Pre-treatment [18F]FDG PET/CT biomarkers for the prediction of antibody-drug conjugates efficacy in metastatic breast cancer.

PURPOSE: This study aimed to evaluate the association between pretreatment [18F]FDG PET/CT-derived biomarkers and outcomes in metastatic breast cancer (mBC) patients treated with antibody-drug conjugates (ADCs) Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd). METHODS: A retrospective bicentric analysis was conducted on triple-negative mBC (mTNBC) patients treated with SG and HER2-low mBC patients treated with T-DXd, who underwent [18F]FDG PET/CT scans before therapy. Key biomarkers, including maximum standardized uptake value (SUVmax), total metabolic tumor volume (TMTV) and maximum tumor dissemination (Dmax), were measured. Their prognostic value for progression-free survival (PFS) and overall survival (OS) was assessed using Cox models and Kaplan-Meier curves. RESULTS: 128 patients were included: 71 mTNBC treated with SG and 57 HR-positive and -negative HER2-low mBC treated with T-DXd. Median follow-up was 12.9 months. In the SG cohort, median PFS and OS were 4.8 and 8.9 months, respectively. High Dmax (HR 2.1, 95% CI 1.1-4.3) and high TMTV (HR 2.9, 95% CI 1.2-6.6) were independently associated with shorter OS. In the T-DXd cohort, median PFS and OS were 5.8 and 9.0 months, respectively. High Dmax (HR 2.1, 95% CI 1.2-3.9) and high TMTV (HR 2.4, 95% CI 1.0-6.5) independently correlated with shorter PFS and shorter OS, respectively. CONCLUSION: Pretreatment [18F]FDG PET/CT-derived biomarkers, namely TMTV and Dmax, have significant prognostic value in patients with mTNBC and HER2-low mBC treated with SG and T-DXd. These biomarkers improve prognostic prediction and may optimize treatment strategies, warranting their clinical use, but larger studies are needed to validate these findings.

Analysis of the different pathways of ectopic recurrence of craniopharyngioma in pediatric patients: presentation of cases and review of the literature.

PURPOSE: Craniopharyngioma is a tumor derived from the squamous epithelium of Rathke's pouch. Despite successful excision, recurrence is common, typically occurring at the original tumor site. More rarely, recurrences can manifest at distant locations. This article reports on three distinct types of ectopic recurrence and reviews the existing literature. METHODS: We reviewed clinical records and neuroimaging data of craniopharyngioma patients at our institution, identifying three cases of ectopic recurrence. Additionally, we conducted a literature review of similar cases published between 1975 and 2023, focusing on historical background, pathophysiology, clinical and radiological features, and treatment options. RESULTS: We identified nineteen articles detailing ectopic recurrence of craniopharyngiomas in pediatric patients. The right frontal lobe was the most frequently reported site of recurrence. The shortest interval to recurrence was 11 months, while the longest was 14 years. Most cases were managed with surgical resection, yielding positive outcomes. In our cases, the recurrence sites were temporal intraparenchymal, intraosseous orbital, and occipital intraventricular. All were successfully treated with surgery, with no subsequent recurrences. CONCLUSION: Although craniopharyngiomas are histologically benign, they can recur locally and, more rarely, at distant sites. Surgical intervention is generally well-tolerated. Further research into tumor cell dissemination mechanisms is essential to develop strategies for preventing ectopic recurrence.

Lymphoma: The Added Value of Radiomics, Volumes and Global Disease Assessment.

Lymphoma represents a condition that holds promise for cure with existing treatment modalities; nonetheless, the primary clinical obstacle lies in advancing therapeutic outcomes by pinpointing high-risk individuals who are unlikely to respond favorably to standard therapy. In this article, the authors will delineate the significant strides achieved in the lymphoma field, with a particular emphasis on the 3 prevalent subtypes: Hodgkin lymphoma, diffuse large B-cell lymphomas, and follicular lymphoma.

Nonepithelial cancer dissemination: specificities and challenges.

Epithelial cancers have served as a paradigm to study tumor dissemination but recent data have highlighted significant differences with nonepithelial cancers. Here, we review the current knowledge on nonepithelial tumor dissemination, drawing examples from the latest developments in melanoma, glioma, and sarcoma research. We underscore the importance of the reactivation of developmental processes during cancer progression and describe the nongenetic mechanisms driving nonepithelial tumor spread. We also outline therapeutic opportunities and ongoing clinical approaches to fight disseminating cancers. Finally, we discuss remaining challenges and emerging questions in the field. Defining the core principles underlying nonepithelial cancer dissemination may uncover actionable vulnerabilities of metastatic tumors and help improve the prognosis of patients with cancer.

Gastroesophageal adenocarcinoma metastasizing to the chest wall: A case report and mini­review of the literature.

Subcutaneous metastasis from esophageal cancer (EC), particularly to the chest wall, is a very rare phenomenon. The present study describes a case of gastroesophageal adenocarcinoma that metastasized to the chest wall, invading the fourth anterior rib. A 70-year-old female presented with acute chest pain 4 months after undergoing Ivor-Lewis esophagectomy for gastroesophageal adenocarcinoma. A chest ultrasound revealed a solid hypoechoic mass on the right side of the chest. A contrast-enhanced computed tomography scan of the chest revealed a destructive mass on the right anterior fourth rib (7.5x5 cm). Fine needle aspiration revealed a metastatic moderately differentiated adenocarcinoma to the chest wall. Fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography revealed a large FDG avid deposit on the right side of the chest wall. Under general anesthesia, a right-side anterior chest incision was made and the second, third and fourth ribs were resected with overlying soft tissues, including the pectoralis muscle and overlying skin. The histopathological examination confirmed a metastasized gastroesophageal adenocarcinoma to the chest wall. There are two common assumptions regarding chest wall metastasis from EC. The first one states that this metastasis can occur due to the implantation of the carcinoma during tumor resection. The latter supports the notion of tumor cell dissemination along the esophageal lymphatic and hematogenous systems. Chest wall metastasis from EC invading ribs is an extremely rare incident. However, its likelihood of occurrence should not be neglected following primary cancer treatment.

FDG PET/CT Maximum Tumor Dissemination to Predict Recurrence in Patients with Diffuse Large B-Cell Lymphoma.

Purpose: We investigated the prognostic value of maximum tumor dissemination (Dmax), the distance between malignant lesions that were farthest apart, as assessed by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), and other clinical factors in patients with diffuse large B-cell lymphoma (DLBCL).We investigated the prognostic value of maximum tumor dissemination (Dmax), the distance between malignant lesions that were farthest apart, as assessed by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), and other clinical factors in patients with diffuse large B-cell lymphoma (DLBCL). Methods: Patients who underwent FDG PET/CT for initial staging and treatment response evaluation of DLBCL were reviewed retrospectively. Baseline Dmax, maximum standardized uptake value, total summation of all metabolic tumor volumes (tMTV), and total summation of all total lesion glycolysis (tTLG) were measured. The treatment response was evaluated at the interim and end of first-line treatment (EOT) using the Deauville score (DS). FDG PET/CT parameters and other clinical factors including sex, age, serum lactate dehydrogenase (LDH) level, stage, performance status, and the International Prognostic Index (IPI) were analyzed to identify factors prognostic of the time to progression (TTP) and disease-specific survival (DSS). Results: A total of 63 patients were included. Univariate survival analysis identified Dmax (> 275 mm), tMTV (> 180 mL), tTLG (> 1300), interim DS (≥ 4), and EOT DS (≥ 4) as significant predictors of poor TTP. Serum LDH level (> 640 IU/L), IPI (≥ 4), tMTV (> 180 mL), tTLG (> 1300), interim DS (≥ 4), and EOT DS (≥ 4) were significant predictors of DSS. After multivariate survival analysis, Dmax (P = 0.008) and EOT DS (P = 0.005) were independent predictors of TTP. EOT DS was an independent predictor of DSS (P = 0.029). Conclusions: Dmax at the time of diagnosis and the EOT response assessed by FDG PET/CT provide useful prognostic information additive to the IPI in patients with DLBCL.

Risk for hydrocephalus, hygroma, and tumor dissemination after ventricular opening during resection of supratentorial neoplasms in children.

PURPOSE: The possibility that ventricular opening generates postoperative complications after surgical tumor treatment often restricts the degree of tumor resection. This study aims to determine whether the ventricular opening is associated with more complications in surgeries for resectioning supratentorial intra-axial brain tumors in the pediatric population. METHODS: A retrospective review analysis was performed of patients treated at IOP/GRAACC between 2002 and 2020 under 19 years of age and underwent surgery for supratentorial intra-axial primary brain tumor resection. Data were collected from 43 patients. RESULTS: Glial tumor was more common than non-glial (65% vs. 35%, p = 0.09). The ventricular opening was not related to neoplastic spreads to the neuroaxis (6% vs. 0, p > 0.9) or leptomeningeal (3% vs. 0, p > 0.9). Of the patients whose ventricle was opened, 10% developed hydrocephalus requiring treatment, while none of the patients in the group without ventricular opening developed hydrocephalus (p = 0.5). There was also no statistical difference regarding ventriculitis. Postoperative subdural hygroma formation correlated with the ventricular opening (43% vs. 0, p = 0.003). The survival at 1, 5, and 10 years of cases with the ventricular opening was 93.2%, 89.7%, and 75.7%, respectively, while in cases without ventricular opening, it was 100%, 83%, and 83%, respectively, respectively, with no statistical difference between the mortality curves. CONCLUSION: Our study demonstrated that ventricular violation was not associated with the occurrence of significant complications. It was related to the formation of subdural hygroma, which did not require additional treatment.

Visualizing the Interactions Shaping the Imaging of the Microenvironment in Human Cancers.

The Visium Spatial Gene Expression Solution (Visium 10×) allows for the mRNA analysis using high throughput sequencing and maps a transcriptional expression pattern in tissue sections using high-resolution microscope imaging in ex-vivo human and mice samples. The workflow surveys spatial global gene expression in tissue sections, exploiting the whole transcriptome profiling and defining the set of transcripts via targeted gene panels. An automated cell type annotation allows a comparison with control tissue samples. This technique delineates cancerous or diseased tissue boundaries and details gene expression gradients in the tissue surrounding the tumor or pathologic nests. Remarkably, the Visium 10× allows for whole transcriptome and targeted analysis without the loss of spatial information. This approach provides gene expression data within the context of tissue architecture, tissue microenvironments, and cell groups. It can be used in association with therapy, anti-angiogenic therapy, and immunotherapy to improve treatment response.

Prognostic value of lesion dissemination in doxorubicin, bleomycin, vinblastine, and dacarbazine-treated, interimPET-negative classical Hodgkin Lymphoma patients: A radio-genomic study.

We evaluated the prognostic role of the largest distance between two lesions (Dmax), defined by positron emission tomography (PET) in a retrospective cohort of newly diagnosed classical Hodgkin Lymphoma (cHL) patients. We also explored the molecular bases underlying Dmax through a gene expression analysis of diagnostic biopsies. We included patients diagnosed with cHL from 2007 to 2020, initially treated with ABVD, with available baseline PET for review, and with at least two FDG avid lesions. Patients with available RNA from diagnostic biopsy were eligible for gene expression analysis. Dmax was deduced from the three-dimensional coordinates of the baseline metabolic tumor volume (MTV) and its effect on progression free survival (PFS) was evaluated. Gene expression profiles were correlated with Dmax and analyzed using CIBERSORTx algorithm to perform deconvolution. The study was conducted on 155 eligible cHL patients. Using its median value of 20 cm, Dmax was the only variable independently associated with PFS (HR = 2.70, 95% CI 1.1-6.63, pValue = 0.03) in multivariate analysis of PFS for all patients and for those with early complete metabolic response (iPET-). Among patients with iPET-low Dmax was associated with a 4-year PFS of 90% (95% CI 82.0-98.9) significantly better compared to high Dmax (4-year PFS 72.4%, 95% CI 61.9-84.6). From the analysis of gene expression profiles differences in Dmax were mostly associated with variations in the expression of microenvironmental components. In conclusion our results support tumor dissemination measured through Dmax as novel prognostic factor for cHL patients treated with ABVD.

Endometrioid Cancer Associated With Endometriosis: From the Seed and Soil Theory to Clinical Practice.

Endometriosis is a benign condition characterized by the presence of ectopic endometrial tissue. It is still debated whether endometriosis is a disease that can predispose to the pathogenesis of endometrial cancer outside the uterus. Deficiencies in mismatch repair (MMR) genes are a known risk factor for developing endometrioid cancer. Starting from two cases of patients with abnormal MMR endometrioid carcinoma of the uterus and synchronous endometrioid carcinoma in non-ovarian and ovarian endometriosis, we performed a somatic mutation profile and phylogenetic analysis of the lesions in order to identify if they were metastasis or primary de novo tumors. In the first case, we identified de novo activating mutations in PIK3CA and KRAS in endometrioid cancer lesions but not in endometriosis. Although the acquisition of a de novo mutation in ESR1 and a decrease in mutant allele fraction (MAF) from the endometrial tumor to the localizations in the endometriosis lesions, the clonal relationship was confirmed by the limited number of heteroplasmic mutations in D-loop mitochondrial DNA region. In the other case, the clonal behavior was demonstrated by the overlap of MAF at each site. Our data support the hypothesis of a retrograde dissemination of tumor cells, moving from the primary carcinoma in the endometrium to ectopic sites of endometriosis where localizations of tumor arise.

Discovery of Lijianmin-Chengkun Complexes and Their Oncological Application in Osseous and Intraarticular Lesions Around the Knee.

Objective: This research aims to refresh the limited understanding about the canal and vascular structures within the epiphysis and metaphysis of the tibia and femur and their oncological significance. Methods: This study was started with characterization of a novel structure using radiographs and anatomic dissections, followed by a descriptive clinical study with 55 participants to investigate the effects of tumors on this novel discovery and a retrospective cohort study with 82 participants to investigate whether the structure would be a risk factor for tumor recurrence after the curettage of giant cell tumor of bone. Results: A new anatomical knee structure, the Lijianmin-Chengkun (LC) complex, was discovered in healthy adults, and its clinical implications were examined in this study. This new-found anatomical structure is composed of an epiphyseal and metaphyseal canal which surrounds a blood vessel, foramen, and foramen-covered synovium. All LC complexes showed similar radiographical, anatomical, and histological characteristics and were located within specific tibial and femoral intercondylar regions. These LC complexes seem to facilitate tumor residue and extension and may be a risk factor for tumor recurrence after curettage of femoral and tibial giant cell tumors (P = 0.031). Conclusion: The LC complexes are related to local tumor recurrence and bidirectional tumor dissemination between intraosseous and intraarticular regions. These findings have opened up a new perspective and may provide new targets for intervention in malignant and aggressive tumors around the knee joint.

Engineering a 3D collective cancer invasion model with control over collagen fiber alignment.

Prior to cancer cell invasion, the structure of the extracellular matrix (ECM) surrounding the tumor is remodeled, such that circumferentially oriented matrix fibers become radially aligned. This predisposed radially aligned matrix structure serves as a critical regulator of cancer invasion. However, a biomimetic 3D model recapitulating a tumor's behavioral response to these ECM structures is not yet available. In this study, we have developed a phase-specific, force-guided method to establish a 3D dual topographical tumor model in which each tumor spheroid/organoid is surrounded by radially aligned collagen I fibers on one side and circumferentially oriented fibers on the opposite side. A coaxial rotating cylinder system was employed to construct the dual fiber topography and to pre-seed tumor spheroids/organoids within a single device. This system enables the application of different force mechanisms in the nucleation and elongation phases of collagen fiber polymerization to guide fiber alignment. In the nucleation phase, fiber alignment is enhanced by a horizontal laminar Couette flow driven by the inner cylinder rotation. In the elongation phase, fiber growth is guided by a vertical gravitational force to form a large aligned collagen matrix gel (35 × 25 × 0.5 mm) embedded with >1000 tumor spheroids. The fibers above each tumor spheroid are radially aligned along the direction of gravitational force in contrast to the circumferentially oriented fibers beneath each tumor spheroid/organoid, where the presence of the tumor interferes with the gravity-induced fiber alignment. After tumor invasion, there are more disseminated multicellular clusters on the radially aligned side, compared to the side of the tumor spheroid/organoid facing circumferentially oriented fibers. These results indicate that our 3D dual topographical model recapitulates the preference of tumors to invade and disseminate along radially aligned fibers. We anticipate that this 3D dual topographical model will have broad utility to those studying collective tumor invasion and that it has the potential to identify cancer invasion-targeted therapeutic agents.

Tumor-draining lymph nodes are survival niches that support T cell priming against lymphatic transported tumor antigen and effects of immune checkpoint blockade in TNBC.

Triple negative breast cancer (TNBC) is a significant clinical problem to which immunotherapeutic strategies have been applied with limited success. Using the syngeneic E0771 TNBC mouse model, this work explores the potential for antitumor CD8+ T cell immunity to be primed extratumorally in lymphoid tissues and therapeutically leveraged. CD8+ T cell viability and responses within the tumor microenvironment (TME) were found to be severely impaired, effects coincident with local immunosuppression that is recapitulated in lymphoid tissues in late stage disease. Prior to onset of a locally suppressed immune microenvironment, however, CD8+ T cell priming within lymph nodes (LN) that depended on tumor lymphatic drainage remained intact. These results demonstrate tumor-draining LNs (TdLN) to be lymphoid tissue niches that support the survival and antigenic priming of CD8+ T lymphocytes against lymph-draining antigen. The therapeutic effects of and CD8+ T cells response to immune checkpoint blockade were furthermore improved when directed to LNs within the tumor-draining lymphatic basin. Therefore, TdLNs represent a unique potential tumor immunity reservoir in TNBC for which strategies may be developed to improve the effects of ICB immunotherapy.

Organotypic Modeling of the Tumor Landscape.

Cancer is a complex disease and it is now clear that not only epithelial tumor cells play a role in carcinogenesis. The tumor microenvironment is composed of non-stromal cells, including endothelial cells, adipocytes, immune and nerve cells, and a stromal compartment composed of extracellular matrix, cancer-associated fibroblasts and mesenchymal cells. Tumorigenesis is a dynamic process with constant interactions occurring between the tumor cells and their surroundings. Even though all connections have not yet been discovered, it is now known that crosstalk between actors of the microenvironment drives cancer progression. Taking into account this complexity, it is important to develop relevant models to study carcinogenesis. Conventional 2D culture models fail to represent the entire tumor microenvironment properly and the use of animal models should be decreased with respect to the 3Rs rule. To this aim, in vitro organotypic models have been significantly developed these past few years. These models have different levels of complexity and allow the study of tumor cells alone or in interaction with the microenvironment actors during the multiple stages of carcinogenesis. This review depicts recent insights into organotypic modeling of the tumor and its microenvironment all throughout cancer progression. It offers an overview of the crosstalk between epithelial cancer cells and their microenvironment during the different phases of carcinogenesis, from the early cell autonomous events to the late metastatic stages. The advantages of 3D over classical 2D or in vivo models are presented as well as the most promising organotypic models. A particular focus is made on organotypic models used for studying cancer progression, from the less complex spheroids to the more sophisticated body-on-a-chip. Last but not least, we address the potential benefits of these models in personalized medicine which is undoubtedly a domain paving the path to new hopes in terms of cancer care and cure.

Do malignant cells sleep at night?

Biological rhythms regulate the biology of most, if not all living creatures, from whole organisms to their constitutive cells, their microbiota, and also parasites. Here, we present the hypothesis that internal and external ecological variations induced by biological cycles also influence or are exploited by cancer cells, especially by circulating tumor cells, the key players in the metastatic cascade. We then discuss the possible clinical implications of the effect of biological cycles on cancer progression, and how they could be exploited to improve and standardize methods used in the liquid biopsy field.

Telomerase-specific attenuated viruses, a definitive strategy or just one more in circulating tumor cells detection anthology?

The quantification and isolation of Circulating Tumor Cells (CTC) is being the battleground during last years. There are many groups that are investing economic resources in trying to solve this jigsaw. Technological platforms based on different proofs of concept have been developed achieving in some cases excellent results despite not having been able to detect the total compute of the patient's CTC population. The handicap of this matter has been the lack of universal markers. Several years have gone so that in detection of CTC is take into account a basic characteristic that possesses the most of tumor cells, the loss of inactivation of the enzyme telomerase. Gene therapy has been combined with telomerase activity concept for develop a molecular tool that makes it possible to identify CTC: Telomerase-specific replication-selective viruses. This review includes for the first time all the scientific studies that have been published to date with this advanced technology. Furthermore, it describes the role in the diagnosis and prognosis that Telomerase-specific attenuated viruses have been playing in cancer patients study during this last decade.

Natural killer cells and pigment epithelial-derived factor control the infiltrative and nodular growth of hepatic metastases in an Orthotopic murine model of ocular melanoma.

BACKGROUND: Metastases account for 90% of all cancer-related deaths, becoming a therapeutic problem. Approximately 50% of all uveal melanoma (UM) patients will develop metastases, mainly in the liver. Post-mortem analyses of livers from metastatic UM patients showed two different metastatic growth patterns: infiltrative and nodular. The infiltrative pattern exhibits tumor infiltration directly to the hepatic lobule and minimal angiogenesis. The nodular pattern shows clusters of tumor cells around the portal venules that efface the liver parenchyma. We recently demonstrated Natural Killer (NK) cells play a pivotal role in the control of hepatic metastases and the pigment epithelial-derived factor (PEDF) controls angiogenesis in the liver using our established ocular melanoma animal model. In this study we investigated the role of NK cells and PEDF in the development of metastatic growth patterns, as this can contribute to the development of novel therapeutics specific towards each growth pattern. METHODS: We utilize our established ocular melanoma animal model by inoculation of B16-LS9 melanoma cells into C57BL/6 J mice (WT), anti-asialo GM1-treated C57BL/6 J mice (NK-depleted), and PEDF-/- C57BL/6 J mice. Three weeks after inoculation we evaluated the metastatic growth patterns and stratified them based of the numbers of tumor cells. To evaluate angiogenesis the mean vascular density (MVD) was calculated. The immune compartment of the liver was analyzed by flow cytometry. RESULTS: Our in vivo work showed two distinct metastatic growth patterns, the infiltrative and nodular, recapitulating the post-mortem analyses on human liver tissue. We discovered NK cells control the infiltrative growth. In contrast, PEDF controlled anti-angiogenic responses, showing higher MVD values compared to NK-depleted and WT animals. The myeloid lineage, comprised of monocytes, macrophages, and myeloid-derived suppressor cells, was reduced in the absence of NK cells or PEDF. CONCLUSIONS: Our animal model recapitulates the metastatic growth patterns observed in the human disease. We demonstrated a role for NK cells in the development of the infiltrative growth pattern, and a role for PEDF in the development of the nodular pattern. The understanding of the complexity associated with the metastatic progression has profound clinical implications in the diagnostic and disease-management as we can develop and direct more effective therapies.

Cytoplasmic cyclin D1 regulates glioblastoma dissemination.

Glioblastoma (GBM) is a highly invasive brain neoplasia with an elevated recurrence rate after surgical resection. The cyclin D1 (Ccnd1)/Cdk4-retinoblastoma 1 (RB1) axis is frequently altered in GBM, leading to overproliferation by RB1 deletion or by Ccnd1-Cdk4 overactivation. High levels of Ccnd1-Cdk4 also promote GBM cell invasion by mechanisms that are not so well understood. The purpose of this work is to elucidate the in vivo role of cytoplasmic Ccnd1-Cdk4 activity in the dissemination of GBM. We show that Ccnd1 activates the invasion of primary human GBM cells through cytoplasmic RB1-independent mechanisms. By using GBM mouse models, we observed that evaded GBM cells showed cytoplasmic Ccnd1 colocalizing with regulators of cell invasion such as RalA and paxillin. Our genetic data strongly suggest that, in GBM cells, the Ccnd1-Cdk4 complex is acting upstream of those regulators. Accordingly, expression of Ccnd1 induces focal adhesion kinase, RalA and Rac1 activities. Finally, in vivo experiments demonstrated increased GBM dissemination after expression of membrane-targeted Ccnd1. We conclude that Ccnd1-Cdk4 activity promotes GBM dissemination through cytoplasmic and RB1-independent mechanisms. Therefore, inhibition of Ccnd1-Cdk4 activity may be useful to hinder the dissemination of recurrent GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Pancreatic ductal adenocarcinoma cell secreted extracellular vesicles containing ceramide-1-phosphate promote pancreatic cancer stem cell motility.

The high mortality rate associated with pancreatic ductal adenocarcinoma (PDAC) is in part due to lack of effective therapy for this highly chemoresistant tumor. Cancer stem cells, a subset of cancer cells responsible for tumor initiation and metastasis, are not targeted by conventional cytotoxic agents, which renders the identification of factors that facilitate cancer stem cell activation useful in defining targetable mechanisms. We determined that bioactive sphingolipid induced migration of pancreatic cancer stem cells (PCSC) and signaling was specific to ceramide-1-phosphate (C1P). Furthermore, PDAC cells were identified as a rich source of C1P. Importantly, PDAC cells express the C1P converting enzyme ceramide kinase (CerK), secrete C1P-containing extracellular vesicles that mediate PCSC migration, and when co-injected with PCSC reduce animal survival in a PDAC peritoneal dissemination model. Our findings suggest that PDAC secrete C1P-containing extracellular vesicles as a means of recruiting PCSC to sustain tumor growth therefore making C1P release a mechanism that could facilitate tumor progression.

[Aerogenic tumor seeding : A new invasive criterion for lung carcinomas]. / Aerogene Tumoraussaat (STAS) : Ein neues Invasionskriterium für Lungenkarzinome.

The new concept of spread through air spaces (STAS) was introduced for pulmonary adenocarcinomas in the 2015 WHO classification for lung cancer. Yet, available data demonstrate that STAS is of high prognostic impact and associated with specific clinic-pathological characteristics. This article provides a comprehensive overview of recent developments in this field.