Purpose Intensive screening in BRCA1/2 mutation carriers aims to improve breast cancer (BC) prognosis. Our aim is to clarify the prognostic impact of tumor size in BRCA mutation carriers with a pT1... Show morePurpose Intensive screening in BRCA1/2 mutation carriers aims to improve breast cancer (BC) prognosis. Our aim is to clarify the prognostic impact of tumor size in BRCA mutation carriers with a pT1 BC, which is currently unclear. We are especially interested in differences between pT1a, pT1b, and pT1c regarding the prognosis of node-negative breast cancer, the effect of chemotherapy, and the prevalence of lymph node involvement. Methods For this study, BRCA1/2-associated BC patients were selected from a nationwide cohort. Primary outcomes were 10-year overall survival (OS) per pT1a-b-c group and the effect of chemotherapy on prognosis of node-negative BC, using Kaplan-Meier and Cox models. Finally, we evaluated lymph node involvement per pT1a-b-c group. Results 963 women with pT1 BRCA1/2-associated BC diagnosed between 1990 and 2017 were included, of which 679 had pN0 BC. After a median follow-up of 10.5 years, 10-year OS in patients without chemotherapy was 77.1% in pT1cN0 and lower than for pT1aN0 (91.4%, p = 0.119) and pT1bN0 (90.8%, p = 0.024). OS was better with than without chemotherapy for pT1cN0 (91.6% vs. 77.1%, p = 0.001; hazard ratio (HR) 0.56, 95% confidence interval (CI): 0.21-1.48). Lymph node involvement was 24.9% in pT1c, 18.8% in pT1b, and 8.6% in pT1a. Conclusion Smaller tumor size is associated with better OS and less lymph node involvement in pT1 BRCA1/2-associated BC patients. The results suggest that early detection in BRCA1/2 mutation carriers of pT1a/b BC may reduce mortality and the need for systemic therapy. Show less
Background and Objectives: With the current advanced data-driven approach to health care, machine learning is gaining more interest. The current study investigates the added value of machine... Show moreBackground and Objectives: With the current advanced data-driven approach to health care, machine learning is gaining more interest. The current study investigates the added value of machine learning to linear regression in predicting anastomotic leakage and pulmonary complications after upper gastrointestinal cancer surgery. Methods: All patients in the Dutch Upper Gastrointestinal Cancer Audit undergoing curatively intended esophageal or gastric cancer surgeries from 2011 to 2017 were included. Anastomotic leakage was defined as any clinically or radiologically proven anastomotic leakage. Pulmonary complications entailed: pneumonia, pleural effusion, respiratory failure, pneumothorax, and/or acute respiratory distress syndrome. Different machine learning models were tested. Nomograms were constructed using Least Absolute Shrinkage and Selection Operator. Results: Between 2011 and 2017, 4228 patients underwent surgical resection for esophageal cancer, of which 18% developed anastomotic leakage and 30% a pulmonary complication. Of the 2199 patients with surgical resection for gastric cancer, 7% developed anastomotic leakage and 15% a pulmonary complication. In all cases, linear regression had the highest predictive value with the area under the curves varying between 61.9 and 68.0, but the difference with machine learning models did not reach statistical significance. Conclusion: Machine learning models can predict postoperative complications in upper gastrointestinal cancer surgery, but they do not outperform the current gold standard, linear regression Show less
Levink, I.J.M.; Klatte, D.C.F.; Hanna Sawires, R.G.; Vreeker, G.C.M.; Ibrahim, I.S.; Burgt, Y.E.M. van der; ... ; Mesker, W.E. 2022
Background: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities... Show moreBackground: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals. Methods: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature. Results: 165 individuals ("FPC-cohort" N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri-and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans).The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%. Conclusion: Serum N-glycan monitoring may support early detection in a pancreas surveillance program.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Purpose: The recently developed fibroblast activation protein inhibitor (FAPI) tracer for PET/CT, binding tumour-stromal cancer-associated fibroblasts, is a promising tool for detection of positive... Show morePurpose: The recently developed fibroblast activation protein inhibitor (FAPI) tracer for PET/CT, binding tumour-stromal cancer-associated fibroblasts, is a promising tool for detection of positive lymph nodes. This study provides an overview of features, including sizes and tumour-stromal content, of lymph nodes and their respective lymph node metastases (LNM) in colorectal cancer (CRC), since literature lacks on whether LNMs contain sufficient stroma to potentially allow FAPI-based tumour detection. Methods: Haematoxylin and eosin-stained tissue slides from 73 stage III colon cancer patients were included. Diameters and areas of all lymph nodes and their LNMs were assessed, the amount of stroma by measuring the stromal compartment area, the conventional and total tumour-stroma ratios (TSR-c and TSR-t, respectively), as well as correlations between these parameters. Also, subgroup analysis using a minimal diameter cut off of 5.0 mm was performed. Results: In total, 126 lymph nodes were analysed. Although positive correlations were observed between node and LNM for diameter and area (r = 0.852, p < 0.001 and r = 0.960, p < 0.001, respectively), and also between the LNM stromal compartment area and nodal diameter (r = 0.612, p < 0.001), nodal area (r = 0.747, p < 0.001) and LNM area (r = 0.746, p < 0.001), novel insight was that nearly all (98%) LNMs contained stroma, with median TSR-c scores of 35% (IQR 20-60%) and TSR-t of 20% (IQR 10-30%). Moreover, a total of 32 (25%) positive lymph nodes had a diameter of < 5.0 mm. Conclusion: In LNMs, stroma is abundantly present, independent of size, suggesting a role for FAPI PET/CT in improved lymph node detection in CRC. Show less
Purpose The tumor-stroma ratio (TSR) has repeatedly proven to be correlated with patient outcomes in breast cancer using large retrospective cohorts. However, studies validating the TSR often show... Show morePurpose The tumor-stroma ratio (TSR) has repeatedly proven to be correlated with patient outcomes in breast cancer using large retrospective cohorts. However, studies validating the TSR often show variability in methodology, thereby hampering comparisons and uniform outcomes. Method This paper provides a detailed description of a simple and uniform TSR scoring method using Hematoxylin and Eosin (H&E)-stained core biopsies and resection tissue, specifically focused on breast cancer. Possible histological challenges that can be encountered during scoring including suggestions to overcome them are reported. Moreover, the procedure for TSR estimation in lymph nodes, scoring on digital images and the automatic assessment of the TSR using artificial intelligence are described. Conclusion Digitized scoring of tumor biopsies and resection material offers interesting future perspectives to determine patient prognosis and response to therapy. The fact that the TSR method is relatively easy, quick, and cheap, offers great potential for its implementation in routine diagnostics, but this requires high quality validation studies. Show less
Background: Complications after colorectal cancer surgery can worsen long-term survival. The aim of this nationwide study was to determine the impact of different types of complications on overall... Show moreBackground: Complications after colorectal cancer surgery can worsen long-term survival. The aim of this nationwide study was to determine the impact of different types of complications on overall survival (OS) and conditional survival if still alive one year postoperatively (CS-1) after colorectal cancer surgery.Materials and methods: All patients registered in the Dutch ColoRectal Audit after resection of primary colorectal cancer between 2011 and 2017 and with known survival status were included. Multivariable Cox regression models were used to assess the association of complications with OS and CS-1, thereby calculating the Hazard Ratio (HR) with 95% Confidence Interval.Results: 43,908 colon and 16,955 rectal cancer patients were included. Median follow-up time was 66.1 and 66.5 months, respectively. Five-year OS after colon cancer resection was 73.2% without complications, and 65.4% with surgical, 52.9% with non-surgical and 51.8% with combined type of complications (p < 0.001). Corresponding 5-year OS for rectal cancer patients was 76.9%, 72.7%, 64.9%, and 63.2% (p < 0.001). In colon cancer, multivariable analyses revealed HR 1.198 (1.136-1.264) for surgical, HR 1.489 (1.423-1.558) for non-surgical and HR 1.590 (1.505-1.681) for combined type of complications. For rectal cancer, these HRs were 1.193 (1.097-1.2297), 1.456 (1.346-1.329), and 1.489 (1.357-1.633). Surgical complications were associated with worse CS-1 in rectal cancer (HR 1.140 (1.050-1.260), but not in colon cancer (HR 1.007 (0.943-1.075)).Conclusion: Non-surgical complications have higher impact on survival than surgical complications. The impact of surgical complications on survival was still measurable after surviving the first year in rectal cancer but not in colon cancer patients. (C) 2021 Elsevier Ltd, BASO -The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. Show less
Warps, A.K.; Saraste, D.; Westerterp, M.; Detering, R.; Sjovall, A.; Martling, A.; ... ; Swedish Colorectal Canc Registry 2022
Background: The timing and degree of implementation of minimally invasive surgery (MIS) for colorectal cancer vary among countries. Insights in national differences regarding implementation of new... Show moreBackground: The timing and degree of implementation of minimally invasive surgery (MIS) for colorectal cancer vary among countries. Insights in national differences regarding implementation of new surgical techniques and the effect on postoperative outcomes are important for quality assurance, can show potential areas for country-specific improvement, and might be illustrative and supportive for similar implementation programs in other countries. Therefore, this study aimed to evaluate differences in patient selection, applied techniques, and results of minimal invasive surgery for colorectal cancer between the Netherlands and Sweden. Methods: Patients who underwent elective minimally invasive surgery for T1-3 colon or rectal cancer (2012-2018) registered in the Dutch ColoRectal Audit or Swedish ColoRectal Cancer Registry were included. Time trends in the application of MIS were determined. Outcomes were compared for time periods with a similar level of MIS implementation (Netherlands 2012-2013 versus Sweden 2017-2018). Multilevel analyses were performed to identify factors associated with adverse short-term outcomes.Results: A total of 46,095 Dutch and 8,819 Swedish patients undergoing MIS for colorectal cancer were included. In Sweden, MIS implementation was approximately 5 years later than in the Netherlands, with more robotic surgery and lower volumes per hospital. Although conversion rates were higher in Sweden, oncological and surgical outcomes were comparable. MIS in the Netherlands for the years 2012- 2013 resulted in a higher reoperation rate for colon cancer and a higher readmission rate but lower non- surgical complication rates for rectal cancer if compared with MIS in Sweden during 2017-2018.Conclusion: This study showed that the implementation of MIS for colorectal cancer occurred later in Sweden than the Netherlands, with comparable outcomes despite lower volumes. Our study demonstrates that new surgical techniques can be implemented at a national level in a controlled and safe way, with thorough quality assurance. Show less
Huang, Y.S.; Liu, S.J.; Shan, M.J.; Hagenaars, S.C.; Mesker, W.E.; Cohen, D.; ... ; Dijke, P. ten 2022
Transforming growth factor-beta (TGF-beta) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-beta signaling by binding to the inhibitory SMAD7... Show moreTransforming growth factor-beta (TGF-beta) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-beta signaling by binding to the inhibitory SMAD7 and inducing its proteasomal degradation. How RNF12 activity is regulated and its exact role in cancer is incompletely understood. Here we report that RNF12 was overexpressed in invasive breast cancers and its high expression correlated with poor prognosis. RNF12 promoted breast cancer cell migration, invasion, and experimental metastasis in zebrafish and murine xenograft models. RNF12 levels were positively associated with the phosphorylated AKT/protein kinase B (PKB) levels, and both displayed significant higher levels in the basal-like subtype compared with the levels in luminal-like subtype of breast cancer cells. Mechanistically, AKT-mediated phosphorylation induced the nuclear localization of RNF12, maintained its stability, and accelerated the degradation of SMAD7 mediated by RNF12. Furthermore, we demonstrated that RNF12 and AKT cooperated functionally in breast cancer cell migration. Notably, RNF12 expression strongly correlated with both phosphorylated AKT and phosphorylated SMAD2 levels in breast cancer tissues. Thus, our results uncovered RNF12 as an important determinant in the crosstalk between the TGF-beta and AKT signaling pathways during breast cancer progression. Show less
OBJECTIVES: Persistent air leak (PAL; >5days after surgery) is the most common complication after pulmonary resection and associated with prolonged hospital stay and increased morbidity.... Show moreOBJECTIVES: Persistent air leak (PAL; >5days after surgery) is the most common complication after pulmonary resection and associated with prolonged hospital stay and increased morbidity. Literature is contradictory about the prevention and treatment of PAL. Variation is therefore hypothesized. The aim of this study is to understand the variation in the incidence, preventive management and treatment of PAL.METHODS: Data from the Dutch Lung Cancer Audit for Surgery were combined with results of an online survey among Dutch thoracic surgeons. The national incidence of PAL and case-mix corrected between-hospital variation were calculated in patients who underwent an oncological (bi)lobectomy or segmentectomy between January 2012 and December 2018. By multivariable logistic regression, factors associated with PAL were assessed. A survey was designed to assess variation in (preventive) management and analysed using descriptive statistics. Hospital-level associations between management strategies and PAL were assessed by univariable linear regression.RESULTS: Of 12382 included patients, 9.0% had PAL, with a between-hospital range of 2.6-19.3%. Factors associated with PAL were male sex, poor lung function, low body mass index, high American Society of Anesthesiologists (ASA) score, pulmonary comorbidity, upper lobe resection, (bi)lobectomy (vs segmentectomy), right-sided tumour and robotic-assisted thoracic surgery. Perioperative (preventive) management of PAL differed widely between hospitals. When using water seal compared to suction drainage, the average incidence of PAL decreased 2.9%.CONCLUSIONS: In the Netherlands, incidence and perioperative (preventive) management of PAL vary widely. Using water seal instead of suction drainage and increasing awareness are potential measures to reduce this variation. Show less
Ravensbergen, C.J.; Kuruc, M.; Polack, M.; Crobach, S.; Putter, H.; Gelderblom, H.; ... ; Mesker, W.E. 2022
Simple Summary Liquid biopsy offers a novel minimally invasive approach to tumor sampling and is believed to capture a comprehensive overview of the molecular tumor landscape. However, current... Show moreSimple Summary Liquid biopsy offers a novel minimally invasive approach to tumor sampling and is believed to capture a comprehensive overview of the molecular tumor landscape. However, current liquid biopsy analytes in cancer are principally derived from the malignant cells without regard to the tumor microenvironment. The Stroma Liquid Biopsy(TM) (SLB) proteomics panel contains proteins from key stromal pathways in cancer and was designed to address the tumor microenvironment in liquid biopsy. We aimed to explore and characterize SLB panel constituents using an in-silico transcriptomics approach in colon cancer. Additionally, the association between the SLB panel constituents and histologic intratumoral stromal content, a poor prognostic tumor characteristic, was investigated. This explorative study presents an alternative workflow to gene signature development and provides a molecular characterization of the SLB panel. We believe that our findings contribute to the ever-increasing appreciation of the tumor microenvironment in cancer. Liquid biopsy has emerged as a novel approach to tumor characterization, offering advantages in sample accessibility and tissue heterogeneity. However, as mutational analysis predominates, the tumor microenvironment has largely remained unacknowledged in liquid biopsy research. The current work provides an explorative transcriptomic characterization of the Stroma Liquid Biopsy(TM) (SLB) proteomics panel in colon carcinoma by integrating single-cell and bulk transcriptomics data from publicly available repositories. Expression of SLB genes was significantly enriched in tumors with high histologic stromal content in comparison to tumors with low stromal content (median enrichment score 0.308 vs. 0.222, p = 0.036). In addition, we identified stromal-specific and epithelial-specific expression of the SLB genes, that was subsequently integrated into a gene signature ratio. The stromal-epithelial signature ratio was found to have prognostic significance in a discovery cohort of 359 colon adenocarcinoma patients (OS HR 2.581, 95%CI 1.567-4.251, p < 0.001) and a validation cohort of 229 patients (OS HR 2.590, 95%CI 1.659-4.043, p < 0.001). The framework described here provides transcriptomic evidence for the prognostic significance of the SLB panel constituents in colon carcinoma. Plasma protein levels of the SLB panel may reflect histologic intratumoral stromal content, a poor prognostic tumor characteristic, and hence provide valuable prognostic information in liquid biopsy. Show less
Patients undergoing complex gastrointestinal surgery are at high risk of major postoperative complications (e.g., anastomotic leakage, sepsis), classified as Clavien-Dindo (CD) >= IIIa.... Show morePatients undergoing complex gastrointestinal surgery are at high risk of major postoperative complications (e.g., anastomotic leakage, sepsis), classified as Clavien-Dindo (CD) >= IIIa. Identification of preoperative risk factors can lead to the identification of high-risk patients. These risk factors can also be used to design personalized perioperative care. This systematic review focuses on the identification of these factors. The Medline and Embase databases were searched for prospective, retrospective cohort studies and randomized controlled trials investigating the effect of risk factors on the occurrence of major postoperative complications and/or mortality after complex gastrointestinal cancer surgery. Risk of bias was assessed using the Quality in Prognostic Studies tool. The level of evidence was graded based on the number of studies reporting a significant association between risk factors and major complications. A total of 207 eligible studies were retrieved, identifying 33 risk factors for major postoperative complications and 13 preoperative laboratory results associated with postoperative complications. The present systematic review provides a comprehensive overview of preoperative risk factors associated with major postoperative complications. A wide range of risk factors are amenable to actions in perioperative care and prehabilitation programs, which may lead to improved outcomes for high-risk patients. Additionally, the knowledge of this study is important for benchmarking surgical outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd. Show less
Introduction: Pancreatic cancer is associated with a high risk of venous thromboembolism (VTE). However, comprehensive data on incidence, timing and relevant determinants of VTE in this particular... Show moreIntroduction: Pancreatic cancer is associated with a high risk of venous thromboembolism (VTE). However, comprehensive data on incidence, timing and relevant determinants of VTE in this particular population are scarce. Current study assesses incidence, timing and predictors of VTE in pancreatic cancer through different phases of disease. Methods: All pancreatic cancer patients treated in our tertiary referral center between 2013 through 2017 were studied. Occurrence of VTE was evaluated from diagnosis through end of follow-up or death. Relevant de-terminants of VTE were identified in logistic regression models. Hazard ratios were calculated to evaluate impact of VTE on overall survival. Results: In total, 361 patients were followed for a median period of 43 months; 64 were diagnosed with VTE (18%). Most were tumor related thrombosis (59%), incidental (75%) and occurred after anti-cancer treatment had been stopped (80%), only 1.6% occurred during remission phase. Stage IV pancreatic cancer was a predictor for VTE (hazard ratio (HR) 2.46, 95% confidence interval (CI) 0.9-6.8). Biliary drainage (HR 0.52, 95%CI 0.28-0.98) and tumor resection (HR 0.45, 95%CI 0.45-1.83) were protective factors. VTE was not associated with worse survival (HR 1.3; 95% CI 0.97-1.74). Conclusions: VTE in pancreatic cancer is disease-stage dependent, with 80% occurring in advanced phases of disease when patients no longer receive active treatment. We speculate that this is the main reason for the absence of a survival effect of VTE in our cohort. These practice-based findings should be taken into account when considering wide-spread introduction of primary thromboprophylaxis in patients with pancreatic cancer. Show less
The best current biomarker strategies for predicting response to immune checkpoint inhibitor (ICI) therapy fail to account for interpatient variability in response rates. The histologic tumor... Show moreThe best current biomarker strategies for predicting response to immune checkpoint inhibitor (ICI) therapy fail to account for interpatient variability in response rates. The histologic tumor-stroma ratio (TSR) quantifies intratumoral stromal content and was recently found to be predictive of response to neoadjuvant therapy in multiple cancer types. In the current work, we predicted the likelihood of ICI therapy responsivity of 335 therapy-naive colon adenocarcinoma tumors from The Cancer Genome Atlas, using bioinformatics approaches. The TSR was scored on diagnostic tissue slides, and tumor-infiltrating immune cells (TIICs) were inferred from transcriptomic data. Tumors with high stromal content demonstrated increased T regulatory cell infiltration (p = 0.014) but failed to predict ICI therapy response. Consequently, we devised a hybrid tumor microenvironment classification of four stromal categories, based on histological stromal content and transcriptomic-deconvoluted immune cell infiltration, which was associated with previously established transcriptomic and genomic biomarkers for ICI therapy response. By integrating these biomarkers, stroma-low/immune-high tumors were predicted to be most responsive to ICI therapy. The framework described here provides evidence for expansion of current histological TIIC quantification to include the TSR as a novel, easy-to-use biomarker for the prediction of ICI therapy response. Show less
Purpose Scarce data are available on differences among index colectomies for colon cancer regarding reoperation for anastomotic leakage (AL) and clinical consequences. Therefore, this nationwide... Show morePurpose Scarce data are available on differences among index colectomies for colon cancer regarding reoperation for anastomotic leakage (AL) and clinical consequences. Therefore, this nationwide observational study aimed to evaluate reoperations for AL after colon cancer surgery and short-term postoperative outcomes for the different index colectomies. Methods Patients who underwent resection with anastomosis for a first primary colon carcinoma between 2013 and 2019 and were registered in the Dutch ColoRectal Audit were included. Primary outcomes were mortality, ICU admission, and stoma creation. Results Among 39,565 patients, the overall AL rate was 4.8% and ranged between 4.0% (right hemicolectomy) and 15.4% (subtotal colectomy). AL was predominantly managed with reoperation, ranging from 81.2% after transversectomy to 92.4% after sigmoid resection (p < 0.001). Median time to reoperation differed significantly between index colectomies (range 4-8 days, p < 0.001), with longer and comparable intervals for non-surgical reinterventions (range 13-18 days, p = 0.747). After reoperation, the highest mortality rates were observed for index transversectomy (15.4%) and right hemicolectomy (14.4%) and lowest for index sigmoid resection (5.6%) and subtotal colectomy (5.9%) (p < 0.001). Reoperation with stoma construction was associated with a higher mortality risk than without stoma construction after index right hemicolectomy (17.7% vs. 8.5%, p = 0.001). ICU admission rate was 62.6% overall (range 56.7-69.2%), and stoma construction rate ranged between 65.5% (right hemicolectomy) and 93.0% (sigmoid resection). Conclusion Significant differences in AL rate, reoperation rate, time to reoperation, postoperative mortality after reoperation, and stoma construction for AL were found among the different index colectomies for colon cancer, with relevance for patient counseling and perioperative management. Show less
The tumour-stroma ratio (TSR) and tumour budding (TB) are two high-risk factors with potential to be implemented in the next TNM classification. The aim of the current study was to evaluate the... Show moreThe tumour-stroma ratio (TSR) and tumour budding (TB) are two high-risk factors with potential to be implemented in the next TNM classification. The aim of the current study was to evaluate the practical application of the two biomarkers based on reproducibility, independency and prognostic value. Patients diagnosed with stage II or III colon cancer who underwent surgery between 2005 and 2016 were included. Both TSR and TB were scored on haematoxylin and eosin-stained tissue sections. The TSR, based on the relative amount of stroma, was scored in increments of 10%. TB was scored following the consensus guidelines; a bud was defined as <= 4 tumour cells. For analysis, three categories were used. Cohen's kappa was used for reproducibility. The prognostic value was determined with survival analysis. In total, 246 patients were included. The TSR distribution was N = 137 (56%) stroma-low and N = 109 (44%) stroma-high. The TB distribution was TB-low N = 194 (79%), TB-intermediate N = 35 (14%) and TB-high N = 17 (7%). The reproducibility of the TSR was good (interobserver agreement kappa = 0.83 and intraobserver agreement kappa = 0.82), whereas the inter- and intraobserver agreement for scoring TB was moderate (kappa 0.47 and 0.45, respectively). The survival analysis showed an independent prognostic value for disease-free survival for TSR (HR 1.57; 95% CI 1.01-2.44; p = 0.048) and for TB-high (HR 2.01; 95% CI 1.02-3.96; p = 0.043). Based on current results, we suggest the TSR is a more reliable parameter in daily practice due to better reproducibility and independent prognostic value for disease-free survival. Show less
Objective The aim of this study is to identify preoperative patient-related prognostic factors for anastomotic leakage, mortality, and major complications in patients undergoing oncological... Show moreObjective The aim of this study is to identify preoperative patient-related prognostic factors for anastomotic leakage, mortality, and major complications in patients undergoing oncological esophagectomy. Background Esophagectomy is a high-risk procedure with an incidence of major complications around 25% and short-term mortality around 4%. Methods We systematically searched the Medline and Embase databases for studies investigating the associations between patient-related prognostic factors and anastomotic leakage, major postoperative complications (Clavien-Dindo >= IIIa), and/or 30-day/in-hospital mortality after esophagectomy for cancer. Results Thirty-nine eligible studies identifying 37 prognostic factors were included. Cardiac comorbidity was associated with anastomotic leakage, major complications, and mortality. Male sex and diabetes were prognostic factors for anastomotic leakage and major complications. Additionally, American Society of Anesthesiologists (ASA) score > III and renal disease were associated with anastomotic leakage and mortality. Pulmonary comorbidity, vascular comorbidity, hypertension, and adenocarcinoma tumor histology were identified as prognostic factors for anastomotic leakage. Age > 70 years, habitual alcohol usage, and body mass index (BMI) 18.5-25 kg/m(2) were associated with increased risk for mortality. Conclusions Various patient-related prognostic factors are associated with anastomotic leakage, major postoperative complications, and postoperative mortality following oncological esophagectomy. This knowledge may define case-mix adjustment models used in benchmarking or auditing and may assist in selection of patients eligible for surgery or tailored perioperative care. Show less
Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an... Show moreBackground Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited. Show less
Hagenaars, S.C.; Groot, S. de; Cohen, D.; Dekker, T.J.A.; Charehbili, A.; Kranenbarg, E.M.K.; ... ; Dutch Breast Can 2021
The tumor-stroma ratio (TSR) has proven to be a strong prognostic factor in breast cancer, demonstrating better survival for patients with stroma-low tumors. Since the role of the TSR as a... Show moreThe tumor-stroma ratio (TSR) has proven to be a strong prognostic factor in breast cancer, demonstrating better survival for patients with stroma-low tumors. Since the role of the TSR as a predictive marker for neoadjuvant chemotherapy outcome is yet unknown, this association was evaluated for HER2-negative breast cancer in the prospective DIRECT and NEOZOTAC trials. The TSR was assessed on 375 hematoxylin and eosin-stained sections of pre-treatment biopsies. Associations between the TSR and chemotherapy response according to the Miller-Payne (MP) grading system, and between the TSR and pathological response were examined using Pearson's chi-square, Cochran-Armitage test for trend and regression analyses. A stroma-low tumor prior to neoadjuvant chemotherapy was significantly associated with a higher MP score (P = .005). This relationship remained significant in the estrogen receptor (ER)-negative subgroup (P = .047). The univariable odds ratio (OR) of a stroma-low tumor on pathological complete response (pCR) was 2.46 (95% CI 1.34-4.51, P = .004), which attenuated to 1.90 (95% CI 0.85-4.25, P = .119) after adjustment for relevant prognostic factors. Subgroup analyses revealed an OR of 5.91 in univariable analyses for ER-negativity (95% CI 1.19-29.48, P = .030) and 1.48 for ER-positivity (95% CI 0.73-3.01, P = .281). In conclusion, a low amount of stroma on pre-treatment biopsies is associated with a higher MP score and pCR rate. Therefore, the TSR is a promising biomarker in predicting neoadjuvant treatment outcome. Incorporating this parameter in routine pathological diagnostics could be worthwhile to prevent overtreatment and undertreatment. Show less
ABSTRACTBackground: Textbook outcome is a composite measure of combined outcome indicators, which has been suggested to be of additional value over single outcome parameters in clinical auditing of... Show moreABSTRACTBackground: Textbook outcome is a composite measure of combined outcome indicators, which has been suggested to be of additional value over single outcome parameters in clinical auditing of surgical treatment. This study aimed to assess textbook outcome after rectal cancer surgery as short-term marker for quality of care.Methods: Patients who underwent elective rectal cancer surgery between 2012 and 2019 and registered in the Dutch ColoRectal Audit were included when the following criteria were met: 30-day and primary hospital admission survival, no reintervention, tumor-free margins, no postoperative complications, a hospital stay of less than 14 days and no readmission. Hospital variation was evaluated in case-mix corrected funnel-plots. A multilevel logistic regression analysis was performed to identify associated factors with textbook outcome.Results: The study population consisted of 20,521 patients who underwent primary rectal cancer surgery, of whom 56.3% achieved textbook outcome. Postoperative complications were the main contributor to not achieving textbook outcome. Case-mix corrected funnel plots demonstrated that underperforming hospitals in 2012-2015 were no underperformers in 2016-2019 anymore. Female sex, laparoscopic surgery, and rectal resection without defunctioning stoma creation were positively associated with textbook outcome.Conclusion: Textbook outcome after rectal cancer resection is mainly driven by postoperative complications. Although textbook outcome showed some discriminating value for identifying underperforming hospitals, it does not fit the plan-do-check-act cycle of clinical auditing. In our opinion, textbook outcome has little added value to the current outcome indicators for rectal cancer surgery.KEYWORDS: Rectal cancer - Surgery - Textbook outcome - Clinical auditing - Hospital variation - Outcome indicator Show less
