Nutritional support in pancreatic cancer patients and its effect on nutritional status: an observational regional HPB network study investigating current practice.

PURPOSE: Preoperative malnutrition is associated with poor postoperative outcomes in patients with pancreatic cancer. This study evaluated the effectiveness of current practice in nutritional support for patients with pancreatic cancer. METHODS: Observational multicenter HPB network study conducted at the Isala Clinics Zwolle, Medical Spectrum Twente, Medical Center Leeuwarden, and University Medical Center Groningen between October 2021 and May 2023. Patients with a suspected pancreatic malignancy scheduled for surgery were screened for malnutrition using the Patient-Generated Subjective Global Assessment (PG-SGA) questionnaire and referred to a dedicated dietician for nutritional support comprising pancreatic enzyme replacement therapy, dietary advice, and nutritional supplements to achieve adequate caloric and protein intake. At baseline, 1 day preoperatively, and 3 months postoperatively, the nutritional status and muscle thickness were evaluated. RESULTS: The study included 30 patients, of whom 12 (40%) classified as malnourished (PG-SGA ≥ 4) at baseline. Compared to well-nourished patients, malnourished patients were younger, were predominantly female, and had a higher body mass index, despite having lost more body weight in the past 6 months. All malnourished patients and 78% of the well-nourished patients received nutritional support. Consequently, a preoperative increase in caloric and protein intake and body weight were observed. Postoperatively, despite a further increase in caloric intake, a considerable decrease in protein intake, body weight, and muscle thickness was observed. CONCLUSION: Malnutrition is prevalent in patients undergoing pancreatic surgery. Nutritional support by a dedicated dietician is effective in enhancing patients' preoperative nutritional status. However, postoperative monitoring of adequate nutritional intake in patients could be improved.

Implementation and Outcome of Robotic Liver Surgery in the Netherlands: A Nationwide Analysis.

OBJECTIVE: To determine the nationwide implementation and surgical outcome of minor and major robotic liver surgery (RLS) and assess the first phase of implementation of RLS during the learning curve. BACKGROUND: RLS may be a valuable alternative to laparoscopic liver surgery. Nationwide population-based studies with data on implementation and outcome of RLS are lacking. METHODS: Multicenter retrospective cohort study including consecutive patients who underwent RLS for all indications in 9 Dutch centers (August 2014-March 2021). Data on all liver resections were obtained from the mandatory nationwide Dutch Hepato Biliary Audit (DHBA) including data from all 27 centers for liver surgery in the Netherlands. Outcomes were stratified for minor, technically major, and anatomically major RLS. Learning curve effect was assessed using cumulative sum analysis for blood loss. RESULTS: Of 9437 liver resections, 400 were RLS (4.2%) procedures including 207 minor (52.2%), 141 technically major (35.3%), and 52 anatomically major (13%). The nationwide use of RLS increased from 0.2% in 2014 to 11.9% in 2020. The proportion of RLS among all minimally invasive liver resections increased from 2% to 28%. Median blood loss was 150 mL (interquartile range 50-350 mL] and the conversion rate 6.3% (n=25). The rate of Clavien-Dindo grade ≥III complications was 7.0% (n=27), median length of hospital stay 4 days (interquartile range 2-5) and 30-day/in-hospital mortality 0.8% (n=3). The R0 resection rate was 83.2% (n=263). Cumulative sum analysis for blood loss found a learning curve of at least 33 major RLS procedures. CONCLUSIONS: The nationwide use of RLS in the Netherlands has increased rapidly with currently one-tenth of all liver resections and one-fourth of all minimally invasive liver resections being performed robotically. Although surgical outcomes of RLS in selected patient seem favorable, future prospective studies should determine its added value.

Dose finding study for unilobar radioembolization using holmium-166 microspheres to improve resectability in patients with HCC: the RALLY protocol.

BACKGROUND: High dose unilobar radioembolization (also termed 'radiation lobectomy')-the transarterial unilobar infusion of radioactive microspheres as a means of controlling tumour growth while concomitantly inducing future liver remnant hypertrophy-has recently gained interest as induction strategy for surgical resection. Prospective studies on the safety and efficacy of the unilobar radioembolization-surgery treatment algorithm are lacking. The RALLY study aims to assess the safety and toxicity profile of holmium-166 unilobar radioembolization in patients with hepatocellular carcinoma ineligible for surgery due to insufficiency of the future liver remnant. METHODS: The RALLY study is a multicenter, interventional, non-randomized, open-label, non-comparative safety study. Patients with hepatocellular carcinoma who are considered ineligible for surgery due to insufficiency of the future liver remnant (< 2.7%/min/m2 on hepatobiliary iminodiacetic acid scan will be included. A classical 3 + 3 dose escalation model will be used, enrolling three to six patients in each cohort. The primary objective is to determine the maximum tolerated treated non-tumourous liver-absorbed dose (cohorts of 50, 60, 70 and 80 Gy). Secondary objectives are to evaluate dose-response relationships, to establish the safety and feasibility of surgical resection following unilobar radioembolization, to assess quality of life, and to generate a biobank. DISCUSSION: This will be the first clinical study to assess the unilobar radioembolization-surgery treatment algorithm and may serve as a stepping stone towards its implementation in routine clinical practice. TRIAL REGISTRATION: Netherlands Trial Register NL8902 , registered on 2020-09-15.

Personalized multimodal prehabilitation reduces cardiopulmonary complications after pancreatoduodenectomy: results of a propensity score matching analysis.

BACKGROUND: The purpose of prehabilitation is to improve postoperative outcomes by increasing patients' resilience against the stress of surgery. This study investigates the effect of personalized multimodal prehabilitation on patients undergoing pancreatoduodenectomy. METHODS: Included patients were screened for six modifiable risk factors: (1) low physical fitness, (2) malnutrition, (3) low mental resilience, (4) anemia and hyperglycemia, (5) frailty, and (6) substance abuse. Interventions were performed as needed. Using 1:1 propensity score matching (PSM), patients were compared to a historical cohort. RESULTS: From 120 patients, 77 (64.2%) performed a cardiopulmonary exercise test to assess their physical fitness and provide them with a preoperative training advice. Furthermore, 88 (73.3%) patients received nutritional support, 15 (12.5%) mental support, 17 (14.2%) iron supplementation to correct for iron deficiency, 18 (15%) regulation support for hyperglycemia, 14 (11.7%) a comprehensive geriatric assessment, and 19 (15.8%) substance abuse support. Of all patients, 63% required ≥2 prehabilitation interventions. Fewer cardiopulmonary complications were observed in the prehabilitation cohort (9.2% versus 23.3%; p = 0.002). In surgical outcomes and length of stay no differences were observed. CONCLUSION: Our prehabilitation program is effective in detecting risk factors in patients; most patients required multiple interventions. Consequently, a reduction in cardiopulmonary complications was observed.

Intra-observer agreements in multidisciplinary team assessments of pancreatic cancer patients.

BACKGROUND AND METHODS: Treatment strategies for pancreatic cancer patients are made by a multidisciplinary team (MDT) board. We aimed to assess intra-observer variance at MDT boards. Participating units staged, assessed resectability, and made treatment allocations for the same patients as they did two years earlier. We disseminated clinical information and CT images of pancreatic cancer patients judged by one MDT board to have nonmetastatic pancreatic cancer to the participating units. All units were asked to re-assess the TNM stage, resectability, and treatment allocation for each patient. To assess intra-observer variance, we computed %-agreements for each participating unit, defined as low (<50%), moderate (50%-75%), and high (>75%) agreement. RESULTS: Eighteen patients were re-assessed by six MDT boards. The overall agreement was moderate for TNM-stage (ranging from 50%-70%) and resectability assessment (53%) but low for treatment allocation (46%). Agreement on resectability assessments was low to moderate. Findings were similar but more pronounced for treatment allocation. We observed a shift in treatment strategy towards increasing use of neoadjuvant chemotherapy, particularly in patients with borderline resectable and locally advanced tumors. CONCLUSIONS: We found substantial intra-observer agreement variations across six different MDT boards of 18 pancreatic cancer patients with two years between the first and second assessment.

Laparoscopic hemi-splenectomy.

Laparoscopic splenectomy is now established as a safe and feasible procedure. However, it remains associated with some short- and long-term postoperative complications, especially infectious complications. To our knowledge, this is the first report (with video) focusing on the safety and feasibility of laparoscopic hemi-splenectomy and its surgical outcomes for the treatment of splenic abscesses causing septic emboli. This technique combines the immunological benefits of partial splenectomy and the postoperative benefits of a minimally invasive approach. Further studies are needed to standardize this technique and to assess its immunological and surgical benefits.

Clinical and pathological outcomes after irreversible electroporation of the pancreas using two parallel plate electrodes: a porcine model.

BACKGROUND: Irreversible electroporation (IRE) by inserting needles around the tumor as treatment for locally advanced pancreatic cancer entails several disadvantages, such as incomplete ablation due to field inhomogeneity, technical difficulties in needle placement and a risk of pancreatic fistula development. This experimental study evaluates outcomes of IRE using paddles in a porcine model. METHODS: Six healthy pigs underwent laparotomy and were treated with 2 separate ablations (in head and tail of the pancreas). Follow-up consisted of clinical and laboratory parameters and contrast-enhanced computed tomography (ceCT) imaging. After 2 weeks, pancreatoduodenectomy was performed for histology and the pigs were terminated. RESULTS: All animals survived 14 days. None of the animals developed signs of infection or significant abdominal distention. Serum amylase and lipase peaked at day 1 postoperatively in all pigs, but normalized without signs of pancreatitis. On ceCT-imaging the ablation zone was visible as an ill-defined, hypodense lesion. No abscesses, cysts or ascites were seen. Histology showed a homogenous fibrotic lesion in all pigs. CONCLUSION: IRE ablation of healthy porcine pancreatic tissue using two plate electrodes is feasible and safe and creates a homogeneous fibrotic lesion. IRE-paddles should be tested on pancreatic adenocarcinoma to determine the effect in cancer tissue.

Multipolar radiofrequency ablation for colorectal liver metastases close to major hepatic vessels.

BACKGROUND: Resection of colorectal liver metastases (CRLM) is often hindered by their location close to the major hepatic vessels. So far, radiofrequency ablation for perivascular tumours was thought to be ineffective and unsafe due to either the heat sink effect or vascular thrombosis. The aim of this study was to examine whether RFA using multipolar probes could be a safe and effective option for CRLM adjacent to major hepatic vessels. METHODS: Patients were treated with multipolar RFA during an open procedure using 3 simultaneously placed electrodes. In 52 consecutive patients with CRLM, 144 tumours were ablated with RFA. In 16 out of 52 (31%) patients, metastases were abutting major hepatic vessels. We examined whether perivascular location was a risk factor for local tumour progression. The relation between perivascular location and time to local tumour progression and recurrence free survival was assessed using cox-regression analysis. RESULTS: All patients were followed for at least 3 years after RFA unless they deceased before this time. Local tumour progression following RFA occurred in 17 out of 144 tumours (12%), of which 4 out of 21 were perivascular tumours. Tumour size was the only risk factor for local tumour progression in this study. Proximity to large vessels was neither a risk factor for local local tumour progression, nor for time to local tumour progression or recurrence free survival. DISCUSSION: This study indicates that patients with CRLM abutting any of the large hepatic vessels can be safe and effectively treated with RFA when using a multipolar system.

Hypoxia after liver surgery imposes an aggressive cancer stem cell phenotype on residual tumor cells.

OBJECTIVE: To assess the contribution of hypoxia and bone marrow-derived cells to aggressive outgrowth of micrometastases after liver surgery. BACKGROUND: Liver surgery generates a microenvironment that fosters aggressive tumor recurrence. These areas are characterized by chronic hypoxia and influx of bone marrow-derived cells. METHODS: The contribution of hematopoietic cell types was studied in mice lacking specific components of the immune system and in irradiated mice lacking all bone marrow-derived cells. Tumor cells were derived from colorectal cancer patients and from a metastatic tumor cell line. Hypoxia-induced changes in stem cell and differentiation marker expression, clone-forming potential, and metastatic capacity were assessed. The effect of vascular clamping on cancer stem cell (CSC) characteristics was performed in mice bearing patient-derived liver metastases. RESULTS: Immune cells and bone marrow-derived cells were not required for aggressive outgrowth of micrometastases in livers treated with surgery. Rather, hypoxia was sufficient to promote invasion and accelerate metastatic outgrowth. This was associated with a rapid loss of differentiation markers and increased expression of CSC markers and clone-forming capacity. Likewise, metastases residing in ischemia-reperfusion-injured liver lobes acquired CSC characteristics. Despite their renowned general resistance to chemotherapy, clone-forming CSCs were readily killed by the hypoxia-activated prodrug tirapazamine. CONCLUSIONS: Surgery-generated hypoxia in the liver causes rapid dedifferentiation of tumor cells into immature CSCs with high clone- and metastasis-forming capacity. The results help explain the phenomenon of aggressive local tumor recurrence after liver surgery and offer a potential strategy to kill aggressive CSCs by hypoxia-activated prodrugs.

Impact of Preoperative Diabetes Mellitus on Postoperative Outcomes in Elective Pancreatic Surgery and Its Implications for Prehabilitation Practice.

OBJECTIVES: Patients with pancreatic disease(s) have a high risk of developing diabetes mellitus (DM). Diabetes mellitus is associated with adverse postoperative outcomes. This study aimed to investigate the prevalence and effects of DM on postoperative outcomes in pancreatic surgery. METHODS: Subgroup analysis of a prospective cohort study conducted at an academic hospital. Patients undergoing pancreatoduodenectomy between January 2019 and November 2022 were included and screened for DM preoperatively using glycated hemoglobin (HbA1c). New-onset DM was diagnosed based on HbA1c ≥ 6.5% (48 mmol/mol). Postoperative outcomes were compared between patients with and without DM. RESULTS: From 117 patients, 29 (24.8%) were given a diagnosis of DM, and of those, 5 (17.2%) were diagnosed with new-onset DM, and 15 (51.8%) displayed poorly controlled preoperative DM (HbA 1c ≥ 7% [53 mmol/mol]). The incidence of surgical site infections (48.3% vs 27.3% in the non-DM group; P = 0.04) was higher for patients with DM. This association remained significant after adjusting for confounders (odds ratio, 2.60 [95% confidence interval, 1.03-6.66]; P = 0.04). CONCLUSIONS: One-quarter of the patients scheduled for pancreatoduodenectomy had DM; over half of them had poor glycemic control. The association between DM status and surgical site infections revealed in this study emphasizes the importance of adequate preoperative glycemic control.

Treatment of iron deficiency in patients scheduled for pancreatic surgery: implications for daily prehabilitation practice in pancreatic surgery.

BACKGROUND: Preoperative anemia is a frequent complication in pancreatic surgical patients, and it adversely affects morbidity, mortality, and postoperative red blood cell (RBC) transfusion rates. Iron deficiency (ID) is often the underlying cause of anemia and constitutes a modifiable risk factor. METHODS: Single-center, longitudinal prospective cohort study conducted between May 2019 and August 2022 at the University Medical Center Groningen in the Netherlands. Patients scheduled for pancreatic surgery were referred to the outpatient prehabilitation clinic for preoperative optimization of patient-related risk factors. Patients were screened for anemia (< 12.0 g/dL in women and < 13.0 g/dL in men) and ID (either absolute [ferritin < 30 µg/L] or functional [ferritin ≥ 30 µg/L + transferrin saturation < 20% + C-reactive protein > 5 mg/L]). Intravenous iron supplementation (IVIS) (1,000 mg ferric carboxymaltose) was administered to patients with ID at the discretion of the consulting internist. Pre- and postoperative hemoglobin (Hb) levels were assessed, and perioperative outcomes were compared between patients receiving IVIS (IVIS-group) or standard care (SC-group). RESULTS: From 164 screened patients, preoperative anemia was observed in 55 (33.5%) patients, and in 23 (41.8%) of these patients, ID was the underlying cause. In 21 patients, ID was present without concomitant anemia. Preoperative IVIS was administered to 25 patients, out of 44 patients with ID. Initial differences in mean Hb levels (g/dL) between the IVIS-group and SC-group at the outpatient clinic and one day prior to surgery (10.8 versus 13.2, p < 0.001, and 11.8 versus 13.4, p < 0.001, respectively) did not exist at discharge (10.6 versus 11.1, p = 0.13). Preoperative IVIS led to a significant increase in mean Hb levels (from 10.8 to 11.8, p = 0.03). Fewer SSI were observed in the IVIS-group (4% versus 25.9% in the SC-group, p = 0.02), which remained significant in multivariable regression analysis (OR 7.01 (1.68 - 49.75), p = 0.02). CONCLUSION: ID is prevalent in patients scheduled for pancreatic surgery and is amendable to preoperative correction. Preoperative IVIS increased Hb levels effectively and reduced postoperative SSI. Screening and correction of ID is an important element of preoperative care and should be a standard item in daily prehabilitation practice.

Potential, Limitations and Risks of Cannabis-Derived Products in Cancer Treatment.

The application of cannabis products in oncology receives interest, especially from patients. Despite the plethora of research data available, the added value in curative or palliative cancer care and the possible risks involved are insufficiently proven and therefore a matter of debate. We aim to give a recommendation on the position of cannabis products in clinical oncology by assessing recent literature. Various types of cannabis products, characteristics, quality and pharmacology are discussed. Standardisation is essential for reliable and reproducible quality. The oromucosal/sublingual route of administration is preferred over inhalation and drinking tea. Cannabinoids may inhibit efflux transporters and drug-metabolising enzymes, possibly inducing pharmacokinetic interactions with anticancer drugs being substrates for these proteins. This may enhance the cytostatic effect and/or drug-related adverse effects. Reversely, it may enable dose reduction. Similar interactions are likely with drugs used for symptom management treating pain, nausea, vomiting and anorexia. Cannabis products are usually well tolerated and may improve the quality of life of patients with cancer (although not unambiguously proven). The combination with immunotherapy seems undesirable because of the immunosuppressive action of cannabinoids. Further clinical research is warranted to scientifically support (refraining from) using cannabis products in patients with cancer.

Differentiated human colorectal cancer cells protect tumor-initiating cells from irinotecan.

BACKGROUND & AIMS: Stem cells of normal tissues have resistance mechanisms that allow them to survive genotoxic insults. The stem cell-like cells of tumors are defined by their tumor-initiating capacity and may have retained these resistance mechanisms, making them resistant to chemotherapy. We studied the relationship between resistance to the topoisomerase I inhibitor irinotecan and tumor-initiating potential in human colonosphere cultures and in mice with colorectal xenograft tumors. METHODS: Colonosphere cultures were established from human colorectal tumor specimens obtained from patients who underwent colon or liver resection for primary or metastatic adenocarcinoma. Stem cell and differentiation markers were analyzed by immunoblotting and fluorescence-activated cell sorting. Clone- and tumor-initiating capacities were assessed by single-cell cloning and in immune-deficient mice. Sensitivity to irinotecan was assessed in vitro and in tumor-bearing mice. The relationship between drug resistance and tumor-initiating capacity was tested by fluorescence-activated cell sorting of colonosphere cells, based on expression of ABCB1 and aldehyde dehydrogenase (ALDH) activity. RESULTS: Colonosphere cultures had a high capacity to initiate tumors in mice and were resistant to irinotecan. Inhibition of the drug-efflux pump ABCB1 by PSC-833 allowed irinotecan to eradicate tumor-initiating cells. However, ABCB1 was expressed only by a subpopulation of differentiated tumor cells that did not form clones or tumors. Conversely, tumor-initiating cells were ABCB1-negative and were identified by high ALDH activity. Tumorigenic ALDHhigh/ABCB1negative cells generated nontumorigenic ALDHlow/ABCB1positive daughter cells in vitro and in tumor xenografts. PSC-833 increased the antitumor efficacy of irinotecan in mice. CONCLUSIONS: The resistance of colorectal tumors to irinotecan requires the cooperative action of tumor-initiating ALDHhigh/ABCB1negative cells and their differentiated, drug-expelling, ALDHlow/ABCB1positive daughter cells.

Radio frequency ablation combined with interleukin-2 induces an antitumor immune response to renal cell carcinoma in a murine model.

PURPOSE: Immune based therapy has gained renewed interest in the search for treatment strategies for metastasized renal cell carcinoma. We determined whether radio frequency ablation combined with interleukin-2 would induce a tumor specific immune response and serve as an in situ vaccine against renal cell carcinoma. MATERIALS AND METHODS: Mice with orthotopic renal tumors were treated with radio frequency ablation combined with interleukin-2, radio frequency ablation only, interleukin-2 only or no treatment as the control. Immunohistochemistry was done to determine which cells were present in the tumor after treatment. In vitro tumor specific cytotoxicity assays were performed with CD8+ T and natural killer cells derived from the spleen of treated mice. To study whether treatment could prevent metastasis or affect the growth of established metastases we induced lung metastasis intravenously before or after treatment and subsequently quantified it. RESULTS: The number of natural killer, CD4+ and CD8+ T cells was significantly increased in the tumor tissue of radio frequency ablation/interleukin-2 treated mice (p <0.0001). Natural killer and CD8+ T cells showed strong antitumor activity in vitro after combination treatment. Lung metastatic formation was significantly prevented in mice that received combination therapy (p <0.0001). Lung metastases were significantly smaller after combination treatment (vs interleukin-2 p = 0.025). CONCLUSIONS: Radio frequency ablation of the primary tumor combined with interleukin-2 induces a systemic antitumor immune response to renal cell carcinoma, which is much stronger than that of interleukin-2 monotherapy. This effect appears to be mediated by natural killer and CD8+ T cells. It may have an important role in the development of new immunotherapy strategies for renal cell carcinoma.

Incomplete thermal ablation stimulates proliferation of residual renal carcinoma cells in a translational murine model.

UNLABELLED: What's known on the subject? and What does the study add? Thermal ablation influences the local tissue microenvironment. Several studies have reported that residual tumour cells may exhibit a more aggressive phenotype. This study shows that incomplete CA and RFA cause an increased proliferation and decreased apptosis of residual renal tumour cells. This may be caused by stimulatory factors such as hypoxia, HSPs and inflammatory cells. OBJECTIVE: To compare the effect of incomplete thermal ablation vs partial nephrectomy (PN) on growth stimulation and cellular survival in renal tumours. MATERIALS AND METHODS: Renca renal tumours were transplanted under the renal capsule of mice (four to six mice/group) after which incomplete radiofrequency ablation (RFA), cryoablation (CA) or PN was performed. At several time points after treatment, presence of cell proliferation, apoptosis, hypoxic areas, inflammatory factors and the heat-shock proteins (HSPs) 70 and 90 were evaluated using immunohistochemistry. RESULTS: At 2 h after thermal ablation residual tumour cells showed increased proliferation. This hyperproliferation was significantly stronger after RFA than CA (P < 0.05) and not present after PN. Residual cells showed increased apoptosis after 2 h and decreased apoptosis from 2 days after thermal ablation. Apoptotic cells were significantly less evident at 3 days after RFA (P < 0.001). Hypoxic areas and HSPs were increasingly present from 2 h up to 7 days after thermal ablation (P < 0.001). Inflammatory cells infiltrated mainly the necrotic areas after thermal ablation, and their abundance peaked at 1 week after ablation (P < 0.05). The increased cell growth was preceded by hypoxia and presence of HSPs. CONCLUSIONS: CA and RFA result in an increased proliferation and decreased apoptosis of residual renal tumour cells. This hyperproliferation may be caused by stimulatory factors, e.g. hypoxia, HSPs and inflammatory cells, and could facilitate recurrences of renal tumours after thermal ablation. This study highlights the importance of achieving complete tumour destruction.

External Validation of a Risk Model for Severe Complications following Pancreatoduodenectomy Based on Three Preoperative Variables.

BACKGROUND: Pancreatoduodenectomy (PD) is the only cure for periampullary and pancreatic cancer. It has morbidity rates of 40-60%, with severe complications in 30%. Prediction models to predict complications are crucial. A risk model for severe complications was developed by Schroder et al. based on BMI, ASA classification and Hounsfield Units of the pancreatic body on the preoperative CT scan. These variables were independent predictors for severe complications upon internal validation. Our aim was to externally validate this model using an independent cohort of patients. METHODS: A retrospective analysis was performed on 318 patients who underwent PD at our institution from 2013 to 2021. The outcome of interest was severe complications Clavien-Dindo ≥ IIIa. Model calibration, discrimination and performance were assessed. RESULTS: A total of 308 patients were included. Patients with incomplete data were excluded. A total of 89 (28.9%) patients had severe complications. The externally validated model achieved: C-index = 0.67 (95% CI: 0.60-0.73), regression coefficient = 0.37, intercept = 0.13, Brier score = 0.25. CONCLUSIONS: The performance ability, discriminative power, and calibration of this model were acceptable. Our risk calculator can help surgeons identify high-risk patients for post-operative complications to improve shared decision-making and tailor perioperative management.

Role of Epithelial-to-Mesenchymal Transition for the Generation of Circulating Tumors Cells and Cancer Cell Dissemination.

Tumor-related death is primarily caused by metastasis; consequently, understanding, preventing, and treating metastasis is essential to improving clinical outcomes. Metastasis is mainly governed by the dissemination of tumor cells in the systemic circulation: so-called circulating tumor cells (CTCs). CTCs typically arise from epithelial tumor cells that undergo epithelial-to-mesenchymal transition (EMT), resulting in the loss of cell-cell adhesions and polarity, and the reorganization of the cytoskeleton. Various oncogenic factors can induce EMT, among them the transforming growth factor (TGF)-ß, as well as Wnt and Notch signaling pathways. This entails the activation of numerous transcription factors, including ZEB, TWIST, and Snail proteins, acting as transcriptional repressors of epithelial markers, such as E-cadherin and inducers of mesenchymal markers such as vimentin. These genetic and phenotypic changes ultimately facilitate cancer cell migration. However, to successfully form distant metastases, CTCs must primarily withstand the hostile environment of circulation. This includes adaption to shear stress, avoiding being trapped by coagulation and surviving attacks of the immune system. Several applications of CTCs, from cancer diagnosis and screening to monitoring and even guided therapy, seek their way into clinical practice. This review describes the process leading to tumor metastasis, from the generation of CTCs in primary tumors to their dissemination into distant organs, as well as the importance of subtyping CTCs to improve personalized and targeted cancer therapy.