Reducing rebound pain severity after arthroscopic shoulder surgery under general anesthesia and interscalene block: a two-centre randomized controlled trial of pre-emptive opioid treatment compared with placebo.

PURPOSE: Although a single-injection interscalene block provides effective early postoperative analgesia following shoulder surgery, patients may experience "rebound pain" when the block resolves. Our objective was to determine if oral hydromorphone (2 mg) given six hours after a single-injection interscalene block for arthroscopic shoulder surgery leads to a clinically significant reduction in the severity of rebound pain. METHODS: After approval from research ethics boards, we conducted a two-centre, parallel-group, double-blind, randomized, placebo-controlled superiority trial. Patients received preoperative interscalene block, general anesthesia, and either hydromorphone or placebo six hours after the block. The primary outcome was the worst pain score in the first 24 hr postoperatively, measured on an 11-point (0-10) numerical rating scale. RESULTS: A total of 73 participants were randomly assigned to either the hydromorphone or placebo group. There was no statistically significant difference in the mean (standard deviation) worst pain score within 24 hr between the hydromorphone and placebo groups (6.5 [2.4] vs 5.9 [2.3]; mean difference, 0.6; 95% confidence interval, -0.5 to 1.8). Similarly, we did not find any significant difference in the pain trajectory, opioid use, or incidence of nausea and vomiting between the groups. The mean time to worst pain was 14.6 hr, and the mean time to first rescue analgesia was 11.3 hr after interscalene block. CONCLUSION: Hydromorphone 2 mg given six hours after interscalene block did not reduce the severity of rebound pain postoperatively compared with placebo in patients undergoing arthroscopic shoulder surgery. STUDY REGISTRATION: ClinicalTrials.gov (NCT02939209); registered 19 October 2016.

RéSUMé: OBJECTIF: Bien qu'un bloc interscalénique à injection unique fournisse une analgésie postopératoire précoce efficace après une chirurgie de l'épaule, les patient·es peuvent ressentir une « douleur de rebond ¼ lorsque le bloc se résorbe. Notre objectif était de déterminer si l'hydromorphone orale (2 mg) administrée six heures après une injection unique de bloc interscalénique pour une chirurgie arthroscopique de l'épaule entraînait une réduction cliniquement significative de la gravité de la douleur de rebond. MéTHODE: Après l'approbation des comités d'éthique de la recherche, nous avons mené une étude de supériorité dans deux centres, en groupes parallèles, à double insu, randomisée et contrôlée par placebo. Les patient·es ont reçu un bloc interscalénique préopératoire, une anesthésie générale et de l'hydromorphone ou un placebo six heures après le bloc. Le critère d'évaluation principal était le pire score de douleur au cours des premières 24 heures postopératoires, mesuré sur une échelle d'évaluation numérique de 11 points (0 à 10). RéSULTATS: Au total, 73 personnes ont participé à l'étude et ont été aléatoirement assignées au groupe hydromorphone ou au groupe placebo. Il n'y avait pas de différence statistiquement significative dans le score moyen (écart type) de la pire douleur dans les 24 heures entre les groupes hydromorphone et placebo (6,5 [2,4] vs 5,9 [2,3]; différence moyenne, 0,6; intervalle de confiance à 95 %, −0,5 à 1,8). De même, nous n'avons trouvé aucune différence significative dans la trajectoire de la douleur, la consommation d'opioïdes ou l'incidence de nausées et vomissements entre les groupes. Le temps moyen jusqu'à la pire douleur était de 14,6 heures, et le temps moyen jusqu'à la première analgésie de secours était de 11,3 heures après le bloc interscalénique. CONCLUSION: L'hydromorphone 2 mg administrée six heures après le bloc interscalénique n'a pas réduit la gravité de la douleur de rebond postopératoire par rapport au placebo chez les patient·es bénéficiant d'une chirurgie arthroscopique de l'épaule. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT02939209); enregistrée le 19 octobre 2016.

Comparative efficacy and safety of non-neuraxial analgesic techniques for midline laparotomy: a systematic review and frequentist network meta-analysis of randomised controlled trials.

BACKGROUND: Fascial plane blocks provide effective analgesia after midline laparotomy; however, the most efficacious technique has not been determined. We conducted a systematic review and network meta-analysis of randomised controlled trials to synthesise the evidence with respect to pain, opioid consumption, and adverse events. METHODS: We searched Ovid MEDLINE, Embase, Cochrane Central, and Scopus databases for studies comparing commonly used non-neuraxial analgesic techniques for midline laparotomy in adult patients. The co-primary outcomes of the study were 24-h cumulative opioid consumption and 24-h resting pain score, reported as i.v. morphine equivalents and 11-point numerical rating scale, respectively. We performed a frequentist meta-analysis using a random-effects model and a cluster-rank analysis of the co-primary outcomes. RESULTS: Of 6115 studies screened, 67 eligible studies were included (n=4410). Interventions with the greatest reduction in 24-h cumulative opioid consumption compared with placebo/no intervention were single-injection quadratus lumborum block (sQLB; mean difference [MD] -16.1 mg, 95% confidence interval [CI] -29.9 to -2.3, very low certainty), continuous transversus abdominis plane block (cTAP; MD -14.0 mg, 95% CI -21.6 to -6.4, low certainty), single-injection transversus abdominis plane block (sTAP; MD -13.7 mg, 95% CI -17.4 to -10.0, low certainty), and continuous rectus sheath block (cRSB; MD -13.2 mg, 95% CI -20.3 to -6.1, low certainty). Interventions with the greatest reduction in 24-h resting pain score were cRSB (MD -1.2, 95% CI -1.8 to -0.6, low certainty), cTAP (MD -1.0, 95% CI -1.7 to -0.2, low certainty), and continuous wound infusion (cWI; MD -0.7, 95% CI -1.1 to -0.4, low certainty). Clustered-rank analysis including the co-primary outcomes showed cRSB and cTAP blocks to be the most efficacious interventions. CONCLUSIONS: Based on current evidence, continuous rectus sheath block and continuous transversus abdominis plane block were the most efficacious non-neuraxial techniques at reducing 24-h cumulative opioid consumption and 24-h resting pain scores after midline laparotomy (low certainty). Future studies should compare techniques for upper vs lower midline laparotomy and other non-midline abdominal incisions. CLINICAL TRIAL REGISTRATION: PROSPERO Registration Number: CRD42021269044.

Pandemic-related factors predicting physician burnout beyond established organizational factors: cross-sectional results from the COPING survey.

The COVID-19 pandemic has increased physician burnout beyond high baseline levels. We aimed to determine whether pandemic-related factors contribute to physician burnout beyond known organizational factors. This was a cross-sectional survey of Canadian physicians using a convenience sample. Eligible participants included any physician currently holding a license to practice in Canada. Responses were gathered from May 13 to 12 June 2020. Risk factors measured included the newly developed Pandemic Experiences and Perceptions Scale (PEPS) subscales, contact with virus, pandemic preparation, and provincial caseload. The primary outcome was the Maslach Burnout Inventory (MBI). The primary outcome was completed by 309 respondents. Latent profile analysis found 107 (34.6%) respondents were burned out. In multivariate analysis, exhaustion was independently associated with PEPS adequacy, risk perception, and worklife subscales (adjusted R2 = 0.236, P < 0.001). Cynicism was associated with exhaustion, and PEPS worklife (adjusted R2 = 0.543, P < 0.001). Efficacy was associated with cynicism, PEPS worklife, and active cases (adjusted R2 = 0.152, P < 0.001). Structural equation modelling showed statistically significant direct paths between PEPS areas of worklife and all MBI subscales. Contact with virus, preparation, and PEPS risk perception added to the prediction of MBI exhaustion. Among a sample of Canadian physicians during the COVID-19 pandemic, adequacy of resources, risk perception, and quality of worklife were associated with burnout indices. To mitigate physician burnout organizations should work to improve working conditions, ensure adequate resources, and foster perceived control of risk of transmission.Trial Registration: NCT04379063.

Factors associated with rebound pain after peripheral nerve block for ambulatory surgery.

BACKGROUND: Rebound pain is a common, yet under-recognised acute increase in pain severity after a peripheral nerve block (PNB) has receded, typically manifesting within 24 h after the block was performed. This retrospective cohort study investigated the incidence and factors associated with rebound pain in patients who received a PNB for ambulatory surgery. METHODS: Ambulatory surgery patients who received a preoperative PNB between March 2017 and February 2019 were included. Rebound pain was defined as the transition from well-controlled pain (numerical rating scale [NRS] ≤3) while the block is working to severe pain (NRS ≥7) within 24 h of block performance. Patient, surgical, and anaesthetic factors were analysed for association with rebound pain by univariate, multivariable, and machine learning methods. RESULTS: Four hundred and eighty-two (49.6%) of 972 included patients experienced rebound pain as per the definition. Multivariable analysis showed that the factors independently associated with rebound pain were younger age (odds ratio [OR] 0.98; 95% confidence interval [CI] 0.97-0.99), female gender (OR 1.52 [1.15-2.02]), surgery involving bone (OR 1.82 [1.38-2.40]), and absence of perioperative i.v. dexamethasone (OR 1.78 [1.12-2.83]). Despite a high incidence of rebound pain, there were high rates of patient satisfaction (83.2%) and return to daily activities (96.5%). CONCLUSIONS: Rebound pain occurred in half of the patients and showed independent associations with age, female gender, bone surgery, and absence of intraoperative use of i.v. dexamethasone. Until further research is available, clinicians should continue to use preventative strategies, especially for patients at higher risk of experiencing rebound pain.

Genomic markers of panitumumab resistance including ERBB2/ HER2 in a phase II study of KRAS wild-type (wt) metastatic colorectal cancer (mCRC).

A prospective study was conducted to identify biomarkers associated with resistance to panitumumab monotherapy in patients with metastatic colorectal cancer (mCRC). Patients with previously treated, codon 12/13 KRAS wt, mCRC were prospectively administered panitumumab 6 mg/kg IV q2weeks. Of 34 panitumumab-treated patients, 11 (32%) had progressive disease at 8 weeks and were classified as non-responders. A Nanostring nCounter-based assay identified a 5-gene expression signature (ERBB2, MLPH, IRX3, MYRF, and KLK6) associated with panitumumab resistance (P = 0.001). Immunohistochemistry and in situ hybridization determined that the HER2 (ERBB2) protein was overexpressed in 4/11 non-responding and 0/21 responding cases (P = 0.035). Two non-responding tumors had ERBB2 gene amplification only, and one demonstrated both ERBB2 amplification and mutation. A non-codon 12/13 KRAS mutation occurred in one panitumumab-resistant patient and was mutually exclusive with ERBB2/HER2 abnormalities. This study identifies a 5-gene signature associated with non-response to single agent panitumumab, including a subgroup of non-responders with evidence of aberrant ERBB2/HER2 signaling. KRAS wt tumors resistant to EGFRi may be identified by gene signature analysis, and the HER2 pathway plays an important role in resistance to therapy.

Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies.

PURPOSE: To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers). PATIENTS AND METHODS: Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays. RESULTS: The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P < .001 for time to progression). CONCLUSION: Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.

Prognostic and predictive investigation of PAM50 intrinsic subtypes in the NCIC CTG MA.21 phase III chemotherapy trial.

PAM50-defined breast cancer intrinsic subtypes and risk-of-relapse (ROR) scores are prognostic and predictive of endocrine therapy and some chemotherapy. We investigated the prognostic and predictive effect of PAM50 classifications by chemotherapy type. NCIC CTG MA.21 randomized 2,104 patients to doxorubicin, cyclophosphamide, and paclitaxel (AC/T); dose-intense cyclophosphamide, epirubicin, and flurouracil (CEF); or dose-dense, dose-intense epirubicin, cyclophosphamide, and paclitaxel (EC/T). Patients were ≤60 years, with node-positive or high-risk node-negative disease, with median 8-year follow-up. Intrinsic subtypes and ROR were determined from RNA extracted from formalin-fixed paraffin-embedded sections by the NanoString PAM50 test. Univariate effects on relapse-free survival (RFS) were assessed with stratified log-rank test; multivariate analyses utilized stratified Cox regression. Among 1094 cases completing PAM50 intrinsic subtyping, 27 % were classified as luminal A, 23 % luminal B, 18 % HER2E, and 32 % basal-like. CEF and EC/T were superior to AC/T (p = 0.01). Higher continuous ROR was multivariately associated with worse RFS (p = 0.03), although categorical ROR was neither prognostic nor predictive. Intrinsic subtypes had a significant multivariate prognostic effect on RFS (p = 0.002). Compared with luminal A, hazard ratios were luminal B = 1.48 (95 % CI 0.92-2.37); HER2E = 2.68 (95 % CI 1.60-4.48); and basal-like = 1.97 (95 % CI 1.10-3.53). Intrinsic subtypes were not predictive of treatment benefit (AC/T vs. EC/T + CEF); however, subgroup analysis indicated subtypes (non-luminal vs. luminal) was predictive of taxane benefit (EC/T vs. CEF; p = 0.05). Both NanoString PAM50 subtypes and continuous ROR had significant prognostic effects on RFS for breast cancer patients treated with CEF, EC/T, and AC/T. Non-luminal tumors differentially responded to EC/T (with taxane) over CEF.

Analytical validation of the PAM50-based Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Analysis System using formalin-fixed paraffin-embedded breast tumor specimens.

BACKGROUND: NanoString's Prosigna™ Breast Cancer Prognostic Gene Signature Assay is based on the PAM50 gene expression signature. The test outputs a risk of recurrence (ROR) score, risk category, and intrinsic subtype (Luminal A/B, HER2-enriched, Basal-like). The studies described here were designed to validate the analytical performance of the test on the nCounter Analysis System across multiple laboratories. METHODS: Analytical precision was measured by testing five breast tumor RNA samples across 3 sites. Reproducibility was measured by testing replicate tissue sections from 43 FFPE breast tumor blocks across 3 sites following independent pathology review at each site. The RNA input range was validated by comparing assay results at the extremes of the specified range to the nominal RNA input level. Interference was evaluated by including non-tumor tissue into the test. RESULTS: The measured standard deviation (SD) was less than 1 ROR unit within the analytical precision study and the measured total SD was 2.9 ROR units within the reproducibility study. The ROR scores for RNA inputs at the extremes of the range were the same as those at the nominal input level. Assay results were stable in the presence of moderate amounts of surrounding non-tumor tissue (<70% by area). CONCLUSIONS: The analytical performance of NanoString's Prosigna assay has been validated using FFPE breast tumor specimens across multiple clinical testing laboratories.