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PURPOSE: This study evaluated the accuracy of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) calculator in predicting outcomes after hepatectomy for colorectal cancer (CRC) liver metastasis in a Southeast Asian population. METHODS: Predicted and actual outcomes were compared for 166 patients undergoing hepatectomy for CRC liver metastasis identified between 2017 and 2022, using receiver operating characteristic curves with area under the curve (AUC) and Brier score. RESULTS: The ACS-NSQIP calculator accurately predicted most postoperative complications (AUC > 0.70), except for surgical site infection (AUC = 0.678, Brier score = 0.045). It also exhibited satisfactory performance for readmission (AUC = 0.818, Brier score = 0.011), reoperation (AUC = 0.945, Brier score = 0.002), and length of stay (LOS, AUC = 0.909). The predicted LOS was close to the actual LOS (5.9 vs. 5.0 days, P = 0.985). CONCLUSION: The ACS-NSQIP calculator demonstrated generally accurate predictions for 30-day postoperative outcomes after hepatectomy for CRC liver metastasis in our patient population.
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Neoplasias Colorrectales , Hepatectomía , Neoplasias Hepáticas , Complicaciones Posoperatorias , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Asia Sudoriental , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Tiempo de Internación , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/secundario , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Medición de Riesgo , Pueblos del Sudeste AsiáticoRESUMEN
BACKGROUND: This study evaluated the cost-effectiveness of open, laparoscopic, and robotic liver resection. METHODS: A comprehensive literature review and Bayesian network meta-analysis were conducted. Surface under cumulative ranking area values, mean difference, odds ratio, and 95% credible intervals were calculated for all outcomes. Cluster analysis was performed to determine the most cost-effective clustering approach. Costs-morbidity, costs-mortality, and costs-efficacy were the primary outcomes assessed, with postoperative overall morbidity, mortality, and length of stay associated with total costs for open, laparoscopic, and robotic liver resection. RESULTS: Laparoscopic liver resection incurred the lowest total costs (laparoscopic liver resection versus open liver resection: mean difference -2,529.84, 95% credible intervals -4,192.69 to -884.83; laparoscopic liver resection versus robotic liver resection: mean difference -3,363.37, 95% credible intervals -5,629.24 to -1,119.38). Open liver resection had the lowest procedural costs but incurred the highest hospitalization costs compared to laparoscopic liver resection and robotic liver resection. Conversely, robotic liver resection had the highest total and procedural costs but the lowest hospitalization costs. Robotic liver resection and laparoscopic liver resection had a significantly reduced length of stay than open liver resection and showed less postoperative morbidity. Laparoscopic liver resection resulted in the lowest readmission and liver-specific complication rates. Laparoscopic liver resection and robotic liver resection demonstrated advantages in costs-morbidity efficiency. While robotic liver resection offered notable benefits in mortality and length of stay, these were balanced against its highest total costs, presenting a nuanced trade-off in the costs-mortality and costs-efficacy analyses. CONCLUSION: Laparoscopic liver resection represents a more cost-effective option for hepatectomy with superior postoperative outcomes and shorter length of stay than open liver resection. Robotic liver resection, though costlier than laparoscopic liver resection, along with laparoscopic liver resection, consistently exceeds open liver resection in surgical performance.
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Hepatectomía , Laparoscopía , Procedimientos Quirúrgicos Robotizados , Humanos , Análisis Costo-Beneficio , Hepatectomía/economía , Hepatectomía/métodos , Hepatectomía/efectos adversos , Laparoscopía/economía , Laparoscopía/métodos , Laparoscopía/efectos adversos , Tiempo de Internación/economía , Tiempo de Internación/estadística & datos numéricos , Metaanálisis en Red , Complicaciones Posoperatorias/economía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Procedimientos Quirúrgicos Robotizados/economía , Procedimientos Quirúrgicos Robotizados/efectos adversosRESUMEN
This systematic review and meta-analysis aimed to evaluate the impact of prospective payment systems (PPSs) on cholecystectomy. A comprehensive literature review was conducted, examining studies published until December 2023. The review process focused on identifying research across major databases that reported critical outcomes such as length of stay (LOS), mortality, complications, admissions, readmissions, and costs following PPS for cholecystectomy. The studies were specifically selected for their relevance to the impact of PPS or the transition from fee-for-service (FFS) to PPS. The study analyzed six papers, with three eligible for meta-analysis, to assess the impact of the shift from FFS to PPS in laparoscopic and open cholecystectomy procedures. Our findings indicated no significant changes in LOS and mortality rates following the transition from FFS to PPS. Complication rates varied and were influenced by the diagnosis-related group categorization and surgeon cost profiles under episode-based payment. There was a slight increase in admissions and readmissions, and mixed effects on hospital costs and financial margins, suggesting varied responses to PPS for cholecystectomy procedures. The impact of PPS on cholecystectomy is nuanced and varies across different aspects of healthcare delivery. Our findings indicate a need for adaptable, patient-centered PPS models that balance economic efficiency with high-quality patient care. The study emphasizes the importance of considering specific surgical procedures and patient demographics in healthcare payment reforms.
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BACKGROUND: This study compared the cost-effectiveness of open (ODP), laparoscopic (LDP), and robotic (RDP) distal pancreatectomy (DP). METHODS: Studies reporting the costs of DP were included in a literature search until August 2023. Bayesian network meta-analysis was conducted, and surface under cumulative ranking area (SUCRA) values, mean difference (MD), odds ratio (OR), and 95% credible intervals (CrIs) were calculated for outcomes of interest. Cluster analysis was performed to examine the similarity and classification of DP approaches into homogeneous clusters. A decision model-based cost-utility analysis was conducted for the cost-effectiveness analysis of DP strategies. RESULTS: Twenty-six studies with 29,164 patients were included in the analysis. Among the three groups, LDP had the lowest overall costs, while ODP had the highest overall costs (LDP vs. ODP: MD - 3521.36, 95% CrI - 6172.91 to - 1228.59). RDP had the highest procedural costs (ODP vs. RDP: MD - 4311.15, 95% CrI - 6005.40 to - 2599.16; LDP vs. RDP: MD - 3772.25, 95% CrI - 4989.50 to - 2535.16), but incurred the lowest hospitalization costs. Both LDP (MD - 3663.82, 95% CrI - 6906.52 to - 747.69) and RDP (MD - 6678.42, 95% CrI - 11,434.30 to - 2972.89) had significantly reduced hospitalization costs compared to ODP. LDP and RDP demonstrated a superior profile regarding costs-morbidity, costs-mortality, costs-efficacy, and costs-utility compared to ODP. Compared to ODP, LDP and RDP cost $3110 and $817 less per patient, resulting in 0.03 and 0.05 additional quality-adjusted life years (QALYs), respectively, with positive incremental net monetary benefit (NMB). RDP costs $2293 more than LDP with a negative incremental NMB but generates 0.02 additional QALYs with improved postoperative morbidity and spleen preservation. Probabilistic sensitivity analysis suggests that LDP and RDP are more cost-effective options compared to ODP at various willingness-to-pay thresholds. CONCLUSION: LDP and RDP are more cost-effective than ODP, with LDP exhibiting better cost savings and RDP demonstrating superior surgical outcomes and improved QALYs.
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Análisis Costo-Beneficio , Laparoscopía , Metaanálisis en Red , Pancreatectomía , Procedimientos Quirúrgicos Robotizados , Pancreatectomía/economía , Pancreatectomía/métodos , Humanos , Procedimientos Quirúrgicos Robotizados/economía , Procedimientos Quirúrgicos Robotizados/métodos , Laparoscopía/economía , Laparoscopía/métodos , Tiempo de Internación/economía , Tiempo de Internación/estadística & datos numéricosRESUMEN
INTRODUCTION: Total mesorectal excision (TME) with delayed coloanal anastomosis (DCAA) is surgical option for low rectal cancer, replacing conventional immediate coloanal anastomosis (ICAA) with bowel diversion. This study aimed to assess the outcomes of transanal TME (TaTME) with DCAA versus laparoscopic TME (LTME) with ICAA versus robotic TME (RTME) with ICAA. METHODS: This was a retrospective propensity score-matched analysis of patients who underwent elective TaTME-DCAA between November 2021 and June 2022. Patients were propensity-score matched in a ratio of 1:3 to patients who underwent LTME-ICAA and RTME-ICAA from January 2019 to December 2020. Outcome measures were histopathologic results, postoperative morbidity, function, and inpatient costs. RESULTS: Twelve patients in the TaTME-DCAA group were compared with 36 patients in the LTME-ICAA and RTME-ICAA groups each after propensity score matching. Histopathologic results and postoperative morbidity rates were statistically similar. Overall stoma-related complication rates in the ICAA groups were 11%. Median total length of hospital stays for TME plus stoma reversal surgery was similar across all techniques (10 vs. 10 vs. 9 days; P =0.532). Despite a significantly shorter duration of follow-up, bowel function after TaTME-DCAA was comparable to that of LTME-ICAA and RTME-ICAA. Overall median inpatient costs of TaTME-DCAA were comparable to LTME-ICAA and significantly cheaper than RTME-ICAA ($31,087 vs. $29,927 vs. $36,750; P =0.002). CONCLUSIONS: TaTME with DCAA is a feasible and safe technique compared with other minimally invasive methods of TME, while avoiding bowel diversion and stoma-related complications, as well as comparing favorably in terms of overall hospitalization costs.
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Ajmalina/análogos & derivados , Laparoscopía , Neoplasias del Recto , Procedimientos Quirúrgicos Robotizados , Cirugía Endoscópica Transanal , Humanos , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/métodos , Defecación , Puntaje de Propensión , Cirugía Endoscópica Transanal/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Neoplasias del Recto/patología , Recto/cirugía , Laparoscopía/métodos , Anastomosis Quirúrgica/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: This study aims to compare the outcomes of high-volume, medium-volume, and low-volume hospitals performing hepatic resections using a network meta-analysis. METHODS: A literature search until June 2023 was conducted across major databases to identify studies comparing outcomes in high-volume, medium-volume, and low-volume hospitals for liver resection. Bayesian network meta-analysis was conducted, and surface under cumulative ranking area values, odds ratio, and mean difference with 95% credible intervals were reported for postoperative mortality, failure-to-rescue, morbidity, length of stay, and hospital costs. RESULTS: Twenty studies comprising 248,707 patients undergoing liver resection were included. For the primary mortality outcome, overall and subgroup analyses were performed: group I: high-volume = 5 to 20 resections/year; group II: high-volume = 21 to 49 resections/year; group III: high-volume ≥50 resections/year. Results demonstrated a significant association between hospital volume and mortality (overall-high-volume versus medium-volume: odds ratio 0.66, 95% credible interval 0.49-0.87; high-volume versus low-volume: odds ratio 0.52, 95% credible interval 0.41-0.65; group I-high-volume versus low-volume: odds ratio 0.34, 95% credible interval 0.22-0.50; medium-volume versus low-volume: odds ratio 0.56, 95% credible interval 0.33-0.92; group II-high-volume versus low-volume: odds ratio 0.67, 95% credible interval 0.45-0.91), as well as length of stay (high-volume versus low-volume: mean difference -1.24, 95% credible interval -2.07 to -0.41), favoring high-volume hospitals. No significant difference was observed in failure-to-rescue, morbidity, or hospital costs across the 3 groups. CONCLUSION: This study supports a positive relationship between hospital volume and surgical outcomes in liver resection. Patients from high-volume hospitals experience superior outcomes in terms of lower postoperative mortality and shorter lengths of stay than medium-volume and low-volume hospitals.
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Hepatectomía , Hospitales de Alto Volumen , Humanos , Teorema de Bayes , Hepatectomía/métodos , Mortalidad Hospitalaria , Hospitales , Hígado , Metaanálisis en RedRESUMEN
This study aims to assess the quality and performance of predictive models for colorectal cancer liver metastasis (CRCLM). A systematic review was performed to identify relevant studies from various databases. Studies that described or validated predictive models for CRCLM were included. The methodological quality of the predictive models was assessed. Model performance was evaluated by the reported area under the receiver operating characteristic curve (AUC). Of the 117 articles screened, seven studies comprising 14 predictive models were included. The distribution of included predictive models was as follows: radiomics (n = 3), logistic regression (n = 3), Cox regression (n = 2), nomogram (n = 3), support vector machine (SVM, n = 2), random forest (n = 2), and convolutional neural network (CNN, n = 2). Age, sex, carcinoembryonic antigen, and tumor staging (T and N stage) were the most frequently used clinicopathological predictors for CRCLM. The mean AUCs ranged from 0.697 to 0.870, with 86% of the models demonstrating clear discriminative ability (AUC > 0.70). A hybrid approach combining clinical and radiomic features with SVM provided the best performance, achieving an AUC of 0.870. The overall risk of bias was identified as high in 71% of the included studies. This review highlights the potential of predictive modeling to accurately predict the occurrence of CRCLM. Integrating clinicopathological and radiomic features with machine learning algorithms demonstrates superior predictive capabilities.
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PURPOSE: In 2017, the National Surgical Quality Improvement Program (NSQIP) was introduced in the Department of Colorectal Surgery at Singapore General Hospital as a pilot quality improvement initiative. This study aimed to examine the cost-effectiveness of NSQIP by evaluating its effects on surgical outcomes, length of stay (LOS), and costs. METHODS: We retrospectively reviewed patients undergoing colorectal surgery (2017-2020). Patients were divided into two cohorts: pre-NSQIP (2017-2018) and post-NSQIP (2019-2020). Outcomes evaluated were 30-day postoperative complications, LOS, and costs. Total cost-savings from NSQIP intervention's impact on LOS were estimated using a decision model with a one-way sensitivity analysis. Multivariate logistic regression was performed to identify factors for prolonged LOS. RESULTS: 1905 patients underwent colorectal surgery, with 996 in the pre-NSQIP cohort and 909 in the post-NSQIP cohort. A significant reduction in overall postoperative complications of 4.7% was observed in the post-NSQIP cohort (36.5% vs. 31.8%, p = 0.029). Patients in the post-NSQIP cohort had a shorter median LOS (8.0 vs. 6.0 days, p < 0.001). The implementation of NSQIP resulted in an 8.5% decrease in prolonged LOS > 6 days (p < 0.001), saving S$0.31 million on LOS. Total costs per case were reduced by 20.8% following NSQIP (S$39,539.05 vs. S$31,311.93, p < 0.001). CONCLUSION: Implementing NSQIP has significantly reduced overall postoperative complications, LOS, and costs and achieved cost savings following colorectal surgery.
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Cirugía Colorrectal , Humanos , Análisis Costo-Beneficio , Tiempo de Internación , Mejoramiento de la Calidad , Estudios Retrospectivos , Singapur , Complicaciones Posoperatorias/etiología , HospitalesRESUMEN
The tumor suppressor Liver Kinase B1 (LKB1) is a multifunctional serine/threonine protein kinase that regulates cell metabolism, polarity, and growth and is associated with Peutz-Jeghers Syndrome and cancer predisposition. The LKB1 gene comprises 10 exons and 9 introns. Three spliced LKB1 variants have been documented, and they reside mainly in the cytoplasm, although two possess a nuclear-localization sequence (NLS) and are able to shuttle into the nucleus. Here, we report the identification of a fourth and novel LKB1 isoform that is, interestingly, targeted to the mitochondria. We show that this mitochondria-localized LKB1 (mLKB1) is generated from alternative splicing in the 5' region of the transcript and translated from an alternative initiation codon encoded by a previously unknown exon 1b (131 bp) hidden within the long intron 1 of LKB1 gene. We found by replacing the N-terminal NLS of the canonical LKB1 isoform, the N-terminus of the alternatively spliced mLKB1 variant encodes a mitochondrial transit peptide that allows it to localize to the mitochondria. We further demonstrate that mLKB1 colocalizes histologically with mitochondria-resident ATP Synthase and NAD-dependent deacetylase sirtuin-3, mitochondrial (SIRT3) and that its expression is rapidly and transiently upregulated by oxidative stress. We conclude that this novel LKB1 isoform, mLKB1, plays a critical role in regulating mitochondrial metabolic activity and oxidative stress response.
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Quinasas de la Proteína-Quinasa Activada por el AMP , Mitocondrias , Mutación , Estrés Oxidativo , Proteínas Serina-Treonina Quinasas , Quinasas de la Proteína-Quinasa Activada por el AMP/genética , Quinasas de la Proteína-Quinasa Activada por el AMP/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Estrés Oxidativo/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Sirtuina 3/metabolismo , Señales de Clasificación de Proteína , Transporte de Proteínas , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Empalme Alternativo , Codón IniciadorRESUMEN
BACKGROUND: Surgery remains the primary treatment for localized colorectal cancer (CRC). Improving surgical decision-making for elderly CRC patients necessitates an accurate predictive tool. AIM: To build a nomogram to predict the overall survival of elderly patients over 80 years undergoing CRC resection. METHODS: Two hundred and ninety-five elderly CRC patients over 80 years undergoing surgery at Singapore General Hospital between 2018 and 2021 were identified from the American College of Surgeons - National Surgical Quality Improvement Program (ACS-NSQIP) database. Prognostic variables were selected using univariate Cox regression, and clinical feature selection was performed by the least absolute shrinkage and selection operator regression. A nomogram for 1- and 3-year overall survival was constructed based on 60% of the study cohort and tested on the remaining 40%. The performance of the nomogram was evaluated using the concordance index (C-index), area under the receiver operating characteristic curve (AUC), and calibration plots. Risk groups were stratified using the total risk points derived from the nomogram and the optimal cut-off point. Survival curves were compared between the high- and low-risk groups. RESULTS: Eight predictors: Age, Charlson comorbidity index, body mass index, serum albumin level, distant metastasis, emergency surgery, postoperative pneumonia, and postoperative myocardial infarction, were included in the nomogram. The AUC values for the 1-year survival were 0.843 and 0.826 for the training and validation cohorts, respectively. The AUC values for the 3-year survival were 0.788 and 0.750 for the training and validation cohorts, respectively. C-index values of the training cohort (0.845) and validation cohort (0.793) suggested the excellent discriminative ability of the nomogram. Calibration curves demonstrated a good consistency between the predictions and actual observations of overall survival in both training and validation cohorts. A significant difference in overall survival was seen between elderly patients stratified into low- and high-risk groups (P < 0.001). CONCLUSION: We constructed and validated a nomogram predicting 1- and 3-year survival probability in elderly patients over 80 years undergoing CRC resection, thereby facilitating holistic and informed decision-making among these patients.
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PURPOSE: The growth of Singapore's geriatric population, coupled with the rise in colorectal cancer (CRC), has increased the number of colorectal surgeries performed on elderly patients. This study aimed to compare the clinical outcomes and costs of laparoscopic versus open elective colorectal resections in elderly CRC patients over 80 years. METHODS: A retrospective cohort study using data from the American College of Surgeons National Surgery Quality Improvement Program (ACS-NSQIP) identified patients over 80 years undergoing elective colectomy and proctectomy between 2018 and 2021. Patient demographics, length of stay (LOS), 30-day postoperative complications, and mortality rates were analysed. Cost data in Singapore dollars were obtained from the finance database. Univariate and multivariate regression models were used to determine cost drivers. The 5-year overall survival (OS) for the entire octogenarian CRC cohort with and without postoperative complications was estimated using the Kaplan-Meier curves. RESULTS: Of the 192 octogenarian CRC patients undergoing elective colorectal surgery between 2018 and 2021, 114 underwent laparoscopic resection (59.4%), while 78 underwent open surgery (40.6%). The proportion of proctectomy cases was similar between laparoscopic and open groups (24.6% vs. 23.1%, P = 0.949). Baseline characteristics, including Charlson Comorbidity Index, albumin level, and tumour staging, were comparable between both groups. Median operative duration was 52.5 min longer in the laparoscopic group (232.5 vs. 180.0 min, P < 0.001). Both groups had no significant differences in postoperative complications and 30-day and 1-year mortality rates. Median LOS was 6 days in the laparoscopic group compared to 9 days in the open group (P < 0.001). The mean total cost was 11.7% lower in the laparoscopic group (S$25,583.44 vs. S$28,970.85, P = 0.012). Proctectomy (P = 0.024), postoperative pneumonia (P < 0.001) and urinary tract infection (P < 0.001), and prolonged LOS > 6 days (P < 0.001) were factors contributing to increased costs in the entire cohort. The 5-year OS of octogenarians with minor or major postoperative complications was significantly lower than those without complications (P < 0.001). CONCLUSION: Laparoscopic resection is associated with significantly reduced overall hospitalization costs and decreased LOS compared to open resection among octogenarian CRC patients, with comparable postoperative outcomes and 30-day and 1-year mortality rates. The extended operative time and higher consumables costs from laparoscopic resection were mitigated by the decrease in other inpatient hospitalization costs, including ward accommodation, daily treatment fees, investigation costs, and rehabilitation expenditures. Comprehensive perioperative care and optimised surgical approach to mitigate the impact of postoperative complications can improve survival in elderly patients undergoing CRC resection.
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Colectomía , Colon , Neoplasias Colorrectales , Laparoscopía , Recto , Anciano , Anciano de 80 o más Años , Humanos , Colectomía/economía , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Costos y Análisis de Costo , Laparoscopía/economía , Tiempo de Internación , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Resultado del Tratamiento , Colon/cirugía , Recto/cirugíaRESUMEN
BACKGROUND: While Singapore attains good health outcomes, Singapore's healthcare system is confronted with bed shortages and prolonged stays for elderly people recovering from surgery in acute hospitals. An Acute Hospital-Community Hospital (AH-CH) care bundle has been developed to assist patients in postoperative rehabilitation. The core concept is to transfer patients out of AHs when clinically recommended and into CHs, where they can receive more beneficial dedicated care to aid in their recovery, while freeing up bed capacities in AHs. AIM: To analyze the AH length of stay (LOS), costs, and savings associated with the AH-CH care bundle intervention initiated and implemented in elderly patients aged 75 years and above undergoing elective orthopedic surgery. METHODS: A total of 862 1:1 propensity score-matched patients aged 75 years and above who underwent elective orthopedic surgery in Singapore General Hospital (SGH) before (2017-2018) and after (2019-2021) the care bundle intervention period was analyzed. Outcome measures were AH LOS, CH LOS, hospitalization metrics, postoperative 30-d mortality, and modified Barthel Index (MBI) scores. The costs of AH inpatient hospital stay in the matched cohorts were compared using cost data in Singapore dollars. RESULTS: Of the 862 matched elderly patients undergoing elective orthopedic surgery before and after the care bundle intervention, the age distribution, sex, American Society of Anesthesiologists classification, Charlson Comorbidity Index, and surgical approach were comparable between both groups. Patients transferred to CHs after the surgery had a shorter median AH LOS (7 d vs 9 d, P < 0.001). The mean total AH inpatient cost per patient was 14.9% less for the elderly group transferred to CHs (S$24497.3 vs S$28772.8, P < 0.001). The overall AH U-turn rates for elderly patients within the care bundle were low, with a 0% mortality rate following orthopedic surgery. When elderly patients were discharged from CHs, their MBI scores increased significantly (50.9 vs 71.9, P < 0.001). CONCLUSION: The AH-CH care bundle initiated and implemented in the Department of Orthopedic Surgery appears to be effective and cost-saving for SGH. Our results indicate that transitioning care between acute and community hospitals using this care bundle effectively reduces AH LOS in elderly patients receiving orthopedic surgery. Collaboration between acute and community care providers can assist in closing the care delivery gap and enhancing service quality.
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PURPOSE: This study compares the cost-effectiveness of open, laparoscopic (LAP), laparoscopic-assisted (LAPA), hand-assisted laparoscopic (HAL), and robotic colorectal surgery using a network meta-analysis. METHODS: Randomized clinical trials (RCTs) evaluating the cost-effectiveness of comparing the five different approaches in colorectal surgery were included in a literature search until September 2022. Bayesian network meta-analysis was conducted, and surface under cumulative ranking area (SUCRA) values, odds ratio (OR), and 95% credible intervals (CrIs) were reported for total costs, surgical costs, operating time, length of stay (LOS), and postoperative outcomes. Cluster analysis was performed to examine the similarity and classification of surgical approaches into homogeneous clusters. The cophenetic correlation coefficient (cc) was evaluated to identify the most cost-effective clustering method. The primary outcomes assessed were: costs-morbidity, costs-mortality, and costs-efficacy, measuring total costs against postoperative complications, mortality rate, and LOS, respectively. RESULTS: 22 RCTs with 4239 patients were included. Open surgery had the lowest total costs, surgical costs, and operating time but the longest LOS and most postoperative complications. LOS was significantly decreased in LAP compared to open surgery (OR 0.67, 95% CrI 0.46-0.96). Robotic surgery resulted in the highest total costs, surgical costs, and most extended operative duration but the shortest LOS and lowest mortality. LAPA and robotic surgery were superior in the costs-morbidity analysis. HAL was associated with the worst costs-mortality profile. LAP, LAPA, and HAL were better in terms of costs-efficacy. CONCLUSION: Overall, LAP and LAPA are the most cost-effective approaches for colorectal surgery in terms of overall postoperative complications, mortality, and LOS.
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Cirugía Colorrectal , Laparoscopía , Procedimientos Quirúrgicos Robotizados , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Análisis Costo-Beneficio , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como Asunto , Laparoscopía/métodos , Tiempo de Internación , Complicaciones Posoperatorias/etiologíaRESUMEN
Mammalian cell cytoskeletal reorganization for efficient directional movement requires tight coordination of actomyosin and microtubule networks. In this study, we show that LRAP35a potentiates microtubule stabilization by promoting CLASP2/EB1 interaction besides its complex formation with MRCK/MYO18A for retrograde actin flow. The alternate regulation of these two networks by LRAP35a is tightly regulated by a series of phosphorylation events that dictated its specificity. Sequential phosphorylation of LRAP35a by Protein Kinase A (PKA) and Glycogen Synthase Kinase-3ß (GSK3ß) initiates the association of LRAP35a with CLASP2, while subsequent binding and further phosphorylation by Casein Kinase 1δ (CK1δ) induce their dissociation, which facilitates LRAP35a/MRCK association in driving lamellar actomyosin flow. Importantly, microtubule dynamics is directly moderated by CK1δ activity on CLASP2 to regulate GSK3ß phosphorylation of the SxIP motifs that blocks EB1 binding, an event countered by LRAP35a interaction and its competition for CK1δ activity. Overall this study reveals an essential role for LRAP35a in coordinating lamellar contractility and microtubule polarization in cell migration.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Quinasa Idelta de la Caseína/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Microtúbulos/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Actinas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Quinasa Idelta de la Caseína/antagonistas & inhibidores , Quinasa Idelta de la Caseína/genética , Línea Celular Tumoral , Movimiento Celular , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Humanos , Proteínas Asociadas a Microtúbulos/química , Mutagénesis Sitio-Dirigida , Fosforilación , Unión Proteica , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/genéticaRESUMEN
The activity of extracellular protein kinase A (PKA) is known to be a biomarker for cancer. However, conventional PKA assays based on colorimetric, radioactive, and fluorometric techniques suffer from intensive labeling-related preparations, background interference, photobleaching, and safety concerns. While surface-enhanced Raman spectroscopy (SERS)-based assays have been developed for various enzymes to address these limitations, their use in probing PKA activity is limited due to subtle changes in the Raman spectrum with phosphorylation. Here, we developed a robust colloidal SERS-based scheme for label-free quantitative measurement of PKA activity using gold nanostars (AuNS) as a SERS substrate functionalized with bovine serum albumin (BSA)-kemptide (Kem) bioconjugate (AuNS-BSA-Kem), where BSA conferred colloidal stability and Kem is a high-affinity peptide substrate for PKA. By performing principle component analysis (PCA) on the SERS spectrum, we identified two Raman peaks at 725 and 1395 cm-1, whose ratiometric intensity change provided a quantitative measure of Kem phosphorylation by PKA in vitro and allowed us to distinguish MDA-MB-231 and MCF-7 breast cancer cells known to overexpress extracellular PKA catalytic subunits from noncancerous human umbilical vein endothelial cells (HUVEC) based on their PKA activity in cell culture supernatant. The outcome demonstrated potential application of AuNS-BSA-Kem as a SERS probe for cancer screening based on PKA activity.
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Proteínas Quinasas Dependientes de AMP Cíclico/análisis , Oro/química , Nanopartículas del Metal/química , Oligopéptidos/química , Albúmina Sérica Bovina/química , Animales , Bovinos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Humanos , Oligopéptidos/metabolismo , Fosforilación , Albúmina Sérica Bovina/metabolismo , Espectrometría Raman , Propiedades de SuperficieRESUMEN
Myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK) has been shown to localize to the lamella of mammalian cells through its interaction with an adaptor protein, leucine repeat adaptor protein 35a (LRAP35a), which links it with myosin 18A (MYO18A) for activation of the lamellar actomyosin network essential for cell migration. Here, we report the identification of another adaptor protein LRAP25 that mediates MRCK association with LIM kinase 1 (LIMK1). The lamellipodium-localized LRAP25-MRCK complex is essential for the regulation of local LIMK1 and its downstream F-actin regulatory factor cofilin. Functionally, inhibition of either MRCK or LRAP25 resulted in a marked suppression of LIMK1 activity and down-regulation of cofilin phosphorylation in response to aluminum fluoride induction in B16-F1 cells, which eventually resulted in deregulation of lamellipodial F-actin and reorganization of cytoskeletal structures causing defects in cell polarization and motility. These biochemical and functional characterizations thus underline the functional relevance of the LRAP25-MRCK complex in LIMK1-cofilin signaling and the importance of LRAP adaptors as key determinants of MRCK cellular localization and downstream specificities.
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Actinas/metabolismo , Regulación Enzimológica de la Expresión Génica/fisiología , Quinasas Lim/biosíntesis , Proteína Quinasa de Distrofia Miotónica/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Seudópodos/metabolismo , Receptores Virales/metabolismo , Factores Despolimerizantes de la Actina/genética , Factores Despolimerizantes de la Actina/metabolismo , Actinas/genética , Compuestos de Aluminio/farmacología , Animales , Células COS , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Chlorocebus aethiops , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Fluoruros/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Quinasas Lim/genética , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Proteína Quinasa de Distrofia Miotónica/genética , Proteínas Serina-Treonina Quinasas/genética , Seudópodos/genética , Ratas , Receptores Virales/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Whether the Hippo pathway has downstream targets other than YAP and TAZ is unknown. In this report, we have identified angiomotin (Amot) family members as novel substrates of Hippo core kinases. The N-terminal regions of Amot proteins contain a conserved HXRXXS consensus site for LATS1/2-mediated phosphorylation. Phospho-specific antibodies showed that Hippo core kinases could mediate phosphorylation of endogenous as well as exogenous Amot family members. Knockdown of LATS1 and LATS2 endogenously reduced the phosphorylation of Amots detected by the phospho-specific antibodies. Mutation of the serine to alanine within this HXRXXS site in Amot and AmotL2 established that this site was essential for Hippo core kinase-mediated phosphorylation. Wild-type and non-phosphorylated Amot (Amot-S175A) were targeted to actin filaments, whereas phospho-mimic Amot (Amot-S175D) failed to be localized with actin. Overexpression of LATS2 caused dissociation of Amot from actin but not Amot-S175A. Mapping of the actin-binding site of Amot showed that serine 175 of Amot was important for the actin-binding activity. Amot-S175A promoted, whereas Amot and Amot-S175D inhibited, cell proliferation. These results collectively suggest that the Hippo pathway negatively regulates the actin-binding activity of Amot family members through direct phosphorylation.
Asunto(s)
Actinas/metabolismo , Proteínas Portadoras/metabolismo , Proliferación Celular , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Actinas/genética , Sustitución de Aminoácidos , Angiomotinas , Animales , Proteínas Portadoras/genética , Perros , Células HEK293 , Vía de Señalización Hippo , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Células de Riñón Canino Madin Darby , Proteínas de la Membrana/genética , Proteínas de Microfilamentos/genética , Mutación Missense , Proteínas Serina-Treonina Quinasas/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Cell movement requires forces generated by non-muscle myosin II (NM II) for coordinated protrusion and retraction. The Cdc42/Rac effector MRCK regulates a specific actomyosin network in the lamella essential for cell protrusion and migration. Together with the Rho effector ROK required for cell rear retraction, they cooperatively regulate cell motility and tumour cell invasion. Despite the increasing importance of ROK inhibitors for both experimental and clinical purposes, there is a lack of specific inhibitors for other related kinases such as MRCK. Here, we report the identification of chelerythrine chloride as a specific MRCK inhibitor. Its ability to block cellular activity of MRCK resulted in the specific loss of NM II-associated MLC phosphorylation in the lamella, and the consequential suppression of cell migration.
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Actomiosina/metabolismo , Benzofenantridinas/farmacología , Movimiento Celular/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Amidas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Benzofenantridinas/química , Biocatálisis/efectos de los fármacos , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Citoesqueleto/efectos de los fármacos , Citoesqueleto/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Células HeLa , Humanos , Immunoblotting , Microscopía Fluorescente , Estructura Molecular , Miosinas/metabolismo , Proteína Quinasa de Distrofia Miotónica , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Piridinas/farmacología , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Serina/metabolismo , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismoRESUMEN
Actomyosin retrograde flow underlies the contraction essential for cell motility. Retrograde flow in both lamellipodia and lamella is required for membrane protrusion and for force generation by coupling to cell adhesion. We report that the Rac/Cdc42-binding kinase MRCK and myosin II-related MYO18A linked by the adaptor protein LRAP35a form a functional tripartite complex, which is responsible for the assembly of lamellar actomyosin bundles and of a subnuclear actomyosin network. LRAP35a binds independently to MYO18A and MRCK. This binding leads to MRCK activation and its phosphorylation of MYO18A, independently of ROK and MLCK. The MRCK complex moves in concert with the retrograde flow of actomyosin bundles, with MRCK being able to influence other flow components such as MYO2A. The promotion of persistent protrusive activity and inhibition of cell motility by the respective expression of wild-type and dominant-negative mutant components of the MRCK complex show it to be crucial to cell protrusion and migration.
Asunto(s)
Actomiosina/metabolismo , Movimiento Celular , Miosinas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Secuencia de Aminoácidos , Animales , Células COS , Moléculas de Adhesión Celular/metabolismo , Chlorocebus aethiops , Células HeLa , Humanos , Datos de Secuencia Molecular , Miosina Tipo II/metabolismo , RatasRESUMEN
Myosin phosphatase targeting subunit 3 (MYPT3) and transforming growth factor-beta-inhibited membrane-associated protein (TIMAP) are two closely related myosin-binding targeting subunits of protein phosphatase 1 (PP1c) with a characteristic CAAX (where AA indicates aliphatic amino acid) box at the C termini. Here we show that MYPT3 can be a substrate for protein kinase A (PKA). We first mapped the multiple phosphorylation sites within a central conserved motif. Deletion or mutations of this motif resulted in enhancement of the associated PP1c activity, suggesting that phosphorylation of MYPT3 may play an important role in regulating PP1c catalytic activity. However, unlike the other known MYPTs, which upon phosphorylation inhibit PP1c, PKA phosphorylation of MYPT3 resulted in PP1c activation, indicating a different mode of action. There is a direct interaction between the central conserved phosphorylated site motif with the N-terminal ankyrin repeat region; this interaction was significantly reduced with MYPT3 phosphorylation or acidic phosphorylation site mutations, with concomitant alterations in biochemical and morphological consequences. We therefore propose a novel mechanism for the phosphorylation of MYPT3 by PKA and activation of the catalytic activity through direct interaction of a central region of MYPT3 with its N-terminal region.