Weekday-dependent long-term outcomes in gastrointestinal cancer surgery: a German population-based retrospective cohort study.

BACKGROUND: For most solid cancers, surgery represents the mainstay of curative treatment. Several studies investigating the effects of the weekday of surgery (WOS) on patient outcomes have yielded conflicting results. Barmer, the second-largest health insurance company in Germany, serves roughly 10% of the German population. The authors have used the Barmer database to evaluate how the weekday on which the surgery is performed influences long-term oncologic outcomes. METHODS: For this retrospective cohort study, the Barmer database was used to investigate the effect of the WOS (Monday-Friday) on outcomes following oncological resections of the colorectum ( n =49 003), liver ( n =1302), stomach ( n =5027), esophagus ( n =1126), and pancreas ( n =6097). In total, 62 555 cases from 2008 to 2018 were included in the analysis. The endpoints were overall survival (OS), postoperative complications, and the necessity for therapeutic interventions or reoperations. The authors further examined whether the annual caseload or certification as a cancer center influenced the weekday effect. RESULTS: The authors observed a significantly impaired OS for patients receiving gastric or colorectal resections on a Monday. Colorectal surgery performed on Mondays was associated with more postoperative complications and a higher probability of reoperations. The annual caseload or a certification as a colorectal cancer center had no bearing on the observed weekday effect. There is evidence that hospitals schedule older patients with more comorbidities earlier in the week, possibly explaining these findings. CONCLUSION: This is the first study investigating the influence of the WOS on long-term survival in Germany. Our findings indicate that, in the German healthcare system, patients undergoing colorectal cancer surgery on Mondays have more postoperative complications and, therefore, require significantly more reoperations, ultimately lowering the OS. This surprising finding appears to reflect an attempt to schedule patients with higher postoperative risk earlier in the week as well as semi-elective patients admitted on weekends scheduled for surgery on the next Monday.

ARID1A mutations in lung cancer: biology, prognostic role, and therapeutic implications.

Mutations in the AT-interacting domain-rich protein 1A (ARID1A) gene, a critical component of the switch/sucrose nonfermentable (SWI/SNF) complex, are frequently found in most human cancers. Approximately 5-10% of lung cancers carry ARID1A mutations. ARID1A loss in lung cancer correlates with clinicopathological features and poor prognosis. Co-mutation of ARID1A and epidermal growth factor receptor (EGFR) results in the limited efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) but increases the clinical benefit of immune checkpoint inhibitors (ICIs). ARID1A gene mutation plays a role in cell cycle regulation, metabolic reprogramming, and epithelial-mesenchymal transition. We present the first comprehensive review of the relationship between ARID1A gene mutations and lung cancer and discuss the potential of ARID1A as a new molecular target.

Primary tumor-derived systemic nANGPTL4 inhibits metastasis.

Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we identified the proteolytically cleaved fragments of angiopoietin-like 4 (ANGPTL4) as contextually active protumorigenic and antitumorigenic contributors in this communication ecosystem. Preclinical studies in multiple tumor models revealed that the C-terminal fragment (cANGPTL4) promoted tumor growth and metastasis. In contrast, the N-terminal fragment of ANGPTL4 (nANGPTL4) inhibited metastasis and enhanced overall survival in a postsurgical metastasis model by inhibiting WNT signaling and reducing vascularity at the metastatic site. Tracing ANGPTL4 and its fragments in tumor patients detected full-length ANGPTL4 primarily in tumor tissues, whereas nANGPTL4 predominated in systemic circulation and correlated inversely with disease progression. The study highlights the spatial context of the proteolytic cleavage-dependent pro- and antitumorigenic functions of ANGPTL4 and identifies and validates nANGPTL4 as a novel biomarker of tumor progression and antimetastatic therapeutic agent.

Lumbar Spondylodiscitis Mimicking Cholecystitis: A Case Report and Review of Literature.

BACKGROUND: Lower back pain is a frequent cause of emergency department visits and one of the leading causes of the disease burden worldwide. The purpose of this case report and literature review was to discuss atypical abdominal entities mimicking spinal diseases typically presenting with lower back pain. METHODS: A 79-year-old man presented with lower back pain and urinary incontinence after receiving a non-image-guided lumbar infiltration treatment 4 weeks prior to admission. The magnetic resonance imaging (MRI) highlighted multisegmental hyperintensities in the intervertebral disk spaces of the lumbar spine indicative for spondylodiscitis. Antibiotic treatment over a week did not lead to significant clinical improvement. Blood cultures, cardiologic, otorhinolaryngologic, and dental examinations turned out negative for a focus of infection. A computed tomography (CT) guided biopsy was indicated after discontinuation of antibiotic treatment for less than 24 hours. Rapid clinical deterioration with concomitant onset of abdominal pain resulted in the diagnosis of cholecystitis, which required cholecystectomy. We performed a systematic literature review using the Pubmed database for the keywords "spondylodiscitis," "spine," "abdominal," and "cholecystitis," to identify abdominal diseases that mimic spine pathologies and spinal diseases that mimic abdominal pathologies. RESULTS: No other report in English literature of cholecystitis associated with initial onset of lower back pain was identified. Eighteen reports referred to abdominal conditions that mimic spinal diseases, among them a patient with cyclic lumbar back pain who received a lumbar spinal fusion who, after persisting symptoms led to further diagnostic procedures, was ultimately diagnosed with endometriosis. Spinal symptoms included paraplegia and urinary incontinence as results of acute aortic pathologies. Eleven reports presented spinal pain mimicking abdominal conditions including abdominal pain and diarrhea as well as have had surgical procedures such as an appendectomy before the spinal condition was discovered. CONCLUSION: Clinical symptoms of the spine such as lower back pain can be unspecific and lead to false conclusions in the presence of concomitant pathologies in MRI. Only clinical deterioration in our case patient prompted correction of the diagnosis on day 7. Initial workup for alternative common infectious foci such as lung and urinary tract was performed, but further abdominal workup despite the absence of abdominal symptoms may have led to an earlier diagnosis. Our literature review found several cases of misdiagnosed spinal and abdominal conditions. Some had undergone unnecessary surgical procedures before the right diagnosis was made. Because of the high incidence of symptoms such as lumbar back pain and abdominal pain, considering optimal patient care as well as economic aspects, it would be essential to conduct an interdisciplinary clinical management to avoid errors in the early stage of diagnostics.

Circulating tumour cells in patients with lung cancer universally indicate poor prognosis.

BACKGROUND: In lung cancer, the relevance of various circulating tumour cell (CTC) subgroups in different lung cancer subtypes is unclear. We performed a comprehensive meta-analysis to assess the prognostic value of CTCs in the different histological types of lung cancer, with particular respect to CTC subtypes, cut-offs and time points of CTC enumeration. METHODS: We searched MEDLINE, Web of Science and Embase alongside relevant studies evaluating the prognostic value of CTCs in lung cancer patients. A random-effects model was used for meta-analysis, calculating hazard ratios (HRs), 95% confidence intervals and p-values. RESULTS: 27 studies enrolling 2957 patients were included. CTC detection indicates poor prognosis, especially in small cell lung cancer (SCLC) patients (overall survival HR 3.11, 95% CI 2.59-3.73) and predicts a worse outcome compared to nonsmall cell lung cancer patients. Epithelial CTCs predict a worse outcome for lung cancer than mesenchymal CTCs or epithelial-mesenchymal hybrids. CONCLUSION: CTCs indicate poor prognosis in patients with primary lung cancer, with CTCs in SCLC having a more pronounced prognostic effect. The prognostic value of CTCs detected by different markers varies; most evidence is available for the strong negative prognostic effect of epithelial CTCs.

Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities.

Tuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10-20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited "lineage ambiguity" as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft cell-like LCNECs might be crucial given their close kinship with tuft cell-like SCLC.

Prognostic value of primary tumor sidedness in patients with non-metastatic IBD related CRC - Is it the exception to the rule?

BACKGROUND: Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed to evaluate the prognostic role of PTS in patients with IBD-CRC. METHODS: All eligible patients with surgically treated, non-metastatic IBD-CRC were retrospectively identified from institutional databases at ten European and Asian academic centers. Long term endpoints included recurrence-free (RFS) and overall survival (OS). Multivariable Cox proportional hazard regression as well as propensity score analyses were performed to evaluate whether PTS was significantly associated with RFS and OS. RESULTS: A total of 213 patients were included in the analysis, of which 32.4% had right-sided (RS) tumors and 67.6% had left-sided (LS) tumors. PTS was not associated with OS and RFS even on univariable analysis (5-year OS for RS vs LS tumors was 68.0% vs 77.3%, respectively, p = 0.31; 5-year RFS for RS vs LS tumors was 62.8% vs 65.4%, respectively, p = 0.51). Similarly, PTS was not associated with OS and RFS on propensity score matched analysis (5-year OS for RS vs LS tumors was 82.9% vs 91.3%, p = 0.79; 5-year RFS for RS vs LS tumors was 85.1% vs 81.5%, p = 0.69). These results were maintained when OS and RFS were calculated in patients with RS vs LS tumors after excluding patients with rectal tumors (5-year OS for RS vs LS tumors was 68.0% vs 77.2%, respectively, p = 0.38; 5-year RFS for RS vs LS tumors was 62.8% vs 59.2%, respectively, p = 0.98). CONCLUSIONS: In contrast to sporadic CRC, PTS does not appear to have a prognostic role in IBD-CRC.

Robot-assisted esophagectomy may improve perioperative outcome in patients with esophageal cancer - a single-center experience.

Background: Although the introduction of minimally invasive surgical techniques has improved surgical outcomes in recent decades, esophagectomy for esophageal cancer is still associated with severe complications and a high mortality rate. Robot-assisted surgery is already established in certain fields and robot-assisted esophagectomy may be a possible alternative to the standard minimally invasive esophagectomy. The goal of this study was to investigate whether robot assistance in esophagectomy can improve patient outcome while maintaining good oncological control. Material and methods: Data of all patients who underwent minimally invasive esophagectomy between January 2018 and November 2021 at University Hospital Mannheim was collected retrospectively. Patients were divided into two cohorts according to operative technique (standard minimally invasive (MIE) vs. robot-assisted esophagectomy (RAMIE), and their outcomes compared. In a separate analysis, patients were propensity score matched according to age, gender and histological diagnosis, leading to 20 matching pairs. Results: 95 patients were included in this study. Of those, 71 patients underwent robot-assisted esophagectomy and 24 patients underwent standard minimally invasive esophagectomy. Robot-assisted esophagectomy showed a lower incidence of general postoperative complications (52.1% vs. 79.2%, p=0.0198), surgical complications (42.3% vs. 75.0%, p=0.0055), a lower rate of anastomotic leakage (21.1% vs. 50.0%, p=0.0067), a lower Comprehensive Complication Index (median of 20.9 vs. 38.6, p=0.0065) as well as a shorter duration of hospital stay (median of 15 vs. 26 days, p=0.0012) and stay in the intensive care unit (median of 4 vs. 7 days, p=0.028) than standard minimally invasive surgery. After additionally matching RAMIE and MIE patients according to age, gender and diagnosis, we found significant improvement in the RAMIE group compared to the MIE group regarding the Comprehensive Complication Index (median of 20.9 vs. 38.6, p=0.0276), anastomotic leakage (20% vs. 55%, p=0.0484) and severe toxicity during neoadjuvant treatment (0 patients vs. 9 patients, p=0.005). Conclusion: Robot-assisted surgery can significantly improve outcomes for patients with esophageal cancer. It may lead to a shorter hospital stay as well as lower rates of complications, including anastomotic leakage.

Cell-Cell Interactions Drive Metastasis of Circulating Tumor Microemboli.

Circulating tumor cells are the cellular mediators of distant metastasis in solid malignancies. Their metastatic potential can be augmented by clustering with other tumor cells or nonmalignant cells, forming circulating tumor microemboli (CTM). Cell-cell interactions are key regulators within CTM that convey enhanced metastatic properties, including improved cell survival, immune evasion, and effective extravasation into distant organs. However, the cellular and molecular mechanism of CTM formation, as well as the biology of interactions between tumor cells and immune cells, platelets, and stromal cells in the circulation, remains to be determined. Here, we review the current literature on cell-cell interactions in homotypic and heterotypic CTM and provide perspectives on therapeutic strategies to attenuate CTM-mediated metastasis by targeting cell-cell interactions.

Comparative Study of the Role of Interepithelial Mucosal Mast Cells in the Context of Intestinal Adenoma-Carcinoma Progression.

Mast cells (MCs) are crucial players in the relationship between the tumor microenvironment (TME) and cancer cells and have been shown to influence angiogenesis and progression of human colorectal cancer (CRC). However, the role of MCs in the TME is controversially discussed as either pro- or anti-tumorigenic. Genetically engineered mouse models (GEMMs) are the most frequently used in vivo models for human CRC research. In the murine intestine there are at least three different MC subtypes: interepithelial mucosal mast cells (ieMMCs), lamina proprial mucosal mast cells (lpMMCs) and connective tissue mast cells (CTMCs). Interepithelial mucosal mast cells (ieMMCs) in (pre-)neoplastic intestinal formalin-fixed paraffin-embedded (FFPE) specimens of mouse models (total lesions n = 274) and human patients (n = 104) were immunohistochemically identified and semiquantitatively scored. Scores were analyzed along the adenoma-carcinoma sequence in humans and 12 GEMMs of small and large intestinal cancer. The presence of ieMMCs was a common finding in intestinal adenomas and carcinomas in mice and humans. The number of ieMMCs decreased in the course of colonic adenoma-carcinoma sequence in both species (p < 0.001). However, this dynamic cellular state was not observed for small intestinal murine tumors. Furthermore, ieMMC scores were higher in GEMMs with altered Wnt signaling (active ß-catenin) than in GEMMs with altered MAPK signaling and wildtypes (WT). In conclusion, we hypothesize that, besides stromal MCs (lpMMCs/CTMCs), particularly the ieMMC subset is important for onset and progression of intestinal neoplasia and may interact with the adjacent neoplastic epithelial cells in dependence on the molecular environment. Moreover, our study indicates the need for adequate GEMMs for the investigation of the intestinal immunologic TME.

Metabolic Profiling of Thymic Epithelial Tumors Hints to a Strong Warburg Effect, Glutaminolysis and Precarious Redox Homeostasis as Potential Therapeutic Targets.

Thymomas and thymic carcinomas (TC) are malignant thymic epithelial tumors (TETs) with poor outcome, if non-resectable. Metabolic signatures of TETs have not yet been studied and may offer new therapeutic options. Metabolic profiles of snap-frozen thymomas (WHO types A, AB, B1, B2, B3, n = 12) and TCs (n = 3) were determined by high resolution magic angle spinning 1H nuclear magnetic resonance (HRMAS 1H-NMR) spectroscopy. Metabolite-based prediction of active KEGG metabolic pathways was achieved with MetPA. In relation to metabolite-based metabolic pathways, gene expression signatures of TETs (n = 115) were investigated in the public "The Cancer Genome Atlas" (TCGA) dataset using gene set enrichment analysis. Overall, thirty-seven metabolites were quantified in TETs, including acetylcholine that was not previously detected in other non-endocrine cancers. Metabolite-based cluster analysis distinguished clinically indolent (A, AB, B1) and aggressive TETs (B2, B3, TCs). Using MetPA, six KEGG metabolic pathways were predicted to be activated, including proline/arginine, glycolysis and glutathione pathways. The activated pathways as predicted by metabolite-profiling were generally enriched transcriptionally in the independent TCGA dataset. Shared high lactic acid and glutamine levels, together with associated gene expression signatures suggested a strong "Warburg effect", glutaminolysis and redox homeostasis as potential vulnerabilities that need validation in a large, independent cohort of aggressive TETs. If confirmed, targeting metabolic pathways may eventually prove as adjunct therapeutic options in TETs, since the metabolic features identified here are known to confer resistance to cisplatin-based chemotherapy, kinase inhibitors and immune checkpoint blockers, i.e., currently used therapies for non-resectable TETs.

GTF2I Mutation in Thymomas: Independence From Racial-Ethnic Backgrounds. An Indian/German Comparative Study.

Thymomas are the most frequent adult mediastinal cancers. Their etiology is unknown and their pathogenesis poorly understood. Racial, ethnic and environmental factors influence tumorigenesis in many cancers, but their role in thymomas remains unclear to date. In this study that included pretreatment thymoma cases from India and Germany (n = 37 and n = 77, respectively) we compared i) the prevalence of the thymoma-specific chromosome 7 c.74146970T > A mutation of the GTF2I gene in type A and AB thymomas; ii) epidemiological features; and iii) the frequency of myasthenia gravis (MG). Due to a known predominance of GTF2I mutation in A and AB histotypes, we included only a marginal number of type B thymomas as a control group in both cohorts. While the distribution of histological types between the cohorts was similar (p = 0.1622), Indian patients were strikingly younger (p < 0.0001; median age 50 vs. 65 years) and showed significantly lower tumour stage (Masaoka-Koga stage I) at primary diagnosis (p = 0.0005) than the German patients. In patients with known MG status (n = 17 in Indian and n = 25 in German cohort), a clear trend towards more frequent MG was observed in the Indian group (p = 0.0504; 48 vs. 82%). The prevalence of the GTF2I mutation (analysed in n = 34 Indian and n = 77 German patients) was identical in the two cohorts. We conclude that racial-ethnic and environmental factors do not significantly influence the most common molecular feature of thymomas but may have an impact on the timing of clinical presentation.

Patient-Derived Organoids of Cholangiocarcinoma.

Cholangiocarcinoma (CC) is an aggressive malignancy with an inferior prognosis due to limited systemic treatment options. As preclinical models such as CC cell lines are extremely rare, this manuscript reports a protocol of cholangiocarcinoma patient-derived organoid culture as well as a protocol for the transition of 3D organoid lines to 2D cell lines. Tissue samples of non-cancer bile duct and cholangiocarcinoma were obtained during surgical resection. Organoid lines were generated following a standardized protocol. 2D cell lines were generated from established organoid lines following a novel protocol. Subcutaneous and orthotopic patient-derived xenografts were generated from CC organoid lines, histologically examined, and treated using standard CC protocols. Therapeutic responses of organoids and 2D cell lines were examined using standard CC agents. Next-generation exome and RNA sequencing was performed on primary tumors and CC organoid lines. Patient-derived organoids closely recapitulated the original features of the primary tumors on multiple levels. Treatment experiments demonstrated that patient-derived organoids of cholangiocarcinoma and organoid-derived xenografts can be used for the evaluation of novel treatments and may therefore be used in personalized oncology approaches. In summary, this study establishes cholangiocarcinoma organoids and organoid-derived cell lines, thus expanding translational research resources of cholangiocarcinoma.

Differential Effects of Trp53 Alterations in Murine Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC. METHODS: Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing. RESULTS: The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC. CONCLUSIONS: This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development.

Molecular pathology of thymomas: implications for diagnosis and therapy.

Thymomas exhibit a unique genomic landscape, comprising the lowest on average total mutational burden among adult human cancers; a unique point mutation in the GTF2I gene in WHO type A and AB thymomas (and rarely others); almost unique KMT2A-MAML2 translocations in rare WHO type B2 and B3 thymomas; a unique YAP1-MAML2 translocation in almost all metaplastic thymomas; and unique miRNA profiles in relation to GTF2I mutational status and WHO histotypes. While most thymomas can be diagnosed solely on the basis of morphological features, mutational analyses can solve challenging differential diagnostic problems. No molecular biomarkers have been identified that predict the response of unresectable thymomas to chemotherapy or agents with known molecular targets. Despite the common and strong expression of PDL1 in thymomas, immune checkpoint inhibitors are rarely applicable due to the poor predictability of common, life-threatening autoimmune side effects that are related to the unrivaled propensity of thymomas towards autoimmunity.

[Postoperative hypocalcemia - the most common complication of endocrine head and neck surgery: acute management]. / Postoperative Hypokalzämie ­ die häufigste Komplikation der endokrinen Chirurgie der Halsregion: Akutes Management.

BACKGROUND: In Germany, 8000 patients are affected by postoperative hypoparathyroidism per year following surgery of the thyroid gland, parathyroidal glands and the larynx. Patients do not only suffer from paresthesia in the acute phase of this complication, but are also adversely affected by the fear of loss of control following episodes of tetany even years after the first episode. OBJECTIVES: Discussion of a diagnostic pathway and presentation of a management pathway for postoperative hypocalcemia. METHODS: Narrative review, analysis and discussion of current literature and expert recommendations. RESULTS: Early determination of calcium and parathyroid hormone allows timely diagnosis and treatment of postoperative hypoparathyroidism. Active vitamin D is pivotal for the resorption of calcium. Only the combined treatment with active vitamin D and calcium can mitigate or prevent the postoperative drop of calcium levels. CONCLUSIONS: A standard operating procedure (SOP) for postoperative hypoparathyroidism should be implemented in every surgical department. An SOP for diagnosis and treatment of postoperative hypoparathyroidism is proposed for institutional individualization and implementation.

GAS2L1 Is a Potential Biomarker of Circulating Tumor Cells in Pancreatic Cancer.

Pancreatic cancer is a malignant disease with high mortality and a dismal prognosis. Circulating tumor cell (CTC) detection and characterization have emerged as essential techniques for early detection, prognostication, and liquid biopsy in many solid malignancies. Unfortunately, due to the low EPCAM expression in pancreatic cancer CTCs, no specific marker is available to identify and isolate this rare cell population. This study analyzed single-cell RNA sequencing profiles of pancreatic CTCs from a genetically engineered mouse model (GEMM) and pancreatic cancer patients. Through dimensionality reduction analysis, murine pancreatic CTCs were grouped into three clusters with different biological functions. CLIC4 and GAS2L1 were shown to be overexpressed in pancreatic CTCs in comparison with peripheral blood mononuclear cells (PBMCs). Further analyses of PBMCs and RNA-sequencing datasets of enriched pancreatic CTCs were used to validate the overexpression of GAS2L1 in pancreatic CTCs. A combinatorial approach using both GAS2L1 and EPCAM expression leads to an increased detection rate of CTCs in PDAC in both GEMM and patient samples. GAS2L1 is thus proposed as a novel biomarker of pancreatic cancer CTCs.

Characterization of Stem-like Circulating Tumor Cells in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth most frequent cause of death from cancer. Circulating tumor cells (CTCs) with stem-like characteristics lead to distant metastases and thus contribute to the dismal prognosis of PDAC. Our purpose is to investigate the role of stemness in CTCs derived from a genetically engineered mouse model of PDAC and to further explore the potential molecular mechanisms. The publically available RNA sequencing dataset GSE51372 was analyzed, and CTCs with (CTC-S) or without (CTC-N) stem-like features were discriminated based on a principal component analysis (PCA). Differentially expressed genes, weighted gene co-expression network analysis (WGCNA), and further functional enrichment analyses were performed. The prognostic role of the candidate gene (CTNNB1) was assessed in a clinical PDAC patient cohort. Overexpression of the pluripotency marker Klf4 (Krüppel-like factor 4) in CTC-S cells positively correlates with Ctnnb1 (ß-Catenin) expression, and their interaction presumably happens via protein-protein binding in the nucleus. As a result, the adherens junction pathway is significantly enriched in CTC-S. Furthermore, the overexpression of Ctnnb1 is a negative prognostic factor for progression-free survival (PFS) and relapse-free survival (RFS) in human PDAC cohort. Overexpression of Ctnnb1 may thus promote the metastatic capabilities of CTCs with stem-like properties via adherens junctions in murine PDAC.

The prognostic role of circulating tumor cells in colorectal cancer.

Introduction: Metastasis is the main cause of cancer-associated death in colorectal cancer (CRC). The presence of circulating tumor cells (CTC) in the blood is associated with an increased risk of recurrence and poor prognosis. The clinical significance of CTCs as a novel biomarker has been extensively studied in the last decade. It has been shown that CTC detection applies to early cancer detection. The presence of CTCs is associated with metastatic spread and poor survival and is also useful as a marker for therapy response.Areas covered: We summarize the role of CTC in CRC, their clinical significance, current methods for CTC detection and challenges as well as future perspectives of CTC research.Expert commentary: The clinical significance of CTC in CRC patients is well established. Although insightful, the available marker-based approaches hampered our understanding of the CTCs and their biology, as such approaches do not take into account the heterogeneity of these cell populations. New technologies should expand the marker-based detection to multi biomarker-based approaches together with recent technological advances in microfluidics for single cell enrichment and analysis.

The overall potential of CD47 in cancer immunotherapy: with a focus on gastrointestinal tumors.

Introduction: CD47 is an anti-phagocytic ('don't eat me') signal overexpressed in many malignant diseases. It acts as myeloid immune checkpoint and thus has prognostic and therapeutic implications.Areas covered: This review presents and discusses the currently available data on the prognostic role and therapeutic value of CD47 in gastrointestinal tumors.Expert opinion: CD47 is overexpressed on the great majority of gastrointestinal tumors, cancer stem cells and circulating tumor cells. Overexpression of CD47 usually predicts a negative prognosis and seems to contribute to cancer immune evasion. The inhibition of CD47 has shown impressive results in clinical trials in hematologic malignancies. However, for gastrointestinal tumors only preclinical data is available. Inhibition of this myeloid immune checkpoint may yield great clinical benefit due to the abundance of myeloid effector cells. However, due to the ubiquitous expression of CD47 and the resulting antigen sink, vast amounts of antibody are required in order to reach therapeutic concentrations. QPCTL inhibitors blocking post-translational modification of CD47 protein may be a solution to this problem.