Semaglutide and Tirzepatide for the Management of Weight Recurrence After Sleeve Gastrectomy: A Retrospective Cohort Study.

BACKGROUND: Metabolic and bariatric surgery (MBS) is the most effective treatment for obesity and improvement of obesity-associated comorbidities. However, a proportion of these patients may suffer from weight recurrence and recurrence of obesity-associated comorbidities. METHOD: A retrospective cohort study of patients who underwent SG between January 2008 and August 2022 and sought treatment for weight recurrence with semaglutide or tirzepetide from January 2022 onwards. RESULT: A total of 115 patients were included, of which 70 had SG and treated for weight recurrence with semaglutide and 45 had SG and treated with tirzepatide. The mean age of patients was 38.8 (10.4) and 80.9% of patients were female. The mean pre-treatment weight and BMI was 94.0 (23.8) kg and 35.1 (6.0) kg/m2. Following treatment with semaglutide and tirzepatide, the mean post-treatment weight at 6 months was 81.0 (19.0) kg from 90.1 (19.6) kg and 87.6 (28.3) kg from 100.2 (28.5) kg respectively, corresponding to a clinically significant mean weight loss from baseline to 6 months of 10.3 (5.9)% (p < 0.05) and 15.5 (6.3)% (p < 0.05). Weight loss in tirzepatide patients was significantly greater than the semaglutide patients at 6 months (p < 0.02). There were no reported severe adverse events to the treatment. CONCLUSION: Short-term outcomes show that semaglutide and tirzepatide can be an effective treatment for managing weight recurrence after SG. Studies with longer follow-up are needed to determine the durability, as weight regain after discontinuation of the medication is highly likely, and the high cost of these medications can limit their use.

Prescription and consumption of opioids after bariatric surgery: a multicenter prospective cohort study.

INTRODUCTION: In the current opioid crisis, bariatric surgical patients are at increased risk of harms related to postoperative opioid overprescribing. This study aimed to assess the extent to which opioids prescribed at discharge after bariatric surgery are consumed by patients. METHODS: This multicenter prospective cohort study included adult patients (≥ 18yo) undergoing laparoscopic bariatric surgery. Preoperative assessments included demographics and patient-reported measures. Information regarding surgical and perioperative care interventions (including discharge prescriptions) was obtained from medical records. Self-reported opioid consumption was assessed weekly up to 30 days post-discharge. Number of opioid pills prescribed and consumed was compared using Wilcoxon signed-rank test. Zero-inflated negative binomial regression was used to identify predictors of post-discharge opioid consumption. RESULTS: We analyzed 351 patients (mean age 44 ± 11 years, BMI 45 ± 8.0 kg/m2, 77% female, 71% sleeve gastrectomy, length of stay 1.6 ± 0.6 days). The quantity of opioids prescribed at discharge (median 15 pills [IQR 15-16], 112.5 morphine milligram equivalents (MMEs) [IQR 80-112.5]) was significantly higher than patient-reported consumption (median 1 pill [IQR 0-5], 7.5 MMEs [IQR 0-37.5]) (p < 0.001). Overall, 37% of patients did not take any opioids post-discharge and 78.5% of the opioid pills prescribed were unused. Increased post-discharge opioid consumption was associated with male sex (IRR 1.54 [95%CI 1.14 to 2.07]), higher BMI (1.03 [95%CI 1.01 to 1.05]), preoperative opioid use (1.48 [95%CI 1.04 to 2.10]), current smoking (2.32 [95%CI 1.44 to 3.72]), higher PROMIS-29 depression score (1.03 [95% CI 1.01 to 1.04]), anastomotic procedures (1.33 [95%CI 1.01 to 1.75]), and number of pills prescribed (1.04 [95%CI 1.01 to 1.06]). CONCLUSION: This study supports that most opioid pills prescribed to bariatric surgery patients at discharge are not consumed. Patient and procedure-related factors may predict opioid consumption. Individualized post-discharge analgesia strategies with minimal or no opioids may be feasible and should be further investigated in future research.

Predictors of post-discharge pain and satisfaction with pain management after laparoscopic bariatric surgery: a prospective cohort study.

BACKGROUND: Pain management after bariatric surgery remains challenging given the risk for analgesia-related adverse events (e.g., opioid use disorder, marginal ulcers). Identifying modifiable factors associated with patient-reported pain outcomes may improve quality of care. We evaluated the extent to which patient and procedural factors predict 7-day post-discharge pain intensity, pain interference, and satisfaction with pain management after bariatric surgery. METHODS: This prospective cohort study included adults undergoing laparoscopic bariatric surgery at two university-affiliated hospitals and one private clinic. Preoperative assessments included demographics, Pain Catastrophizing Scale (score range 0-52), Patient Activation Measure (low [< 55.1] vs. high [≥ 55.1]), pain expectation (0-10), and Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) anxiety and depression scales. At 7 days post-discharge, assessments included PROMIS-29 pain intensity (0-10) and pain interference scales (41.6-75.6), and satisfaction with pain management (high [10-9] vs. lower [8-0]). Linear and logistic regression were used to assess the association of pain outcomes with potential predictors. RESULTS: Three hundred and fifty-one patients were included (mean age = 44 ± 11 years, BMI = 45 ± 8 kg/m2, 77% female, 71% sleeve gastrectomy). At 7 days post-discharge, median (IQR) patient-reported pain intensity was 2.5 (1-5), pain interference was 55.6 (52.0-61.2), and 76% of patients reported high satisfaction with pain management. Pain intensity was predicted by preoperative anxiety (ß + 0.04 [95% CI + 0.01 to + 0.07]) and pain expectation (+ 0.15 [+ 0.05 to + 0.25]). Pain interference was predicted by preoperative anxiety (+ 0.22 [+ 0.11 to + 0.33]), pain expectation (+ 0.47 [+ 0.10 to + 0.84]), and age (- 0.09 [- 0.174 to - 0.003]). Lower satisfaction was predicted by low patient activation (OR 1.94 [1.05-3.58]), higher pain catastrophizing (1.03 [1.003-1.05]), 30-day complications (3.27 [1.14-9.38]), and age (0.97 [0.948-0.998]). CONCLUSION: Patient-related factors are important predictors of post-discharge pain outcomes after bariatric surgery. Our findings highlight the value of addressing educational, psychological, and coping strategies to improve postoperative pain outcomes.

Feasibility of Prospectively Comparing Opioid Analgesia With Opioid-Free Analgesia After Outpatient General Surgery: A Pilot Randomized Clinical Trial.

Importance: The overprescription of opioids to surgical patients is recognized as an important factor contributing to the opioid crisis. However, the value of prescribing opioid analgesia (OA) vs opioid-free analgesia (OFA) after postoperative discharge remains uncertain. Objective: To investigate the feasibility of conducting a full-scale randomized clinical trial (RCT) to assess the comparative effectiveness of OA vs OFA after outpatient general surgery. Design, Setting, and Participants: This parallel, 2-group, assessor-blind, pragmatic pilot RCT was conducted from January 29 to September 3, 2020 (last follow-up on October 2, 2020). at 2 university-affiliated hospitals in Montreal, Quebec, Canada. Participants were adult patients (aged ≥18 years) undergoing outpatient abdominal (ie, cholecystectomy, appendectomy, or hernia repair) or breast (ie, partial or total mastectomy) general surgical procedures. Exclusion criteria were contraindications to drugs used in the trial, preoperative opioid use, conditions that could affect assessment of outcomes, and intraoperative or early complications requiring hospitalization. Interventions: Patients were randomized 1:1 to receive OA (around-the-clock nonopioids and opioids for breakthrough pain) or OFA (around-the-clock nonopioids with increasing doses and/or addition of nonopioid medications for breakthrough pain) after postoperative discharge. Main Outcomes and Measures: Main outcomes were a priori RCT feasibility criteria (ie, rates of surgeon agreement, patient eligibility, patient consent, treatment adherence, loss to follow-up, and missing follow-up data). Secondary outcomes included pain intensity and interference, analgesic intake, 30-day unplanned health care use, and adverse events. Between-group comparison of outcomes followed the intention-to-treat principle. Results: A total of 15 surgeons were approached; all (100%; 95% CI, 78%-100%) agreed to have patients recruited and adhered to the study procedures. Rates of patient eligibility and consent were 73% (95% CI, 66%-78%) and 57% (95% CI, 49%-65%), respectively. Seventy-six patients were randomized (39 [51%] to OA and 37 [49%] to OFA) and included in the intention-to-treat analysis (mean [SD] age, 55.5 [14.5] years; 50 [66%] female); 40 (53%) underwent abdominal surgery, and 36 (47%) underwent breast surgery. Seventy-five patients (99%; 95% CI, 93%-100%) adhered to the allocated treatment; 1 patient randomly assigned to OFA received an opioid prescription. Seventeen patients (44%) randomly assigned to OA consumed opioids after discharge. Seventy-three patients (96%; 95% CI, 89%-99%) completed the 30-day follow-up. The rate of missing questionnaires was 37 of 3724 (1%; 95% CI, 0.7%-1.4%). All the a priori RCT feasibility criteria were fulfilled. Conclusions and Relevance: The findings of this pilot RCT support the feasibility of conducting a robust, full-scale RCT to inform evidence-based prescribing of analgesia after outpatient general surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT04254679.

The impact of the first wave of the COVID-19 pandemic on the exposure of general surgery trainees to operative procedures.

INTRODUCTION: During the COVID-19 pandemic, the redeployment of operating room (OR) staff resulted in a significant ramp-down of elective surgery. To mitigate the negative effects of the pandemic on surgical education, this study was planned to estimate the impact of the first wave of the pandemic on the participation of general surgery residency and fellowship trainees in operative procedures. METHODS: This study is a retrospective review of all adult general surgery procedures performed at 3 sites of an academic health care network. Cases performed during the first wave of the pandemic (March-June 2020) were compared to the same period of the previous year pre-pandemic (March-June 2019). Trainees were categorized as junior (Post-Graduate-Year [PGY] 1-2), senior (PGY3-5), or fellows (PGY6-7). Operating exposure was defined as (1) the total number of cases attended by at least one trainee and (2) total time spent in the OR by all trainees (hours). The impact of the pandemic was estimated as percentage of baseline (2019). RESULTS: During the first wave of the pandemic, a total of 914 cases were performed, compared to 1328 in the pre-pandemic period (69%). Junior trainees were more affected than senior trainees with reductions in both case volume (68% versus 78% of baseline attendance) and time (68% versus 77% of baseline operating time). Minimally invasive surgery fellows were most severely affected trainees and colorectal fellows were least affected (14% and 75% of baseline cases, respectively). Participation in emergency surgery cases and surgical oncology cases was relatively preserved (87% and 105% of baseline, respectively). CONCLUSIONS: The first wave of the COVID-19 pandemic reduced operative exposure for general surgery trainees by approximately 30%. Procedure-specific patterns reflected institutional policies for prioritizing cancer operations and emergency surgeries. These findings may inform the design of remediation activities to mitigate the impact of the pandemic on surgical training.

The association of alvimopan treatment with postoperative outcomes after abdominal surgery: A systematic review across different surgical procedures and contexts of perioperative care.

BACKGROUND: Alvimopan is a Food and Drug Administration-approved treatment to accelerate gastrointestinal recovery after abdominal surgery; however, benefits may vary across different procedures and contexts of care. The purpose of this study is to summarize the evidence regarding the effect of alvimopan on postoperative outcomes after abdominal surgery. METHODS: Major databases (Medline, Embase, Biosis, Cochrane, Web of Science, and Scopus) were searched for randomized controlled trials and nonrandomized studies comparing alvimopan versus control. Risk of bias was assessed using Cochrane's risk of bias tool 2.0 (for randomized controlled trials) and Risk of Bias in Nonrandomized Studies-of Intervention tool (for nonrandomized studies). Results were appraised descriptively as heterogeneity in reporting and risk of bias hindered meta-analysis. Quality of evidence across different surgical procedures and contexts of care (ie, open versus minimally invasive surgery, traditional care versus enhanced recovery pathway) was evaluated using Grading of Recommendations Assessment, Development, and Evaluation. RESULTS: Nine randomized controlled trials and 35 nonrandomized studies were identified. Evidence of low to moderate certainty supports that alvimopan reduces length of stay and improves gastrointestinal recovery after open bowel resection and open radical cystectomy. Limited evidence supports alvimopan for surgeries not listed in Food and Drug Administration labels (ie, total abdominal hysterectomy and retroperitoneal lymph node dissection). Similar effects were observed in traditional and enhanced recovery pathway settings, but enhanced recovery pathway elements varied across studies. There is very low certainty of evidence supporting alvimopan for patients undergoing minimally invasive surgery. CONCLUSION: Evidence supports that alvimopan improves outcomes after open bowel resection and open radical cystectomy. Benefits for patients undergoing minimally invasive surgery and treated in contemporary enhanced recovery pathway settings remain uncertain. These findings contribute important new knowledge to inform evidence-based alvimopan prescribing.

Impact of Facilitation of Early Mobilization on Postoperative Pulmonary Outcomes After Colorectal Surgery: A Randomized Controlled Trial.

OBJECTIVE: To estimate the extent to which staff-directed facilitation of early mobilization impacts recovery of pulmonary function and 30-day postoperative pulmonary complications (PPCs) after colorectal surgery. SUMMARY BACKGROUND DATA: Early mobilization after surgery is believed to improve pulmonary function and prevent PPCs; however, adherence is low. The value of allocating resources (eg, staff time) to increase early mobilization is unknown. METHODS: This study involved the analysis of a priori secondary outcomes of a pragmatic, observer-blind, randomized trial. Consecutive patients undergoing colorectal surgery were randomized 1:1 to usual care (preoperative education) or facilitated mobilization (staff dedicated to assist transfers and walking during hospital stay). Forced vital capacity, forced expiratory volume in 1 second (FEV1), and peak cough flow were measured preoperatively and at 1, 2, 3 days and 4 weeks after surgery. PPCs were defined according to the European Perioperative Clinical Outcome Taskforce. RESULTS: Ninety-nine patients (57% male, 80% laparoscopic, median age 63, and predicted FEV1 97%) were included in the intention-to-treat analysis (usual care 49, facilitated mobilization 50). There was no between-group difference in recovery of forced vital capacity [adjusted difference in slopes 0.002 L/d (95% CI -0.01 to 0.01)], FEV1 [-0.002 L/d (-0.01 to 0.01)] or peak cough flow [-0.002 L/min/d (-0.02 to 0.02)]. Thirty-day PPCs were also not different between groups [adjusted odds ratio 0.67 (0.23-1.99)]. CONCLUSIONS: In this randomized controlled trial, staff-directed facilitation of early mobilization did not improve postoperative pulmonary function or reduce PPCs within an enhanced recovery pathway for colorectal surgery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02131844.

Validity of the I-FEED score for postoperative gastrointestinal function in patients undergoing colorectal surgery.

BACKGROUND: Postoperative ileus (POI) is common after gastrointestinal surgery and is associated with significant morbidity and costs. However, POI is poorly defined. The I-FEED score is a novel outcome measure for POI, developed by expert consensus. It contains five elements (intake, response to nausea treatment, emesis, exam, and duration, each scored with 0, 1, or 3 points) and classifies patients into normal, postoperative gastrointestinal intolerance (POGI), and postoperative gastrointestinal dysfunction (POGD). However, it has not yet been validated in a clinical context. The objective was to provide validity evidence for the I-FEED score to measure the construct of POI in patients undergoing colorectal surgery. METHODS: Data previously collected from a clinical trial investigating the impact of different perioperative fluid management strategies on primary POI in patients undergoing elective laparoscopic colectomy (2013-2015) were analyzed. Patients were managed by a longstanding Enhanced Recovery program (expected length of stay (LOS): 3 days). Daily I-FEED scores were generated (normal 0-2, POGI 3-5, POGD 6+ points) up to hospital discharge or postoperative day 7. Validity was assessed by testing the hypotheses that I-FEED score was higher (1) in patients with longer time to GI3 (tolerating diet + flatus/bowel movement), (2) with longer LOS (> 3 days vs shorter), (3) in patients with complications vs without, (4) in patients with poorer recovery (measured by Quality of Recovery-9 questionnaire). RESULTS: A total of 128 patients were included for analysis (mean age 61.7 years (SD 15.2), 57% male, 71% malignancy, and 39.1% rectal resection). Median LOS was 4 days [IQR3-5], and 32% experienced postoperative in-hospital morbidity. Overall, 48% of patients were categorized as normal, 22% POGI, and 30% POGD. The data supported all 4 hypotheses. CONCLUSIONS: This study contributes preliminary validity evidence for the I-FEED score as a measure for POI after colorectal surgery.

A mobile device application (app) to improve adherence to an enhanced recovery program for colorectal surgery: a randomized controlled trial.

BACKGROUND: Increased adherence with enhanced recovery pathways (ERP) is associated with improved outcomes. However, adherence to postoperative elements that rely on patient participation remains suboptimal. Mobile device apps may improve delivery of health education material and have the potential to foster behavior change and improve patient compliance. The objective of this study was to estimate the extent to which a novel mobile device app affects adherence to an ERP for colorectal surgery in comparison to standard written education. METHODS: This was a superiority, parallel-group, assessor-blind, sham-controlled randomized trial involving 97 patients undergoing colorectal resection. Participants were randomly assigned with a 1:1 ratio into one of two groups: (1) iPad including a novel mobile device app for postoperative education and self-assessment of recovery, or (2) iPad without the app. The primary outcome measure was mean adherence (%) to a bundle of five postoperative ERP elements requiring patient participation: mobilization, gastrointestinal motility stimulation, breathing exercises, and consumption of oral liquids and nutritional drinks. RESULTS: In the intervention group, app usage was high (94% completed surveys on POD0, 82% on POD1, 72% on POD2). Mean overall adherence to the bundle on the two first postoperative days was similar between groups: 59% (95% CI 52-66%) in the intervention group and 62% (95% CI 56-68%) in the control group [Adjusted mean difference 2.4% (95% CI - 5 to 10%) p = 0.53]. CONCLUSIONS: In this randomized trial, access to a mobile health application did not improve adherence to a well-established enhanced recovery pathway in colorectal surgery patients, when compared to standard written patient education. Future research should evaluate the impact of applications integrating novel behavioral change techniques, particularly in contexts where adherence is low.

Intracorporeal versus extracorporeal anastomosis for right colectomy does not affect gastrointestinal recovery within an enhanced recovery after surgery program.

INTRODUCTION: Delayed gastrointestinal (GI) recovery remains a significant morbidity after colorectal surgery. Intracorporeal anastomosis for right colectomy may hasten GI recovery. Therefore, the objective of this study was to determine the effect of intracorporeal versus extracorporeal anastomosis on GI recovery after elective laparoscopic right colectomy within an established ERAS program. METHODS: Adult patients undergoing elective laparoscopic right colectomy at a single high-volume institution from 07/2014 to 12/2018 were reviewed. Patients were divided into two groups: intracorporeal (IC) and extracorporeal (EC). The primary outcome was time to GI-3 defined as days to tolerance of solid diet and first flatus/bowel movement. Prolonged postoperative ileus (PPOI) was defined as GI-3 not met by postoperative day 4. Secondary outcomes were length of stay (LOS) and overall 30-day complications. Sensitivity analysis was performed using coarsened exact matching to account for unmeasured confounding. Multiple regression was performed using a Cox proportional hazard model to identify predictors of GI recovery. RESULTS: A total of 346 patients were reviewed, of which 226 were included (71IC, 155EC). Patient characteristics were well balanced between groups: mean age was 64.9 years (SD 15.9), BMI was 26.3 (SD 5.7), 38.1% of patients had ASA ≥ 3, and 78.3% underwent surgery for neoplasms. IC anastomosis was associated with longer operative duration (165 min (SD 40); 144 min (SD 48), p = 0.002). There was no difference in the median time to GI-3 (IC 2 days [IQR1-2]; EC 2 days [IQR2-3], p = 0.135). The incidence of PPOI (IC 8.5%; EC 10.3%, p = 0.659), superficial SSI (4.2% vs. 5.8%, p = 0.757), deep SSI (2.8% vs. 5.2%, p = 0.729), and median LOS (3 days [IQR 2-4] vs. 3 [IQR 3-5], p = 0.059) were also similar. On multivariate analysis, IC anastomosis did not independently predict faster GI recovery (HR 0.98, 95% CI 0.71-1.34). Similar results were observed in the matched cohort (185 patients (61IC, 124EC)). CONCLUSION: In this study, IC anastomosis was not associated with faster GI recovery or reduced complication rate compared to EC anastomosis. Longer term studies may be required to determine the potential benefits of IC anastomosis.

Incidence and predictors of prolonged postoperative ileus after colorectal surgery in the context of an enhanced recovery pathway.

BACKGROUND: Prolonged postoperative ileus (PPOI) is common after colorectal surgery but has not been widely studied in the context of enhanced recovery pathways (ERPs) that include interventions aimed to accelerate gastrointestinal recovery. The aim of this study is to estimate the incidence and predictors of PPOI in the context of an ERP for colorectal surgery. METHODS: We analyzed data from an institutional colorectal surgery ERP registry. Incidence of PPOI was estimated according to a definition adapted from Vather (intolerance of solid food and absence of flatus or bowel movement for ≥ 4 days) and compared to other definitions in the literature. Potential risk factors for PPOI were identified from previous studies, and their predictive ability was evaluated using Bayesian model averaging (BMA). Results are presented as posterior effect probability (PEP). Evidence of association was categorized as: no evidence (PEP < 50%), weak evidence (50-75%), positive evidence (75-95%), strong evidence (95-99%), and very strong evidence (> 99%). RESULTS: There were 323 patients analyzed (mean age 63.5 years, 51% males, 74% laparoscopic, 33% rectal resection). The incidence of PPOI was 19% according to the primary definition, but varied between 11 and 59% when using other definitions. On BMA analysis, intraoperative blood loss (PEP 99%; very strong evidence), administration of any intravenous opioids in the first 48 h (PEP 94%; strong evidence), postoperative epidural analgesia (PEP 56%; weak evidence), and non-compliance with intra-operative fluid management protocols (3 ml/kg/h for laparoscopic and 5 ml/kg/h for open; PEP 55%, weak evidence) were predictors of PPOI. CONCLUSIONS: The incidence of PPOI after colorectal surgery is high even within an established ERP and varied considerably by diagnostic criteria, highlighting the need for a consensus definition. The use of intravenous opioids is a modifiable strong predictor of PPOI within an ERP, while the role of epidural analgesia and intraoperative fluid management should be further evaluated.

Impact of miniport laparoscopic cholecystectomy versus standard port laparoscopic cholecystectomy on recovery of physical activity: a randomized trial.

INTRODUCTION: We conducted a randomized trial comparing minilaparoscopic cholecystectomy (MLC) to conventional laparoscopic cholecystectomy (CLC) to determine whether MLC accelerated recovery of physical activity after elective surgery (NCT01397565). METHODS: A total of 115 patients scheduled for elective cholecystectomy were randomized to either CLC or MLC. Both procedures used a 10-mm umbilical port, but the three upper abdominal ports were 5 mm in CLC and 3 mm in MLC. Primary outcome was self-reported physical activity 1 month after surgery as estimated by Community Health Activities Model Program for Seniors questionnaire (kcal/kg/week). Secondary outcomes were umbilical pain, abdominal pain, nausea and fatigue (VAS, 1-10), and cosmetic result at one and 3 months. Patients received identical surgical dressings for 1 week, and assessors were blinded to group allocation. RESULTS: Forty-two patients randomized to CLC group and 33 patients randomized to MLC remained in the trial and were analyzed. Both groups were similar at baseline characteristics. In the MLC group, at least one 5-mm port was used in 17 (51.5 %) mainly due to unavailability of ML equipment. Median (IQR) physical activity for the CLC and MLC groups was similar at baseline (23.4 [13.1, 44.6] vs 23.6 [14.2, 66.9] kcal/kg/week, p = 0.35) and at 1 month (20 [7.9, 52.5] vs 16.8 [11.8, 28.6] kcal/kg/week, p = 0.90). One month post-op, umbilical pain and abdominal pain were similar, but the CLC group reported higher fatigue (4 [1-5] vs 1 [0-4], p = 0.05) and worse scar appearance scores (4 [3, 4] vs 4.5 [4, 5], p = 0.009). At 3 months, the CLC group had worse scar appearance (4 [3-5] vs 5 [4-5], p = 0.02) and lower scar satisfaction scores (4 [3, 4] vs 4 [3.5-4], p = 0.04). CONCLUSION: Recovery of physical activity was similar after MLC and CLC. MLC resulted in less fatigue and better scar appearance and satisfaction. These benefits were seen despite the need to upsize one or more ports in more than half of patients related to availability of the miniature instruments.

Pluripotency markers are differentially induced by MEK inhibition in thyroid and melanoma BRAFV600E cell lines.

Oncogenic mutations in BRAF are common in melanoma and thyroid carcinoma and drive constitutive activation of the MAPK pathway. Molecularly targeted therapies of this pathway improves survival compared to chemotherapy; however, responses tend to be short-lived as resistance invariably occursCell line models of melanoma and thyroid carcinoma, +/- BRAF(V600E) activating mutation, were treated with the MEK inhibitor PD0325901. Treated and naive samples were assayed for expression of key members of the MAPK pathway. Global microRNA expression profiling of naive and resistant cells was performed via next generation sequencingand indicated pluripotency pathways in resistance. Parental cell lines were progressed to holoclones to confirm the miRNA stemness profileMembers of the MIR302/373/374/520 family of embryonic stem cell specific cell cycle regulating (ESCC) microRNAs were identified as differentially expressed between resistant BRAF(V600E) melanoma and thyroid cell lines. Upregulated expression of gene and protein stemness markers, upregulated expression of MAPK pathway genes and downregulation of the ESCC MIR302 cluster in BRAF(V600E) melanoma indicated an increased stem-like phenotype in resistant BRAF(V600E) melanoma. Conversely, downregulated expression of gene and protein stemness markers, downregulated expression of MAPK pathway genes, upregulation of the ESCC MIR520 cluster, reeexpression of cell surface receptors, and induced differentiation-associated morphology in resistant BRAF(V600E) indicate a differentiated phenotype associated with MEK inhibitor resistance in BRAF(V600E) thyroid cellsThe differential patterns of resistance observed between BRAF(V600E) melanoma and thyroid cell lines may reflect tissue type or de novo differentiation, but could have significant impact on the response of primary and metastatic cells to MEK inhibitor treatment. This study provides a basis for the investigation of the cellular differentiation/self-renewal access and its role in resistance to MEK inhibition.