Detection of Circulating Tumor Cells Using the Attune NxT.

Circulating tumor cells (CTCs) have been detected in many patients with different solid malignancies. It has been reported that presence of CTCs correlates with worse survival in patients with multiple types of cancer. Several techniques have been developed to detect CTCs in liquid biopsies. Currently, the only method for CTC detection that is approved by the Food and Drug Administration is CellSearch. Due to low abundance of CTCs in certain cancer types and in early stages of disease, its clinical application is currently limited to metastatic colorectal cancer, breast cancer and prostate cancer. Therefore, we aimed to develop a new method for the detection of CTCs using the Attune NxT-a flow cytometry-based application that was specifically developed to detect rare events in biological samples without the need for enrichment. When healthy donor blood samples were spiked with variable amounts of different EpCAM+EGFR+ tumor cell lines, recovery yield was on average 75%. The detection range was between 1000 and 10 cells per sample. Cell morphology was confirmed with the Attune CytPix. Analysis of blood samples from metastatic colorectal cancer patients, as well as lung cancer patients, demonstrated that increased EpCAM+EGFR+ events were detected in more than half of the patient samples. However, most of these cells showed no (tumor) cell-like morphology. Notably, CellSearch analysis of blood samples from a subset of colorectal cancer patients did not detect CTCs either, suggesting that these blood samples were negative for CTCs. Therefore, we anticipate that the Attune NxT is not superior to CellSearch in detection of low amounts of CTCs, although handling and analysis of samples is easier. Moreover, morphological confirmation is essential to distinguish between CTCs and false positive events.

Advanced analytics and artificial intelligence in gastrointestinal cancer: a systematic review of radiomics predicting response to treatment.

PURPOSE: Advanced medical image analytics is increasingly used to predict clinical outcome in patients diagnosed with gastrointestinal tumors. This review provides an overview on the value of radiomics in predicting response to treatment in patients with gastrointestinal tumors. METHODS: A systematic review was conducted, according to PRISMA guidelines. The protocol was prospectively registered (PROSPERO: CRD42019128408). PubMed, Embase, and Cochrane databases were searched. Original studies reporting on the value of radiomics in predicting response to treatment in patients with a gastrointestinal tumor were included. A narrative synthesis of results was conducted. Results were stratified by tumor type. Quality assessment of included studies was performed, according to the radiomics quality score. RESULTS: The comprehensive literature search identified 1360 unique studies, of which 60 articles were included for analysis. In 37 studies, radiomics models and individual radiomic features showed good predictive performance for response to treatment (area under the curve or accuracy > 0.75). Various strategies to construct predictive models were used. Internal validation of predictive models was often performed, while the majority of studies lacked external validation. None of the studies reported predictive models implemented in clinical practice. CONCLUSION: Radiomics is increasingly used to predict response to treatment in patients suffering from gastrointestinal cancer. This review demonstrates its great potential to help predict response to treatment and improve patient selection and early adjustment of treatment strategy in a non-invasive manner.

Incomplete patient information exchange and unnecessary repeat diagnostics during oncological referrals in the Netherlands: exploring the role of information exchange.

Data management in transmural care is complex. Without digital innovations like Health Information Exchange (HIE), patient information is often dispersed and inaccessible across health information systems between hospitals. The extent of information loss and consequences remain unclear. We aimed to quantify patient information availability of referred oncological patients and to assess its impact on unnecessary repeat diagnostics by observing all oncological multidisciplinary team meetings (MDTs) in a tertiary hospital. During 84 multidisciplinary team meetings, 165 patients were included. Complete patient information was provided in 17.6% (29/165, CI = 12.3-24.4) of patients. Diagnostic imaging was shared completely in 52.5% (74/141, CI = 43.9-60.9), imaging reports in 77.5% (100/129, CI = 69.2-84.2), laboratory results in 55.2% (91/165, CI = 47.2-62.8), ancillary test reports in 58.0% (29/50, CI = 43.3-71.5), and pathology reports in 60.0% (57/95, CI = 49.4-69.8). A total of 266 tests were performed additionally, with the main motivation not previously performed followed by inconclusive or insufficient quality of previous tests. Diagnostics were repeated unnecessarily in 15.8% (26/165, CI = 10.7-22.4) of patients. In conclusion, patient information was provided incompletely in majority of referrals discussed in oncological multidisciplinary team meetings and led to unnecessary repeat diagnostics in a small number of patients. Additional research is needed to determine the benefit of Health Information Exchange to improve data transfer in oncological care.

Optimization of transmural care by implementation of an online expert panel to assess treatment strategy in patients suffering from colorectal cancer liver metastases: A prospective analysis.

INTRODUCTION: Centralization of oncological care results in a growing demand for specialized consultations and referrals. Improved telemedicine solutions are needed to facilitate access to specialist care and select patients eligible for referral. The purpose of this quality improvement initiative was to optimize transmural care for patients suffering from colorectal cancer liver metastases through implementation of an online expert panel. METHODS: A digital communication platform was developed to share medical data, including high-quality diagnostic imaging of patients suffering from colorectal cancer liver metastases. Feasibility of local treatment strategies was assessed by a panel of liver specialists to select patients for referral. After implementation, an observational cohort study was conducted to evaluate quality improvement in transmural care using revised Standards for Quality Improvement Reporting Excellence guidelines. RESULTS: From September 2016-September 2018, eight hospitals were connected to the platform, covering a population of 3 m. In total, 123 cases were assessed, of which 54 (43.9%) were prevented from needless physical referral. Assessment of treatment strategy by an online expert panel significantly reduced the average lead time during multidisciplinary team meetings from 3.73 min to 2.12 min per patient (p < 0.01). CONCLUSIONS: Implementation of an online expert panel is an innovative, accessible and user-friendly way to provide cancer-specific expertise to regional hospitals. E-consultation of such panels may result in more efficient multidisciplinary team meetings and prevent fragile patients from needless referral. Sustainability of these panels however is subject to structural financial compensation, so a cost-effectiveness analysis is warranted.

Epidermal Growth Factor Receptor as Target for Perioperative Elimination of Circulating Colorectal Cancer Cells.

Surgical resection of the tumor is the primary treatment of colorectal cancer patients. However, we previously demonstrated that abdominal surgery promotes the adherence of circulating tumor cells (CTC) in the liver and subsequent liver metastasis development. Importantly, preoperative treatment with specific tumor-targeting monoclonal antibodies (mAb) prevented surgery-induced liver metastasis development in rats. This study investigated whether the epidermal growth factor receptor (EGFR) represents a suitable target for preoperative antibody treatment of colorectal cancer patients undergoing surgery. The majority of patients with resectable colorectal liver metastases were shown to have EGFR + CTCs. Three different anti-EGFR mAbs (cetuximab, zalutumumab, and panitumumab) were equally efficient in the opsonization of tumor cell lines. Additionally, all three mAbs induced antibody-dependent cellular phagocytosis (ADCP) of tumor cells by macrophages at low antibody concentrations in vitro, independent of mutations in EGFR signaling pathways. The plasma of cetuximab-treated patients efficiently opsonized tumor cells ex vivo and induced phagocytosis. Furthermore, neither proliferation nor migration of epithelial cells was affected in vitro, supporting that wound healing will not be hampered by treatment with low anti-EGFR mAb concentrations. These data support the use of a low dose of anti-EGFR mAbs prior to resection of the tumor to eliminate CTCs without interfering with the healing of the anastomosis. Ultimately, this may reduce the risk of metastasis development, consequently improving long-term patient outcome significantly.

Limited Effect of Perioperative Systemic Therapy in Patients Selected for Repeat Local Treatment of Recurrent Colorectal Cancer Liver Metastases.

Objectives: The aim of this study was to determine the potential benefit of perioperative systemic therapy on overall and progression-free survival after repeat local treatment in patients suffering from recurrent colorectal cancer liver metastasis (CRLM). Background: The optimal treatment strategy in patients with recurrent CRLM needs to be clarified, in particular for those suffering from early recurrence of CRLM. Methods: In this multicenter observational cohort study, consecutive patients diagnosed with recurrent CRLM between 2009 and 2019 were retrospectively identified in 4 academic liver surgery centers. Disease-free interval after initial local treatment of CRLM was categorized into recurrence within 6, between 6 and 12, and after 12 months. Perioperative systemic therapy consisted of induction, (neo)adjuvant, or combined regimens. Overall and progression-free survival after repeat local treatment of CRLM were analyzed by multivariable Cox regression analyses, resulting in adjusted hazard ratios (aHRs). Results: Out of 303 patients included for analysis, 90 patients received perioperative systemic therapy for recurrent CRLM. Favorable overall (aHR, 0.45; 95% confidence interval [CI], 0.26-0.75) and progression-free (aHR, 0.53; 95% CI, 0.35-0.78) survival were observed in patients with a disease-free interval of more than 12 months. No significant difference in overall and progression-free survival was observed in patients receiving perioperative systemic therapy at repeat local treatment of CRLM, stratified for disease-free interval, previous exposure to chemotherapy, and RAS mutation status. Conclusions: No benefit of perioperative systemic therapy was observed in overall and progression-free survival after repeat local treatment of recurrent CRLM.

Repeat hepatectomy justified in patients with early recurrence of colorectal cancer liver metastases: A systematic review and meta-analysis.

BACKGROUND: The benefit of repeat hepatectomy in patients with early recurrence of colorectal cancer liver metastases (CRLM) is questioned, in particular in those suffering from recurrence within three to six months following initial hepatectomy. The aim of this review was therefore to assess whether disease-free interval was associated with overall survival in patients undergoing repeat hepatectomy for recurrent CRLM. METHODS: A systematic review and meta-analysis was conducted, according to PRISMA guidelines. PubMed, Embase and Cochrane Library databases were searched from database inception to 6th June 2020. Observational studies describing results of repeat hepatectomy for recurrent CRLM, including (disease-free) interval between hepatic resections and overall survival were included. Patients undergoing repeat hepatectomy within three months or additional resection of extrahepatic disease were excluded from meta-analysis. RESULTS: The initial search identified 2159 records, of which 28 were included for qualitative synthesis. A meta-analysis of 15 cohort studies was performed, comprising 1039 eligible patients. Median overall survival of 54.0 months [95 %-CI: 38.6-69.4] was observed after repeat hepatectomy in patients suffering from recurrent CRLM between three to six months compared to 53.0 months [95 %-CI: 44.3-61.6] for patients with recurrent CRLM between seven to twelve months (adjusted HR = 0.89, 95 %-CI: 0.66-1.18; p = 0.410), and 60.0 months [95 %-CI: 52.7-67.3] for patients with recurrent CRLM after twelve months (adjusted HR = 0.70, 95 %-CI: 0.53-0.92; p = 0.012). CONCLUSIONS: Disease-free interval is considered a prognostic factor for overall survival, but should not be used as selection criterion per se for repeat hepatectomy in patients suffering from recurrent CRLM.

Augmented antibody-based anticancer therapeutics boost neutrophil cytotoxicity.

Most clinically used anticancer mAbs are of the IgG isotype, which can eliminate tumor cells through NK cell-mediated antibody-dependent cellular cytotoxicity and macrophage-mediated antibody-dependent phagocytosis. IgG, however, ineffectively recruits neutrophils as effector cells. IgA mAbs induce migration and activation of neutrophils through the IgA Fc receptor (FcαRI) but are unable to activate NK cells and have poorer half-life. Here, we combined the agonistic activity of IgG mAbs and FcαRI targeting in a therapeutic bispecific antibody format. The resulting TrisomAb molecules recruited NK cells, macrophages, and neutrophils as effector cells for eradication of tumor cells in vitro and in vivo. Moreover, TrisomAb had long in vivo half-life and strongly decreased B16F10gp75 tumor outgrowth in mice. Importantly, neutrophils of colorectal cancer patients effectively eliminated tumor cells in the presence of anti-EGFR TrisomAb but were less efficient in mediating killing in the presence of IgG anti-EGFR mAb (cetuximab). The clinical application of TrisomAb may provide potential alternatives for cancer patients who do not benefit from current IgG mAb therapy.

Survival Benefit of Repeat Local Treatment in Patients Suffering From Early Recurrence of Colorectal Cancer Liver Metastases.

BACKGROUND: A uniform treatment strategy for patients suffering from early recurrence after local treatment of CRLM is currently lacking. The aim of this observational cohort study was to assess the potential survival benefit of repeat local treatment compared to systemic therapy in patients suffering from early recurrence of CRLM. PATIENTS AND METHODS: Patients who developed recurrent CRLM within 12 months after initial local treatment with curative intent were retrospectively identified in Amsterdam University Medical Centers between 2009-2019. Differences in overall and progression-free survival among treatment strategies were assessed using multivariable Cox regression analyses. RESULTS: A total of 135 patients were included. Median overall survival of 41 months [range 4-135] was observed in patients who received repeat local treatment, consisting of upfront or repeat local treatment after neoadjuvant systemic therapy, compared to 24 months [range 1-55] in patients subjected to systemic therapy alone (adjusted HR = 0.42 [95%-CI: 0.25-0.72]; P = .002). Prolonged progression-free survival was observed after neoadjuvant systemic therapy followed by repeat local treatment, as compared to upfront repeat local treatment in patients with recurrent CRLM within 4 months following initial local treatment of CRLM (adjusted HR = 0.36 [95%-CI: 0.15-0.86]; P = .021). CONCLUSION: Patients with early recurrence of CRLM should be considered for repeat local treatment strategies. A multimodality approach, consisting of neoadjuvant systemic therapy followed by repeat local treatment, appeared favorable in patients with recurrence within 4 months following initial local treatment of CRLM.

A multidisciplinary neuro-oncological triage panel reduces the time to referral and treatment for patients with a brain tumor.

BACKGROUND: Regional collaboration and appropriate referral management are crucial in neuro-oncological care. Lack of electronic access to medical records across health care organizations impedes interhospital consultation and may lead to incomplete and delayed referrals. To improve referral management, we have established a multidisciplinary neuro-oncological triage panel (NOTP) with digital image exchange and determined the effects on lead times, costs, and time investment. METHODS: A prospective cohort study was conducted from February 2019 to March 2020. All newly diagnosed patients referred to Brain Tumor Center Amsterdam were analyzed according to referral pathway: (1) standard referral (SR), (2) NOTP. The primary outcome was lead time, defined as time-to-referral, time-to-treatment, and total time (median days [interquartile range]). Secondary outcomes were costs and time investment. RESULTS: In total, 225 patients were included, of whom 153 had SR and 72 NOTP referral. Patients discussed in the NOTP were referred more frequently for first neurosurgical consultation (44.7% vs 28.8%) or combined neurological and neurosurgical consultation (12.8% vs 2.5%, P = .002). Time-to-referral was reduced for NOTP referral compared to SR (1 [0.25-4] vs 6 [1.5-10] days, P < .001). Total time decreased from 27 [14-48] days for the standard group to 15 [12-38.25] days for the NOTP group (P = .040). Costs and time investment were comparable for both groups. CONCLUSION: Implementation of digital referral to a multidisciplinary NOTP is feasible and leads to more swift patient-tailored referrals at comparable costs and time investment as SR. This quality improvement initiative has the potential to improve collaboration and coordination of multidisciplinary care in the field of neuro-oncology.

Junctional bradycardia caused by ciguatera intoxication.

Ciguatera is a common but underreported tropical disease caused by the consumption of coral reef fish contaminated by ciguatoxins. Gastrointestinal and neurological symptoms predominate, but may be accompanied by cardiovascular features such as hypotension and sinus bradycardia. Here, we report an unusual case of junctional bradycardia caused by ciguatera in the Caribbean; to our knowledge, the first such report from the region. An increase in global sea temperatures is predicted to lead to the spread of ciguatera beyond traditional endemic areas, and the globalisation of trade in coral reef fish has resulted in sporadic cases occurring in developed countries far away from endemic areas. This case serves as a reminder to consider environmental intoxications such as ciguatera within the differential diagnosis of bradycardias.

[Sharing oncological knowledge via expert panels; are there legal obstacles or practical objections?] / Oncologische kennis delen via expertpanels.

Concentration and increasing specialization of oncological care makes it impossible for each hospital to have in-house access to the most up-to-date knowledge on diagnostic and therapeutic options. Therefore, knowledge is increasingly shared through consultation collaboratives. If such consultations do not suffice, then expert panels can be asked to answer specific questions about, for example, primary tumours or metastases. With this new type of consultation it is essential that the rights of both the patients and the professionals are guaranteed. In this article we describe the legal frameworks in which an expert panel can and is allowed to operate. If certain quality requirements regarding the use of medical data, the application procedure for and composition of an expert panel are met, then there should be no legal obstacles or practical objections to introduce expert panels in clinical practice.