECM) plays a critical role in regulating cell-matrix interactions during tumor progression. These interactions are due in large part to the biophysical properties responding to cancer cell interactions. Within in vitro models, the ECM is mimicked by hydrogels, which possess adjustable biophysical properties that are integral to tumor development. This work presents a systematic and comparative study on the impact of the biophysical properties of two widely used natural hydrogels, Matrigel and collagen gel, on tumor growth and drug response. The biophysical properties of Matrigel and collagen including complex modulus, loss tangent, diffusive permeability, and pore size, were characterised. Then the spheroid growth rates in these two hydrogels were monitored for spheroids with two different sizes (140 µm and 500 µm in diameters). An increased migratory growth was observed in the lower concentration of both the gels. The effect of spheroid incorporation within the hydrogel had a minimal impact on the hydrogel's complex modulus. Finally, 3D tumor models using different concentrations of hydrogels were applied for drug treatment using paclitaxel. Spheroids cultured in hydrogels with different concentrations showed different drug response, demonstrating the significant effect of the choice of hydrogels and their concentrations on the drug response results despite using the same spheroids. This study provides useful insights into the effect of hydrogel biophysical properties on spheroid growth and drug response and highlights the importance of hydrogel selection and in vitro model design.

Barriers to High-quality Postoperative Glycemic Management by Surgical Teams: A Theory-informed Qualitative Analysis.

OBJECTIVE: Our aim in this study was to identify the barriers to following recommendations for postoperative glycemic management among surgical team members. METHODS: We conducted semistructured interviews with surgical team members guided by 2 theoretical frameworks for understanding the barriers and drivers of health-care behaviours: the Theoretical Domains Framework and the Consolidated Framework for Implementation Research. Interview data were coded deductively by 2 study team members. RESULTS: Sixteen surgical team members from 7 surgical disciplines at a single hospital participated in this investigation. The most important barriers to management of postoperative hyperglycemia were knowledge of glycemic targets, belief about consequences of hyper- and hypoglycemia, available resources to manage hyperglycemia, adaptability of usual insulin regimens to complex postoperative patients, and skills to initiate insulin. CONCLUSIONS: Interventions to reduce postoperative hyperglycemia are unlikely to be effective unless they use implementation science to address local barriers to high-quality management among surgical team members, including setting and systems-level barriers.

Implementation of a Perioperative Glycemic Management Quality Improvement Pathway in Gynecologic Oncology Patients: A Single-cohort Interrupted Time-series Analysis.

OBJECTIVE: We evaluated implementation and clinical outcomes of a perioperative glycemic management pathway in gynecologic oncology. METHODS: Interrupted time-series analysis was used to compare process, balancing and outcome measures and clinical outcomes from 18 months preimplementation to 18 months postimplementation. RESULTS: Compared with in the preimplementation period, the proportion of patients who underwent preoperative screening with glycated hemoglobin in the postimplementation period increased by 11.3% (95% confidence interval [CI], 5.0% to 17.7%; p=0.001). The proportion of patients with diabetes who had at least 1 blood glucose measurement after surgery increased by 15.3% (95% CI, -3.2% to 33.8%; p=0.10). There was no change in the proportion of patients who had any hyperglycemia or moderate or severe hyperglycemia. The median length of stay decreased by 0.42 days (95% CI, -0.91 to 0.07 days; p=0.09). There were major quality gaps in perioperative glycemic management that did not clearly improve after implementation of a multidisciplinary care pathway. CONCLUSION: Optimal strategies for improvement of perioperative glycemic management are not yet known.

Alginate Particles for Enzyme Immobilization Using Spray Drying.

Enzymes are important catalysts for biological processes due to their high catalytic activity and selectivity. However, their low thermal stability limited their industrial applications. The present work demonstrates a simple and effective method for enzyme immobilization via spray drying. Alginate was used as a support material. Phytase, an important enzyme in the animal feed industry, was selected to study the effect of enzyme immobilization using alginate particles on its thermal stability. The physicochemical properties of alginate particles such as size, surface morphology, and heat resistance were studied. Successful immobilization of phytase was confirmed by confocal microscopy, and the immobilized phytase retained 58% of its original activity upon heating at 95 °C, compared to 4% when the alginate support material was absent. Phytase was released promptly in a simulated gastrointestinal tract with >95% of its original activity recovered. The spray drying method for phytase immobilization is scalable and applicable to other enzymes for various applications.

Biophysical properties of hydrogels for mimicking tumor extracellular matrix.

The extracellular matrix (ECM) is an essential component of the tumor microenvironment. It plays a critical role in regulating cell-cell and cell-matrix interactions. However, there is lack of systematic and comparative studies on different widely-used ECM mimicking hydrogels and their properties, making the selection of suitable hydrogels for mimicking different in vivo conditions quite random. This study systematically evaluates the biophysical attributes of three widely used natural hydrogels (Matrigel, collagen gel and agarose gel) including complex modulus, loss tangent, diffusive permeability and pore size. A new and facile method was developed combining Critical Point Drying, Scanning Electron Microscopy imaging and a MATLAB image processing program (CSM method) for the characterization of hydrogel microstructures. This CSM method allows accurate measurement of the hydrogel pore size down to nanometer resolution. Furthermore, a microfluidic device was implemented to measure the hydrogel permeability (Pd) as a function of particle size and gel concentration. Among the three gels, collagen gel has the lowest complex modulus, medium pore size, and the highest loss tangent. Agarose gel exhibits the highest complex modulus, the lowest loss tangent and the smallest pore size. Collagen gel and Matrigel produced complex moduli close to that estimated for cancer ECM. The Pd of these hydrogels decreases significantly with the increase of particle size. By assessing different hydrogels' biophysical characteristics, this study provides valuable insights for tailoring their properties for various three-dimensional cancer models.

Progression-free survival and quality of life in metastatic breast cancer: The patient perspective.

INTRODUCTION: Treatment advances for metastatic breast cancer (mBC) have improved overall survival (OS) in some mBC subtypes; however, there remains no cure for mBC. Considering the use of progression-free survival (PFS) and other surrogate endpoints in clinical trials, we must understand patient perspectives on measures used to assess treatment efficacy. OBJECTIVE: To explore global patient perceptions of the concept of PFS and its potential relation to quality of life (QoL). MATERIALS AND METHODS: Virtual roundtables in Europe and the United States and interviews in Japan with breast cancer patients, patient advocates, and thought leaders. Discussions were recorded, transcribed, and analyzed thematically. RESULTS: Lengthened OS combined with no worsening or improvement in QoL remain the most important endpoints for mBC patients. Time when the disease is not progressing is meaningful to patients when coupled with improvements in QoL and no added treatment toxicity. Clinical terminology such as "PFS" is not well understood, and participants underscored the need for patient-friendly terminology to better illustrate the concept. Facets of care that patients with mBC value and that may be related to PFS include relief from cancer-related symptoms and treatment-related toxicities as well as the ability to pursue personal goals. Improved communication between patients and providers on managing treatment-related toxicities and addressing psychosocial challenges to maintain desired QoL is needed. CONCLUSION: While OS and QoL are considered the most relevant endpoints, patients also value periods of time without disease progression. Incorporation of these considerations into the design and conduct of future clinical trials in mBC, as well as HTA and reimbursement decision-making, is needed to better capture the potential value of a therapeutic innovation.

Quality gaps in screening and monitoring for postoperative hyperglycemia in a Canadian hospital: a retrospective cohort study.

INTRODUCTION: Evidence-based preoperative, intraoperative and postoperative glycemic management may reduce poor surgical outcomes. Previous studies suggest that quality gaps in perioperative glycemic management may be common. RESEARCH DESIGN AND METHODS: This retrospective cohort study used administrative health and laboratory data from a single center to estimate quality gaps in perioperative glycemic management in patients with and without diabetes between April 2019 and March 2020. We examined the proportion of patients with preoperative hemoglobin A1c (HbA1c) measurement, postoperative point-of-care testing (POCT) for glucose, hyperglycemia, and basal bolus insulin regimens. We compared the median length of stay (LOS) in patients with and without postoperative hyperglycemia, adjusted for age and sex. RESULTS: There were 6576 patients in our cohort; 1165 (17.8%) had diabetes. Most patients with diabetes had an HbA1c measured prior to surgery (n=697, 59.8%). Postoperatively, 16.9% of patients with diabetes had no POCT monitoring (n=197) and 65.7% had hyperglycemia (n=636). Only 35.9% of patients who received insulin had a basal bolus insulin regimen (n=229). Patients with diabetes who had postoperative hyperglycemia had a longer median LOS compared with those who did not have postoperative hyperglycemia (8.4 days (95% CI 7.5 to 9.4) and 6.7 days (95% CI 6.3 to 7.1), respectively). In patients without diabetes, median LOS was 7.4 days (95% CI 4.4 to 10.4) for those with hyperglycemia and 5.2 days (95% CI 5.1 to 5.4) for those with in-target glucose. CONCLUSIONS: Quality gaps in perioperative glycemic management include measurement of blood glucose after surgery and treatment of postoperative hyperglycemia. These gaps may contribute to longer LOS.

Are patients with inflammatory bowel disease on chronic immunosuppressive therapy at increased risk of cervical high-grade dysplasia/cancer? A meta-analysis.

BACKGROUND: Immunosuppression is a mainstay of therapy for both induction and maintenance of remission for inflammatory bowel disease (IBD). Women who are chronically immunosuppressed have been shown to be at higher risk of developing cervical high-grade dysplasia and/or carcinoma. There is contradictory data whether immunosuppressed patients with IBD have the same risk profile for cervical cancer as patients with solid organ transplant or HIV infection. OBJECTIVE: To determine whether the risk of cervical high-grade dysplasia and/or cancer is higher in patients with IBD on immunosuppressive therapy compared with the rates in the general population. METHODS: The studies were restricted to full-text retrospective cohort studies and case controls that had a high (6-9) Newcastle-Ottawa Score. RESULTS: All pooled analyses were based on a random-effects model. Five cohort studies and 3 case-control studies of patients with IBD on any immunosuppression with cervical high-grade dysplasia/cancer (n = 995) were included in the meta-analysis. The total IBD population in these studies was 77,116. Patients with IBD had an increased risk of cervical high-grade dysplasia/cancer compared with healthy controls (odds ratio = 1.34, 95% confidence interval: 1.23-1.46). Heterogeneity was detected (I = 34.23, Q = 10.64, df = 7; P = 0.15). The source was found to be the type of study, as well as the odds ratio presented (crude versus adjusted). CONCLUSIONS: There is sufficient evidence to suggest an increased risk of cervical high-grade dysplasia/cancer in patients with IBD on immunosuppressive medications compared with the general population. Given this increased risk, increased screening intervals are indicated.