Nationwide validation of the distal fistula risk score (D-FRS).

PURPOSE: Distal pancreatectomy (DP) is associated with a high complication rate of 30-50% with postoperative pancreatic fistula (POPF) as a dominant contributor. Adequate risk estimation for POPF enables surgeons to use a tailor-made approach. Assessment of the risk of POPF prior to DP can lead to the application of preventive strategies. The current study aims to validate the recently published preoperative and intraoperative distal fistula risk score (D-FRS) in a nationwide cohort. METHODS: This nationwide retrospective Dutch cohort study included all patients after DP for any indication, all of whom were registered in the Dutch Pancreatic Cancer Audit (DPCA) database between 2013 and 2021. The D-FRS was validated by filling in the probability equations with data from this cohort. The predictive capacity of the models was represented by an area under the receiver operating characteristic (AUROC) curve. RESULTS: A total of 896 patients underwent DP of which 152 (17%) developed POPF of whom 144 grade B (95%) and 8 grade C (5%). The preoperative D-FRS, consisting of the variables pancreatic neck thickness and pancreatic duct diameter, showed an AUROC of 0.73 (95%CI 0.68-0.78). The intraoperative D-FRS, comprising pancreatic neck, duct diameter, BMI, operating time, and soft pancreatic aspect, showed an AUROC of 0.69 (95%CI 0.64-0.74). CONCLUSION: The current study is the first nationwide validation of the preoperative and intraoperative D-FRS showing acceptable distinguishing capacity for only the preoperative D-FRS for POPF. Therefore, the preoperative score could improve prevention and mitigation strategies such as drain management, which is currently investigated in the multicenter PANDORINA trial.

Survey of the attitudes of hepatopancreatobiliary surgeons in northern Europe to resection of choledochal cysts in asymptomatic Western adults.

Background: Todani type 1 and 4 choledochal cysts are associated with a risk of developing cholangiocarcinoma. Resection is usually recommended, but data for asymptomatic Western adults are sparse. The aim of this study was to investigate diagnostic interpretation and attitudes towards resection of bile ducts for choledochal cysts in this subgroup of patients across northern European centres. Methods: Thirty hepatopancreatobiliary centres were provided with magnetic resonance cholangiopancreatograms and asked to discuss the management of six cases: asymptomatic non-Asian women, aged 30 or 60 years, with variable common bile duct (CBD) dilatations and different risk factors in the setting of a multidisciplinary team (MDT). The Fleiss κ value was calculated to estimate overall inter-rater agreement. Results: For all case scenarios combined, 83·3 and 86·7 per cent recommended resection for a CBD of 20 and 26 mm respectively, compared with 19·4 per cent for a CBD of 13 mm (P < 0·001). For patients aged 30 and 60 years, resection was recommended in 68·5 and 57·8 per cent respectively (P = 0·010). There was a trend towards recommending resection in the presence of a common channel, most pronounced in the 60-year-old patient. High amylase levels in the CBD aspirate led to recommendations to resect, but only for the 13-mm CBD dilatation. There were no differences related to centre size or region. MDT discussion was associated with recommendations to resect. Inter-rater agreement was 73·3 per cent (κ = 0·43, 95 per cent c.i. 0·38 to 0·48). Conclusion: The inter-rater agreement to resect was intermediate, and the recommendation was dependent mainly on the diameter of the CBD dilatation.

Antecedentes: Los quistes de colédoco (choledochal cysts, CC) tipo 1 y tipo 4 de Todani se asocian con un riesgo de desarrollar colangiocarcinoma. Generalmente se recomienda la resección de los mismos, pero los datos para pacientes adultos occidentales son escasos. El objetivo del presente estudio fue investigar la interpretación diagnóstica y actitudes respecto a la resección de las vías biliares por CC en este subgrupo de pacientes atendidos en centros del norte de Europa. Métodos: Se proporcionaron imágenes de colangiopancreatografía por resonancia magnética (magnetic resonance cholangiopancreatography, MRCP) a un total de 30 centros especializados en patología hepatobiliar y se les solicitó que discutieran el tratamiento de seis casos: pacientes del sexo femenino no asiáticas asintomáticas, de edad entre 30 y 60 años con dilataciones variables del colédoco (common bile duct, CBD) y con diferentes factores de riesgo en el marco de un equipo multidisciplinario (multidisciplinary team, MDT). Se calculó el índice kappa de Fleiss para estimar el acuerdo global entre los evaluadores. Resultados: Para todos los escenarios de casos combinados, un 83,3% y un 86,7% recomendaron la resección para un CBD de 20 y 26 mm, respectivamente, en comparación con un 19,4% para un CBD de 13 mm (P < 0,001). En el caso de un paciente de 30 y de 60 años, la resección se recomendó en el 68,5% y 57,8%, respectivamente (P = 0,010). Se observaron tendencias hacia recomendar la resección en presencia de un canal pancreático­biliar común, más pronunciado en el paciente de 60 años. Los niveles elevados de amilasa en el aspirado del CBD condujeron a la recomendación de resecar, pero solo en la dilatación del CBD de 13 mm. No hubo diferencias relacionadas con el tamaño del centro o la región. La discusión en el MDT se asoció con recomendaciones para la resección. El acuerdo entre evaluadores fue 73,3% con un índice kappa de 0,43 (i.c. del 95% 0,38­0,48). Conclusión: El acuerdo entre evaluadores para indicar la resección fue intermedio y la recomendación dependió principalmente del diámetro de la dilatación del CBD.

Systematic review and meta-analysis of enhanced recovery after pancreatic surgery with particular emphasis on pancreaticoduodenectomies.

BACKGROUND: In the past decade, Enhanced Recovery after Surgery (ERAS) protocols have been implemented in several fields of surgery. With these protocols, a faster recovery and shorter hospital stay can be accomplished without an increase in morbidity or mortality. The purpose of this study was to review systematically the evidence for implementation of an ERAS protocol in pancreatic resections, with particular emphasis on pancreaticoduodenectomies (PDs). METHODS: A systematic search was performed in Medline, Embase, Pubmed, CINAHL, and the Cochrane library for papers describing an ERAS program in adult patients undergoing elective pancreatic surgery published between January 1966 and December 2012. The primary outcome measure was postoperative length of stay. Secondary outcome measures were time to recovery of normal function, overall postoperative complication rates, readmissions, and mortality. Subsequently, a meta-analysis of outcome measures focusing on PD was conducted. This systematic review and meta-analysis was performed according to the PRISMA statement. RESULTS: The literature search produced 248 potentially relevant papers. Of these, eight papers met the predefined inclusion criteria: five case-control studies, two retrospective studies, and one prospective study, describing a total of 1,558 patients. Only three of the studies reported data on discharge criteria and assessed time to recovery and return to normal function. Implementation of an ERAS protocol led in four of five comparative studies to a significant decrease in length of stay (reduction of 2-6 days in different studies). Meta-analysis of four studies focusing on PDs showed that there was a significant difference in complication rates in favor of the ERAS group (absolute risk difference 8.2 %, 95 % confidence interval (CI) 2.0-14.4, p = 0.008). Introduction of an ERAS protocol did not result in an increase in mortality or readmissions. Delayed gastric emptying and incidence of pancreatic fistula did not differ significantly between groups. All studies reporting on hospital costs showed a decrease after implementation of ERAS. CONCLUSIONS: This systematic review suggests that using an ERAS protocol in pancreatic resections may help to shorten hospital length of stay without compromising morbidity and mortality. This seemed to apply to distal pancreatectomy, total pancreatectomy, and PD. Meta-analysis was performed for those studies focusing on PD and showed that there were no differences in readmission or mortality. Morbidity rates were significantly lower for patients managed according ERAS principles.

Hypertrophic differentiation during chondrogenic differentiation of progenitor cells is stimulated by BMP-2 but suppressed by BMP-7.

OBJECTIVE: Bone morphogenic protein (BMP)-2 and BMP-7 are clinically approved and their recombinant proteins are used for bone tissue regenerative purposes and widely evaluated for cartilage regeneration. Previous comparison of the in vitro chondrogenic characteristics of BMP-2 vs BMP-7 did not address hypertrophic differentiation and characterizing their chondrogenic properties with a focus in on chondrocyte hypertrophy was topic of investigation in this study. DESIGN: Equimolar concentrations of BMP-2 or BMP-7 were added to chondrogenic differentiating ATDC5, human bone marrow stem cells or rabbit periosteal explants. Expression of Col2a1, Sox9, Acan, Col10a1, Runx2, ALP, Mmp13, Mef2c and Bapx1/Nkx3.2 was determined by reverse transcription-quantitative PCR (RT-qPCR) and immunoblotting. Glycosaminoglycan content, cell proliferation capacity and ALP activity were analysed by colourimetric analyses. Expression of Bapx1/Nkx3.2 and Sox9 was targeted by transfection of target specific siRNA duplexes. RESULTS: BMP-2 dose-dependently increased chondrocyte hypertrophy during chondrogenic differentiation of progenitor cells, whereas BMP-7 acted hypertrophy-suppressive and chondro-promotive. Both BMPs did not influence cell proliferation, but they did increase total glycosaminoglycan content. In a candidate approach Bapx1/Nkx3.2 was found to be involved in the BMP-7 mediated suppression of chondrocyte hypertrophy in ATDC5 cells. CONCLUSIONS: BMP-2 and BMP-7 display opposing actions on the chondrogenic outcome of differentiating progenitor cells: BMP-2 acts a specific inducer of chondrocyte hypertrophy, while BMP-7 appears to increase or maintain chondrogenic potential and prevent chondrocyte hypertrophy. Our results pave the way for an application-dependent differential use of BMP-2 or BMP-7.

Redifferentiation of dedifferentiated human articular chondrocytes: comparison of 2D and 3D cultures.

OBJECTIVE: Three-dimensional (3D) cultures are widely used to redifferentiate chondrocytes. However, the rationale behind the choice for 3D above two-dimensional (2D) cultures is poorly systematically investigated and mainly based on mRNA expression and glycosaminoglycan (GAG) content. The objective was to determine the differential redifferentiation characteristics of human articular chondrocytes (HACs) in monolayer, alginate beads and pellet culture by investigating mRNA expression, protein expression, GAG content and cell proliferation. DESIGN: Dedifferentiated HACs from six individuals were redifferentiated in identical medium conditions for 7 days in monolayer, alginate beads or pellet culture. Read-out parameters were expression of chondrogenic and hypertrophic mRNAs and proteins, GAG content and cell proliferation. RESULTS: 3D cultures specifically expressed chondrogenic mRNAs [collagen type II (COL2A1), SRY (sex determining region Y)-box 9 (SOX9), aggrecan (ACAN)), whereas 2D cultures did not. Hypertrophic mRNAs (collagen type X (COL10A1), runt-related transcription factor 2 (RUNX2), matrix metalloproteinase 13 (MMP13), vascular endothelial growth factor A (VEGFA), osteopontin (OPN), alkaline phosphatase (ALP)) were highly increased in 2D cultures and lower in 3D cultures. Collagen type I (COL1A1) mRNA expression was highest in 3D cultures. Protein expression supports most of the mRNA data, although an important discrepancy was found between mRNA and protein expression of COL2A1 and SOX9 in monolayer culture, stressing on the importance of protein expression analysis. GAG content was highest in 3D cultures, whereas chondrocyte proliferation was almost specific for 2D cultures. CONCLUSIONS: For redifferentiation of dedifferentiated HACs, 3D cultures exhibit the most potent chondrogenic potential, whereas a hypertrophic phenotype is best achieved in 2D cultures. This is the first human study that systematically evaluates the differences between proliferation, GAG content, protein expression and mRNA expression of commonly used 2D and 3D chondrocyte culture techniques.

Inhibition of cyclooxygenase-2 impacts chondrocyte hypertrophic differentiation during endochondral ossification.

Skeletogenesis and bone fracture healing involve endochondral ossification, a process during which cartilaginous primordia are gradually replaced by bone tissue. In line with a role for cyclooxygenase-2 (COX-2) in the endochondral ossification process, non-steroidal anti-inflammatory drugs (NSAIDs) were reported to negatively affect bone fracture healing due to impaired osteogenesis. However, a role for COX-2 activity in the chondrogenic phase of endochondral ossification has not been addressed before. We show that COX-2 activity fulfils an important regulatory function in chondrocyte hypertrophic differentiation. Our data reveal essential cross-talk between COX-2 and bone morphogenic protein-2 (BMP-2) during chondrocyte hypertrophic differentiation. BMP-2 mediated chondrocyte hypertrophy is associated with increased COX-2 expression and pharmacological inhibition of COX-2 activity by NSAIDs (e.g., Celecoxib) decreases hypertrophic differentiation in various chondrogenic models in vitro and in vivo, while leaving early chondrogenic development unaltered. Our findings demonstrate that COX-2 activity is a novel factor partaking in chondrocyte hypertrophy in the context of endochondral ossification and these observations provide a novel etiological perspective on the adverse effects of NSAIDs on bone fracture healing and have important implications for the use of NSAIDs during endochondral skeletal development.

Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.

BACKGROUND: Accelerated recovery from surgery has been achieved when patients are managed within a multimodal Enhanced Recovery After Surgery (ERAS) protocol. This study evaluated the benefit of an ERAS programme for patients undergoing liver resection. METHODS: The ERAS protocol of epidural analgesia, early oral intake and early mobilization was studied prospectively in a consecutive series of 61 patients. Outcomes were compared with those in a consecutive series of 100 patients who underwent liver resection before the start of the study. Endpoints were postoperative length of hospital stay, postoperative resumption of oral intake, readmissions, morbidity and mortality. RESULTS: Fifty-six patients (92 per cent) in the ERAS group tolerated fluids within 4 h of surgery and a normal diet on day 1 after surgery. Median hospital stay, including readmissions, was 6.0 days compared with 8.0 days in the control group (P < 0.001). There were no significant differences in rates of readmission (13 and 10.0 per cent respectively), morbidity (41 and 31.0 per cent) and mortality (0 and 2.0 per cent) between ERAS and control groups. CONCLUSION: The ERAS fast-track protocol is safe and effective for patients undergoing liver resection. It allows early oral intake, promotes faster postoperative recovery and reduces hospital stay.