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Background: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases, with a focus on terminology, diagnosis, and management., Methods: This project was a multiorganizational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis, and management. Statements were refined during an online Delphi process, and those with 70 per cent agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising 12 key statements., Results: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term 'early metachronous metastases' applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour, the term 'late metachronous metastases' applies to those detected after 12 months. 'Disappearing metastases' applies to lesions that are no longer detectable on MRI after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards, and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways, including systemic chemotherapy, synchronous surgery, and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed., Conclusion: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd and published by Elsevier Ltd on behalf of the International Hepato-Pancreato-Biliary Association Inc.)

Objectives: Coronavirus disease 2019 has put unprecedented pressure on healthcare systems worldwide, leading to a reduction of the available healthcare capacity. Our objective was to develop a decision model to estimate the impact of postponing semielective surgical procedures on health, to support prioritization of care from a utilitarian perspective., Methods: A cohort state-transition model was developed and applied to 43 semielective nonpediatric surgical procedures commonly performed in academic hospitals. Scenarios of delaying surgery from 2 weeks were compared with delaying up to 1 year and no surgery at all. Model parameters were based on registries, scientific literature, and the World Health Organization Global Burden of Disease study. For each surgical procedure, the model estimated the average expected disability-adjusted life-years (DALYs) per month of delay., Results: Given the best available evidence, the 2 surgical procedures associated with most DALYs owing to delay were bypass surgery for Fontaine III/IV peripheral arterial disease (0.23 DALY/month, 95% confidence interval [CI]: 0.13-0.36) and transaortic valve implantation (0.15 DALY/month, 95% CI: 0.09-0.24). The 2 surgical procedures with the least DALYs were placing a shunt for dialysis (0.01, 95% CI: 0.005-0.01) and thyroid carcinoma resection (0.01, 95% CI: 0.01-0.02)., Conclusion: Expected health loss owing to surgical delay can be objectively calculated with our decision model based on best available evidence, which can guide prioritization of surgical procedures to minimize population health loss in times of scarcity. The model results should be placed in the context of different ethical perspectives and combined with capacity management tools to facilitate large-scale implementation., (Copyright © 2021 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: To optimize the postoperative phase following bariatric surgery, the enhanced recovery after bariatric surgery pathway (ERABS) has been developed. The aim of ERABS is to create a care path that is as safe, efficient and patient-friendly as possible. Continuous evaluation and optimization of ERABS are important to ensure a safe treatment path and may result in better outcomes. The objective of this study was to compare the clinical outcomes of patients undergoing bariatric surgery over 2014-2017, during which the ERABS protocol was continuously evaluated and optimized., Methods: This is a retrospective cohort study. Data were collected from patients undergoing a primary Roux-en-Y gastric bypass or sleeve gastrectomy between January 2014 and December 2017. Outcomes were early complications, unplanned hospital revisits, readmissions, duration of surgery and length of hospital stay., Results: 2889 patients underwent a primary bariatric procedure in a single center. There was a significant decrease in minor complications over the years from 7.0 to 1.9% (p < 0.001). Hospital revisit rates decreased after 2015 (p < 0.001). Readmission rates decreased over time (p < 0.001). The mean duration of surgery decreased from 52 (in 2014) to 41 (in 2017) minutes (p < 0.001). Median length of hospital stay decreased from 1.8 to 1.5 days in 2015 (p = 0.002) and remained stable since., Conclusion: An improvement of the ERABS protocol was associated with a decrease in minor complication rates, number of unplanned hospital revisits and readmission rates after primary bariatric procedures.

Anti-cancer T-cell responses are often halted due to the immune-suppressive micro-environment, in part related to tumor-associated macrophages. In the current study, we assessed indigestible β-glucans (oatβG, curdlan, grifolan, schizophyllan, lentinan, yeast whole glucan particles (yWGP), zymosan and two additional yeast-derived β-glucans a and b) for their physicochemical properties as well as their effects on the plasticity of human monocyte-derived macrophages that were polarized with IL-4 to immune-suppressive macrophages. Beta-glucans were LPS/LTA free, and tested for solubility, molecular masses, protein and monosaccharide contents. Curdlan, yeast-b and zymosan re-polarized M(IL-4) macrophages towards an M1-like phenotype, in particular showing enhanced gene expression of CCR7, ICAM1 and CD80, and secretion of TNF-α and IL-6. Notably, differential gene expression, pathway analysis as well as protein expressions demonstrated that M(IL-4) macrophages treated with curdlan, yeast-b or zymosan demonstrated enhanced production of chemo-attractants, such as CCL3, CCL4, and CXCL8, which contribute to recruitment of monocytes and neutrophils. The secretion of chemo-attractants was confirmed when using patient-derived melanoma-infiltrating immune cells. Taken together, the bacterial-derived curdlan as well as the yeast-derived β-glucans yeast-b and zymosan have the unique ability to preferentially skew macrophages towards a chemo-attractant-producing phenotype that may aid in anti-cancer immune responses.

Background: OX40 (CD134) is a costimulatory molecule of the tumor necrosis factor receptor superfamily that is currently being investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic αOX40 antibodies in the treatment of patients with cancer has fallen short of the high expectation in earlier-stage trials., Methods: Using lymphocytes from resected tumor, tumor-free (TF) tissue and peripheral blood mononuclear cells (PBMC) of 96 patients with hepatocellular and colorectal cancers, we determined OX40 expression and the in vitro T-cell agonistic activity of OX40-targeting compounds. RNA-Seq was used to evaluate OX40-mediated transcriptional changes in CD4+ and CD8+ human tumor-infiltrating lymphocytes (TILs)., Results: Here, we show that OX40 was overexpressed on tumor-infiltrating CD4+ T cells compared with blood and TF tissue-derived T cells. In contrast to a clinical candidate αOX40 antibody, treatment with an Fc-engineered αOX40 antibody (αOX40&#95;v12) with selectively enhanced FcγRIIB affinity, stimulated in vitro CD4+ and CD8+ TIL expansion, as well as cytokine and chemokine secretions. The activity of αOX40&#95;v12 was dependent on FcγRIIB engagement and intrinsic CD3/CD28 signals. The transcriptional landscape of CD4+ and CD8+ TILs shifted toward a prosurvival, inflammatory and chemotactic profile on treatment with αOX40&#95;v12., Conclusions: OX40 is overexpressed on CD4+ TILs and thus represents a promising target for immunotherapy. Targeting OX40 with currently used agonistic antibodies may be inefficient due to lack of OX40 multimerization. Thus, Fc engineering is a powerful tool in enhancing the agonistic activity of αOX40 antibody and may shape the future design of antibody-mediated αOX40 immunotherapy., Competing Interests: Competing interests: JW, TSF, KC, WY, IN, YAY and SS-A are employees of Pfizer and have stocks and ownership interests (including patents) at Pfizer., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: During oncoplastic breast-conserving surgery (BCS), the surgical cavity is closed to reduce seroma formation. This makes the radiotherapy target definition using clips challenging, leading to poor inter-observer agreement and potentially geographical misses. We hypothesize that injecting a radiopaque hydrogel in the lumpectomy cavity before closure improves radiotherapy target definition and agreement between observers., Materials and Methods: Women undergoing BCS in a single university hospital were prospectively accrued in the study. Three to 9 ml of iodined PolyEthylene Glycol (PEG) hydrogel and clips were inserted in the lumpectomy cavity. A CT-scan was performed at 4 to 6 weeks. CT images of BCS patients with standard clips only were used as control group, matched on age, specimen weight, and distance between clips. Six radiation oncologists delineated the tumor bed volumes and rated the cavity visualization scores (CVS). The primary endpoint was the agreement between observers measured using a Conformity Index (Cx)., Results: Forty-two patients were included, 21 hydrogel procedures and 21 controls, resulting in 315 observer pairs. The feasibility of the intervention was 100%. The median Cx was higher in the intervention group (Cx = 0.70, IQR [0.54-0.79]) than in the control group (Cx = 0.54, IQR [0.42-0.66]), p < 0.00, as were the CVS (3.5 [2.5-4.5] versus 2.5 [2-3.5], p < 0.001). The rate of surgical site infections was similar to literature., Conclusions: The use of radiopaque PEG enables to identify the lumpectomy cavity, resulting in a high inter-observer agreement for radiotherapy target definition. This intervention is easy to perform and blend well into current practice., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Post-hepatectomy liver insufficiency (PHLI) is a significant cause of morbidity and mortality after liver resection. Quantitative imaging analysis using CT scans measures variations in pixel intensity related to perfusion. A preliminary study demonstrated a correlation between quantitative imaging features of the future liver remnant (FLR) parenchyma from preoperative CT scans and PHLI. The objective of this study was to explore the potential application of quantitative imaging analysis in PHLI in an expanded, multi-institutional cohort., Study Design: We retrospectively identified patients from 5 high-volume academic centers who developed PHLI after major hepatectomy, and matched them to control patients without PHLI (by extent of resection, preoperative chemotherapy treatment, age [±5 years], and sex). Quantitative imaging features were extracted from the FLR in the preoperative CT scan, and the most discriminatory features were identified using conditional logistic regression. Percent remnant liver volume (RLV) was defined as follows: (FLR volume)/(total liver volume) × 100. Significant clinical and imaging features were combined in a multivariate analysis using conditional logistic regression., Results: From 2000 to 2015, 74 patients with PHLI and 74 matched controls were identified. The most common indications for surgery were colorectal liver metastases (53%), hepatocellular carcinoma (37%), and cholangiocarcinoma (9%). Two CT imaging features (FD1&#95;4: image complexity; ACM1&#95;10: spatial distribution of pixel intensity) were strongly associated with PHLI and remained associated with PHLI on multivariate analysis (p = 0.018 and p = 0.023, respectively), independent of clinical variables, including preoperative bilirubin and %RLV., Conclusions: Quantitative imaging features are independently associated with PHLI and are a promising preoperative risk stratification tool., (Copyright © 2018 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: In 1 of 3 patients with initial lymph node-positive (cN + ) breast cancer, neoadjuvant chemotherapy (NAC) results in an axillary pathologic complete response (ax-pCR). This urges the need for a less-invasive axillary staging method. Recently introduced less-invasive procedures have been insufficient in accurately identifying ax-pCR. Therefore, we propose a novel less-invasive axillary staging procedure: the Radioactive Iodine Seed localization in the Axilla with the Sentinel node procedure (RISAS), a combination of the procedure of marking axillary lymph nodes with radioactive iodine seeds (MARI) and sentinel lymph node biopsy (SLNB)., Patients and Methods: In the present open single-arm multicenter validation study, 225 cN + (biopsy-proven) patients will undergo the RISAS procedure, in which a positive lymph node is marked by an iodine-125 seed before NAC. After NAC completion, this iodine-125 seed-marked lymph node is removed, together with any additional sentinel lymph nodes. The RISAS procedure is subsequently followed by completion axillary lymph node dissection (ALND). The RISAS lymph nodes will be compared with the lymph nodes from the completion ALND specimen. The primary endpoint is accuracy of the RISAS procedure. The identification rate, false-negative rate, negative predictive value, and possible concordance between the MARI and SLNB will be reported., Conclusion: The present prospective multicenter RISAS trial will enable us to validate the combination of MARI and SLNB for assessing the axillary response to NAC in cN + patients. If RISAS proves to be an accurate axillary staging procedure, ALND could safely be abandoned in the case of ax-pCR confirmed using the RISAS procedure., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In the 7 th edition of the AJCC staging system, the mitotic rate criterion replaced Clark level to increase correct classification of high-risk thin melanoma patients (pT1B). Additionally, sentinel node biopsy (SNB) was recommended for nodal staging of pT1B melanomas. The aim of this article was to evaluate the effects on pT1 substaging and clinical implications in the national pT1 melanoma population. All pT1 melanomas diagnosed in the Netherlands between 2003 and 2014 were selected from the Netherlands Cancer Registry (IKNL). Patients were stratified by cohort according to AJCC edition: (1) 2003-2009 (6 th ) and (2) 2010-2014 (7 th ). Relative survival was calculated to estimate melanoma-specific survival. A total of 29.546 pT1 melanoma patients were included. The pT1b proportion increased from 10.1% in Cohort 1 to 21.5% in Cohort 2. The proportion of performed SNBs per cohort increased: for pT1b melanomas alone from 4.5% to 13.0%. SNB positivity rate decreased from 10.5% to 8.8% for the entire pT1 population, and for pT1b melanomas from 11.3% to 8.6%. At 5 years, the relative survival rate was similar for pT1a and pT1b in both cohorts, namely, pT1a 100% vs pT1b 97% (Cohort 1), and pT1a 100% vs pT1b 98% (Cohort 2). The 7 th edition of the AJCC staging system has caused an increased number of patients to undergo SNB, without an increase in SNB positivity rate. Survival between pT1 subgroups remains similar. The mitotic rate criterion for pT1b classification and the recommendation to perform SNB for pT1b melanomas should be reconsidered., (© 2017 UICC.)

Goals and Background: Spontaneous rupture is a rare complication of hepatocellular carcinoma (HCC). Treatment options consist of transcatheter arterial embolization (TAE), hepatic resection, and conservative therapy. The best approach is under debate., Study: This study presents a review of clinical data of patients with a ruptured HCC admitted to a European tertiary care center., Results: Eleven patients were included; six (55%) had underlying cirrhosis. The majority of patients (73%) had no previous history of HCC. Spontaneous HCC rupture was diagnosed using abdominal computed tomography with or without a diagnostic paracentesis. Computed tomography showed one or two tumors in eight (73%) patients; the other patients had multiple tumors or diffuse infiltrative HCC. Seven (64%) patients were initially treated by TAE and one (9%) patient underwent hepatic resection. The remaining three (27%) patients, all of whom had liver cirrhosis, received conservative therapy. Two patients initially treated by TAE underwent a delayed resection and ultimately received systemic therapy. Overall, at the end of the follow-up period, three patients were still alive at 84, 991, and 1026 days after the initial presentation. Eight (73%) patients had died after a median of 88 days (range 7-417). One year after presentation, none of the conservatively treated patients was alive compared with three out of seven (43%) patients treated with TAE with or without delayed resection., Conclusion: Patients with a spontaneously ruptured HCC have a poor prognosis. In selected patients, however, prolonged survival is possible using TAE as initial therapy with or without a delayed resection and systemic therapy.

How are bilinguals able to switch from one language to another? The prevailing inhibition hypothesis takes larger reaction-time (RT) costs for switching to the first language (L1) than to the second language (L2) as evidence for suppression of the non-target language. Switch cost asymmetries can alternatively be explained by an L1-repeat-benefit, assuming selective absence of language competition in repeating L1. To test the latter hypothesis, RTs and event-related brain potentials (ERPs) were recorded when unbalanced Dutch-English bilinguals switched between overt picture naming in L1 and L2. Preparation time (short versus long cue-stimulus intervals) modulated the degree to which top-down inhibitory control biased language competition, as indexed by the N2 component of the ERP. RT switch costs were asymmetrical on short intervals and symmetrical on long intervals. Preparation interval effects were observed in all conditions except for L1 repeat trials. This pattern was present both for RT and N2 data, thereby supporting the L1-repeat-benefit hypothesis. These results suggest that inhibition is not necessary, but can modulate the efficiency of language switching.

Live attenuated human immunodeficiency virus type 1 (HIV-1) vaccines are considered unsafe because more quickly replicating pathogenic virus variants may evolve after vaccination. As an alternative vaccine approach, we have previously presented a doxycycline (dox)-dependent HIV-1 variant that was constructed by incorporating the tetracycline-inducible gene expression system (Tet-On system) into the viral genome. Replication of this HIV-rtTA variant is driven by the dox-inducible transcriptional activator rtTA and can be switched on and off at will. A large scale evolution study was performed to test the genetic stability of this conditional live vaccine candidate. In several long term cultures, we selected for HIV-rtTA variants that no longer required dox for replication. These evolved variants acquired a typical amino acid substitution either at position 19 or 37 in the rtTA protein. Both mutations caused rtTA activity and viral replication in the absence of dox. We designed a novel rtTA variant with a higher genetic barrier toward these undesired evolutionary routes. The corresponding HIV-rtTA variant did not lose dox control in long term cultures, demonstrating its improved genetic stability.

We present viral evolution as a novel and powerful method to optimize non-viral proteins. We used this approach to optimize the tetracycline (Tc)-regulated gene expression system (Tet system) for its function in mammalian cells. The components of the Tet system were incorporated in the human immunodeficiency virus (HIV)-1 virus such that viral replication is controlled by this regulatory system. Upon long term replication of this HIV-rtTA virus in human T cells, we obtained a virus variant with an enhanced replication potential resulting from an improved rtTA component of the introduced Tet system. We identified a single amino acid exchange, F86Y, which enhances the transcriptional activity and doxycycline (dox) sensitivity of rtTA. We generated a new rtTA variant that is 5-fold more active at high dox levels than the initial rtTA, and 25-fold more sensitive to dox, whereas the background activity in the absence of dox is not increased. This new rtTA variant will be very useful in biological applications that require a more sensitive or active Tet system. Our results demonstrate that the viral evolution strategy can be used to improve the activity of genes by making them an integral and essential part of the virus.

Scanning arrays of antisense DNA oligonucleotides provide a novel and systematic means to study structural features within an RNA molecule. We used this approach to probe the structure of the untranslated leader of the human immunodeficiency virus type 1 (HIV-1) RNA genome. This 335 nt RNA encodes multiple important replication signals and adopts two mutually exclusive conformations. The poly(A) and the dimer initiation signal (DIS) sequences of the leader RNA are base-paired in the long-distance interaction (LDI) conformation, but both domains form distinct hairpins in the branched multiple hairpins (BMH) conformation. An RNA switch mechanism has been proposed to regulate the activity of the DIS dimerization signal that is masked in one, yet exposed in the other conformation. The two RNA conformations demonstrate discrete differences in the array-based hybridization patterns. LDI shows increased hybridization in the poly(A) region and decreased hybridization in the DIS region when compared with BMH. These results provide additional evidence for the structure models of the two alternative leader RNA conformations. We also found a correlation between the efficiency of oligonucleotide hybridization and the accessibility of the RNA structure as determined by chemical and enzymatic probing in previous studies. The array approach therefore provides a very sensitive method to detect structural differences in related transcripts.