Citations

Background Frailty increases risk for complications after total joint arthroplasty (TJA). Whether this association is influenced by anesthetic administered is unknown. We hypothesized that use of neuraxial (spinal or epidural) anesthesia is associated with better outcomes compared with general anesthesia, and that the effect of anesthesia type on outcomes differs by frailty status. Methods This single-institution cohort study included all patients (≥50 years) from January 2005 through December 2016 undergoing unilateral, primary and revision TJA. Using multivariable Cox regression, we assessed relationships between anesthesia type, a preoperative frailty deficit index (FI) categorized as non-frail (FI <0.11), vulnerable (FI 0.11 to 0.20), and frail (FI >0.20), and complications (mortality, infection, wound complications/hematoma, reoperation, dislocation, and periprosthetic fracture) within 1 year after surgery. Interactions between anesthesia type and frailty were tested, and stratified models were presented when an interaction (p<0.1) was observed. Results Among 18 458 patients undergoing TJA, more patients were classified as frail (21.5%) and vulnerable (36.2%) than non-frail (42.3%). Anesthesia type was not associated with complications after adjusting for age, joint, and revision type. However, in analyzes stratified by frailty, vulnerable patients under neuraxial block had less mortality (HR=0.49; 95% CI 0.27 to 0.89) and wound complications/hematoma (HR=0.71; 95% CI 0.55 to 0.90), whereas no difference in risk by anesthesia type was observed among patients found non-frail or frail. Conclusions Neuraxial anesthesia use among vulnerable patients was associated with improved survival and less wound complications. Calculating preoperative frailty prior to TJA informs perioperative risk and enhances shared-decision making for selection of anesthesia type.

Abstract Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients and Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples. Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.

AimsVarus-valgus constrained (VVC) implants are often used during revision total knee arthroplasty (TKA) to gain coronal plane stability. However, the increased mechanical torque applied to the bone-cement interface theoretically increases the risk of aseptic loosening. We assessed mid-term survivorship, complications, and clinical outcomes of a fixed-bearing VVC device in revision TKAs.MethodsA total of 416 consecutive revision TKAs (398 patients) were performed at our institution using a single fixed-bearing VVC TKA from 2007 to 2015. Mean age was 64 years (33 to 88) with 50% male (199). Index revision TKA diagnoses were: instability (n = 122, 29%), aseptic loosening (n = 105, 25%), and prosthetic joint infection (PJI) (n = 97, 23%). All devices were cemented on the epiphyseal surfaces. Femoral stems were used in 97% (n = 402) of cases, tibial stems in 95% (n = 394) of cases; all were cemented. In total, 93% (n = 389) of cases required a stemmed femoral and tibial component. Femoral cones were used in 29%, and tibial cones in 40%. Survivorship was assessed via competing risk analysis; clinical outcomes were determined using Knee Society Scores (KSSs) and range of movement (ROM). Mean follow-up was four years (2 to 10).ResultsThe five-year cumulative incidence of subsequent revision for aseptic loosening and instability were 2% (95% confidence interval (CI) 0.2 to 3, number at risk = 154) and 4% (95% CI 2 to 6, number at risk = 153), respectively. The five-year cumulative incidence of any subsequent revision was 14% (95% CI 10 to 18, number at risk = 150). Reasons for subsequent revision included PJI (n = 23, of whom 12 had previous PJI), instability (n = 13), and aseptic loosening (n = 11). The use of this implant without stems was found to be a significant risk factor for subsequent revision (hazard ratio (HR) 7.58 (95% CI 3.98 to 16.03); p = 0.007). KSS improved from 46 preoperatively to 81 at latest follow-up (p < 0.001). ROM improved from 96° prerevision to 108° at latest follow-up (p = 0.016).ConclusionThe cumulative incidence of subsequent revision for aseptic loosening and instability was very low at five years with this fixed-bearing VVC implant in revision TKAs. Routine use of cemented and stemmed components with targeted use of metaphyseal cones likely contributed to this low rate of aseptic loosening. Cite this article: Bone Joint J 2020;102-B(4):458–462.

9058 Background: Lung Cancer is the leading cause of cancer related deaths in the USA. NSCLC comprises about 85% of lung cancer cases. Although timeliness of care in patients with NSCLC is considered an important aspect of quality care, there are conflicting data about its impact on clinical outcomes. The primary objective of this study is to determine if there is an association between TTI and survival in patients with NSCLC. Methods: In this retrospective study, we reviewed data from our multi-site Mayo Clinic Cancer Center registry and identified patients with newly diagnosed NSCLC from 2000 to 2016. TTI was calculated from time of diagnosis to time of first treatment (surgery, radiation therapy or systemic therapy). Analyses were performed by SAS software 9.4. Log-Rank test was used to compare survival. Cox regression multivariate model was used to evaluate the prognostic value of variables to survival. Results: 10010 patients (53% males and 47%) were reviewed. Median age at diagnosis was 70. Median TTI was 12 days for stage I, and 20 days for stage II, III and IV. We compared outcomes of patients with TTI > 20 days to TTI ≤20 days. Outcomes were stratified based on age, gender, grade, and stage. Median Overall Survival (OS) was significantly better for patients with TTI ≤20 days compared to TTI > 20 days (39.1 vs 28.6 months P-value < 0.0001). Further stratification, based on stage, showed significantly better OS for stage I and II patients with TTI ≤20 days compared to TTI > 20 days (103.4 vs. 63.9 months P-value < 0.0001 and 72.3 vs. 46.8 months P-value 0.0014 respectively). OS for stage III patients with TTI ≤20 days was not significantly different from patients with TTI > 20 days (30.6 vs. 28.5 months P-value 0.118). Interestingly, stage IV patients had worse OS if TTI ≤20 days compared to TTI > 20 days (8.3 vs. 12.8 months P-value < 0.0001). Conclusions: Our study showed an association between TTI and survival of patients with NSCLC. Shorter TTI was associated with better survival in stage I and II patients and worse survival in stage IV patients. Our study further highlights the controversy surrounding the topic of impact of timeliness of care on survival in patients with cancer, specifically NSCLC across different stages.

7021 Background: Case-control studies (CCS) have identified germline variants (GVs) & genes associated with AML risk and/or outcome. However, whether these genes also harbor somatic mutations (SMs) in AML and whether these SMs are associated with clinical phenotypes and outcome is unknown. We systemically interrogated PubMed (terms "AML genetic polymorphisms"), yielding 612 reports (1981-2018), from which we identified unique variants/single nucleotide polymorphisms (SNPs) in 100 genes associated with AML risk and/or outcome in CCS. To determine the prevalence and relevance of SMs in these genes in an unselected AML population, we performed an analysis using WES of cases in the highly-annotated MCAEC (Finn, Ca Epidemiol 2015). Methods: We performed WES using remnant cytogenetic pellets from AML diagnosis in 98 MCAEC patients with available samples, sequenced at a depth of ~100 million paired-end 100bp reads using Agilent SureSelectXT Human All Exon V5 + UTRs target enrichment kit. Sequencing reads were aligned to human reference genome, and SMs including non-synonymous (NS) and truncating single nucleotide variants (SNVs) and small INDELs were identified and filtered using Exome Sequencing Project, 1000 genome, HapMap, & Mayo Clinic (MC) internal Biobank GV database. Copy number aberrations (CNAs) were identified & filtered using public CN polymorphism databases. For this analysis we evaluated the prevalence of somatic SNVs, INDELs, & CNAs in the 100 nominated genetic risk genes in collaboration with MC Cancer Center to determine their association with clinical phenotype and outcome. Results: Of the 100 unique genes, there were 40 with SM in our dataset, with 126 total mutations. Most were mutated in a very small number of patients, allowing insufficient statistical power to perform association analyses. However, an NS mutation in CYP2B6 (c.785A > G, p.Lys262Arg) had a minor allele frequency of 12.0%; this variant has been reported in association with breast cancer risk, but not with AML. Conclusions: We studied SM’s in AML genetic risk genes using WES of tumor samples. While representing a smaller sample size, this suggests their contribution to AML development may be limited in a broader clinical population. These results & prevalence of the novel CYP2B6 rs2279343 variant in AML must be confirmed in larger cohorts.

Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with improved survival for patients with colorectal peritoneal metastases (CR-PM). However, the role of neoadjuvant chemotherapy (NAC) prior to CRS-HIPEC is poorly understood. A retrospective review of adult patients with CR-PM who underwent CRS+/-HIPEC from 2000–2017 was performed. Among 298 patients who underwent CRS+/-HIPEC, 196 (65.8%) received NAC while 102 (34.2%) underwent surgery first (SF). Patients who received NAC had lower peritoneal cancer index score (12.1 + 7.9 vs. 14.3 + 8.5, p = 0.034). There was no significant difference in grade III/IV complications (22.4% vs. 16.7%, p = 0.650), readmission (32.3% vs. 23.5%, p = 0.114), or 30-day mortality (1.5% vs. 2.9%, p = 0.411) between groups. NAC patients experienced longer overall survival (OS) (median 32.7 vs. 22.0 months, p = 0.044) but similar recurrence-free survival (RFS) (median 13.8 vs. 13.0 months, p = 0.456). After controlling for confounding factors, NAC was not independently associated with improved OS (OR 0.80) or RFS (OR 1.04). Among patients who underwent CRS+/-HIPEC for CR-PM, the use of NAC was associated with improved OS that did not persist on multivariable analysis. However, NAC prior to CRS+/-HIPEC was a safe and feasible strategy for CR-PM, which may aid in the appropriate selection of patients for aggressive cytoreductive surgery.

AbstractThe dense formation of abnormal scar tissue after total knee arthroplasty results in arthrofibrosis, an unfortunate sequela of inflammation. The purpose of this study was to use a validated rabbit model to assess the effects on surgically‐induced knee joint contractures of two combined pharmacological interventions: celecoxib (CXB) loaded on an implanted collagen membrane, and subcutaneously (SQ) injected ketotifen. Thirty rabbits were randomly divided into five groups. The first group received no intervention after the index surgery. The remaining four groups underwent intra‐articular implantation of collagen membranes loaded with or without CXB at the time of the index surgery; two of which were also treated with SQ ketotifen. Biomechanical joint contracture data were collected at 8, 10, 16, and 24 weeks. At the time of necropsy (24 weeks), posterior capsule tissue was collected for messenger RNA and histopathologic analyses. At 24 weeks, there was a statistically significant increase in passive extension among rabbits in all groups treated with CXB and/or ketotifen compared to those in the contracture control group. There was a statistically significant decrease in COL3A1, COL6A1, and ACTA2 gene expression in the treatment groups compared to the contracture control group (P < .001). Histopathologic data also demonstrated a trend towards decreased fibrous tissue density in the CXB membrane group compared to the vehicle membrane group. The present data suggest that intra‐articular placement of a treated collagen membrane blunts the severity of contracture development in a rabbit model of arthrofibrosis, and that ketotifen and CXB may independently contribute to the prevention of arthrofibrosis. Statement of clinical significance: Current literature has demonstrated that arthrofibrosis may affect up to 5% of primary total knee arthroplasty patients. For that reason, novel pharmacologic prophylaxis and treatment modalities are critical to mitigating reoperations and revisions while improving the quality of life for patients with this debilitating condition.

Dissatisfaction following total knee arthroplasty is a well-documented phenomenon. Although many factors have been implicated, including modifiable and nonmodifiable patient factors, emphasis over the past decade has been on implant alignment and stability as both a cause of, and a solution to, this problem. Several alignment targets have evolved with a proliferation of techniques following the introduction of computer and robotic-assisted surgery. Mechanical alignment targets may achieve mechanically-sound alignment while ignoring the soft tissue envelope; kinematic alignment respects the soft tissue envelope while ignoring the mechanical environment. Functional alignment is proposed as a hybrid technique to allow mechanically-sound, soft tissue-friendly alignment targets to be identified and achieved.Cite this article: Bone Joint J 2020;102-B(3):276–279.

Background: The efficacy and safety of tranexamic acid (TXA) in primary total knee arthroplasty (TKA) have been well established. However, there have been limited data for revision TKAs. The primary aim was to assess the impact of intravenous TXA on transfusion rates and symptomatic venous thromboembolic events (VTEs) in a large revision TKA cohort with or without intravenous TXA utilization. Methods: A retrospective review of revision TKAs performed from 2005 to 2014 was performed, identifying 2,951 procedures (2,219 patients), in which TXA was utilized in 1,144 procedures (39%). The mean age was 65 years with 52% female patients in the TXA revision group and 67 years with 52% female patients in the non-TXA revision group. Transfusion rates and symptomatic VTEs were the primary outcomes assessed. Comparisons were performed between cohorts, utilizing a unique propensity model to mitigate bias, on the basis of TXA use and subsequently for aseptic or septic revision etiology. Results: Significant reductions in transfusion rates with use of TXA were identified in revision TKAs overall (13% compared with 39%; p < 0.001 [adjusted relative risk, 1.7]), including revisions for both aseptic etiology (6% with TXA compared with 28% without TXA; p < 0.001) and septic etiology (31% with TXA compared with 54% without TXA; p < 0.001). The risk of a postoperative symptomatic VTE was not significantly different (adjusted p = 0.63) with use of TXA at 11 events (1.0%) compared with 24 events (1.3%) in the non-TXA group). Conclusions: Intravenous TXA significantly reduced transfusion rates in revision TKAs by approximately twofold, including cohorts revised for aseptic and septic etiologies. There was a very low rate of VTEs (1.2%) with no significant difference in the number of VTEs between groups after adjusting risk utilizing propensity modeling. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Background: Cardiac rehabilitation (CR) is recommended in clinical practice guidelines, but dose prescribed varies highly by country. This study characterized the dose offered in supervised CR programs and alternative models worldwide and their potential correlates. Methods and Results: In this cross-sectional study, an online survey was administered to CR programs globally. Cardiac associations and local champions facilitated program identification. Countries were classified based on region and income categories. Dose was operationalized as program duration×sessions per week. Generalized linear mixed models were performed to assess correlates. Of 203 countries in the world, 111 (54.7%) offered CR; data were collected in 93 (83.8% country response rate; n=1082 surveys, 32.1% program response rate). Globally, supervised CR programs were a median of 24 sessions (n=619, 57.3% programs ≥12 sessions); home-based and community-based programs offered 6 and 20 sessions, respectively. There was significant variation in supervised CR dose by region ( P ≤0.001), with the Americas (median, 36 sessions) offering a significantly greater dose than several other regions; there was also a trend for variation by country income classification. There was no difference in home-based dose by region ( P =0.43) but there was for community-based programs ( P <0.05; Americas offering greater dose). There was a significant dose variation in both home- and community-based programs by income classification ( P =0.002 and P <0.001, respectively), with higher doses offered by upper-middle-income than high-income countries. Correlates of supervised CR dose included more involvement of physicians ( P =0.026), proximity to other programs ( P =0.002), and accepting patients with noncardiac indications ( P =0.037). Conclusions: CR programs in many countries may need to increase their dose, which could be supported through physician champions.