Patients with cancer, both hematologic and solid malignancies, are at increased risk for thrombosis and thromboembolism. In addition to general risk factors such as immobility and major surgery, shared by non-cancer patients, cancer patients are exposed to specific thrombotic risk factors. These include, among other factors, cancer-induced hypercoagulation, and chemotherapy-mediated endothelial dysfunction as well as tumor-cell-derived microparticles. After an episode of thrombosis in a cancer patient, secondary thromboprophylaxis to prevent recurrent thromboembolism has long been established and is typically continued as long as the cancer is active or actively treated. On the other hand, primary prophylaxis, even though firmly established in hospitalized cancer patients, has only recently been studied in ambulatory patients. This recent change is mostly due to the emergence of direct oral anticoagulants (DOACs). DOACs have a shorter half-life than vitamin K antagonists (VKA), and they overcome the need for parenteral application, the latter of which is associated with low-molecular-weight heparins (LMWH) and can be difficult for the patient to endure in the long term. Here, first, we discuss the clinical trials of primary thromboprophylaxis in the population of cancer patients in general, including the use of VKA, LMWH, and DOACs, and the potential drug interactions with pre-existing medications that need to be taken into account. Second, we focus on special situations in cancer patients where primary prophylactic anticoagulation should be considered, including myeloma, major surgery, indwelling catheters, or immobilization, concomitant diseases such as renal insufficiency, liver disease, or thrombophilia, as well as situations with a high bleeding risk, particularly thrombocytopenia, and specific drugs that may require primary thromboprophylaxis. We provide a novel algorithm intended to aid specialists but also family practitioners and nurses who care for cancer patients in the decision process of primary thromboprophylaxis in the individual patient. Full article

Neuroblastoma, a pediatric cancer of the peripheral sympathetic nervous system, is characterized by an important clinical heterogeneity, and high-risk tumors are associated with a poor overall survival. Neuroblastoma cells may present with diverse morphological and biochemical properties in vitro, and seminal observations suggested that interconversion between two phenotypes called N-type and S-type may occur. In 2017, two main studies provided novel insights into these subtypes through the characterization of the transcriptomic and epigenetic landscapes of a panel of neuroblastoma cell lines. In this review, we focus on the available data that define neuroblastoma cell identity and propose to use the term noradrenergic (NOR) and mesenchymal (MES) to refer to these identities. We also address the question of transdifferentiation between both states and suggest that the plasticity between the NOR identity and the MES identity defines a noradrenergic-to-mesenchymal transition, reminiscent of but different from the well-established epithelial-to-mesenchymal transition. Full article

Collecting duct carcinoma (CDC) is a rare and highly aggressive kidney cancer subtype with poor prognosis and no standard treatments. To date, only a few studies have examined the transcriptomic portrait of CDC. Through integration of multiple datasets, we compared CDC to normal tissue, upper-tract urothelial carcinomas, and other renal cancers, including clear cell, papillary, and chromophobe histologies. Association between CDC gene expression signatures and in vitro drug sensitivity data was evaluated using the Cancer Therapeutic Response Portal, Genomics of Drug Sensitivity in Cancer datasets, and connectivity map. We identified a CDC-specific gene signature that predicted in vitro sensitivity to different targeted agents and was associated to worse outcome in clear cell renal cell carcinoma. We showed that CDC are transcriptionally related to the principal cells of the collecting ducts providing evidence that this tumor originates from this normal kidney cell type. Finally, we proved that CDC is a molecularly heterogeneous disease composed of at least two subtypes distinguished by cell signaling, metabolic and immune-related alterations. Our findings elucidate the molecular features of CDC providing novel biological and clinical insights. The identification of distinct CDC subtypes and their transcriptomic traits provides the rationale for patient stratification and alternative therapeutic approaches. Full article

Background: We aim to validate a seven-marker immunohistochemical signature, consisting of Bax, Bcl-X, PTEN, COX-2, (loss of) ß-Catenin, (loss of) MTAP and (presence of) CD20, in an independent patient cohort and test clinical feasibility. Methods: We performed staining of the mentioned antibodies in tissue of 88 primary melanomas and calculated a risk score for each patient. Data were correlated with clinical parameters and outcome (recurrence-free, distant metastasis-free and melanoma-specific survival). Results: The seven-marker signature was able to identify high-risk patients within stages IB-III melanoma patients that have a significantly higher risk of disease recurrence, metastasis, and death. In particular, the high sensitivity of relapse prediction (>94%) in sentinel negative patients (stages IB–IIC) was striking (negative predictive value of 100% for melanoma-specific survival and distant metastasis-free survival, and 97.5% for relapse-free survival). For stage III patients (positive nodal status), the negative predictive value was 100% with the seven-marker signature. Conclusions: The seven-marker signature can help to further select high-risk patients in stages IIB-C but also in earlier stages IB–IIA and be a useful tool for therapy decisions in the adjuvant and future neo-adjuvant settings. Stage III patients with measurable lymph node disease classified as high-risk with the seven-marker signature are potential candidates for neoadjuvant immunotherapy. Full article

Developing reliable experimental models that can predict clinical response before treating the patient is a high priority in gynecologic cancer research, especially in advanced or recurrent endometrial and ovarian cancers. Patient-derived organoids (PDOs) represent such an opportunity. Herein, we describe our successful creation of 43 tumor organoid cultures and nine adjacent normal tissue organoid cultures derived from patients with endometrial or ovarian cancer. From an initial set of 45 tumor tissues and seven ascites fluid samples harvested at surgery, 83% grew as organoids. Drug sensitivity testing and organoid cell viability assays were performed in 19 PDOs, a process that was accomplished within seven days of obtaining the initial surgical tumor sample. Sufficient numbers of cells were obtained to facilitate testing of the most commonly used agents for ovarian and endometrial cancer. The models reflected a range of sensitivity to platinum-containing chemotherapy as well as other relevant agents. One PDO from a patient treated prior to surgery with neoadjuvant trastuzumab successfully predicted the patient’s postoperative chemotherapy and trastuzumab resistance. In addition, the PDO drug sensitivity assay identified alternative treatment options that are currently used in the second-line setting. Our findings suggest that PDOs could be used as a preclinical platform for personalized cancer therapy for gynecologic cancer patients. Full article

The study of low-molecular-weight metabolites that exist in cells and organisms is known as metabolomics and is often conducted using mass spectrometry laboratory platforms. Definition of oncometabolites in the context of the metabolic phenotype of cancer cells has been accomplished through metabolomics. Oncometabolites result from mutations in cancer cell genes or from hypoxia-driven enzyme promiscuity. As a result, normal metabolites accumulate in cancer cells to unusually high concentrations or, alternatively, unusual metabolites are produced. The typical oncometabolites fumarate, succinate, (2R)-hydroxyglutarate and (2S)-hydroxyglutarate inhibit 2-oxoglutarate-dependent dioxygenases, such as histone demethylases and HIF prolyl-4-hydroxylases, together with DNA cytosine demethylases. As a result of the cancer cell acquiring this new metabolic phenotype, major changes in gene transcription occur and the modification of the epigenetic landscape of the cell promotes proliferation and progression of cancers. Stabilization of HIF1α through inhibition of HIF prolyl-4-hydroxylases by oncometabolites such as fumarate and succinate leads to a pseudohypoxic state that promotes inflammation, angiogenesis and metastasis. Metabolomics has additionally been employed to define the metabolic phenotype of cancer cells and patient biofluids in the search for cancer biomarkers. These efforts have led to the uncovering of the putative oncometabolites sarcosine, glycine, lactate, kynurenine, methylglyoxal, hypotaurine and (2R,3S)-dihydroxybutanoate, for which further research is required. Full article

Hepatocellular carcinoma represents the most prevalent primary liver cancer worldwide, and it is either caused by intrinsic genetic mutations or by a multitude of extrinsic risk factors. Even though the interplay between chronic inflammatory changes and hepatocarcinogenesis has been at the forefront of clinical investigation for the past few decades, the role of tumor-associated neutrophils (TANs) in HCC development still remains ambiguous. On the one hand, N1 TANs exhibit an anti-tumorigenic activity, mediated by direct or indirect tumor cell lysis, whereas on the other hand, N2 TANs have been correlated with increased HCC growth, invasiveness, and metastasis. The association of an elevated Neutrophil-to-Lymphocyte Ratio (NLR) with poor prognosis in patients with HCC, has been recently brought into spotlight, consolidating its widespread use as a reliable biomarker. Due to the decisive involvement of TANs in HCC pathogenesis and development, the utilization of various neutrophil-centered anticancer treatment modalities has been under clinical experimentation, selectively targeting and modulating the processes of neutrophil recruitment, activation, and migration. This review summarizes current evidence on the role of TANs in HCC pathogenesis and progression, as well as in their potential involvement in tumor therapy, shedding light on emerging anticancer treatment methods targeting neutrophils. Full article

Metastatic breast cancer (BC) is currently an incurable disease. Besides endocrine therapy and targeted agents, chemotherapy is often used in the treatment of this disease. However, lack of tumor specificity and toxicity associated with dose exposure limit the manageability of cytotoxic agents. Antibody–drug conjugates (ADCs) are a relatively new class of anticancer drugs. By merging the selectivity of monoclonal antibodies with the cytotoxic properties of chemotherapy, they improve the therapeutic index of antineoplastic agents. Three core components characterize ADCs: the antibody, directed to a target antigen; the payload, typically a cytotoxic agent; a linker, connecting the antibody to the payload. The most studied target antigen is HER2 with some agents, such as trastuzumab deruxtecan, showing activity not only in HER2-positive, but also in HER2-low BC patients, possibly due to a bystander effect. This property to provide a cytotoxic impact also against off-target cancer cells may overcome the intratumoral heterogeneity of some target antigens. Other cancer-associated antigens represent a strategy for the development of ADCs against triple-negative BC, as shown by the recent approval of sacituzumab govitecan. In this review, we discuss the current landscape of ADC development for the treatment of BC, as well as the possible limitations of this treatment. Full article

After the first wave of COVID-19, the Spanish Society of Thoracic Surgeons (SECT) surveyed its members to assess the impact of the pandemic on thoracic oncology surgery in Spain. In May 2020, all SECT members were invited to complete an online, 40-item, multiple choice questionnaire. The questionnaire was developed by the SECT Scientific Committee and sent via email. The overall response rate was 19.2%. The respondents answered at least 91.5% of the items, with only one exception (a question about residents). Most respondents (89.3%) worked in public hospitals. The reported impact of the pandemic on routine clinical activity was considered extreme or severe by 75.5% of respondents (25.5% and 50%, respectively). Multidisciplinary tumour boards were held either with fewer members attending or through electronic platforms (44.6% and 35.9%, respectively). Surgical activity decreased by 95.7%, with 41.5% of centers performing surgery only on oncological patients and 11.7% only in emergencies. Nearly 60% of respondents reported modifying standard protocols for early-stage cancer and in the preoperative workup. Most centers (≈80%) reported using full personal protective equipment when operating on COVID-19 positive patients. The COVID-19 pandemic severely affected thoracic oncology surgery in Spain. The lack of common protocols led to a variable care delivery to lung cancer patients. Full article

Severe acute respiratory virus-2 (SARS-CoV-2) has spread globally leading to a devastating loss of life. Large registry studies have begun to shed light on the epidemiological and clinical vulnerabilities of cancer patients who succumb to or endure poor outcomes of SARS-CoV-2. Specific treatment for COVID-19 infections in cancer patients is lacking while the demand for treatment is increasing. Therefore, we explored the effect of Rintatolimod (Ampligen^®) (AIM ImmunoTech, Ocala, FL, USA), a Toll-like receptor 3 (TLR3) agonist, to treat uninfected human pancreatic cancer cells (HPACs). The direct effect of Rintatolimod was measured by targeted gene expression profiling and by proteomics measurements. Our results show that Rintatolimod induces an antiviral effect in HPACs by inducing RNase-L-dependent and independent pathways of the innate immune system. Treatment with Rintatolimod activated the interferon signaling pathway, leading to the overexpression of several cytokines and chemokines in epithelial cells. Furthermore, Rintatolimod treatment increased the expression of angiogenesis-related genes without promoting fibrosis, which is the main cause of death in patients with COVID-19. We conclude that Rintatolimod could be considered an early additional treatment option for cancer patients who are infected with SARS-CoV-2 to prevent the complicated severity of the disease. Full article

Despite evidence for the superiority of twice-daily (BID) radiotherapy schedules, their utilization in practice remains logistically challenging. Hypofractionation (HFRT) is a commonly implemented alternative. We aim to compare the outcomes and toxicities in limited-stage small-cell lung cancer (LS-SCLC) patients treated with hypofractionated versus BID schedules. A bi-institutional retrospective cohort review was conducted of LS-SCLC patients treated with BID (45 Gy/30 fractions) or HFRT (40 Gy/15 fractions) schedules from 2007 to 2019. Overlap weighting using propensity scores was performed to balance observed covariates between the two radiotherapy schedule groups. Effect estimates of radiotherapy schedule on overall survival (OS), locoregional recurrence (LRR) risk, thoracic response, any ≥grade 3 (including lung, and esophageal) toxicity were determined using multivariable regression modelling. A total of 173 patients were included in the overlap-weighted analysis, with 110 patients having received BID treatment, and 63 treated by HFRT. The median follow-up was 20.4 months. Multivariable regression modelling did not reveal any significant differences in OS (hazard ratio [HR] 1.67, p = 0.38), LRR risk (HR 1.48, p = 0.38), thoracic response (odds ratio [OR] 0.23, p = 0.21), any ≥grade 3+ toxicity (OR 1.67, p = 0.33), ≥grade 3 pneumonitis (OR 1.14, p = 0.84), or ≥grade 3 esophagitis (OR 1.41, p = 0.62). HFRT, in comparison to BID radiotherapy schedules, does not appear to result in significantly different survival, locoregional control, or toxicity outcomes. Full article

Targeting metastasis is a vital strategy to improve the clinical outcome of cancer patients, specifically in cases with high-grade malignancies. Here, we employed a Salmonella-based treatment to address metastasis. The potential of Salmonella as an anticancer agent has been extensively studied; however, the mechanism through which it affects metastasis remains unclear. This study found that the epithelial-to-mesenchymal transition (EMT) inducer SNAI1 was markedly reduced in Salmonella-treated melanoma cells, as revealed by immunoblotting. Furthermore, wound healing and transwell assays showed a reduced in vitro cell migration following Salmonella treatment. Transfection experiments confirmed that Salmonella acted against metastasis by suppressing protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, which in turn inhibited SNAI1 expression. Since it is known that metastasis is also influenced by inflammation, we partly characterized the immune infiltrates in melanoma as affected by Salmonella treatment. We found through tumor-macrophage co-culture that Salmonella treatment increased high mobility group box 1 (HMGB1) secretion in tumors to coax the polarization of macrophages in favor of an M1-like phenotype, as shown by increased inducible nitric oxide synthase (iNOS) expression and Interleukin 1 Beta (IL-1β) secretion. Data from our animal study corroborated the in vitro findings, wherein the Salmonella-treated group obtained the lowest lung metastases, longer survival, and increased iNOS-expressing immune infiltrates. Full article

Lymphoma research is a paradigm of the integration of basic and clinical research within the fields of diagnosis and therapy. Clinical, phenotypic, and genetic data are currently used to predict which patients could benefit from standard treatment. However, alternative therapies for patients at higher risk from refractoriness or relapse are usually empirically proposed, based on trial and error, without considering the genetic complexity of aggressive B-cell lymphomas. This is primarily due to the intricate mosaic of genetic and epigenetic alterations in lymphomas, which are an obstacle to the prediction of which drug will work for any given patient. Matching a patient’s genes to drug sensitivity by directly testing live tissues comprises the “precision medicine” concept. However, in the case of lymphomas, this concept should be expanded beyond genomics, eventually providing better treatment options for patients in need of alternative therapeutic approaches. We provide an overview of the most recent findings in diffuse large B-cell lymphomas genomics, from the classic functional models used to study tumor biology and the response to experimental treatments using cell lines and mouse models, to the most recent approaches with spheroid/organoid models. We also discuss their potential relevance and applicability to daily clinical practice. Full article

(1) Background: In response to the global COVID-19 pandemic, governmental measures have been undertaken. The impact of the crisis on the healthcare of patients with cancer is largely unexplored. This multicenter cohort study aimed to investigate a potential screening delay and its consequences in patients with oral cancer (OC) during the pandemic. (2) Material and Methods: Data of patients who were first diagnosed with OC during different periods were collected, especially in terms of OC incidence, tumor stage/entity and time to intervention. The periods lockdown (LD) (13 March–16 June 2020), post-lockdown (PLD) (17 June–1 November 2020), and the corresponding equivalents in 2018/19 were differentiated and compared. (3) Results: There was no obvious trend towards a higher incidence of OC or higher tumor stages, whereas a trend towards a shorter time to intervention during the LD2020 could be observed. Subgroup analyses revealed an increased incidence in OC within the PLD2020 in Mainz, which might be explained by the partial closure of dental practices in this federal state during LD. (4) Conclusions: While there was no overall higher incidence of OC, we found closure of practices during LD to possibly delay cancer diagnosis. Therefore, measures must be taken to identify patients at risk and to ensure basic healthcare, especially in the context of dental screening measures. Full article

Brain metastases are the most severe clinical manifestation of aggressive tumors. Melanoma, breast, and lung cancers are the types that prefer the brain as a site of metastasis formation, even if the reasons for this phenomenon still remain to be clarified. One of the main characteristics that makes a cancer cell able to form metastases in the brain is the ability to interact with the endothelial cells of the microvasculature, cross the blood–brain barrier, and metabolically adapt to the nutrients available in the new microenvironment. In this review, we analyzed what makes the brain a suitable site for the development of metastases and how this microenvironment, through the continuous release of neurotransmitters and amino acids in the extracellular milieu, is able to support the metabolic needs of metastasizing cells. We also suggested a possible role for amino acids released by the brain through the endothelial cells of the blood–brain barrier into the bloodstream in triggering the process of extravasation/invasion of the brain parenchyma. Full article