Search

A. Overall survival in derivation (MSKCC) and validation (European) cohorts. B. Recurrence free survival in derivation (MSKCC) and validation (European) cohorts.

Supplementary Data from Liver Colonization by Colorectal Cancer Metastases Requires YAP-Controlled Plasticity at the Micrometastatic Stage

mRNA expression and hierarchical clustering of molecular risk score (MRS) genes in colorectal liver metastases in derivation cohort. Genes are indicated on the x-axis, patients on the y-axis.

Supplementary tables S1-6. Supplementary table S1 Primers used for RT-qPCR analyses. Supplementary table S2 Clinical variables associated with differences in gene expression among 119 resected liver metastases. Supplementary table S3 613 genes whose expression was significantly upregulated and 481 genes whose expression was significantly (p

Purpose: Risk stratification after surgery for colorectal cancer liver metastases (CRLM) is achieved using clinicopathologic variables, however, is of limited accuracy. We sought to derive and externally validate a multigene expression assay prognostic of overall survival (OS) that is superior to clinicopathologic variables in patients with surgically resected CRLM.Experimental Design: We measured mRNA expression in prospectively collected frozen tumor from 96 patients with surgically resected CRLM at Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY). We retrospectively generated a 20-gene molecular risk score (MRS) and compared its prognostic utility for OS and recurrence-free survival (RFS) with three common clinical risk scores (CRS). We then tested the prognostic ability of the MRS in an external validation cohort (European) of 119 patients with surgically resected CRLM at the University Medical Center Utrecht (Utrecht, the Netherlands) and Paul Brousse Hospital (Villejuif, France).Results: For OS in the MSKCC cohort, MRS was the strongest independent prognosticator (HR, 3.7–4.9; P < 0.001) followed by adjuvant chemotherapy (HR, 0.3; P ≤ 0.001). For OS in the European cohort, MRS was the only independent prognosticator (HR, 3.5; P = 0.007). For RFS, MRS was also independently prognostic in the MSKCC cohort (HR, 2.4–2.6; P ≤ 0.001) and the European cohort (HR, 1.6–2.5; P ≤ 0.05).Conclusions: Compared with CRSs, the MRS is more accurate, broadly applicable, and an independent prognostic biomarker of OS in resected CRLM. This MRS is the first externally validated prognostic multigene expression assay after metastasectomy for CRLM and warrants prospective validation. Clin Cancer Res; 22(10); 2575–82. ©2016 AACR.

Univariate and multivariate analyses of recurrence free survival in derivation (Table 1) and validation (Table 2) cohorts.

Micrometastases of colorectal cancer can remain dormant for years prior to the formation of actively growing, clinically detectable lesions (i.e., colonization). A better understanding of this step in the metastatic cascade could help improve metastasis prevention and treatment. Here we analyzed liver specimens of patients with colorectal cancer and monitored real-time metastasis formation in mouse livers using intravital microscopy to reveal that micrometastatic lesions are devoid of cancer stem cells (CSC). However, lesions that grow into overt metastases demonstrated appearance of de novo CSCs through cellular plasticity at a multicellular stage. Clonal outgrowth of patient-derived colorectal cancer organoids phenocopied the cellular and transcriptomic changes observed during in vivo metastasis formation. First, formation of mature CSCs occurred at a multicellular stage and promoted growth. Conversely, failure of immature CSCs to generate more differentiated cells arrested growth, implying that cellular heterogeneity is required for continuous growth. Second, early-stage YAP activity was required for the survival of organoid-forming cells. However, subsequent attenuation of early-stage YAP activity was essential to allow for the formation of cell type heterogeneity, while persistent YAP signaling locked micro-organoids in a cellularly homogenous and growth-stalled state. Analysis of metastasis formation in mouse livers using single-cell RNA sequencing confirmed the transient presence of early-stage YAP activity, followed by emergence of CSC and non-CSC phenotypes, irrespective of the initial phenotype of the metastatic cell of origin. Thus, establishment of cellular heterogeneity after an initial YAP-controlled outgrowth phase marks the transition to continuously growing macrometastases.Significance:Characterization of the cell type dynamics, composition, and transcriptome of early colorectal cancer liver metastases reveals that failure to establish cellular heterogeneity through YAP-controlled epithelial self-organization prohibits the outgrowth of micrometastases.See related commentary by LeBleu, p. 1870

Genes selected for molecular risk score (MRS).

Purpose: Chemotherapy treatment of metastatic colon cancer ultimately fails due to development of drug resistance. Identification of chemotherapy-induced changes in tumor biology may provide insight into drug resistance mechanisms.Experimental Design: We studied gene expression differences between groups of liver metastases that were exposed to preoperative chemotherapy or not. Multiple patient-derived colonosphere cultures were used to assess how chemotherapy alters energy metabolism by measuring mitochondrial biomass, oxygen consumption, and lactate production. Genetically manipulated colonosphere-initiated tumors were used to assess how altered energy metabolism affects chemotherapy efficacy.Results: Gene ontology and pathway enrichment analysis revealed significant upregulation of genes involved in oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis in metastases that were exposed to chemotherapy. This suggested chemotherapy induces a shift in tumor metabolism from glycolysis towards OXPHOS. Indeed, chemotreatment of patient-derived colonosphere cultures resulted in an increase of mitochondrial biomass, increased expression of respiratory chain enzymes, and higher rates of oxygen consumption. This was mediated by the histone deacetylase sirtuin-1 (SIRT1) and its substrate, the transcriptional coactivator PGC1α. Knockdown of SIRT1 or PGC1α prevented chemotherapy-induced OXPHOS and significantly sensitized patient-derived colonospheres as well as tumor xenografts to chemotherapy.Conclusions: Chemotherapy of colorectal tumors induces a SIRT1/PGC1α-dependent increase in OXPHOS that promotes tumor survival during treatment. This phenomenon is also observed in chemotherapy-exposed resected liver metastases, strongly suggesting that chemotherapy induces long-lasting changes in tumor metabolism that potentially interfere with drug efficacy. In conclusion, we propose a novel mechanism of chemotherapy resistance that may be clinically relevant and therapeutically exploitable. Clin Cancer Res; 21(12); 2870–9. ©2015 AACR.

Supplementary Figures S1-3. Supplementary figure S1 Cytochrome c oxidase (COX IV) is highly expressed in chemotherapy-treated liver metastases Supplementary figure S2 Expression changes of glycolytic and OXPHOS genes in response to chemotherapy. Supplementary figure S3 Oxygen consumption rates of colonospheres treated with chemotherapy +/- nicotinamide

Supplementary Figure S3. Loss of GPx2 reduces tumor growth.

Supplementary Figure Legends. Legends for Supplementary Figures S1-S6.

Supplementary Materials and Methods. Description of additional methods and procedures used in the study.

Supplementary Table S4. The epithelial signature.

Colorectal tumorigenesis is accompanied by the generation of oxidative stress, but how this controls tumor development is poorly understood. Here, we studied how the H2O2-reducing enzyme glutathione peroxidase 2 (GPx2) regulates H2O2 stress and differentiation in patient-derived “colonosphere” cultures. GPx2 silencing caused accumulation of radical oxygen species, sensitization to H2O2-induced apoptosis, and strongly reduced clone- and metastasis-forming capacity. Neutralization of radical oxygen species restored clonogenic capacity. Surprisingly, GPx2-suppressed cells also lacked differentiation potential and formed slow-growing undifferentiated tumors. GPx2 overexpression stimulated multilineage differentiation, proliferation, and tumor growth without reducing the tumor-initiating capacity. Finally, GPx2 expression was inversely correlated with H2O2-stress signatures in human colon tumor cohorts, but positively correlated with differentiation and proliferation. Moreover, high GPx2 expression was associated with early tumor recurrence, particularly in the recently identified aggressive subtype of human colon cancer. We conclude that H2O2 neutralization by GPx2 is essential for maintaining clonogenic and metastatic capacity, but also for the generation of differentiated proliferating tumor mass. The results reveal an unexpected redox-controlled link between tumor mass formation and metastatic capacity. Cancer Res; 74(22); 6717–30. ©2014 AACR.

SUMMARYNeuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors and poorly-differentiated carcinomas. Treatment options for patients with NENs are limited, in part due to lack of accurate models. To address this need we established the first patient-derived tumor organoids (PDTOs) from pulmonary neuroendocrine tumors and derived PDTOs from an understudied NEN subtype, large cell neuroendocrine carcinoma (LCNEC). PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through drug sensitivity analyses, we uncover therapeutic sensitivities to an inhibitor of NAD salvage biosynthesis and to an inhibitor of BCL-2. Finally, we identify a dependency on EGF in pulmonary neuroendocrine tumor PDTOs. Consistent with these findings, analysis of an independent cohort showed that approximately 50% of pulmonary neuroendocrine tumors expressed EGFR. This study identifies a potentially actionable vulnerability for a subset of NENs, and further highlights the utility of these novel PDTO models for the study of NENs.Graphical abstractHighlightsPDTOs of pulmonary NETs and LCNEC were establishedPDTOs recapitulate intra-tumoral heterogeneity and evolution of parental tumorsDrug assays reveal therapeutic vulnerabilities and biomarkersPulmonary NET PDTOs are dependent on EGF

Background Decrease in blood pressure (BP) is the major goal of adrenalectomy for primary aldosteronism. Nevertheless, the optimal timing to assess these outcomes and the needed duration of follow-up are uncertain. We systematically reviewed the literature regarding trends in BP-related outcomes during follow-up after adrenalectomy. Methods A systematic literature search of medical literature from PubMed, Embase and the Cochrane Library regarding BP-related outcomes (i.e. cure of hypertension rates, BP and antihypertensives) was performed. The Quality In Prognosis Studies risk of bias tool was used. Results Of the 2057 identified records, 13 articles met the inclusion criteria. Overall study quality was low. In multiple studies, the biggest decrease in BP was shown within the first month(s) after adrenalectomy and afterwards BP often remained stable during long-term follow-up. Conclusions Based on the available studies one might suggest that long follow-up is unnecessary, since outcomes seem to stabilize within the first months.

OBJECTIVE: The aim was to compare the (sentinel) lymph node detection rate of indocyanine green (ICG)-fluorescent imaging versus standard-of-care 99m Tc-nanocoilloid for sentinel lymph node (SLN)-mapping. BACKGROUND: The current gold standard for axillary staging in patients with breast cancer is sentinel lymph node biopsy (SLNB) using radio-guided surgery using radioisotope technetium ( 99m Tc), sometimes combined with blue dye. A promising alternative is fluorescent imaging using ICG. METHODS: In this noninferiority trial, we enrolled 102 consecutive patients with invasive early-stage, clinically node-negative breast cancer. Patients were planned for breast conserving surgery and SLNB between August 2020 and June 2021. The day or morning before surgery, patients were injected with 99m Tc-nanocolloid. In each patient, SLNB was first performed using ICG-fluorescent imaging, after which excised lymph nodes were tested with the gamma-probe for 99m Tc-uptake ex vivo, and the axilla was checked for residual 99m Tc-activity. The detection rate was defined as the proportion of patients in whom at least 1 (S)LN was detected with either tracer. RESULTS: In total, 103 SLNBs were analyzed. The detection rate of ICG-fluorescence was 96.1% [95% confidence interval (95% CI)=90.4%-98.9%] versus 86.4% (95% CI=78.3%-92.4%) for 99m Tc-nanocoilloid. The detection rate for pathological lymph nodes was 86.7% (95% CI=59.5%-98.3%) for both ICG and 99m Tc-nanocoilloid. A median of 2 lymph nodes were removed. ICG-fluorescent imaging did not increase detection time. No adverse events were observed. CONCLUSIONS: ICG-fluorescence showed a higher (S)LN detection rate than 99m Tc-nanocoilloid, and equal detection rate for pathological (S)LNs. ICG-fluorescence may be used as a safe and effective alternative to 99m Tc-nanocoilloid for SLNB in patients with early-stage breast cancer.

We aimed to investigate the postoperative trend in blood pressure (BP)-related outcomes [BP and antihypertensive (AHT) drug use] during the year following adrenalectomy for primary aldosteronism (PA) to determine the optimal timing for outcome assessment and to determine the necessary follow-up length.Since the course of BP-related outcomes after adrenalectomy is unknown, the optimal timing of outcome assessment and follow-up duration are not clear.In this retrospective single center cohort study, we used a prospectively collected database with all patients referred for difficult-to-control-hypertension-analysis. All patients diagnosed with PA who underwent adrenalectomy were included. AHT drug use [in defined daily dose (DDD)] and home blood pressure measurements (HBPMs) during the first postoperative year were collected. A mixed-effects model was developed to assess the stability of DDD and HBPM over time and adjust for potential confounders.In total 1784 patients were assessed for difficult-to-control-hypertension of whom 41 were included. Both the DDD and HBPM showed the strongest decrease in the first postoperative month (mean 1.6DDD; mean 140/85 mm Hg) compared with preoperative values (4.5DDD; 153/92 mm Hg). Thereafter, both outcomes showed a stable course from 4 to 6 months (1.6DDD; 136/86 mm Hg) up to 12 months postoperatively (2.0DDD; 136/83 mm Hg).This study showed that AHT drug use and HBPM decreased substantially within the first month after adrenalectomy for PA and afterwards generally remained stable during the year following adrenalectomy. We propose that BP-related outcomes can be assessed reliably early after adrenalectomy and question the need for routine long-term follow-up in referral centers.

BACKGROUND AND OBJECTIVE: Robotic distal pancreatectomy (DP) is an emerging attractive approach, but its role compared to laparoscopic or open surgery remains unclear. Benchmark values are novel and objective tools for such comparisons. The aim of this study was to identify benchmark cutoffs for many outcome parameters for DP with or without splenectomy beyond the learning curve.METHODS: This study analyzed outcomes from international expert centers from patients undergoing robotic DP for malignant or benign lesions. After excluding the first 10 cases in each center to reduce the effect of the learning curve, consecutive patients were included from the start of robotic DP up to June 2020. Benchmark patients had no significant comorbidities. Benchmark cutoff values were derived from the 75 th or the 25 th percentile of the median values of all benchmark centers. Benchmark values were compared to a laparoscopic control group from four high-volume centers and published open DP landmark series.RESULTS: Sixteen centers contributed 755 cases, whereof 345 benchmark patients (46%) were included the analysis. Benchmark cut-offs included: operation time ≤300min, conversion rate ≤3%, clinically relevant POPF ≤32%, 3 months major complication rate ≤26.7% and lymph node retrieval ≥9. The CCI ® at 3 months was ≤8.7 without deterioration thereafter. Compared to robotic DP, laparoscopy had significantly higher conversion rates (5x) and overall complications, while open DP was associated with more blood loss and longer hospital stay.CONCLUSION: This first benchmark study demonstrates that robotic DP provides superior postoperative outcomes compared to laparoscopic and open DP. Robotic DP may be expected to become the approach of choice in minimally invasive DP.

The lymphatic system is essential in maintaining tissue fluid homeostasis as well as antigen and immune cell transport to lymph nodes. Moreover, lymphatic vasculature plays an important role in various pathological processes, such as cancer. Fundamental to this research field are representative in vitro models. Here we present a microfluidic lymphatic vessel model to study lymphangiogenesis and its interaction with colon cancer organoids using a newly developed lymphatic endothelial cell (LEC) line. We generated immortalized human LECs by lentiviral transduction of human telomerase (hTERT) and BMI-1 expression cassettes into primary LECs. Immortalized LECs showed an increased growth potential, reduced senescence, and elongated lifespan with maintenance of typical LEC morphology and marker expression for over 12 months while remaining nontransformed. Immortalized LECs were introduced in a microfluidic chip, comprising a free-standing extracellular matrix, where they formed a perfusable vessel-like structure against the extracellular matrix. A gradient of lymphangiogenic factors over the extracellular matrix gel induced the formation of luminated sprouts. Adding mouse colon cancer organoids adjacent to the lymphatic vessel resulted in a stable long-lived coculture model in which cancer cell-induced lymphangiogenesis and cancer cell motility can be investigated. Thus, the development of a stable immortalized lymphatic endothelial cell line in a membrane-free, perfused microfluidic chip yields a highly standardized lymphangiogenesis and lymphatic vessel-tumor cell coculture assay.

Male breast cancer (MBC) is a rare disease. Due to its rarity, treatment is still directed by data mainly extrapolated from female breast cancer (FBC) treatment, despite the fact that it has recently become clear that MBC has its own molecular characteristics. DDX3 is a RNA helicase with tumor suppressor and oncogenic potential that was described as a prognosticator in FBC and can be targeted by small molecule inhibitors of DDX3. The aim of this study was to evaluate if DDX3 is a useful prognosticator for MBC patients. Nuclear as well as cytoplasmic DDX3 expression was studied by immunohistochemistry in a Dutch retrospective cohort of 106 MBC patients. Differences in 10-year survival by DDX3 expression were analyzed using log-rank test. The association between clinicopathologic variables, DDX3 expression, and survival was tested in uni- and multivariate Cox-regression analysis. High cytoplasmic DDX3 was associated with high androgen receptor (AR) expression while low nuclear DDX3 was associated with negative lymph node status. Nuclear and cytoplasmic DDX3 were not associated with each other. In a univariate analysis, high cytoplasmic DDX3 (p = 0.045) was significantly associated with better 10-year overall survival. In multivariate analyses, cytoplasmic DDX3 had independent prognostic value (p = 0.017). In conclusion, cytoplasmic DDX3 expression seems to be a useful prognosticator in MBC, as high cytoplasmic DDX3 indicated better 10-year survival.

Background Aims of this study were to describe the stepwise implementation and expansion of robotic HPB surgery in a high volume HPB unit in the Netherlands and to analyze clinical outcomes of all robotic liver resections and robotic pancreatoduodenectomies performed within this program. Methods After proctoring by expert international surgeons, HPB surgeons were introduced to robotic liver resection and robotic pancreatoduodenectomy in a stepwise fashion. Data from two prospective databases containing all consecutive patients who underwent robotic liver resection or robotic pancreatoduodenectomy between August 1st, 2015 and March 1st, 2019 were analyzed post hoc. Results In total, 77 consecutive robotic liver resections and 68 consecutive robotic pancreatoduodenectomies were performed. Five surgeons were consecutively introduced to robotic HPB surgery. Mean operative time for robotic liver resection was 160 ± 78 min. Mean operative time for robotic pancreatoduodenectomy was 420 ± 67 min. Operative times remained stable over time and were not affected by the introduction of new surgeons. Conclusion Stepwise implementation and expansion of robotic HPB surgery within one unit over a three-and-half year period is feasible and associated with good clinical outcomes. Despite introducing new surgeons to the technique, operative times, an indicator of the learning process, remained stable over time.

Micrometastases of colorectal cancer can remain dormant for years prior to the formation of actively growing, clinically detectable lesions (i.e., colonization). A better understanding of this step in the metastatic cascade could help improve metastasis prevention and treatment. Here we analyzed liver specimens of patients with colorectal cancer and monitored real-time metastasis formation in mouse livers using intravital microscopy to reveal that micrometastatic lesions are devoid of cancer stem cells (CSC). However, lesions that grow into overt metastases demonstrated appearance of de novo CSCs through cellular plasticity at a multicellular stage. Clonal outgrowth of patient-derived colorectal cancer organoids phenocopied the cellular and transcriptomic changes observed during in vivo metastasis formation. First, formation of mature CSCs occurred at a multicellular stage and promoted growth. Conversely, failure of immature CSCs to generate more differentiated cells arrested growth, implying that cellular heterogeneity is required for continuous growth. Second, early-stage YAP activity was required for the survival of organoid-forming cells. However, subsequent attenuation of early-stage YAP activity was essential to allow for the formation of cell type heterogeneity, while persistent YAP signaling locked micro-organoids in a cellularly homogenous and growth-stalled state. Analysis of metastasis formation in mouse livers using single-cell RNA sequencing confirmed the transient presence of early-stage YAP activity, followed by emergence of CSC and non-CSC phenotypes, irrespective of the initial phenotype of the metastatic cell of origin. Thus, establishment of cellular heterogeneity after an initial YAP-controlled outgrowth phase marks the transition to continuously growing macrometastases. Significance: Characterization of the cell type dynamics, composition, and transcriptome of early colorectal cancer liver metastases reveals that failure to establish cellular heterogeneity through YAP-controlled epithelial self-organization prohibits the outgrowth of micrometastases. See related commentary by LeBleu, p. 1870

Background: Early recognition of postoperative pancreatic fistula might decrease the risk of subsequent life threatening complications. The aim of this review was to systematically evaluate the accuracy of postoperative clinical, biochemical and radiologic variables for early recognition of clinically relevant postoperative pancreatic fistula. Methods: A systematic literature search was performed up to August 2018. Clinical studies reporting on the association between postoperative variables and clinically relevant postoperative pancreatic fistula were included. Variables were stratified: early prediction (postoperative day 1–2) versus early diagnosis (day 3) and had to be reported in 2 cohorts. Results: Overall, 37 included studies reported on 17 different diagnostic variables after 8701 pancreatic resections. Clinically relevant postoperative pancreatic fistula occurred in 1532/8701 patients (18%). Early prediction variables included elevated serum and drain amylase (day 1). Identified variables for early diagnosis were: non-serous drain efflux (day 3); positive drain culture (day 3); elevated temperature (any day); elevated C-Reactive Protein (CRP; day 4); elevated white blood cell count (day 4) and peripancreatic collections on computed tomography (CT; day 5–10). Conclusion: This review provides a comprehensive overview of postoperative variables associated with clinically relevant pancreatic fistula. Incorporation of variables in future algorithms could potentially mitigate the clinical impact of postoperative pancreatic fistula.

Background: While most of the evidence on minimally invasive liver surgery (MILS) is derived from expert centers, nationwide outcomes remain underreported. This study aimed to evaluate the implementation and outcome of MILS on a nationwide scale. Methods: Electronic patient files were reviewed in all Dutch liver surgery centers and all patients undergoing MILS between 2011 and 2016 were selected. Operative outcomes were stratified based on extent of the resection and annual MILS volume. Results: Overall, 6951 liver resections were included, with a median annual volume of 50 resections per center. The overall use of MILS was 13% (n = 916), which varied from 3% to 36% (P < 0.001) between centers. The nationwide use of MILS increased from 6% in 2011 to 23% in 2016 (P < 0.001). Outcomes of minor MILS were comparable with international studies (conversion 0–13%, mortality

Patients with multiple endocrine neoplasia 1 syndrome (MEN1) often develop multifocal duodenopancreatic neuroendocrine tumors (dpNETs). Nonfunctional pancreatic neuroendocrine tumors (PanNETs) and duodenal gastrinomas are the most frequent origins of metastasis. Current guidelines recommend surgery based on tumor functionality, size ≥ 2 cm, grade or presence of lymph node metastases. However, in case of multiple primary tumors it is often unknown which specific tumor metastasized. This study aims to unravel the relationship between primary dpNETs and metastases in patients with MEN1 by studying endocrine differentiation. First, it was shown that expression of the endocrine differentiation markers ARX and PDX1 was concordant in 18 unifocal sporadic neuroendocrine tumors (NETs) and matched metastases. Thereafter, ARX, PDX1, Ki67 and gastrin expression, and the presence of alternative lengthening of telomeres were determined in 137 microscopic and macroscopic dpNETs and 36 matched metastases in 10 patients with MEN1. ARX and PDX1 H-score clustering was performed to infer relatedness. For patients with multiple metastases, similar intrametastases transcription factor expression suggests that most metastases (29/32) originated from a single NET of origin, while few patients may have multiple metastatic primary NETs. In 6 patients with MEN1 and hypergastrinemia, periduodenopancreatic lymph node metastases expressed gastrin, and clustered with minute duodenal gastrinomas, not with larger PanNETs. PanNET metastases often clustered with high grade or alternative lengthening of telomeres-positive primary tumors. In conclusion, for patients with MEN1-related hypergastrinemia and PanNETs, a duodenal origin of periduodenopancreatic lymph node metastases should be considered, even when current conventional and functional imaging studies do not reveal duodenal tumors preoperatively.

BACKGROUND: Surgical resection is the only potentially curative treatment for pancreatic neuroendocrine tumors. The choice for the type of procedure is influenced by the expected oncological benefit and the anticipated risk of procedure-specific complications. Few studies have focused on complications in these patients. This cohort study aimed to assess complications and risk factors after resections of pancreatic neuroendocrine tumors.METHODS: Patients undergoing resection of a pancreatic neuroendocrine tumor were identified within 2 centers of excellence. Complications were assessed according to the Clavien-Dindo classification and the comprehensive complication index. Logistic regression was performed to compare surgical procedures with adjustment for potential confounders (Clavien-Dindo ≥3).RESULTS: The cohort comprised 123 patients, including 12 enucleations, 50 distal pancreatectomies, 51 pancreatoduodenectomies, and 10 total/combined pancreatectomies. Mortality was 0.8%, a severe complication occurred in 41.5%, and the failure-to-rescue rate was 2.0%. The median comprehensive complication index was 22.6 (0-100); the comprehensive complication index increased after more extensive resections. After adjustment, a pancreatoduodenectomy, as compared to a distal pancreatectomy, increased the risk for a severe complication (odds ratio 3.13 [95% confidence interval 1.32-7.41]). Of the patients with multiple endocrine neoplasia type 1 or von Hippel-Lindau, 51.9% developed a severe complication vs 38.5% with sporadic disease. After major resections, morbidity was significantly higher in patients with multiple endocrine neoplasia type 1/von Hippel-Lindau (comprehensive complication index 45.1 vs 28.9, P = .029).CONCLUSION: Surgery for pancreatic neuroendocrine tumors is associated with a high rate of complications but low failure-to-rescue in centers of excellence. Complications are procedure-specific. Major resections in patients with multiple endocrine neoplasia type 1/von Hippel-Lindau appear to increase the risk of complications.

PurposeConventional thyroidectomy has been standard of care for surgical thyroid nodules. For cosmetic purposes different minimally invasive and remote-access surgical approaches have been developed. At present, the most used robotic and endoscopic thyroidectomy approaches are minimally invasive video assisted thyroidectomy (MIVAT), bilateral axillo-breast approach endoscopic thyroidectomy (BABA-ET), bilateral axillo-breast approach robotic thyroidectomy (BABA-RT), transoral endoscopic thyroidectomy via vestibular approach (TOETVA), retro-auricular endoscopic thyroidectomy (RA-ET), retro-auricular robotic thyroidectomy (RA-RT), gasless transaxillary endoscopic thyroidectomy (GTET) and robot assisted transaxillary surgery (RATS). The purpose of this systematic review was to evaluate whether minimally invasive techniques are not inferior to conventional thyroidectomy.MethodsA systematic search was conducted in Medline, Embase and Web of Science to identify original articles investigating operating time, length of hospital stay and complication rates regarding recurrent laryngeal nerve injury and hypocalcemia, of the different minimally invasive techniques.ResultsOut of 569 identified manuscripts, 98 studies met the inclusion criteria. Most studies were retrospective in nature. The results of the systematic review varied. Thirty-one articles were included in the meta-analysis. Compared to the standard of care, the meta-analysis showed no significant difference in length of hospital stay, except a longer stay after BABA-ET. No significant difference in incidence of recurrent laryngeal nerve injury and hypocalcemia was seen. As expected, operating time was significantly longer for most minimally invasive techniques.ConclusionsThis is the first comprehensive systematic review and meta-analysis comparing the eight most commonly used minimally invasive thyroid surgeries individually with standard of care. It can be concluded that minimally invasive techniques do not lead to more complications or longer hospital stay and are, therefore, not inferior to conventional thyroidectomy.

Background: Pancreatic neuroendocrine tumors (pNETs) have a high prevalence in patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Tumor size is still regarded as the main prognostic factor and therefore used for surgical decision-making. We assessed reliability and agreement of radiological and pathological tumor size in a population-based cohort of patients with MEN1-related pNETs. Methods: Patients were selected from the Dutch MEN1 database if they had undergone a resection for a pNET between 2003 and 2018. Radiological (MRI, CT, and endoscopic ultrasonography [EUS]) and pathological tumor size were collected from patient records. Measures of agreement (Bland-Altman plots with limits of agreement [LoA] and absolute agreement) and reliability (intraclass correlation coefficients [ICC] and unweighted kappa) were calculated for continuous and categorized (< or ≥2 cm) pNET size. Results: In 73 included patients, the median radiological and pathological tumor sizes measured were 22 (3–160) and 21 (4–200) mm, respectively. Mean bias between radiological and pathological tumor size was −0.2 mm and LoA ranged from −12.9 to 12.6 mm. For the subgroups of MRI, CT, and EUS, LoA of radiological and pathological tumor size ranged from −9.6 to 10.9, −15.9 to 15.8, and −13.9 to 11.0, respectively. ICCs for the overall cohort, MRI, CT, and EUS were 0.80, 0.86, 0.75, and 0.76, respectively. Based on the 2 cm criterion, agreement was 81.5%; hence, 12 patients (18.5%) were classified differently between imaging and pathology. Absolute agreement and kappa values of MRI, CT, and EUS were 88.6, 85.7, and 75.0%, and 0.77, 0.71, and 0.50, respectively. Conclusion: Within a population-based cohort, MEN1-related pNET size was not systematically over- or underestimated on preoperative imaging. Based on agreement and reliability measures, MRI is the preferred imaging modality.

Background Cure of hypertension after adrenalectomy for primary aldosteronism is no certainty and therefore preoperative patient counseling is essential. The Primary Aldosteronism Surgical Outcome (PASO) Score is a useful prediction model with an area under the curve (AUC) of 0.839. The PASO Score includes ‘Target Organ Damage’ (TOD) (i.e., left ventricular hypertrophy and/or microalbuminuria), which is often unavailable during preoperative counseling and might therefore limit its use in clinical practice. We hypothesized that the PASO score would still be useful if TOD is unknown at time of counseling. Therefore, we aimed to examine the predictive performance of the simplified PASO Score, without taking TOD into account. Materials and methods In this retrospective cohort study, patients who underwent unilateral adrenalectomy between 2010 and 2016 in 16 medical centers from North America, Europe and Australia were included. TOD was unknown in our database and therefore assigned as absent. Patients were classified as complete, partial or absent clinical success using the PASO consensus criteria. Results A total of 380 (73.9%) patients were eligible for analysis. Complete, partial and absent clinical success were observed in 29.5%, 55.8% and 14.7% of patients, respectively. The simplified PASO Score had an AUC of 0.730 (95% confidence interval 0.674–0.785) in our total cohort. Conclusion Without taking TOD into account, the simplified PASO Score had a lower predictive value as compared to the original derivation cohort. Ideally, the complete PASO Score should be used, but when data on TOD are not readily available, the simplified PASO Score is a useful and reasonable alternative., Highlights • We aimed to examine the predictive performance of the PASO Score, without taking ‘target organ damage’ (TOD) into account. • This simplified PASO Score had a lower predictive value as compared to the PASO Score in the original derivation cohort. • The simplified PASO Score increases the applicability of the model and is reasonable for clinicians to use in daily practice. • Ideally, the complete PASO Score should be used, but the simplified PASO Score is a useful and reasonable alternative.

Contains fulltext : 245221.pdf (Publisher’s version ) (Open Access) BACKGROUND: Metastasized pancreatic neuroendocrine tumors are the leading cause of death in patients with multiple endocrine neoplasia type 1. Aside from tumor size, prognostic factors of pancreatic neuroendocrine tumors are largely unknown. The present study aimed to assess whether the prognosis of patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors differs from those with resected multiple endocrine neoplasia type 1-related insulinomas and assessed factors associated with prognosis. METHODS: Patients who underwent resection of a multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors between 1990 and 2016 were identified in 2 databases: the DutchMEN Study Group and the International MEN1 Insulinoma Study Group databases. Cox regression was performed to compare liver metastases-free survival of patients with a nonfunctioning pancreatic neuroendocrine tumors versus those with an insulinoma and to identify factors associated with liver metastases-free survival. RESULTS: Out of 153 patients with multiple endocrine neoplasia type 1, 61 underwent resection for a nonfunctioning pancreatic neuroendocrine tumor and 92 for an insulinoma. Of the patients with resected lymph nodes, 56% (18/32) of nonfunctioning pancreatic neuroendocrine tumors had lymph node metastases compared to 10% (4/41) of insulinomas (P = .001). Estimated 10-year liver metastases-free survival was 63% (95% confidence interval 42%-76%) for nonfunctioning pancreatic neuroendocrine tumors and 87% (72%-91%) for insulinomas. After adjustment for size, World Health Organization tumor grade, and age, nonfunctioning pancreatic neuroendocrine tumors had an increased risk for liver metastases or death (hazard ratio 3.04 [1.47-6.30]). In pancreatic neuroendocrine tumors ≥2 cm, nonfunctioning pancreatic neuroendocrine tumors (2.99 [1.22-7.33]) and World Health Organization grade 2 (2.95 [1.02-8.50]) were associated with liver metastases-free survival. CONCLUSION: Patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors had a significantly lower liver metastases-free survival than patients with insulinomas. Postoperative counseling and follow-up regimens should be tumor type specific and at least consider size and World Health Organization grade.

Introduction The incidence, timing, and implications of recurrence in patients who underwent neoadjuvant treatment and surgical resection of borderline resectable (BRPC) or locally advanced (LAPC) pancreatic cancer are not well established. Materials and methods Patients with BRPC/LAPC who underwent post-neoadjuvant resection between 2007 and 2015 were included. Associations between clinicopathologic characteristics and specific recurrence locations, recurrence-free survival (RFS), and overall survival from resection (OS) were assessed using Cox regression analyses. Results For 231 included patients, median survival from diagnosis and resection were 28.0 and 19.8 months, respectively. After a median RFS of 7.9 months, 189 (81.8%) patients had recurred. Multiple-site (n = 87, 46.0%) and liver-only recurrence (n = 28, 14.8%) generally occurred earlier and resulted in significantly worse OS when compared to local-only (n = 52, 27.5%) or lung-only recurrence (n = 18, 9.5%). Microscopic perineural invasion, yN1-yN2 status and elevated pre-surgery CA 19-9 >100 U/mL were associated with both local-only and multiple-site/liver-only recurrence. R1-margin was associated with local-only recurrence (HR 2.03). yN1-yN2 status and microscopic perineural invasion were independent predictors for both poor RFS and OS, while yT3-yT4 tumor stage (HR 1.39) and poor tumor differentiation (HR 1.60) were only predictive of poor OS. Adjuvant therapy was independently associated with both prolonged RFS (HR 0.73; median 7.0 vs. 10.9 months) and OS (HR 0.69; median 15.4 vs. 22.7 months). Conclusion Despite neoadjuvant therapy leading to resection and relatively favorable pathologic tumor characteristics in BRPC/LAPC patients, more than 80% of patients experienced disease recurrence, 72.5% of which occurred at distant sites.

Background: In a first step toward standardization, the Primary Aldosteronism Surgical Outcomes investigators introduced consensus criteria defining the clinical outcomes after adrenalectomy for primary aldosteronism. Within this retrospective cohort study, we evaluated the use of these consensus criteria in daily clinical practice in 16 centers in Europe, Canada, Australia, and the United States.Methods: Patients who underwent unilateral adrenalectomy for primary aldosteronism between 2010 and 2016 were included. Patients with missing data regarding preoperative or postoperative blood pressure or their defined daily dose were excluded. According to the Primary Aldosteronism Surgical Outcomes criteria, patients were classified as complete, partial, or absent clinical success.Results: A total of 380 patients were eligible for analysis. Complete, partial, and absent clinical success was achieved in 30%, 48%, and 22%, respectively. Evaluation of the Primary Aldosteronism Surgical Outcomes criteria showed that in 11% and 47% of patients with partial and absent clinical success, this classification was incorrect or debatable (16% of the total cohort). This concept of a "debatable classification of success" was due mainly to the cutoff of >= 20 mmHg used to indicate a clinically relevant change in systolic blood pressure and the use of percentages instead of absolute values to indicate a change in defined daily dose.Conclusion: Although introduction of the Primary Aldosteronism Surgical Outcomes consensus criteria induced substantial advancement in the standardization of postoperative outcomes, our study suggests that there is room for improvement in the concept for success given the observed limitations when the criteria were tested within our international cohort. In line, determining clinical success remains challenging, especially in patients with opposing change in blood pressure and defined daily dose. (C) 2019 Elsevier Inc. All rights reserved.

OBJECTIVES: To establish an evidence-based cut-off to differentiate between early and late recurrence and to compare clinicopathologic risk factors between the two groups. SUMMARY BACKGROUND DATA: A clear definition of "early recurrence" after pancreatic ductal adenocarcinoma resection is currently lacking. METHODS: Patients undergoing pancreatectomy for pancreatic ductal adenocarcinoma between 2000 and 2013 were included. Exclusion criteria were neoadjuvant therapy and incomplete follow-up. A minimum P-value approach was used to evaluate the optimal cut-off value of recurrence-free survival to divide the patients into early and late recurrence cohorts based on subsequent prognosis. Potential risk factors for early recurrence were assessed with logistic regression models. RESULTS: Of 957 included patients, 204 (21.3%) were recurrence-free at last follow-up. The optimal length of recurrence-free survival to distinguish between early (n = 388, 51.5%) and late recurrence (n = 365, 48.5%) was 12 months (P < 0.001). Patients with early recurrence had 1-, and 2-year post-recurrence survival rates of 20 and 6% compared with 45 and 22% for the late recurrence group (both P < 0.001). Preoperative risk factors for early recurrence included a Charlson age-comorbidity index ≥4 (OR 1.65), tumor size > 3.0 cm on computed tomography (OR 1.53) and CA 19-9 > 210 U/mL (OR 2.30). Postoperative risk factors consisted of poor tumor differentiation grade (OR 1.66), microscopic lymphovascular invasion (OR 1.70), a lymph node ratio > 0.2 (OR 2.49), and CA 19-9 > 37 U/mL (OR 3.38). Adjuvant chemotherapy (OR 0.28) and chemoradiotherapy (OR 0.29) were associated with a reduced likelihood of early recurrence. CONCLUSION: A recurrence-free interval of 12 months is the optimal threshold for differentiating between early and late recurrence, based on subsequent prognosis.

BACKGROUND: Minor liver resections of posterosuperior segments (1, 4A, 7, 8) are challenging to perform laparoscopically and are mainly performed using an open approach. We determined the feasibility of robotic resections of posterosuperior segments and compared short-term outcomes with the open approach. METHODS: Data on open and robotic minor (≤ 3 segments) liver resections including the posterosuperior segments, performed between 2009 and 2016, were collected retrospectively from four hospitals. Robotic and open liver resections were compared, before and after propensity score matching. RESULTS: In total, 51 robotic and 145 open resections were included. After matching, 31 robotic resections were compared with 31 open resections. Median hospital stay was 4 days (interquartile range [IQR] 3-7) for the robotic group, versus 8 days (IQR 6-10) for the open group (p 0.99). There was no mortality in either group. CONCLUSION: Minor robotic liver resections of the posterosuperior segments are safe and feasible and display a shorter length of stay than open resections in selected patients at expert centers.

High levels of oxidative stress in disseminated colorectal cancer tumor cells may form a therapeutically exploitable vulnerability. However, it is unclear whether oxidative stress and damage persist in metastases. Therefore, we analyzed markers of oxidative damage in primary colorectal tumors and their corresponding liver metastases. Markers of generic and oxidative DNA damage [phosphorylated histone H2AX (γH2AX) and 8-hydroxy-2'-deoxyguanosine (8-OHdG)] were significantly higher in liver metastases compared with their corresponding primary tumors. Chemotherapy and/or radiotherapy before tumor resection was associated with increased persistent oxidative DNA damage, and this effect was more pronounced in metastases. Immunohistochemistry-based molecular classification into epithelial- and mesenchymal-like molecular subtypes revealed that untreated mesenchymal-like tumors contained lower levels of oxidative DNA damage compared with epithelial-like tumors. Treated mesenchymal-like tumors, but not epithelial-like tumors, showed significantly higher levels of γH2AX and 8-OHdG. Mesenchymal-like tumors expressed significantly lower levels of phosphorylated nuclear factor erythroid 2-related factor 2, a master regulator of the antioxidant response, and nuclear factor erythroid 2-related factor 2-controlled genes. Of interest, a positive 8-OHdG status identified a subgroup of mesenchymal-like metastases with a poor overall survival. An increased capacity to tolerate therapy-induced oxidative damage in mesenchymal-like colorectal cancer may explain, at least in part, the poor responsiveness of these tumors to chemotherapy, which could contribute to the poor survival of this patient subgroup.

The liver’s cellular functions are sustained by a hierarchical, segmentally-organized vascular system. Additionally, liver lymphatic vessels are thought to drain to perihepatic lymph nodes. Surprisingly, while recent findings highlight the importance of organ-specific lymphatics, the functional anatomy of liver lymphatics has not been mapped out. In literature, no segmental or preferential lymphatic drainage patterns are known to exist. We employ a novel murine model of liver lymphangiography and in vivo microscopy to delineate the lymphatic drainage patterns of individual liver lobes. Our data from blue dye liver lymphangiography show preferential lymphatic drainage patterns: Right lobe mainly to hepatoduodenal ligament lymph node 1 (LN1); left lobe to hepatoduodenal ligament LN1 + LN2 concurrently; median lobe showed a more variable LN1/LN2 drainage pattern with increased (sometimes exclusive) mediastinal thoracic lymph node involvement, indicating that part of the liver can drain directly to the mediastinum. Upon ferritin lymphangiography, we observed no functional communication between the lobar lymphatics. Altogether, these results show the existence of preferential lymphatic drainage patterns in the murine liver. Moreover, this drainage can occur directly to mediastinal lymph nodes and there is no interlobar lymphatic flow. Collectively, these data provide the first direct evidence that liver lymphatic drainage patterns follow segmental anatomy.

Background Radioembolization is an established treatment modality in colorectal cancer patients with liver-dominant disease in a salvage setting. Selection of patients who will benefit most is of vital importance. The aim of this study was to assess response (and mode of progression) at 3 months after radioembolization and the impact of baseline characteristics. Methods Three months after radioembolization with either yttrium-90 resin/glass or holmium-166, anatomic response, according to RECIST 1.1, was evaluated in 90 patients. Correlations between baseline characteristics and efficacy were evaluated. For more detailed analysis of progressive disease as a dismal clinical entity, distinction was made between intra- and extrahepatic progression, and between progression of existing metastases and new metastases. Results Forty-two patients (47%) had extrahepatic disease (up to five ≥ 1 cm lung nodules, and ≤ 2 cm lymph nodes) at baseline. No patients showed complete response, 5 (5.5%) patients had partial response, 16 (17.8%) had stable disease, and 69 (76.7%) had progressive disease. Most progressive patients (67/69; 97%) had new metastases (intra-hepatic N = 11, extrahepatic N = 32; or both N = 24). Significantly fewer patients had progressive disease in the group of patients presenting without extrahepatic metastases at baseline (63% versus 93%; p = 0.0016). Median overall survival in patients with extrahepatic disease was 6.5 months, versus 10 months in patients without extrahepatic disease at baseline (hazard ratio 1.79, 95%CI 1.24–2.57). Conclusions Response at 3-month follow-up and survival were heavily influenced by new metastases. Patients with extrahepatic disease at baseline had a worse outcome compared to patients without.

Background Differentiated thyroid carcinoma (DTC) is the most common type of thyroid cancer. Treatment with surgery, radioactive iodine (RAI), and TSH suppression is effective in most patients. Five to 15% of patients become RAI refractory and need alternative therapy; however, treatment options are limited. 68Ga-PSMA PET/CT, originally developed for prostate cancer, is also applicable to other malignancies, including thyroid carcinoma. The uptake of PSMA in thyroid carcinoma gives opportunities for imaging and therapy of RAI-refractory DTC. The aim of this study was to analyze imaging on 68Ga-PSMA PET/CT and evaluate the response to 177Lu-PSMA-617 therapy in patients with RAI-refractory DTC. Materials and methods Five patients with RAI-refractory DTC underwent 68Ga-PSMA PET/CT to determine their eligibility for 177Lu-PSMA-617 therapy. 68Ga-PSMA PET/CTs were analyzed visually and quantitatively. Response to 177Lu-PSMA-617 therapy was evaluated using imaging and thyroglobulin (Tg) values. Results Tracer uptake suspicious for distant metastases was depicted in all 68Ga-PSMA PET/CTs. Based on tracer uptake, three patients were eligible for 177Lu-PSMA-617 therapy, of whom two were treated. One patient showed disease progression on imaging 1 month later, while her Tg values gradually increased from 18 to 63 μg/L in the months after treatment. Another patient showed partial, temporary response of lung and liver metastases. Her Tg levels initially decreased from 17 to 9 μg/L. However, 7 months after treatment, there was disease progression on imaging and Tg levels had increased to 14 μg/L. Imaging with 68Ga-PSMA PET/CT could be compared to 18FDG PET/CT in three patients. Two patients showed additional lesions on 68Ga-PSMA PET/CT, and one patient showed concordant imaging. Conclusion 68Ga-PSMA PET/CT appears to have added value in patients with RAI-refractory DTC, as it is able to detect various types of lesions, some of which were not picked up by 18FDG PET/CT. Furthermore, 68Ga-PSMA PET/CT might be used to identify patients eligible for treatment with 177Lu-PSMA-617. One of the two patients who underwent 177Lu-PSMA-617 therapy showed a modest, temporary response. To draw conclusions about the effectiveness of this therapy, more research is needed.