RESUMEN
Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.
Asunto(s)
Carcinoma Ductal Pancreático/patología , Modelos Biológicos , Técnicas de Cultivo de Órganos , Organoides/patología , Neoplasias Pancreáticas/patología , Animales , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Páncreas/metabolismo , Páncreas/patologíaRESUMEN
BACKGROUND: Carbohydrate antigen (CA) 19-9 is an established perioperative prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC). However, it is unclear how CA19-9 monitoring should be used during postoperative surveillance to detect recurrence and to guide the initiation of recurrence-focused therapy. OBJECTIVE: This study aimed to elucidate the value of CA19-9 as a diagnostic biomarker for disease recurrence in patients who underwent PDAC resection. METHODS: Serum CA19-9 levels at diagnosis, after surgery, and during postoperative follow-up were analyzed in patients who underwent PDAC resection. All patients with at least two postoperative follow-up CA19-9 measurements before recurrence were included. Patients deemed to be nonsecretors of CA19-9 were excluded. The relative increase in postoperative CA19-9 was calculated for each patient by dividing the maximum postoperative CA19-9 value by the first postoperative value. Receiver operating characteristic analysis was performed to identify the optimal threshold for the relative increase in CA19-9 levels to identify recurrence in the training set using Youden's index. The performance of this cutoff was validated in a test set by calculating the area under the curve (AUC) and was compared to the performance of the optimal cutoff for postoperative CA19-9 measurements as a continuous value. In addition, sensitivity, specificity, and predictive values were assessed. RESULTS: In total, 271 patients were included, of whom 208 (77%) developed recurrence. Receiver operating characteristic analysis demonstrated that a relative increase in postoperative serum CA19-9 of 2.6× was predictive of recurrence, with 58% sensitivity, 83% specificity, 95% positive predictive value, and 28% negative predictive value. The AUC for a 2.6× relative increase in the CA19-9 level was 0.719 in the training set and 0.663 in the test set. The AUC of postoperative CA19-9 as a continuous value (optimal threshold, 52) was 0.671 in the training set. In the training set, the detection of a 2.6-fold increase in CA19-9 preceded the detection of recurrence by a mean difference of 7 months ( P <0.001) and in the test set by 10 months ( P <0.001). CONCLUSIONS: A relative increase in the postoperative serum CA19-9 level of 2.6-fold is a stronger predictive marker for recurrence than a continuous CA19-9 cutoff. A relative CA19-9 increase can precede the detection of recurrence on imaging for up to 7 to 10 months. Therefore, CA19-9 dynamics can be used as a biomarker to guide the initiation of recurrence-focused treatment.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Antígeno CA-19-9 , Pronóstico , Estudios Retrospectivos , Biomarcadores de Tumor , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/patología , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/patologíaRESUMEN
OBJECTIVE: To establish minimal and optimal lymphadenectomy thresholds for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and evaluate their prognostic value. BACKGROUND: Current guidelines recommend a minimum of 12-15 lymph nodes (LNs) in PDAC. This is largely based on pancreatic intraepithelial neoplasia (PanIN)-derived PDAC, a biologically distinct entity from IPMN-derived PDAC. METHODS: Multicenter retrospective study including consecutive patients undergoing upfront surgery for IPMN-derived PDAC was conducted. The minimum cut-off for lymphadenectomy was defined as the maximum number of LNs where a significant node positivity difference was observed. Maximally selected log-rank statistic was used to derive the optimal lymphadenectomy cut-off (maximize survival). Kaplan-Meier curves and log-rank tests were used to analyze overall survival (OS) and recurrence-free survival (RFS). Multivariable Cox-regression was used to determine hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS: In 341 patients with resected IPMN-derived PDAC, the minimum number of LNs needed to ensure accurate nodal staging was 10 (P=0.040), whereas ≥20 LNs was the optimal number associated with improved OS (80.3 vs. 37.2 mo, P<0.001). Optimal lymphadenectomy was associated with improved OS [HR:0.57 (95%CI 0.39-0.83)] and RFS [HR:0.70 (95%CI 0.51-0.97)] on multivariable Cox-regression. On sub-analysis the optimal lymphadenectomy cut-offs for pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were 20 (P<0.001), 23 (P=0.160), and 25 (P=0.008). CONCLUSION: In IPMN-derived PDAC, lymphadenectomy with at least 10 lymph nodes mitigates under-staging, and at least 20 lymph nodes is associated with the improved survival. Specifically, for pancreatoduodenectomy and total pancreatectomy, 20 and 25 lymph nodes were the optimal cut-offs.
RESUMEN
OBJECTIVE: To assess the nationwide long-term uptake and outcomes of minimally invasive distal pancreatectomy (MIDP) after a nationwide training program and randomized trial. BACKGROUND: Two randomized trials demonstrated the superiority of MIDP over open distal pancreatectomy (ODP) in terms of functional recovery and hospital stay. Data on implementation of MIDP on a nationwide level are lacking. METHODS: Nationwide audit-based study including consecutive patients after MIDP and ODP in 16 centers in the Dutch Pancreatic Cancer Audit (2014 to 2021). The cohort was divided into three periods: early implementation, during the LEOPARD randomized trial, and late implementation. Primary endpoints were MIDP implementation rate and textbook outcome. RESULTS: Overall, 1496 patients were included with 848 MIDP (56.5%) and 648 ODP (43.5%). From the early to the late implementation period, the use of MIDP increased from 48.6% to 63.0% and of robotic MIDP from 5.5% to 29.7% ( P <0.001). The overall use of MIDP (45% to 75%) and robotic MIDP (1% to 84%) varied widely between centers ( P <0.001). In the late implementation period, 5/16 centers performed >75% of procedures as MIDP. After MIDP, in-hospital mortality and textbook outcome remained stable over time. In the late implementation period, ODP was more often performed in ASA score III-IV (24.9% vs. 35.7%, P =0.001), pancreatic cancer (24.2% vs. 45.9%, P <0.001), vascular involvement (4.6% vs. 21.9%, P <0.001), and multivisceral involvement (10.5% vs. 25.3%, P <0.001). After MIDP, shorter hospital stay (median 7 vs. 8 d, P <0.001) and less blood loss (median 150 vs. 500 mL, P <0.001), but more grade B/C postoperative pancreatic fistula (24.4% vs. 17.2%, P =0.008) occurred as compared to ODP. CONCLUSION: A sustained nationwide implementation of MIDP after a successful training program and randomized trial was obtained with satisfactory outcomes. Future studies should assess the considerable variation in the use of MIDP between centers and, especially, robotic MIDP.
Asunto(s)
Laparoscopía , Neoplasias Pancreáticas , Procedimientos Quirúrgicos Robotizados , Humanos , Pancreatectomía/métodos , Procedimientos Quirúrgicos Robotizados/métodos , Resultado del Tratamiento , Laparoscopía/métodos , Neoplasias Pancreáticas/cirugía , Complicaciones Posoperatorias/etiología , Tiempo de Internación , Estudios RetrospectivosRESUMEN
OBJECTIVE: This nationwide multicenter study aimed to define clinically relevant thresholds of relative serum CA19-9 response after 2 months of induction chemotherapy in patients with locally advanced pancreatic cancer (LAPC). BACKGROUND: CA19-9 is seen as leading biomarker for response evaluation in patients with LAPC, but early clinically useful cut-offs are lacking. METHODS: All consecutive patients with LAPC after 4 cycles (m)FOLFIRINOX or 2 cycles gemcitabine-nab-paclitaxel induction chemotherapy (±radiotherapy) with CA19-9 ≥5 U/mL at baseline were analyzed (2015-2019). The association of CA19-9 response with median OS (mOS) was evaluated for different CA19-9 cut-off points. Minimum and optimal CA19-9 response were established via log-rank test. Predictors for OS were analyzed using COX regression analysis. RESULTS: Overall, 212 patients were included, of whom 42 (19.8%) underwent resection. Minimum CA19-9 response demonstrating a clinically significant median OS difference (12.7 vs. 19.6 months) was seen at ≥40% CA19-9 decrease. The optimal cutoff for CA19-9 response was ≥60% decrease (21.7 vs. 14.0 mo, P =0.021). Only for patients with elevated CA19-9 levels at baseline (n=184), CA19-9 decrease ≥60% [hazard ratio (HR)=0.59, 95% CI, 0.36-0.98, P =0.042] was independently associated with prolonged OS, as were SBRT (HR=0.42, 95% CI, 0.25-0.70; P =0.001), and resection (HR=0.25, 95% CI, 0.14-0.46, P <0.001), and duration of chemotherapy (HR=0.75, 95% CI, 0.69-0.82, P <0.001). CONCLUSIONS: CA19-9 decrease of ≥60% following induction chemotherapy as optimal response cut-off in patients with LAPC is an independent predictor for OS when CA19-9 is increased at baseline. Furthermore, ≥40% is the minimum cut-off demonstrating survival benefit. These cut-offs may be used when discussing treatment strategies during early response evaluation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/uso terapéutico , Gemcitabina , Antígeno CA-19-9 , Quimioterapia de Inducción , Neoplasias Pancreáticas/tratamiento farmacológico , Fluorouracilo/uso terapéuticoRESUMEN
OBJECTIVE: To develop a prediction model for long-term (≥5 years) disease-free survival (DFS) after the resection of pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Despite high recurrence rates, ~10% of patients have long-term DFS after PDAC resection. A model to predict long-term DFS may aid individualized prognostication and shared decision-making. METHODS: This nationwide cohort study included all consecutive patients who underwent PDAC resection in the Netherlands (2014-2016). The best-performing prognostic model was selected by Cox-proportional hazard analysis and Akaike's Information Criterion, presented by hazard ratios (HRs) with 95% confidence intervals (CIs). Internal validation was performed, and discrimination and calibration indices were assessed. RESULTS: In all, 836 patients with a median follow-up of 67 months (interquartile range 51-79) were analyzed. Long-term DFS was seen in 118 patients (14%). Factors predictive of long-term DFS were low preoperative carbohydrate antigen 19-9 (logarithmic; HR 1.21; 95% CI 1.10-1.32), no vascular resection (HR 1.33; 95% CI 1.12-1.58), T1 or T2 tumor stage (HR 1.52; 95% CI 1.14-2.04, and HR 1.17; 95% CI 0.98-1.39, respectively), well/moderate tumor differentiation (HR 1.44; 95% CI 1.22-1.68), absence of perineural and lymphovascular invasion (HR 1.42; 95% CI 1.11-1.81 and HR 1.14; 95% CI 0.96-1.36, respectively), N0 or N1 nodal status (HR 1.92; 95% CI 1.54-2.40, and HR 1.33; 95% CI 1.11-1.60, respectively), R0 resection margin status (HR 1.25; 95% CI 1.07-1.46), no major complications (HR 1.14; 95% CI 0.97-1.35) and adjuvant chemotherapy (HR 1.74; 95% CI 1.47-2.06). Moderate performance (concordance index 0.68) with adequate calibration (slope 0.99) was achieved. CONCLUSIONS: The developed prediction model, readily available at www.pancreascalculator.com, can be used to estimate the probability of long-term DFS after resection of pancreatic ductal adenocarcinoma.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Estudios de Cohortes , Supervivencia sin Enfermedad , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios RetrospectivosRESUMEN
OBJECTIVE: To investigate the association between perineural invasion (PNI) and overall survival (OS) in a nationwide cohort of patients with resected pancreatic ductal adenocarcinoma (PDAC), stratified for margin negative (R0) or positive (R1) resection and absence or presence of lymph node metastasis (pN0 or pN1-N2, respectively). BACKGROUND: Patients with R0 and pN0 resected PDAC have a relatively favorable prognosis. As PNI is associated with worse OS, this might be a useful factor to provide further prognostic information for patients counselling. METHODS: A nationwide observational cohort study was performed including all patients who underwent PDAC resection in the Netherlands (2014-2019) with complete information on relevant pathological features (PNI, R status, and N status). OS was assessed using Kaplan-Meier curves, and Cox-proportional hazard analyses were performed to calculate hazard ratio's (HR) with corresponding 95% confidence intervals (CI). RESULTS: In total, 1630 patients were included with a median follow-up of 43 (interquartile range 33-58) months. PNI was independently associated with worse OS in both R0 patients (HR 1.49 [95%CI 1.18-1.88]; P<0.001) and R1 patients (HR 1.39 [95% CI 1.06-1.83]; P=0.02), as well as in pN0 patients (HR 1.75 [95%CI 1.27-2.41]; P<0.001) and pN1-N2 patients (HR 1.35 [95% CI 1.10-1.67]; P<0.01). In 315 patients with R0N0, multivariable analysis showed that PNI was the strongest predictor of OS (HR 2.24 [95% CI 1.52-3.30]; P<0.001). CONCLUSION: PNI is strongly associated with worse survival in patients with resected PDAC, in particular in patients with relatively favorable pathological features. These findings may aid patient stratification and counselling and help guide treatment strategies.
RESUMEN
OBJECTIVE: To compare the long-term outcomes of immediate drainage versus the postponed-drainage approach in patients with infected necrotizing pancreatitis. BACKGROUND: In the randomized POINTER trial, patients assigned to the postponed-drainage approach using antibiotic treatment required fewer interventions, as compared with immediate drainage, and over a third were treated without any intervention. METHODS: Clinical data of those patients alive after the initial 6-month follow-up were re-evaluated. The primary outcome was a composite of death and major complications. RESULTS: Out of 104 patients, 88 were re-evaluated with a median follow-up of 51 months. After the initial 6-month follow-up, the primary outcome occurred in 7 of 47 patients (15%) in the immediate-drainage group and 7 of 41 patients (17%) in the postponed-drainage group (RR 0.87, 95% CI 0.33-2.28; P =0.78). Additional drainage procedures were performed in 7 patients (15%) versus 3 patients (7%) (RR 2.03; 95% CI 0.56-7.37; P =0.34). The median number of additional interventions was 0 (IQR 0-0) in both groups ( P =0.028). In the total follow-up, the median number of interventions was higher in the immediate-drainage group than in the postponed-drainage group (4 vs. 1, P =0.001). Eventually, 14 of 15 patients (93%) in the postponed-drainage group who were successfully treated in the initial 6-month follow-up with antibiotics and without any intervention remained without intervention. At the end of follow-up, pancreatic function and quality of life were similar. CONCLUSIONS: Also, during long-term follow-up, a postponed-drainage approach using antibiotics in patients with infected necrotizing pancreatitis results in fewer interventions as compared with immediate drainage and should therefore be the preferred approach. TRIAL REGISTRATION: ISRCTN33682933.
Asunto(s)
Pancreatitis Aguda Necrotizante , Calidad de Vida , Humanos , Resultado del Tratamiento , Pancreatitis Aguda Necrotizante/complicaciones , Pancreatitis Aguda Necrotizante/cirugía , Antibacterianos/uso terapéutico , Drenaje/métodosRESUMEN
BACKGROUND: Infected necrotizing pancreatitis is a potentially lethal disease that is treated with the use of a step-up approach, with catheter drainage often delayed until the infected necrosis is encapsulated. Whether outcomes could be improved by earlier catheter drainage is unknown. METHODS: We conducted a multicenter, randomized superiority trial involving patients with infected necrotizing pancreatitis, in which we compared immediate drainage within 24 hours after randomization once infected necrosis was diagnosed with drainage that was postponed until the stage of walled-off necrosis was reached. The primary end point was the score on the Comprehensive Complication Index, which incorporates all complications over the course of 6 months of follow-up. RESULTS: A total of 104 patients were randomly assigned to immediate drainage (55 patients) or postponed drainage (49 patients). The mean score on the Comprehensive Complication Index (scores range from 0 to 100, with higher scores indicating more severe complications) was 57 in the immediate-drainage group and 58 in the postponed-drainage group (mean difference, -1; 95% confidence interval [CI], -12 to 10; P = 0.90). Mortality was 13% in the immediate-drainage group and 10% in the postponed-drainage group (relative risk, 1.25; 95% CI, 0.42 to 3.68). The mean number of interventions (catheter drainage and necrosectomy) was 4.4 in the immediate-drainage group and 2.6 in the postponed-drainage group (mean difference, 1.8; 95% CI, 0.6 to 3.0). In the postponed-drainage group, 19 patients (39%) were treated conservatively with antibiotics and did not require drainage; 17 of these patients survived. The incidence of adverse events was similar in the two groups. CONCLUSIONS: This trial did not show the superiority of immediate drainage over postponed drainage with regard to complications in patients with infected necrotizing pancreatitis. Patients randomly assigned to the postponed-drainage strategy received fewer invasive interventions. (Funded by Fonds NutsOhra and Amsterdam UMC; POINTER ISRCTN Registry number, ISRCTN33682933.).
Asunto(s)
Antibacterianos/uso terapéutico , Drenaje , Páncreas/patología , Pancreatitis Aguda Necrotizante/terapia , Tiempo de Tratamiento , Anciano , Terapia Combinada , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Páncreas/cirugía , Pancreatitis Aguda Necrotizante/tratamiento farmacológico , Pancreatitis Aguda Necrotizante/patología , Pancreatitis Aguda Necrotizante/cirugíaRESUMEN
BACKGROUND & AIMS: Cytologic and histopathologic diagnosis of non-ductal pancreatic neoplasms can be challenging in daily clinical practice, whereas it is crucial for therapy and prognosis. The cancer methylome is successfully used as a diagnostic tool in other cancer entities. Here, we investigate if methylation profiling can improve the diagnostic work-up of pancreatic neoplasms. METHODS: DNA methylation data were obtained for 301 primary tumors spanning 6 primary pancreatic neoplasms and 20 normal pancreas controls. Neural Network, Random Forest, and extreme gradient boosting machine learning models were trained to distinguish between tumor types. Methylation data of 29 nonpancreatic neoplasms (n = 3708) were used to develop an algorithm capable of detecting neoplasms of non-pancreatic origin. RESULTS: After benchmarking 3 state-of-the-art machine learning models, the random forest model emerged as the best classifier with 96.9% accuracy. All classifications received a probability score reflecting the confidence of the prediction. Increasing the score threshold improved the random forest classifier performance up to 100% with 87% of samples with scores surpassing the cutoff. Using a logistic regression model, detection of nonpancreatic neoplasms achieved an area under the curve of >0.99. Analysis of biopsy specimens showed concordant classification with their paired resection sample. CONCLUSIONS: Pancreatic neoplasms can be classified with high accuracy based on DNA methylation signatures. Additionally, non-pancreatic neoplasms are identified with near perfect precision. In summary, methylation profiling can serve as a valuable adjunct in the diagnosis of pancreatic neoplasms with minimal risk for misdiagnosis, even in the pre-operative setting.
Asunto(s)
Metilación de ADN , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/clasificación , Neoplasias Pancreáticas/patología , Masculino , Femenino , Anciano , Persona de Mediana EdadRESUMEN
BACKGROUND: Pancreatic adenocarcinoma located in the pancreatic body might require a portomesenteric venous resection (PVR), but data regarding surgical risks after distal pancreatectomy (DP) with PVR are sparse. Insight into additional surgical risks of DP-PVR could support preoperative counseling and intraoperative decision making. This study aimed to provide insight into the surgical outcome of DP-PVR, including its potential risk elevation over standard DP. METHODS: We conducted a retrospective, multicenter study including all patients with pancreatic adenocarcinoma who underwent DP ± PVR (2018-2020), registered in four audits for pancreatic surgery from North America, Germany, Sweden, and The Netherlands. Patients who underwent concomitant arterial and/or multivisceral resection(s) were excluded. Predictors for in-hospital/30-day major morbidity and mortality were investigated by logistic regression, correcting for each audit. RESULTS: Overall, 2924 patients after DP were included, of whom 241 patients (8.2%) underwent DP-PVR. Rates of major morbidity (24% vs. 18%; p = 0.024) and post-pancreatectomy hemorrhage grade B/C (10% vs. 3%; p = 0.041) were higher after DP-PVR compared with standard DP. Mortality after DP-PVR and standard DP did not differ significantly (2% vs. 1%; p = 0.542). Predictors for major morbidity were PVR (odds ratio [OR] 1.500, 95% confidence interval [CI] 1.086-2.071) and conversion from minimally invasive to open surgery (OR 1.420, 95% CI 1.032-1.970). Predictors for mortality were higher age (OR 1.087, 95% CI 1.045-1.132), chronic obstructive pulmonary disease (OR 4.167, 95% CI 1.852-9.374), and conversion from minimally invasive to open surgery (OR 2.919, 95% CI 1.197-7.118), whereas concomitant PVR was not associated with mortality. CONCLUSIONS: PVR during DP for pancreatic adenocarcinoma in the pancreatic body is associated with increased morbidity, but can be performed safely in terms of mortality.
RESUMEN
BACKGROUND: Novel definitions suggest that resectability status for pancreatic ductal adenocarcinoma (PDAC) should be assessed beyond anatomical criteria, considering both biological and conditional factors. This has, however, yet to be validated on a nationwide scale. This study evaluated the prognostic value of biological and conditional factors for staging of patients with resectable PDAC. PATIENTS AND METHODS: A nationwide observational cohort study was performed, including all consecutive patients who underwent upfront resection of National Comprehensive Cancer Network resectable PDAC in the Netherlands (2014-2019) with complete information on preoperative carbohydrate antigen (CA) 19-9 and Eastern Cooperative Oncology Group (ECOG) performance status. PDAC was considered biologically unfavorable (RB+) if CA19-9 ≥ 500 U/mL and favorable (RB-) otherwise. ECOG ≥ 2 was considered conditionally unfavorable (RC+) and favorable otherwise (RC-). Overall survival (OS) was assessed using Kaplan-Meier and Cox-proportional hazard analysis, presented as hazard ratios (HRs) with 95% confidence interval (CI). RESULTS: Overall, 688 patients were analyzed with a median overall survival (OS) of 20 months (95% CI 19-23). OS was 14 months (95% CI 10 months-median not reached) in 20 RB+C+ patients (3%; HR 1.61, 95% CI 0.86-2.70), 13 months (95% CI 11-15) in 156 RB+C- patients (23%; HR 1.86, 95% CI 1.50-2.31), and 21 months (95% CI 12-41) in 47 RB-C+ patients (7%; HR 1.14, 95% CI 0.80-1.62) compared with 24 months (95% CI 22-27) in 465 patients with RB-C- PDAC (68%; reference). CONCLUSIONS: Survival after upfront resection of anatomically resectable PDAC is worse in patients with CA19-9 ≥ 500 U/mL, while performance status had no impact. This supports consideration of CA19-9 in preoperative staging of resectable PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Estadificación de Neoplasias , Pancreatectomía , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Femenino , Masculino , Anciano , Tasa de Supervivencia , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/patología , Estudios de Seguimiento , Pronóstico , Persona de Mediana Edad , Países Bajos/epidemiología , Antígeno CA-19-9/sangre , Biomarcadores de TumorRESUMEN
BACKGROUND: Several international high-volume centers have reported good outcomes after resection of locally advanced pancreatic cancer (LAPC) following chemo(radio)therapy, but it is unclear how this translates to nationwide clinical practice and outcome. This study aims to assess the nationwide use and outcome of resection of LAPC following induction chemo(radio)therapy. PATIENTS AND METHODS: A multicenter retrospective study including all patients who underwent resection for LAPC following chemo(radio)therapy in all 16 Dutch pancreatic surgery centers (2014-2020), registered in the mandatory Dutch Pancreatic Cancer Audit. LAPC is defined as arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion. RESULTS: Overall, 142 patients underwent resection for LAPC, of whom 34.5% met the 2022 National Comprehensive Cancer Network criteria. FOLFIRINOX was the most commonly (93.7%) used chemotherapy [median 5 cycles (IQR 4-8)]. Venous and arterial resections were performed in 51.4% and 14.8% of patients. Most resections (73.9%) were performed in high-volume centers (i.e., ≥ 60 pancreatoduodenectomies/year). Overall median volume of LAPC resections/center was 4 (IQR 1-7). In-hospital/30-day major morbidity was 37.3% and 90-day mortality was 4.2%. Median OS from diagnosis was 26 months (95% CI 23-28) and 5-year OS 18%. Surgery in high-volume centers [HR = 0.542 (95% CI 0.318-0.923)], ypN1-2 [HR = 3.141 (95% CI 1.886-5.234)], and major morbidity [HR = 2.031 (95% CI 1.272-3.244)] were associated with OS. CONCLUSIONS: Resection of LAPC following chemo(radio)therapy is infrequently performed in the Netherlands, albeit with acceptable morbidity, mortality, and OS. Given these findings, a structured nationwide approach involving international centers of excellence would be needed to improve selection of patients with LAPC for surgical resection following induction therapy.
Asunto(s)
Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Inducción , Estudios Retrospectivos , Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Países Bajos/epidemiologíaRESUMEN
BACKGROUND: Although robotic pancreatoduodenectomy has shown promising outcomes in experienced high-volume centres, it is unclear whether implementation on a nationwide scale is safe and beneficial. The aim of this study was to compare the outcomes of the early experience with robotic pancreatoduodenectomy versus open pancreatoduodenectomy in the Netherlands. METHODS: This was a nationwide retrospective cohort study of all consecutive patients who underwent robotic pancreatoduodenectomy or open pancreatoduodenectomy who were registered in the mandatory Dutch Pancreatic Cancer Audit (18 centres, 2014-2021), starting from the first robotic pancreatoduodenectomy procedure per centre. The main endpoints were major complications (Clavien-Dindo grade greater than or equal to III) and in-hospital/30-day mortality. Propensity-score matching (1 : 1) was used to minimize selection bias. RESULTS: Overall, 701 patients who underwent robotic pancreatoduodenectomy and 4447 patients who underwent open pancreatoduodenectomy were included. Among the eight centres that performed robotic pancreatoduodenectomy, the median robotic pancreatoduodenectomy experience was 86 (range 48-149), with a 7.3% conversion rate. After matching (698 robotic pancreatoduodenectomy patients versus 698 open pancreatoduodenectomy control patients), no significant differences were found in major complications (40.3% versus 36.2% respectively; P = 0.186), in-hospital/30-day mortality (4.0% versus 3.1% respectively; P = 0.326), and postoperative pancreatic fistula grade B/C (24.9% versus 23.5% respectively; P = 0.578). Robotic pancreatoduodenectomy was associated with a longer operating time (359 min versus 301 min; P < 0.001), less intraoperative blood loss (200â ml versus 500â ml; P < 0.001), fewer wound infections (7.4% versus 12.2%; P = 0.008), and a shorter hospital stay (11 days versus 12 days; P < 0.001). Centres performing greater than or equal to 20 robotic pancreatoduodenectomies annually had a lower mortality rate (2.9% versus 7.3%; P = 0.009) and a lower conversion rate (6.3% versus 11.2%; P = 0.032). CONCLUSION: This study indicates that robotic pancreatoduodenectomy was safely implemented nationwide, without significant differences in major morbidity and mortality compared with matched open pancreatoduodenectomy patients. Randomized trials should be carried out to verify these findings and confirm the observed benefits of robotic pancreatoduodenectomy versus open pancreatoduodenectomy.
Asunto(s)
Pancreaticoduodenectomía , Procedimientos Quirúrgicos Robotizados , Humanos , Pancreaticoduodenectomía/efectos adversos , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/efectos adversos , Páncreas , Pérdida de Sangre Quirúrgica , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiologíaRESUMEN
BACKGROUND: Non-invasive evaluation of phosphomonoesters (PMEs) and phosphodiesters (PDEs) by 31-phosphorus MR spectroscopy (31 P MRS) may have potential for early therapy (non-)response assessment in cancer. However, 31 P MRS has not yet been applied to investigate the human pancreas in vivo. PURPOSE: To assess the technical feasibility and repeatability of 31 P MR spectroscopic imaging (MRSI) of the pancreas, compare 31 P metabolite levels between pancreas and liver, and determine the feasibility of 31 P MRSI in pancreatic cancer. STUDY TYPE: Prospective cohort study. POPULATION: 10 healthy subjects (age 34 ± 12 years, four females) and one patient (73-year-old female) with pancreatic ductal adenocarcinoma. FIELD STRENGTH/SEQUENCE: 7-T, 31 P FID-MRSI, 1 H gradient-echo MRI. ASSESSMENT: 31 P FID-MRSI of the abdomen (including the pancreas and liver) was performed with a nominal voxel size of 20 mm (isotropic). For repeatability measurements, healthy subjects were scanned twice on the same day. The patient was only scanned once. Test-retest 31 P MRSI data of pancreas and liver voxels (segmented on 1 H MRI) of healthy subjects were quantified by fitting in the time domain and signal amplitudes were normalized to γ-adenosine triphosphate. In addition, the PME/PDE ratio was calculated. Metabolite levels were averaged over all voxels within the pancreas, right liver lobe and left liver lobe, respectively. STATISTICAL TESTS: Repeatability of test-retest data from healthy pancreas was assessed by paired t-tests, Bland-Altman analyses, and calculation of the intrasubject coefficients of variation (CoVs). Significant differences between healthy pancreas and right and left liver lobes were assessed with a two-way analysis of variance (ANOVA) for repeated measures. A P-value <0.05 was considered statistically significant. RESULTS: The intrasubject CoVs for PME, PDE, and PME/PDE in healthy pancreas were below 20%. Furthermore, PME and PME/PDE were significantly higher in pancreas compared to liver. In the patient with pancreatic cancer, qualitatively, elevated relative PME signals were observed in comparison with healthy pancreas. DATA CONCLUSION: In vivo 31 P MRSI of the human healthy pancreas and in pancreatic cancer may be feasible at 7 T. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.
RESUMEN
BACKGROUND AND AIM: Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) management is generally extrapolated from pancreatic intraepithelial neoplasia (PanIN)-derived PDAC guidelines. However, these are biologically divergent, and heterogeneity further exists between tubular and colloid subtypes. METHODS: Consecutive upfront surgery patients with PanIN-derived and IPMN-derived PDAC were retrospectively identified from international centers (2000-2019). One-to-one propensity score matching for clinicopathologic factors generated three cohorts: IPMN-derived versus PanIN-derived PDAC, tubular IPMN-derived versus PanIN-derived PDAC, and tubular versus colloid IPMN-derived PDAC. Overall survival (OS) was compared using Kaplan-Meier and log-rank tests. Multivariable Cox regression determined corresponding hazard ratios (HR) and 95% confidence intervals (95% CI). RESULTS: The median OS (mOS) in 2350 PanIN-derived and 700 IPMN-derived PDAC patients was 23.0 and 43.1 months (P < 0.001), respectively. PanIN-derived PDAC had worse T-stage, CA19-9, grade, and nodal status. Tubular subtype had worse T-stage, CA19-9, grade, nodal status, and R1 margins, with a mOS of 33.7 versus 94.1 months (P < 0.001) in colloid. Matched (n = 495), PanIN-derived and IPMN-derived PDAC had mOSs of 30.6 and 42.8 months (P < 0.001), respectively. In matched (n = 341) PanIN-derived and tubular IPMN-derived PDAC, mOS remained poorer (27.7 vs 37.4, P < 0.001). Matched tubular and colloid cancers (n = 112) had similar OS (P = 0.55). On multivariable Cox regression, PanIN-derived PDAC was associated with worse OS than IPMN-derived (HR: 1.66, 95% CI: 1.44-1.90) and tubular IPMN-derived (HR: 1.53, 95% CI: 1.32-1.77) PDAC. Colloid and tubular subtype was not associated with OS (P = 0.16). CONCLUSIONS: PanIN-derived PDAC has worse survival than IPMN-derived PDAC supporting distinct outcomes. Although more indolent, colloid IPMN-derived PDAC has similar survival to tubular after risk adjustment.
RESUMEN
BACKGROUND: Patients with initially unresectable colorectal cancer liver metastases might qualify for local treatment with curative intent after reducing the tumour size by induction systemic treatment. We aimed to compare the currently most active induction regimens. METHODS: In this open-label, multicentre, randomised, phase 3 study (CAIRO5), patients aged 18 years or older with histologically confirmed colorectal cancer, known RAS/BRAFV600E mutation status, WHO performance status of 0-1, and initially unresectable colorectal cancer liver metastases were enrolled at 46 Dutch and one Belgian secondary and tertiary centres. Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by predefined criteria. Randomisation was done centrally with the minimisation technique via a masked web-based allocation procedure. Patients with right-sided primary tumour site or RAS or BRAFV600E mutated tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B). Patients with left-sided and RAS and BRAFV600E wild-type tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles. Patients were stratified by resectability of colorectal cancer liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAFV600E mutation status (for groups A and B). Bevacizumab was administered intravenously at 5 mg/kg. Panitumumab was administered intravenously at 6 mg/kg. FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m2 with folinic acid at 400 mg/m2, followed by bolus fluorouracil at 400 mg/m2 intravenously, followed by continuous infusion of fluorouracil at 2400 mg/m2. FOLFOX consisted of oxaliplatin at 85 mg/m2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI. FOLFOXIRI consisted of irinotecan at 165 mg/m2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m2 with folinic acid at 400 mg/m2, followed by continuous infusion of fluorouracil at 3200 mg/m2. Patients and investigators were not masked to treatment allocation. The primary outcome was progression-free survival, analysed on a modified intention-to-treat basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic colorectal cancer, or previous liver surgery for colorectal cancer liver metastases). The study is registered with ClinicalTrials.gov, NCT02162563, and accrual is complete. FINDINGS: Between Nov 13, 2014, and Jan 31, 2022, 530 patients (327 [62%] male and 203 [38%] female; median age 62 years [IQR 54-69]) were randomly assigned: 148 (28%) patients to group A, 146 (28%) patients to group B, 118 (22%) patients to group C, and 118 (22%) patients to group D. Groups C and D were prematurely closed for futility. 521 patients were included in the modified intention-to-treat population (147 in group A, 144 in group B, 114 in group C, and 116 in group D). The median follow-up at the time of this analysis was 51·1 months (95% CI 47·7-53·1) in groups A and B and 49·9 months (44·5-52·5) in in groups C and D. Median progression-free survival was 9·0 months (95% CI 7·7-10·5) in group A versus 10·6 months (9·9-12·1) in group B (stratified hazard ratio [HR] 0·76 [95% CI 0·60-0·98]; p=0·032), and 10·8 months (95% CI 9·9-12·6) in group C versus 10·4 months (9·8-13·0) in group D (stratified HR 1·11 [95% CI 0·84-1·48]; p=0·46). The most frequent grade 3-4 events in groups A and B were neutropenia (19 [13%] patients in group A vs 57 [40%] in group B; p<0·0001), hypertension (21 [14%] vs 20 [14%]; p=1·00), and diarrhoea (five [3%] vs 28 [19%]; p<0·0001), and in groups C and D were neutropenia (29 [25%] vs 24 [21%]; p=0·44), skin toxicity (one [1%] vs 29 [25%]; p<0·0001), hypertension (20 [18%] vs eight [7%]; p=0·016), and diarrhoea (five [4%] vs 18 [16%]; p=0·0072). Serious adverse events occurred in 46 (31%) patients in group A, 75 (52%) patients in group B, 41 (36%) patients in group C, and 49 (42%) patients in group D. Seven treatment-related deaths were reported in group B (two due to multiorgan failure, and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), one in group C (multiorgan failure), and three in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis). INTERPRETATION: In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAFV600E mutated primary tumour. In patients with a left-sided and RAS and BRAFV600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab, but was associated with more toxicity. FUNDING: Roche and Amgen.
Asunto(s)
Neoplasias Colorrectales , Hipertensión , Neoplasias Hepáticas , Neutropenia , Humanos , Masculino , Femenino , Persona de Mediana Edad , Bevacizumab , Irinotecán/uso terapéutico , Oxaliplatino/uso terapéutico , Panitumumab/uso terapéutico , Leucovorina , Proteínas Proto-Oncogénicas B-raf/genética , Camptotecina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Fluorouracilo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Hipertensión/inducido químicamente , Neutropenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
OBJECTIVE: The aim of this study was to assess the clinical impact and risk factors of chyle leak (CL). BACKGROUND: In 2017, the International Study Group for Pancreatic Surgery (ISGPS) published the consensus definition of CL. Multicenter series validating this definition are lacking and previous studies investigating risk factors have used different definitions and showed heterogeneous results. METHODS: This observational cohort study included all consecutive patients after pancreatoduodenectomy in all 19 centers in the mandatory nationwide Dutch Pancreatic Cancer Audit (2017-2019). The primary endpoint was CL (ISGPS grade B/C). Multivariable logistic regression analyses were performed. RESULTS: Overall, 2159 patients after pancreatoduodenectomy were included. The rate of CL was 7.0% (n=152), including 6.9% (n=150) grade B and 0.1% (n=2) grade C. CL was independently associated with a prolonged hospital stay [odds ratio (OR)=2.84, 95% confidence interval (CI): 1.85-4.36, P <0.001] but not with mortality (OR=0.3, 95% CI: 0.0-2.3, P =0.244). In multivariable analyses, independent predictors for CL were vascular resection (OR=2.1, 95% CI: 1.4-3.2, P <0.001) and open surgery (OR=3.5, 95% CI: 1.7-7.2, P =0.001). The number of resected lymph nodes and aortocaval lymph node sampling were not identified as predictors in multivariable analysis. CONCLUSIONS: In this nationwide analysis, the rate of ISGPS grade B/C CL after pancreatoduodenectomy was 7.0%. Although CL is associated with a prolonged hospital stay, the clinical impact is relatively minor in the vast majority (>98%) of patients. Vascular resection and open surgery are predictors of CL.
Asunto(s)
Quilo , Neoplasias Pancreáticas , Humanos , Pancreaticoduodenectomía/efectos adversos , Pancreaticoduodenectomía/métodos , Complicaciones Posoperatorias/etiología , Factores de Riesgo , Neoplasias Pancreáticas/cirugíaRESUMEN
OBJECTIVE: The aim of this study was to explore the incidence, risk factors, clinical course and treatment of perforation and fistula of the gastrointestinal (GI) tract in a large unselected cohort of patients with necrotizing pancreatitis. BACKGROUND: Perforation and fistula of the GI tract may occur in necrotizing pancreatitis. Data from large unselected patient populations on the incidence, risk factors, clinical outcomes, and treatment are lacking. METHODS: We performed a post hoc analysis of a nationwide prospective database of 896 patients with necrotizing pancreatitis. GI tract perforation and fistula were defined as spontaneous or iatrogenic discontinuation of the GI wall. Multivariable logistic regression was used to explore risk factors and to adjust for confounders to explore associations of the GI tract perforation and fistula on the clinical course. RESULTS: A perforation or fistula of the GI tract was identified in 139 (16%) patients, located in the stomach in 23 (14%), duodenum in 56 (35%), jejunum or ileum in 18 (11%), and colon in 64 (40%). Risk factors were high C-reactive protein within 48 hours after admission [odds ratio (OR): 1.19; 95% confidence interval (CI): 1.01-1.39] and early organ failure (OR: 2.76; 95% CI: 1.78-4.29). Prior invasive intervention was a risk factor for developing a perforation or fistula of the lower GI tract (OR: 2.60; 95% CI: 1.04-6.60). While perforation or fistula of the upper GI tract appeared to be protective for persistent intensive care unit-admission (OR: 0.11, 95% CI: 0.02-0.44) and persistent organ failure (OR: 0.15; 95% CI: 0.02-0.58), perforation or fistula of the lower GI tract was associated with a higher rate of new onset organ failure (OR: 2.47; 95% CI: 1.23-4.84). When the stomach or duodenum was affected, treatment was mostly conservative (n=54, 68%). Treatment was mostly surgical when the colon was affected (n=38, 59%). CONCLUSIONS: Perforation and fistula of the GI tract occurred in one out of six patients with necrotizing pancreatitis. Risk factors were high C-reactive protein within 48 hours and early organ failure. Prior intervention was identified as a risk factor for perforation or fistula of the lower GI tract. The clinical course was mostly affected by involvement of the lower GI tract.
Asunto(s)
Fístula , Perforación Intestinal , Pancreatitis , Tracto Gastrointestinal Superior , Humanos , Proteína C-Reactiva , Progresión de la EnfermedadRESUMEN
OBJECTIVE: To describe outcome after pancreatic surgery in the first 6 years of a mandatory nationwide audit. BACKGROUND: Within the Dutch Pancreatic Cancer Group, efforts have been made to improve outcome after pancreatic surgery. These include collaborative projects, clinical auditing, and implementation of an algorithm for early recognition and management of postoperative complications. However, nationwide changes in outcome over time have not yet been described. METHODS: This nationwide cohort study included consecutive patients after pancreatoduodenectomy (PD) and distal pancreatectomy from the mandatory Dutch Pancreatic Cancer Audit (January 2014-December 2019). Patient, tumor, and treatment characteristics were compared between 3 time periods (2014-2015, 2016-2017, and 2018-2019). Short-term surgical outcome was investigated using multilevel multivariable logistic regression analyses. Primary endpoints were failure to rescue (FTR) and in-hospital mortality. RESULTS: Overall, 5345 patients were included, of whom 4227 after PD and 1118 after distal pancreatectomy. After PD, FTR improved from 13% to 7.4% [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.50-0.80, P <0.001] and in-hospital mortality decreased from 4.1% to 2.4% (OR 0.68, 95% CI 0.54-0.86, P =0.001), despite operating on more patients with age >75 years (18%-22%, P =0.006), American Society of Anesthesiologists score ≥3 (19%-31%, P <0.001) and Charlson comorbidity score ≥2 (24%-34%, P <0.001). The rates of textbook outcome (57%-55%, P =0.283) and major complications remained stable (31%-33%, P =0.207), whereas complication-related intensive care admission decreased (13%-9%, P =0.002). After distal pancreatectomy, improvements in FTR from 8.8% to 5.9% (OR 0.65, 95% CI 0.30-1.37, P =0.253) and in-hospital mortality from 1.6% to 1.3% (OR 0.88, 95% CI 0.45-1.72, P =0.711) were not statistically significant. CONCLUSIONS: During the first 6 years of a nationwide audit, in-hospital mortality and FTR after PD improved despite operating on more high-risk patients. Several collaborative efforts may have contributed to these improvements.