Gabapentin and Rapidity of Recovery Among Patients Undergoing Minimally Invasive Ambulatory Uro-Oncologic Surgeries.

INTRODUCTION: Gabapentin has been used in enhanced recovery after surgery (ERAS) pathways for pain control for patients undergoing ambulatory uro-oncologic surgery; however, it may cause undesirable side effects. We studied the causal association between gabapentin and rapidity of recovery and perioperative pain management after minimally invasive uro-oncologic surgery. METHODS: We identified 2397 patients ≤ 65 years undergoing prostatectomies or nephrectomies between 2018 and 2022; 131 (5.5%) did not receive gabapentin. We tested the effect of gabapentin use on time of discharge and perioperative opioid consumption, respectively, using multivariable linear regression adjusting for potential confounders including age, gender, BMI, American Society of Anesthesiologists score, and surgery type. RESULTS: On adjusted analysis, we found no evidence of a difference in discharge time among those who did vs did not receive gabapentin (adjusted difference 0.07 hours shorter on gabapentin; 95% CI -0.17, 0.31; P = .6). There was no evidence of a difference in intraoperative opioid consumption by gabapentin receipt (adjusted difference -1.5 morphine milligram equivalents; 95% CI -4.2, 1.1; P = .3) or probability of being in the top quartile of postoperative opioid consumption within 24 hours (adjusted difference 4.2%; 95% CI -4.8%, 13%; P = .4). We saw no important differences in confounders by gabapentin receipt suggesting causal conclusions are justified. CONCLUSIONS: Our confidence intervals did not include clinically meaningful benefits from gabapentin, when used with an ERAS protocol, in terms of length of stay or perioperative opioid use. These results support the omission of gabapentin from ERAS protocols for minimally invasive uro-oncologic surgeries.

Association Between the COVID-19 Pandemic and Insurance-Based Disparities in Mortality After Major Surgery Among US Adults.

Importance: The COVID-19 pandemic caused significant disruptions in surgical care. Whether these disruptions disproportionately impacted economically disadvantaged individuals is unknown. Objective: To evaluate the association between the COVID-19 pandemic and mortality after major surgery among patients with Medicaid insurance or without insurance compared with patients with commercial insurance. Design, Setting, and Participants: This cross-sectional study used data from the Vizient Clinical Database for patients who underwent major surgery at hospitals in the US between January 1, 2018, and May 31, 2020. Exposures: The hospital proportion of patients with COVID-19 during the first wave of COVID-19 cases between March 1 and May 31, 2020, stratified as low (≤5.0%), medium (5.1%-10.0%), high (10.1%-25.0%), and very high (>25.0%). Main Outcomes and Measures: The main outcome was inpatient mortality. The association between mortality after surgery and payer status as a function of the proportion of hospitalized patients with COVID-19 was evaluated with a quasi-experimental triple-difference approach using logistic regression. Results: Among 2 950 147 adults undergoing inpatient surgery (1 550 752 female [52.6%]) at 677 hospitals, the primary payer was Medicare (1 427 791 [48.4%]), followed by commercial insurance (1 000 068 [33.9%]), Medicaid (321 600 [10.9%]), other payer (140 959 [4.8%]), and no insurance (59 729 [2.0%]). Mortality rates increased more for patients undergoing surgery during the first wave of the pandemic in hospitals with a high COVID-19 burden (adjusted odds ratio [AOR], 1.13; 95% CI, 1.03-1.24; P = .01) and a very high COVID-19 burden (AOR, 1.38; 95% CI, 1.24-1.53; P < .001) compared with patients in hospitals with a low COVID-19 burden. Overall, patients with Medicaid had 29% higher odds of death (AOR, 1.29; 95% CI, 1.22-1.36; P < .001) and patients without insurance had 75% higher odds of death (AOR, 1.75; 95% CI, 1.55-1.98; P < .001) compared with patients with commercial insurance. However, mortality rates for surgical patients with Medicaid insurance (AOR, 1.03; 95% CI, 0.82-1.30; P = .79) or without insurance (AOR, 0.85; 95% CI, 0.47-1.54; P = .60) did not increase more than for patients with commercial insurance in hospitals with a high COVID-19 burden compared with hospitals with a low COVID-19 burden. These findings were similar in hospitals with very high COVID-19 burdens. Conclusions and Relevance: In this cross-sectional study, the first wave of the COVID-19 pandemic was associated with a higher risk of mortality after surgery in hospitals with more than 25.0% of patients with COVID-19. However, the pandemic was not associated with greater increases in mortality among patients with no insurance or patients with Medicaid compared with patients with commercial insurance in hospitals with a very high COVID-19 burden.

Intraoperative opioids are associated with decreased recurrence rates in colon adenocarcinoma: a retrospective observational cohort study.

BACKGROUND: Opioid-induced immunomodulation may be important in colon adenocarcinoma, where tumour DNA mismatch repair (MMR) can determine the level of immune activation with consequences for therapeutic response and prognosis. We evaluated the relationship between intraoperative opioid exposure, MMR subtype, and oncological outcomes after surgery for colon adenocarcinoma. METHODS: Intraoperative opioid use (standardised by calculating morphine milligram equivalents) during stage I-III colon adenocarcinoma resection was reviewed retrospectively. Tumours were classified as DNA mismatch repair deficient (dMMR) or proficient (pMMR) by immunohistochemistry. The primary outcome was local tumour recurrence, distant tumour recurrence, or both (multivariable analysis). The exposures of interest were intraoperative analgesia and tumour subtype. Opioid-related gene expression was analysed using The Cancer Genome Atlas Colon Adenocarcinoma transcriptomic data. RESULTS: Clinical and pathological data were analysed from 1157 subjects (median age, 60 [51-70] yr; 49% female) who underwent curative resection for stage I-III colon adenocarcinoma. Higher intraoperative opioid doses were associated with reduced risk of tumour recurrence (hazard ratio=0.92 per 10 morphine milligram equivalents; 95% confidence interval [95% CI], 0.87-0.98; P=0.007), but not with overall survival. In tumours deficient in DNA MMR, tumour recurrence was less likely (HR=0.38; 95% CI, 0.21-0.68; P=0.001), with higher opioid dose associated with eightfold lower recurrence rates. Gene expression related to opioid signalling was different between dMMR and pMMR tumours. CONCLUSIONS: Higher intraoperative opioid dose was associated with a lower risk of tumour recurrence after surgery for stage I-III colon adenocarcinoma, but particularly so in tumours in which DNA MMR was deficient.

Association Between the COVID-19 Pandemic and Disparities in Access to Major Surgery in the US.

Importance: Racial minority groups account for 70% of excess deaths not related to COVID-19. Understanding the association of the Centers for Medicare & Medicaid Services' (CMS's) moratorium delaying nonessential operations with racial disparities will help shape future pandemic responses. Objective: To evaluate the association of the CMS's moratorium on elective operations during the first wave of the COVID-19 pandemic among Black individuals, Asian individuals, and individuals of other races compared with White individuals. Design, Setting, and Participants: This cross-sectional study assessed a 719-hospital retrospective cohort of 3 470 905 adult inpatient hospitalizations for major surgery between January 1, 2018, and October 31, 2020. Exposure: The first wave of COVID-19 infections between March 1, 2020, and May 31, 2020. Main Outcomes and Measures: The main outcome was the association between changes in monthly elective surgical case volumes and the first wave of COVID-19 infections as a function of patient race, evaluated using negative binomial regression analysis. Results: Among 3 470 905 adults (1 823 816 female [52.5%]) with inpatient hospitalizations for major surgery, 70 752 (2.0%) were Asian, 453 428 (13.1%) were Black, 2 696 929 (77.7%) were White, and 249 796 (7.2%) were individuals of other races. The number of monthly elective cases during the first wave was 49% (incident rate ratio [IRR], 0.49; 95% CI, 0.486-0.492; P < .001) compared with the baseline period. The relative reduction in unadjusted elective surgery cases for Black (unadjusted IRR, 0.99; 95% CI, 0.97-1.01; P = .36), Asian (unadjusted IRR, 1.08; 95% CI, 1.03-1.14; P = .001), and other race individuals (unadjusted IRR, 0.97; 95% CI, 0.95-1.00; P = .05) during the surge period compared with the baseline period was very close to the change in cases for White individuals. After adjustment for age, sex, comorbidities, and surgical procedure, there was still no evidence that the first wave of the pandemic was associated with disparities in access to elective surgery. Conclusions and Relevance: In this cross-sectional study, the CMS's moratorium on nonessential operations was associated with a 51% reduction in elective operations. It was not associated with greater reductions in operations for racial minority individuals than for White individuals. This evidence suggests that the early response to the pandemic did not increase disparities in access to surgical care.

The association between modifiable perioperative parameters and renal function after nephrectomy.

OBJECTIVE: To evaluate the association between intraoperative anaesthetic parameters, primarily intraoperative hypotension, and postoperative renal function in patients undergoing nephrectomy. PATIENTS AND METHODS: We reviewed data from 3240 consecutive patients who underwent nephrectomy between 2010 and 2018. Anaesthetic parameters evaluated included duration of hypotension, tachycardia, hypothermia, volatile anaesthetic use and mean arterial pressure in the post-anaesthesia care unit. Outcomes included acute kidney injury (AKI) and estimated glomerular filtration rate (eGFR) within the first year after nephrectomy. Associations between anaesthetic parameters and outcomes were evaluated with multivariable logistic regression and generalised estimating equation, respectively, adjusted for predictors of renal function after nephrectomy. RESULTS: Before nephrectomy, 677 (21%) patients had moderate-severe chronic kidney disease. A quarter of patients (n = 809) had postoperative AKI and 35% (n = 746) had Stage ≥3 chronic kidney disease 12-months after surgery. Only 12% of patients (n = 386) had >5 min of intraoperative hypotension. While not statistically significant, longer duration of intraoperative hypotension was associated with slightly higher rates of AKI (odds ratio [OR] per 10-min 1.14, 95% confidence interval [CI] 0.98, 1.32). Prolonged hypothermia was associated with increased rate of AKI (OR per 10-min 1.02, 95% CI 1.00, 1.04), and decreased eGFR (change in eGFR per 10-min -0.19, 95% CI -0.27, -0.12); however, these results have limited clinical significance. CONCLUSIONS: Under current practice, intraoperative anaesthetic parameters are tightly maintained, restricting the significance of their effect on postoperative renal function. Future studies should evaluate whether haemodynamic parameters during the early postoperative period, when they are monitored less frequently, are associated with renal functional outcome.

Lateralisation of subcortical functional connectivity during and after general anaesthesia.

BACKGROUND: Arousal and awareness are two important components of consciousness states. Functional neuroimaging has furthered our understanding of cortical and thalamocortical mechanisms of awareness. Investigating the relationship between subcortical functional connectivity and arousal has been challenging owing to the relatively small size of brainstem structures and thalamic nuclei, and their depth in the brain. METHODS: Resting state functional MRI scans of 72 healthy volunteers were acquired before, during, 1 h after, and 1 day after sevoflurane general anaesthesia. Functional connectivity of subcortical regions of interest vs whole brain and homotopic functional connectivity for assessment of left-right symmetry analyses of both cortical and subcortical regions of interest were performed. Both analyses used high resolution atlases generated from deep brain stimulation applications. RESULTS: Functional connectivity in subcortical loci within the thalamus and of the ascending reticular activating system was sharply restricted under anaesthesia, featuring a general lateralisation of connectivity. Similarly, left-right homology was sharply reduced under anaesthesia. Subcortical bilateral functional connectivity was not fully restored after emergence from anaesthesia, although greater restoration was seen between ascending reticular activating system loci and specific thalamic nuclei thought to be involved in promoting and maintaining arousal. Functional connectivity was fully restored to baseline by the following day. CONCLUSIONS: Functional connectivity in the subcortex is sharply restricted and lateralised under general anaesthesia. This restriction may play a part in loss and return of consciousness. CLINICAL TRIAL REGISTRATION: NCT02275026.

Cognitive Recovery by Decade in Healthy 40- to 80-Year-Old Volunteers After Anesthesia Without Surgery.

BACKGROUND: Postoperative delirium and postoperative cognitive dysfunction are the most common complications for older surgical patients. General anesthesia may contribute to the development of these conditions, but there are little data on the association of age with cognitive recovery from anesthesia in the absence of surgery or underlying medical condition. METHODS: We performed a single-center cohort study of healthy adult volunteers 40 to 80 years old (N = 71, mean age 58.5 years, and 44% women) with no underlying cognitive dysfunction. Volunteers underwent cognitive testing before and at multiple time points after 2 hours of general anesthesia consisting of propofol induction and sevoflurane maintenance, akin to a general anesthetic for a surgical procedure, although no procedure was performed. The primary outcome was time to recovery to cognitive baseline on the Postoperative Quality of Recovery Scale (PQRS) within 30 days of anesthesia. Secondary cognitive outcomes were time to recovery on in-depth neuropsychological batteries, including the National Institutes of Health Toolbox and well-validated paper-and-pencil tests. The primary hypothesis is that time to recovery of cognitive function after general anesthesia increases across decades from 40 to 80 years of age. We examined this with discrete-time logit regression (for the primary outcome) and linear mixed models for interactions of age decade with time postanesthesia (for secondary outcomes). RESULTS: There was no association between age group and recovery to baseline on the PQRS; 36 of 69 (52%) recovered within 60-minute postanesthesia and 63 of 69 (91%) by day 1. Hazard ratios (95% confidence interval) for each decade compared to 40- to 49-year olds were: 50 to 59 years, 1.41 (0.50-4.03); 60 to 69 years, 1.03 (0.35-3.00); and 70 to 80 years, 0.69 (0.25-1.88). There were no significant differences between older decades relative to the 40- to 49-year reference decade in recovery to baseline on secondary cognitive measures. CONCLUSIONS: Recovery of cognitive function to baseline was rapid and did not differ between age decades of participants, although the number in each decade was small. These results suggest that anesthesia alone may not be associated with cognitive recovery in healthy adults of any age decade.

Enhanced Recovery Programs in an Ambulatory Surgical Oncology Center.

BACKGROUND: We describe the implementation of enhanced recovery after surgery (ERAS) programs designed to minimize postoperative nausea and vomiting (PONV) and pain and reduce opioid use in patients undergoing selected procedures at an ambulatory cancer surgery center. Key components of the ERAS included preoperative patient education regarding the postoperative course, liberal preoperative hydration, standardized PONV prophylaxis, appropriate intraoperative fluid management, and multimodal analgesia at all stages. METHODS: We retrospectively reviewed data on patients who underwent mastectomy with or without immediate reconstruction, minimally invasive hysterectomy, thyroidectomy, or minimally invasive prostatectomy from the opening of our institution on January 2016 to December 2018. Data collected included use of total intravenous anesthesia (TIVA), rate of PONV rescue, time to first oral opioid, and total intraoperative and postoperative opioid consumption. Compliance with ERAS elements was determined for each service. Quality outcomes included time to first ambulation, postoperative length of stay (LOS), rate of reoperation, rate of transfer to acute care hospital, 30-day readmission, and urgent care visits ≤30 days. RESULTS: We analyzed 6781 ambulatory surgery cases (2965 mastectomies, 1099 hysterectomies, 680 thyroidectomies, and 1976 prostatectomies). PONV rescue decreased most appreciably for mastectomy (28% decrease; 95% confidence interval [CI], -36 to -22). TIVA use increased for both mastectomies (28%; 95% CI, 20-40) and hysterectomies (58%; 95% CI, 46-76). Total intraoperative opioid administration decreased over time across all procedures. Time to first oral opioid decreased for all surgeries; decreases ranged from 0.96 hours (95% CI, 2.1-1.4) for thyroidectomies to 3.3 hours (95% CI, 4.5 to -1.7) for hysterectomies. Total postoperative opioid consumption did not change by a clinically meaningful degree for any surgery. Compliance with ERAS measures was generally high but varied among surgeries. CONCLUSIONS: This quality improvement study demonstrates the feasibility of implementing ERAS at an ambulatory surgery center. However, the study did not include either a concurrent or preintervention control so that further studies are needed to assess whether there is an association between implementation of ERAS components and improvements in outcomes. Nevertheless, we provide benchmarking data on postoperative outcomes during the first 3 years of ERAS implementation. Our findings reflect progressive improvement achieved through continuous feedback and education of staff.

ROUTINE USE OF SUGAMMADEX DOES NOT SHORTEN PACU LENGTH OF STAY: A PROSPECTIVE DOUBLE-BLINDED RANDOMIZED CONTROLLED TRIAL.

BACKGROUND: The reversal agent sugammadex has been shown to be more efficacious at reversal from neuromuscular blockade (NMB) induced by the aminosteroid class of non-depolarizing muscle relaxants than the traditionally used medication neostigmine. However, whether these differences lead to significantly faster PACU discharge readiness remains unknown. Given the increased acquisition cost of sugammadex as compared to neostigmine we compared these two reversal agents in our surgical population to determine if its pharmacokinetic superiority warranted a change in current practice. METHODS: We conducted a single-center randomized patient and assessor blinded clinical trial. A total of 201 patients presenting for surgery requiring NMB with an estimated duration of ≤ 6 hours were included in the intention-to-treat (ITT) analysis. The primary outcome was time from reversal agent administration to PACU discharge readiness, measured by either the institutional discharge scoring tool or bedside clinical assessment by a PACU physician or advanced practice provider. Secondary outcomes included subjective assessment of recovery by the patient (pain, visual changes, speaking difficulty, swallowing difficulty, PONV, anxiety) and a simple strength assessment. RESULTS: Median time from reversal administration to PACU discharge readiness was 3.59 hours (IQR 2.49-5.09) in the neostigmine group and 3.62 hours (IQR 2.70-5.87) in the sugammadex group. Patients who received sugammadex had 8% longer reversal to PACU discharge times (exp(estimate) 1.08, 95% CI [0.87-1.34], p=0.499). Patients age 70 or older had 28% longer reversal to PACU discharge times (exp(estimate) of 1.28, 95% CI [0.91-1.80], P=0.158). In the a modified ITT analysis, sugammadex patients were estimated to be in PACU 13% longer than neostigmine arm patients (exp(estimate) 1.13, 95% CI [0.91-1.40], p=0.265) and patients older than or equal to 70 years 31% longer than patients less than 70 years old (exp(estimate) 1.31, 95% CI [0.93-1.84], p=0.121). Treatment arm was not associated with any of the secondary outcomes. CONCLUSION: There was no significant difference in time to readiness to discharge from PACU, and there were no subjective or objective clinically relevant differences in recovery from neuromuscular blockade between the groups. Findings of this study support continued use of either agent at the anesthesiologist's discretion.

Intraoperative opioid exposure, tumour genomic alterations, and survival differences in people with lung adenocarcinoma.

BACKGROUND: Opioids have been linked to worse oncologic outcomes in surgical patients. Studies in certain cancer types have identified associations between survival and intra-tumoural opioid receptor gene alterations, but no study has investigated whether the tumour genome interacts with opioid exposure to affect survival. We sought to determine whether intraoperative opioid exposure is associated with recurrence-specific survival and overall survival in early-stage lung adenocarcinoma, and whether selected tumour genomics are associated with this relationship. Associations between ketamine and dexmedetomidine and outcomes were also studied. METHODS: Surgical patients (N=740) with pathological stage I-III lung adenocarcinoma and next-generation sequencing data were retrospectively reviewed from a prospectively maintained database. RESULTS: On multivariable analysis, ketamine administration was protective for recurrence-specific survival (hazard ratio = 0.44, 95% confidence interval 0.24-0.80; P=0.007), compared with no adjunct. Higher intraoperative oral morphine milligram equivalents were significantly associated with worse overall survival (hazard ratio=1.09/10 morphine milligram equivalents, 95% confidence interval 1.02-1.17; P=0.010). Significant interaction effects were found between morphine milligram equivalents and fraction genome altered and morphine milligram equivalents and CDKN2A, such that higher fraction genome altered or CDKN2A alterations were associated with worse overall survival at higher morphine milligram equivalents (P=0.044 and P=0.052, respectively). In contrast, alterations in the Wnt (P=0.029) and Hippo (P=0.040) oncogenic pathways were associated with improved recurrence-specific survival at higher morphine milligram equivalents, compared with unaltered pathways. CONCLUSIONS: Intraoperative opioid exposure is associated with worse overall survival, whereas ketamine exposure is associated with improved recurrence-specific survival in patients with early-stage lung adenocarcinoma. This is the first study to investigate tumour-specific genomic interactions with intraoperative opioid administration to modify survival associations.

Transient changes in white matter microstructure during general anesthesia.

Cognitive dysfunction after surgery under general anesthesia is a well-recognized clinical phenomenon in the elderly. Physiological effects of various anesthetic agents have been studied at length. Very little is known about potential effects of anesthesia on brain structure. In this study we used Diffusion Tensor Imaging to compare the white matter microstructure of healthy control subjects under sevoflurane anesthesia with their awake state. Fractional Anisotropy, a white mater integrity index, transiently decreases throughout the brain during sevoflurane anesthesia and then returns back to baseline. Other DTI metrics such as mean diffusivity, axial diffusivity and radial diffusivity were increased under sevoflurane anesthesia. Although DTI metrics are age dependent, the transient changes due to sevoflurane were independent of age and sex. Volumetric analysis shows various white matter volumes decreased whereas some gray matter volumes increased during sevoflurane anesthesia. These results suggest that sevoflurane anesthesia has a significant, but transient, effect on white matter microstructure. In spite of the transient effects of sevoflurane anesthesia there were no measurable effects on brain white matter as determined by the DTI metrics at 2 days and 7 days following anesthesia. The role of white matter in the loss of consciousness under anesthesia will need to be studied and MRI studies with subjects under anesthesia will need to take these results into account.

Intraoperative Ketorolac is Associated with Risk of Reoperation After Mastectomy: A Single-Center Examination.

BACKGROUND: Although ketorolac is an effective adjunct for managing pain in the perioperative period, it is associated with a risk of postoperative bleeding. This study retrospectively investigated the association between ketorolac use and both reoperation and postoperative opioid use among mastectomy patients. METHODS: The study identified all women undergoing mastectomy (unilaterally or bilaterally) at our ambulatory surgery cancer center from January 2016 to June 2019. The primary outcome was reoperation for bleeding on postoperative day 0 or 1, and the secondary outcome was postoperative opioid use. The association between ketorolac and outcomes was assessed using multivariable regression models. The covariates were age, body mass index, breast reconstruction, bilateral surgery, peripheral nerve block, and preoperative antiplatelet and/or anticoagulation medication. RESULTS: A cohort of 3469 women were identified. Ketorolac was given to 1549 (45%) of the women, with 922 women (60%) receiving 30 mg and 627 women (40%) receiving 15 mg. The overall reoperation rate for bleeding was 3.1% (1.8% without ketorolac vs 4.8% with ketorolac). In the multivariable analysis, ketorolac was associated with a higher risk of reoperation [odds ratio (OR) 2.43; 95% confidence interval (CI) 1.60-3.70; P < 0.0001]. Ketorolac also was associated with a lower proportion of patients receiving any postoperative narcotic within 24 h (15 mg: OR 0.73; 95% CI 0.57-0.94; P = 0.014 vs 30 mg: OR 0.52; 95% CI 0.42-0.66; P < 0.0001). CONCLUSIONS: Ketorolac use decreased postoperative opioid use, but this benefit was outweighed by the increased risk of bleeding requiring reoperation. This finding led to a change in practice at the authors' center, with ketorolac no longer administered in the perioperative care of the mastectomy patient.

Trends in Peripheral Nerve Block Usage in Mastectomy and Lumpectomy: Analysis of a National Database From 2010 to 2018.

BACKGROUND: Compared to general anesthesia, regional anesthesia confers several benefits including improved pain control and decreased postoperative opioid consumption. While the benefits of peripheral nerve blocks (PNB) have been well studied, there are little epidemiological data on PNB usage in mastectomy and lumpectomy procedures. The primary objective of our study was to assess national trends of the annual proportion of PNB use in breast surgery from 2010 to 2018. We also identified factors associated with PNB use for breast surgery. METHODS: We identified lumpectomy and mastectomy surgical cases with and without PNB between 2010 and 2018 using the Anesthesia Quality Institute National Anesthesia Clinical Outcomes Registry (AQI NACOR). We modeled the nonlinear association between year of procedure and PNB use with segmented mixed-effects logistic regression clustered on facility identifier. The association between PNB use and year of procedure, age, sex, American Society of Anesthesiologists physical status (ASA PS), facility type, facility region, weekday, and tissue expander use was also modeled using mixed-effects logistic regression. RESULTS: Of the 189,854 surgical cases from 2010 to 2018 that met criteria, 86.2% were lumpectomy cases and 13.8% were mastectomy cases. The proportion of lumpectomy cases with PNB was <0.1% in 2010 and increased each subsequent year to 1.9% in 2018 (trend P < .0001). The proportion of mastectomy cases with PNB was 0.5% in 2010 and 13% in 2018 (trend P < .0001). The year 2014 was the breakpoint selected for segmented regression. Before 2014, the odds of PNB among the mastectomy cases was not significantly different from year to year. After 2014, the odds of PNB increased by 2.24-fold each year (95% confidence interval [CI], 2.00-2.49; P < .001); interaction test for pre-2014 versus post-2014 was P < .001. Similar trends were seen in the lumpectomy cases, where after 2014, the odds of PNB increased by 2.03-fold (95% CI, 1.81-2.27; P < .001); interaction test for pre-2014 versus post-2014 was P < .001. In the mastectomy cohort, year of procedure ≥2014, female sex, facility region, and tissue expander use were associated with higher odds of PNB. For lumpectomy cases, year of procedure ≥2014 and facility region were associated with higher odds of PNB use. CONCLUSIONS: We found increased annual utilization of PNB for mastectomy and lumpectomy since 2010, although absolute prevalence is low. PNB use was associated with year of procedure for both lumpectomy and mastectomy, particularly post-2014.

Identifying Clear Cell Renal Cell Carcinoma Coexpression Networks Associated with Opioid Signaling and Survival.

While opioids constitute the major component of perioperative analgesic regimens for surgery in general, a variety of evidence points to an association between perioperative opioid exposure and longer term oncologic outcomes. The mechanistic details underlying these effects are not well understood. In this study, we focused on clear cell renal cell carcinoma (ccRCC) and utilized RNA sequencing and outcome data from both The Cancer Genome Atlas, as well as a local patient cohort to identify survival-associated gene coexpression networks. We then projected drug-induced transcriptional profiles from in vitro cancer cells to predict drug effects on these networks and recurrence-free, cancer-specific, and overall survival. The opioid receptor agonist, leu-enkephalin, was predicted to have antisurvival effects in ccRCC, primarily through Th2 immune- and NRF2-dependent macrophage networks. Conversely, the antagonist, naloxone, was predicted to have prosurvival effects, primarily through angiogenesis, fatty acid metabolism, and hemopoesis pathways. Eight coexpression networks associated with survival endpoints in ccRCC were identified, and master regulators of the transition from the normal to disease state were inferred, a number of which are linked to opioid pathways. These results are the first to suggest a mechanism for opioid effects on cancer outcomes through modulation of survival-associated coexpression networks. While we focus on ccRCC, this methodology may be employed to predict opioid effects on other cancer types and to personalize analgesic regimens in patients with cancer for optimal outcomes. SIGNIFICANCE: This study suggests a possible molecular mechanism for opioid effects on cancer outcomes generally, with implications for personalization of analgesic regimens.

Intraoperative opioids are associated with improved recurrence-free survival in triple-negative breast cancer.

BACKGROUND: Opioid-induced immunomodulation may be of particular importance in triple-negative breast cancer (TNBC) where an immune response is associated with improved outcome and response to immunotherapy. We evaluated the association between intraoperative opioids and oncological outcomes and explored patterns of opioid receptor expression in TNBC. METHODS: Consecutive patients with stage I-III primary TNBC were identified from a prospectively maintained database. Opioid receptor expression patterns in the tumour microenvironment were analysed using publicly available bulk and single-cell RNA-seq data. RESULTS: A total of 1143 TNBC cases were retrospectively analysed. In multivariable analysis, higher intraoperative opioid dose was associated with favourable recurrence-free survival, hazard ratio 0.93 (95% confidence interval 0.88-0.99) per 10 oral morphine milligram equivalents increase (P=0.028), but was not significantly associated with overall survival, hazard ratio 0.96 (95% confidence interval 0.89-1.02) per 10 morphine milligram equivalents increase (P=0.2). Bulk RNA-seq analysis of opioid receptors showed that OPRM1 was nearly non-expressed. Compared with normal breast tissue OGFR, OPRK1, and OPRD1 were upregulated, while TLR4 was downregulated. At a single-cell level, OPRM1 and OPRD1 were not detectable; OPRK1 was expressed mainly on tumour cells, whereas OGFR and TLR4 were more highly expressed on immune cells. CONCLUSIONS: We found a protective effect of intraoperative opioids on recurrence-free survival in TNBC. Opioid receptor expression was consistent with a net protective effect of opioid agonism, with protumour receptors either not expressed or downregulated, and antitumour receptors upregulated. In this era of personalised medicine, efforts to differentiate the effects of opioids across breast cancer subtypes (and ultimately individual patients) should continue.