Authors: Philippa Lantwin Adam Kaczorowski Cathleen Nientiedt Constantin Schwab Martina Kirchner Viktoria Schütz Magdalena Görtz Markus Hohenfellner Anette Duensing Albrecht Stenzinger Stefan Duensing
Introduction: DNA damage repair gene deficiency defines a subgroup of prostate cancer patients with early metastatic progression and unfavorable disease outcome. Whether deficiency in DNA damage repair genes directly promotes metastatic dissemination is not completely understood. Methods: The migratory behavior of prostate cancer cells was analyzed after siRNA-mediated knockdown of DNA damage repair and checkpoint proteins, including BRCA2, ATM, and others, using transwell migration assays, scratch assays and staining for F-actin to ascertain cell circularity. Cells deficient in BRCA2 or ATM were tested for oxidative stress by measuring reactive oxygen species (ROS). The effects of ROS inhibition on cell migration were analyzed using the antioxidant N-acetylcysteine (NAC). The correlation between BRCA2 deficiency and oxidative stress was ascertained via immunohistochemistry for methylglyoxal (MG)-modified proteins in 15 genetically defined primary prostate cancers. Results: Prostate cancer cells showed a significantly increased migratory activity after the knockdown of BRCA2 or ATM. There was a significant increase in ROS production in LNCaP cells after BRCA2 knockdown and in PC-3 cells after BRCA2 or ATM knockdown. Remarkably, the ROS scavenger NAC abolished the enhanced motility of prostate cancer cells after the knockdown of BRCA2 or ATM. Primary prostate cancers harboring genetic alterations in BRCA2 showed a significant increase in MG-modified proteins, indicating enhanced oxidative stress in vivo. Conclusions: Our results indicate that DNA damage repair gene deficiency may contribute to the metastatic dissemination of prostate cancer through enhanced tumor cell migration involving oxidative stress.
]]>Authors: Jiřina Bartůňková
Epithelial ovarian carcinoma (EOC) is the fifth leading cause of cancer-related death in women, largely reflecting the early dissemination of this malignant disease to the peritoneum. Due to its immunological features, EOC has poor response to immune checkpoint inhibitors (ICIs), including a limited tumor mutational burden (TMB), poor infiltration by immune cells, and active immunosuppression. Thus, novel strategies are needed to overcome the frequent lack of pre-existing immunity in patients with EOC. We developed and tested an autologous dendritic cell (DC)-based vaccine (DCVAC), which has recently been shown to be safe and to significantly improve progression-free survival (PFS) in two independent randomized phase II clinical trials enrolling patients with EOC (SOV01, NCT02107937; SOV02, NCT02107950). In addition, our exploratory data analyses suggest that the clinical benefits of the DCVAC were more pronounced in patients with EOC with lower-than-median TMBs and reduced CD8+ T cell infiltration. Thus, the DC-based vaccine stands out as a promising clinical tool to jumpstart anticancer immunity in patients with immunologically “cold” EOC. Our findings underscore the need for personalized immunotherapy and the clinical relevance of potential tumor-related biomarkers within the immunotherapy field. Additional clinical trials are needed to address these strategies as well as the potential value of the TMB and immune infiltration at baseline as biomarkers for guiding the clinical management of EOC.
]]>Authors: Razmik Mirzayans
Most therapeutic strategies for solid tumor malignancies are designed based on the hypothesis that cancer cells evade apoptosis to exhibit therapy resistance. This is somewhat surprising given that clinical studies published since the 1990s have demonstrated that increased apoptosis in solid tumors is associated with cancer aggressiveness and poor clinical outcome. This is consistent with more recent reports demonstrating non-canonical (pro-survival) roles for apoptotic caspases, including caspase 3, as well as the ability of cancer cells to recover from late stages of apoptosis via a process called anastasis. These activities are essential for the normal development and maintenance of a healthy organism, but they also enable malignant cells (including cancer stem cells) to resist anticancer treatment and potentially contribute to clinical dormancy (minimal residual disease). Like apoptosis, therapy-induced cancer cell dormancy (durable proliferation arrest reflecting various manifestations of genome chaos) is also not obligatorily a permanent cell fate. However, as briefly discussed herein, compelling pre-clinical studies suggest that (reversible) dormancy might be the “lesser evil” compared to treacherous apoptosis.
]]>Authors: Mahdi Zirakchian Zadeh
In multiple myeloma (MM), specific cytokines produced by plasma cells disrupt the equilibrium between osteoblasts and osteoclasts. As a result, MM patients experience an increase in osteoclast activity and a decrease in osteoblast activity. This disparity is fundamental to the development of myeloma bone disease. Lytic lesions, which are a feature of MM, can result in pathologic fractures and excruciating pain. For many years, whole-body X-ray radiography has been the standard imaging method for identifying lytic lesions. However, its sensitivity is limited because it can only detect lesions once the bone mass has been reduced by 30% to 50%. Hence, utilizing advanced and sensitive imaging modalities, such as positron emission tomography (PET) fused with computed tomography (CT), is crucial for the early detection of osteolytic lesions. Among radiotracers used in PET imaging, 1⁸F-fluorodeoxyglucose ([18F]FDG) is the most commonly employed in the field of oncology. Currently, most guidelines include [18F]FDG PET/CT in the assessment of myeloma patients, particularly for detecting osteolytic lesions, evaluating treatment response, and assessing extramedullary and residual disease. Nonetheless, in recent years, new applications of PET/CT for evaluating myeloma have been investigated. These include assessing aspects such as bone turnover, dual-time-point imaging (early and delayed scans), the impact of chemotherapy on the brain (commonly known as ‘chemo brain’), innovative PET radiotracers, and the use of artificial intelligence technology. This article aims to provide a comprehensive review of both conventional and innovative uses of PET/CT in evaluating multiple myeloma.
]]>Authors: Arya Mariam Roy Supritha Chintamaneni Sabah Alaklabi Hassan Awada Kristopher Attwood Shipra Gandhi
Background: Multiple randomized controlled trials (RCTs) have investigated the impact of adding checkpoint inhibitors to neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) patients. However, there is a lack of biomarkers that can help identify patients who would benefit from combination therapy. Our research identifies response predictors and assesses the effectiveness of adding immunotherapy to neoadjuvant chemotherapy for TNBC patients. Methods: We identified eligible RCTs by searching PubMed, Cochrane CENTRAL, Embase, and oncological meetings. For this meta-analysis, we obtained odds ratios using the standard random effects model. To assess the heterogeneity of the study outcomes, the I2 statistic was obtained. Potential bias was assessed using a funnel plot and the corresponding Egger’s test. Results: In total, 1637 patients with TNBC were included from five RCTs. Neoadjuvant chemoimmunotherapy significantly improved pCR when compared to neoadjuvant chemotherapy alone. In the subgroup analysis, neoadjuvant chemoimmunotherapy showed higher pCR rates in both Programmed death-ligand 1 (PD-L1)-positive and PD-L1-negative TNBC patients. An Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0 correlated with increased pCRs (OR = 1.9, p < 0.001) in neoadjuvant chemoimmunotherapy vs. neoadjuvant chemotherapy, but no benefit was observed for patients with ECOG PS 1. Nodal positivity was significantly associated with pCR (OR = 2.52, p < 0.001), while neoadjuvant chemoimmunotherapy did not benefit patients with negative lymph nodes. Conclusions: Checkpoint inhibition and neoadjuvant chemotherapy significantly increased pCRs in TNBC patients, regardless of their PDL-1 status. Additional checkpoint inhibitors improved pCR rates, mainly for patients with ECOG PS 0 and lymph node-positive disease.
]]>Authors: Masaru Terasaki Sally Suzuki Takuji Tanaka Hayato Maeda Masaki Shibata Kazuo Miyashita Yasuhiro Kuramitsu Junichi Hamada Tohru Ohta Shigehiro Yagishita Akinobu Hamada Yasunari Sakamoto Susumu Hijioka Chigusa Morizane Mami Takahashi
Pancreatic cancer (PC) is one of the most fatal cancers, and there is an urgent need to develop new anticancer agents with fewer side effects for the treatment of this condition. A patient-derived xenograft (PDX) mouse model transplanted with cancer tissue from patients is widely accepted as the best preclinical model for evaluating the anticancer potential of drug candidates. Fucoxanthin (Fx) is a highly polar carotenoid contained in edible marine brown algae and possesses anticancer activity. However, there is a lack of data on the effects of Fx in PDX models. We investigated the anticancer effects of Fx in PDX mice transplanted with cancer tissues derived from a patient with PC (PC-PDX) using comprehensive protein expression assay. Fx administration (0.3%Fx diet) ad libitum for 27 days significantly abrogated tumor development (0.4-fold) and induced tumor differentiation in PC-PDX mice, as compared to those in the control mice. Fx significantly upregulated the expression of non-glycanated DCN (2.4-fold), tended to increase the expressions of p-p38(Thr180/Tyr182) (1.6-fold) and pJNK(Thr183/Tyr185) (1.8-fold), significantly downregulated IGFBP2 (0.6-fold) and EpCAM (0.7-fold), and tended to decrease LCN2 (0.6-fold) levels in the tumors of the PC-PDX mice, as compared to those in the control mice. Some of the protein expression patterns were consistent with the in vitro experiments. That is, treatment of fucoxanthinol (FxOH), a prime metabolite derived from dietary Fx, enhanced non-glycanated DCN, p-p38(Thr180/Tyr182), and pJNK(Thr183/Tyr185) levels in human PC PANC-1 and BxPC-3 cells.These results suggested that Fx exerts anticancer and differentiation effects in a PC-PDX mice through alterations of some multifunctional molecules.
]]>Authors: Vasiliki Gkioka Olga Balaoura Maria Goulielmaki Constantin N. Baxevanis
Cancer biobanks have a crucial role in moving forward the field of translational cancer research and, therefore, have been promoted as indispensable tools for advancing basic biomedical research to preclinical and clinical research, ultimately leading to the design of clinical trials. Consequently, they play an essential role in the establishment of personalized oncology by combining biological data with registries of detailed medical records. The availability of complete electronic medical reports from individualized patients has led to personalized approaches for diagnosis, prognosis, and prediction. To this end, identifying risk factors at early time points is important for designing more effective treatments unique for each patient. Under this aspect, biobanking is essential for accomplishing improvements in the field of precision oncology via the discovery of biomarkers related to cellular and molecular pathways regulating oncogenic signaling. In general terms, biological samples are thought to reflect the patient’s disease biology, but under certain conditions, these may also represent responses to various biological stresses. Divergent collection, handling, and storage methods may significantly change biosamples’ inherent biological properties. The alteration or loss of biological traits post-collection would lead to the discovery of nonreliable biomarkers and, consequently, to irreproducible results, thus constituting a formidable obstacle regarding the successful translation of preclinical research to clinical approaches. Therefore, a necessary prerequisite for successful biobanking is that the stored biological samples retain their biological characteristics unchanged. The application of quality standards for biospecimen collection and storage could be useful for generating encouraging preclinical data leading to the successful translation to clinical treatment approaches. Herein, we aim to comprehensively review the issues linked to biobank implementation for promoting cancer research.
]]>Authors: Ugo Testa Germana Castelli Elvira Pelosi
Non-small-cell lung cancer (NSCLC) is a heterogeneous group of diseases accounting for 80–85% of lung cancers. A molecular subset of NSCLC (1–2.5%) harboring molecular rearrangements of the tyrosine kinase gene ROS1 is defined as ROS1-positive and is almost exclusively diagnosed in patients with lung adenocarcinoma histology, predominantly nonsmokers. ROS1 is constitutively activated by molecular rearrangements and acts as a main driver of lung carcinogenesis. These findings have provided a strong rationale for the clinical use of tyrosine kinase inhibitors that target ROS1; these inhibitors block ROS1-positive NSCLC and provide clinical benefit. Crizotinib was introduced as a first-line treatment for ROS1-positive NSCLCs, with 75–80% of patients responding and a PFS of about 20 months. More recently developed ROS1-TKIs, such as entrectinib, lorlatinib, taletrectinib, repotrectinib and NVL-520, are active against some resistant ROS1 mutants appearing during crizotinib therapy and more active against brain metastases, frequent in ROS1-positive NSCLC. The development of resistance mechanisms represents a great limitation for the targeted treatment of ROS1-positive NSCLCs with TKIs.
]]>Authors: Emanuel Vigia Luís Ramalhete Edite Filipe Luís Bicho Ana Nobre Paulo Mira Maria Macedo Catarina Aguiar Sofia Corado Beatriz Chumbinho Jorge Balaia Pedro Custódio João Gonçalves Hugo P. Marques
Pancreatic ductal adenocarcinoma is an invasive tumor with similar incidence and mortality rates. Pancreaticoduodenectomy has morbidity and mortality rates of up to 60% and 5%, respectively. The purpose of our study was to assess preoperative features contributing to unfavorable 1-year survival prognosis. Study Design: Retrospective, single-center study evaluating the impact of preoperative features on short-term survival outcomes in head PDAC patients. Forty-four prior features of 172 patients were tested using different supervised machine learning models. Patient records were randomly divided into training and validation sets (80–20%, respectively), and model performance was assessed by area under curve (AUC) and classification accuracy (CA). Additionally, 33 patients were included as an independent revalidation or holdout dataset group. Results: Eleven relevant features were identified: age, sex, Ca-19-9, jaundice, ERCP with biliary stent, neutrophils, lymphocytes, lymphocyte/neutrophil ratio, neoadjuvant treatment, imaging tumor size, and ASA. Tree regression (tree model) and logistic regression (LR) performed better than the other tested models. The tree model had an AUC = 0.92 and CA = 0.85. LR had an AUC = 0.74 and CA = 0.78, allowing the development of a nomogram based on absolute feature significance. The best performance model was the tree model which allows us to have a decision tree to help clinical decisions. Discussion and conclusions: Based only on preoperative data, it was possible to predict 1-year survival (91.5% vs. 78.1% alive and 70.9% vs. 76.6% deceased for the tree model and LR, respectively). These results contribute to informed decision-making in the selection of which patients with PDAC can benefit from pancreatoduodenectomy. A machine learning algorithm was developed for the recognition of unfavorable 1-year survival prognosis in patients with pancreatic ductal adenocarcinoma. This will contribute to the identification of patients who would benefit from pancreatoduodenectomy. In our cohort, the tree regression model had an AUC = 0.92 and CA = 0.85, whereas the logistic regression had an AUC = 0.74 and CA = 0.78. To further inform decision-making, a decision tree based on tree regression was developed.
]]>Authors: Constantin N. Baxevanis Savvas Stokidis Maria Goulielmaki Angelos D. Gritzapis Sotirios P. Fortis
Background: Various studies have reported associations between frequencies of total peripheral blood lymphocytes and prostate cancer prognosis, but none so far has addressed the prognostic role of CD8+ T-lymphocyte subsets. Methods: A total of 43 prostate cancer patients with metastatic disease and 81 patients with non-metastatic disease were included in this study. Flow cytometry analyses were employed for determining the frequencies of peripheral CD8+ T-lymphocyte subsets. Results: Statistically significant lower levels of terminally differentiated effector (TEMRA) cells in patients with non-metastatic disease vs. patients with metastatic disease were observed. Central memory (CM) and effector memory (EM) CD8+ subsets, were found to be significantly higher in patients with non-metastatic disease vs. patients with metastatic disease. A similar profile was revealed when these CD8+ subsets were analyzed based on the patients’ Gleason scores, as well as by combined disease stage (i.e., non-metastatic vs. metastatic disease) and Gleason score. Conclusions: Peripheral blood-derived CD8+ T-lymphocyte memory subsets could function as biomarkers for the prognosis of PCa.
]]>Authors: Sagarajit Mohanty
NUP98 fusions constitute a small subgroup of AML patients and remain a high-risk AML subtype. There are approximately 30 types of NUP98 fusions identified in AML patients. These patients show resistance to currently available therapies and poor clinical outcomes. NUP98 fusions with different fusion partners have oncogenic transformation potential. This review describes how the NUP98 gene acquires oncogenic properties after rearrangement with multiple partners. In the mechanistic part, the formation of nuclear bodies and dysregulation of the HoxA/Meis1 pathway are highlighted. This review also discusses mutational signatures among NUP98 fusions and their significance in leukemogenesis. It also discusses the clinical implications of NUP98 fusions and their associated mutations in AML patients. Furthermore, it highlights therapeutic vulnerabilities in these leukemias that can be exploited as therapeutic strategies. Lastly, this review discusses the gaps in our knowledge regarding NUP98 fusions in AML, as well as future research opportunities.
]]>Authors: Poojarani Panda Henu Kumar Verma Lakkakula V. K. S. Bhaskar
Esophageal cancer is a formidable challenge in the realm of cancer treatment. Conventional methods such as surgery, chemotherapy, and immunotherapy have demonstrated limited success rates in managing this disease. In response, targeted drug therapies have emerged as a promising strategy to improve outcomes for patients. These therapies aim to disrupt specific pathways involved in the growth and development of esophageal cancer cells. This review explores various drugs used to target specific pathways, including cetuximab and monoclonal antibodies (gefitinib) that target the epidermal growth factor receptor (EGFR), trastuzumab that targets human epidermal growth factor receptor 2 (HER-2), drugs targeting the vascular endothelial growth factor receptor (VEGFR), mTOR inhibitors, and cMET inhibitors. Additionally, the article discusses the impact of drug resistance on the effectiveness of these therapies, highlighting factors such as cancer stem cells, cancer-associated fibroblasts, immune-inflammatory cells, cytokines, hypoxia, and growth factors. While drug targeting approaches do not provide a complete cure for esophageal cancer due to drug resistance and associated side effects, they offer potential for improving patient survival rates.
]]>Authors: Constantin N. Baxevanis
As the new Editor-in-Chief of the journal, I believe that I must continue the efforts of my predecessor even more actively and with greater enthusiasm and dedication so that the journal becomes a pole of attraction for the publication of excellent studies of basic, translational and clinical research for the treatment of cancer [...]
]]>Authors: Fnu Amisha Paras Malik Prachi Saluja Nitesh Gautam Tanvi Harishbhai Patel Arya Mariam Roy Sunny R. K. Singh Sindhu Janarthanam Malapati
The human epidermal growth factor receptors (HERs) are expressed abundantly in the human body. The tumorigenic potential of HER2/neu is linked to its overexpression, amplification or somatic mutation. The HER2 gene amplification leading to protein overexpression has been reported in 25–30% of breast cancers and 10–30% of gastric/gastroesophageal cancers. While HER2 is a well-documented predictive, prognostic, and therapeutic marker in breast and gastric/gastroesophageal cancers, its relevance has also been demonstrated in multiple other malignancies. In this article, we will conduct an extensive review of current data pertaining to HER2 amplification, overexpression, or mutation in cancers other than breast and gastric cancers.
]]>Authors: Lawrence P. McKinney Rajesh Singh I. King Jordan Sooryanarayana Varambally Eric B. Dammer James W. Lillard
Prostate cancer (PCa) is the second most common cause of cancer death in American men. Metastatic castration-resistant prostate cancer (mCRPC) is the most lethal form of PCa and preferentially metastasizes to the bones through incompletely understood molecular mechanisms. Herein, we processed RNA sequencing data from patients with mCRPC (n = 60) and identified 14 gene clusters (modules) highly correlated with mCRPC bone metastasis. We used a novel combination of weighted gene co-expression network analysis (WGCNA) and upstream regulator and gene ontology analyses of clinically annotated transcriptomes to identify the genes. The cyan module (M14) had the strongest positive correlation (0.81, p = 4 × 10−15) with mCRPC bone metastasis. It was associated with two significant biological pathways through KEGG enrichment analysis (parathyroid hormone synthesis, secretion, and action and protein digestion and absorption). In particular, we identified 10 hub genes (ALPL, PHEX, RUNX2, ENPP1, PHOSPHO1, PTH1R, COL11A1, COL24A1, COL22A1, and COL13A1) using cytoHubba of Cytoscape. We also found high gene expression for collagen formation, degradation, absorption, cell-signaling peptides, and bone regulation processes through Gene Ontology (GO) enrichment analysis.
]]>Authors: Catharina Lisson Sabitha Manoj Daniel Wolf Jasper Schrader Stefan Schmidt Meinrad Beer Michael Goetz Friedemann Zengerling Christoph Lisson
Accurate retroperitoneal lymph node metastasis (LNM) prediction in early-stage testicular germ cell tumours (TGCTs) harbours the potential to significantly reduce over- or undertreatment and treatment-related morbidity in this group of young patients as an important survivorship imperative. We investigated the role of computed tomography (CT) radiomics models integrating clinical predictors for the individualised prediction of LNM in early-stage TGCT. Ninety-one patients with surgically proven testicular germ cell tumours and contrast-enhanced CT were included in this retrospective study. Dedicated radiomics software was used to segment 273 retroperitoneal lymph nodes and extract features. After feature selection, radiomics-based machine learning models were developed to predict LN metastasis. The robustness of the procedure was controlled by 10-fold cross-validation. Using multivariable logistic regression modelling, we developed three prediction models: a radiomics-only model, a clinical-only model, and a combined radiomics–clinical model. The models’ performances were evaluated using the area under the receiver operating characteristic curve (AUC). Finally, decision curve analysis was performed to estimate the clinical usefulness of the predictive model. The radiomics-only model for predicting lymph node metastasis reached a greater discrimination power than the clinical-only model, with an AUC of 0.87 (±0.04; 95% CI) vs. 0.75 (±0.08; 95% CI) in our study cohort. The combined model integrating clinical risk factors and selected radiomics features outperformed the clinical-only and the radiomics-only prediction models, and showed good discrimination with an area under the curve of 0.89 (±0.03; 95% CI). The decision curve analysis demonstrated the clinical usefulness of our proposed combined model. The presented combined CT-based radiomics–clinical model represents an exciting non-invasive tool for individualised LN metastasis prediction in testicular germ cell tumours. Multi-centre validation is required to generate high-quality evidence for its clinical application.
]]>Authors: Ayako Nomura Takayuki Ishida Hiroshi Hijioka Takuya Yoshimura Hajime Suzuki Eturo Nozoe Norifumi Nakamura
Purpose: To establish a diagnosis method based on imaging findings and histopathological factors associated with cervical lymph node metastasis. Methods: A total of 1587 cervical lymph nodes that were detected using imaging tools in 73 OSCC patients who underwent surgical treatment were enrolled to evaluate the association between imaging findings (long diameter, short diameter, long–short ratio, US findings (hilum and internal echo), contrast effect with enhanced CT, standardized uptake value (SUV) max and SUV average with 18F FDG-Positron Emission Tomography (PET)) and metastatic cervical lymph nodes. In 57 OSCC patients, biopsy specimens were evaluated for histopathologic factors (budding score, lymphatic invasion, vascular invasion, nerve invasion, and YK classification) and the presence of cervical lymph node metastases. Cervical lymph node metastasis was determined based on histopathological examination of the lymph nodes of patients with no metastasis observed 3 years after primary surgery. Results: In total, 22 of the 73 patients had cervical lymph node metastasis pathologically. In the comparison of the presence of metastatic lymph nodes, univariate analysis showed significant differences in cervical lymph node long and short diameter, long/short ratio, internal echo, rim enhancement, SUV max, SUV average, budding score, and vascular invasion. Multivariable analysis showed significant differences in internal echo, rim enhancement, SUV max, and budding score. Conclusions: We propose a chart diagnostic system that combines imaging and histopathological findings to improve the diagnosis of cervical lymph node metastasis.
]]>Authors: Chi-Yuan Yeh Peng-An Lai Fang-Hui Liu Chin-Chiao He
Intracranial metastasis is very common in adult cancer patients with an overall incidence of approximately 10–40%. The most common primary tumors responsible for this in adults are lung and breast cancer. Brain metastasis signifies a grave prognosis, with a median survival of 6 to 12 months. They are traditionally managed with palliative care and whole brain radiotherapy (WBRT). WBRT was an effective method to control brain metastases, decreasing corticosteroid use to control tumor-associated edema, and potentially improving overall survival; however, WBRT was found to be associated with a serious neurocognitive degeneration, this adverse effect (AE) follows a biphasic pattern beginning with a transient decline in mental functioning at around 4 months post-treatment, slowly leading to an irreversible neurologic impairment from months to years later. Evidence supports that WBRT can cause radiation injury to the hippocampus, which in turn will lead to a decline in neurocognitive function (NCF). Volumetric modulated arc therapy (VMAT) is a relatively new type of image-guided radiotherapy that treats multiple brain metastasis simultaneously and efficiently with less neurocognitive sequelae. Eighteen cancer patients with limited (≤5 brain tumors) or oligometastatic brain tumor were treated with a spatially fractionated VMAT technique for a total dose of 30 Gy in 10 fractions, the patients tolerated the VMAT treatment with no radiation-induced neurologic toxicities after a mean follow-up of 1 year. Local control rate was 84%, and the median survival for these 19 patients was 11.3 months (range: 9.1–22.4 months). In conclusion, the VMAT is a suitable technique that is a safe and effective treatment for brain oligometastases.
]]>Authors: Paulina Helisz Weronika Gwioździk Karolina Krupa-Kotara Mateusz Grajek Joanna Głogowska-Ligus Jerzy Słowiński
Gastric cancer (GC) is one of the most common causes of cancer-related deaths. Gastric tumors show a high aggressiveness, which, in turn, contributes to a low survival rate of fewer than 12 months. Considering the above, it was decided to review the current scientific studies that indicate the potential prevention of gastric cancer and clarify the relationship between gastric cancer and the composition of the microorganisms inhabiting the human body. Accordingly, a review paper was prepared based on 97 scientific sources from 2011 to 2022. Particular attention was paid to the most recent scientific studies from the last five years, which account for more than 80% of the cited sources. Taking care of one’s overall health, including undertaking treatment for Helicobacter pylori infection, and following a diet high in anti-inflammatory and immunomodulatory ingredients are the most important factors in reducing the risk of developing gastric cancer.
]]>Authors: Shihori Tanabe Sabina Quader Ryuichi Ono Horacio Cabral Kazuhiko Aoyagi Akihiko Hirose Edward J. Perkins Hiroshi Yokozaki Hiroki Sasaki
Because activity of the epithelial–mesenchymal transition (EMT) is involved in anti-cancer drug resistance, cancer malignancy, and shares some characteristics with cancer stem cells (CSCs), we used artificial intelligence (AI) modeling to identify the cancer-related activity of the EMT-related pathway in datasets of gene expression. We generated images of gene expression overlayed onto molecular pathways with Ingenuity Pathway Analysis (IPA). A dataset of 50 activated and 50 inactivated pathway images of EMT regulation in the development pathway was then modeled by the DataRobot Automated Machine Learning platform. The most accurate models were based on the Elastic-Net Classifier algorithm. The model was validated with 10 additional activated and 10 additional inactivated pathway images. The generated models had false-positive and false-negative results. These images had significant features of opposite labels, and the original data were related to Parkinson’s disease. This approach reliably identified cancer phenotypes and treatments where EMT regulation in the development pathway was activated or inactivated thereby identifying conditions where therapeutics might be applied or developed. As there are a wide variety of cancer phenotypes and CSC targets that provide novel insights into the mechanism of CSCs’ drug resistance and cancer metastasis, our approach holds promise for modeling and simulating cellular phenotype transition, as well as predicting molecular-induced responses.
]]>Authors: Jürgen Germann Andrew Yang Clement T. Chow Brendan Santyr Nardin Samuel Artur Vetkas Can Sarica Gavin J. B. Elias Mathew R. Voisin Walter Kucharczyk Gelareh Zadeh Andres M. Lozano Alexandre Boutet
Background: A common MRI reference space allows for easy communication of findings, and has led to high-impact discoveries in neuroscience. Brain MRI of neuro-oncology patients with mass lesions or surgical cavities can now be accurately transformed into reference space, allowing for a reliable comparison across patients. Despite this, it is currently seldom used in neuro-oncology, leaving analytic tools untapped. The aim of this study was to systematically review the neuro-oncology literature utilizing reference space. Methods: A systematic review of the neuro-oncology publications was conducted according to PRISMA statement guidelines. Studies specially reporting the use of the Montreal Neurological Institute (MNI) reference space were included. Studies were categorized according to their type of input data and their contributions to the field. A sub-analysis focusing on connectomics and transcriptomics was also included. Results: We identified only 101 articles that utilized the MNI brain in neuro-oncology research. Tumor locations (n = 77) and direct electrocortical stimulation (n = 19) were the most common source of data. A majority of studies (n = 51) provided insights on clinical factors such as tumor subtype, growth progression, and prognosis. A small group of studies (n = 21) have used the novel connectomic and transcriptomic tools. Conclusions: Brain MRI of neuro-oncology patients can be accurately transformed to MNI space. This has contributed to enhance our understanding of a wide variety of clinical questions ranging from tumor subtyping to symptom mapping. Many advanced tools such as connectomics and transcriptomics remain relatively untapped, thereby hindering our knowledge of neuro-oncology.
]]>Authors: Chenlu Ke Dipankar Bandyopadhyay Mario Acunzo Robert Winn
Background: Advances in sequencing technologies have allowed collection of massive genome-wide information that substantially advances lung cancer diagnosis and prognosis. Identifying influential markers for clinical endpoints of interest has been an indispensable and critical component of the statistical analysis pipeline. However, classical variable selection methods are not feasible or reliable for high-throughput genetic data. Our objective is to propose a model-free gene screening procedure for high-throughput right-censored data, and to develop a predictive gene signature for lung squamous cell carcinoma (LUSC) with the proposed procedure. Methods: A gene screening procedure was developed based on a recently proposed independence measure. The Cancer Genome Atlas (TCGA) data on LUSC was then studied. The screening procedure was conducted to narrow down the set of influential genes to 378 candidates. A penalized Cox model was then fitted to the reduced set, which further identified a 6-gene signature for LUSC prognosis. The 6-gene signature was validated on datasets from the Gene Expression Omnibus. Results: Both model-fitting and validation results reveal that our method selected influential genes that lead to biologically sensible findings as well as better predictive performance, compared to existing alternatives. According to our multivariable Cox regression analysis, the 6-gene signature was indeed a significant prognostic factor (p-value < 0.001) while controlling for clinical covariates. Conclusions: Gene screening as a fast dimension reduction technique plays an important role in analyzing high-throughput data. The main contribution of this paper is to introduce a fundamental yet pragmatic model-free gene screening approach that aids statistical analysis of right-censored cancer data, and provide a lateral comparison with other available methods in the context of LUSC.
]]>Authors: Fatih M. Uckun Sanjive Qazi
Our main objective was to identify abundantly expressed tyrosine kinases in multiple myeloma (MM) as potential therapeutic targets. We first compared the transcriptomes of malignant plasma cells from newly diagnosed MM patients who were risk-categorized based on the patient-specific EMC-92/SKY-92 gene expression signature values vs. normal plasma cells from healthy volunteers using archived datasets from the HOVON65/GMMG-HD4 randomized Phase 3 study evaluating the clinical efficacy of bortezomib induction/maintenance versus classic cytotoxic drugs and thalidomide maintenance. In particular, ERBB1/EGFR was significantly overexpressed in MM cells in comparison to normal control plasma cells, and it was differentially overexpressed in MM cells from high-risk patients. Amplified expression of EGFR/ERBB1 mRNA in MM cells was positively correlated with increased expression levels of mRNAs for several DNA binding proteins and transcription factors with known upregulating activity on EGFR/ERBB1 gene expression. MM patients with the highest ERBB1/EGFR expression level had significantly shorter PFS and OS times than patients with the lowest ERBB1/EGFR expression level. High expression levels of EGFR/ERBB1 were associated with significantly increased hazard ratios for unfavorable PFS and OS outcomes in both univariate and multivariate Cox proportional hazards models. The impact of high EGFR/ERBB1 expression on the PFS and OS outcomes remained significant even after accounting for the prognostic effects of other covariates. These results regarding the prognostic effect of EGFR/ERBB1 expression were validated using the MMRF-CoMMpass RNAseq dataset generated in patients treated with more recently applied drug combinations included in contemporary induction regimens. Our findings provide new insights regarding the molecular mechanism and potential clinical significance of upregulated EGFR/ERBB1 expression in MM.
]]>Authors: Ramin Abolfath Mitra Khalili Alireza G. Senejani Balachandran Kodery Robert Ivker
Introduction: In this work, we develop a multi-scale model to calculate corrections to the prescription dose to predict compensation required for the DNA repair mechanism and the repopulation of the cancer cells due to the occurrence of patient scheduling variabilities and the treatment time-gap in fractionation scheme. Methods: A system of multi-scale, time-dependent birth-death Master equations is used to describe stochastic evolution of double-strand breaks (DSBs) formed on DNAs and post-irradiation intra and inter chromosomes end-joining processes in cells, including repair and mis-repair mechanisms in microscopic scale, with an extension appropriate for calculation of tumor control probability (TCP) in macroscopic scale. Variabilities in fractionation time due to systematic shifts in patient’s scheduling and randomness in inter-fractionation treatment time are modeled. For an illustration of the methodology, we focus on prostate cancer. Results: We derive analytical corrections to linear-quadratic radiobiological indices α and β as a function of variabilities in treatment time and shifts in patient’s scheduling. We illustrate the dependence of the absolute value of the compensated dose on radio-biological sensitivity, α/β, DNA repair half-time, T1/2, tumor cells repopulation rate, and the time-gaps among treatment fractions due to inter-patient variabilities. At a given tumor size, delays between fractions totaling 24 h over the entire course of treatment, in a typical prostate cancer fractionation scheme, e.g., 81 Gy, 1.8 Gy per fraction and 45 treatment days, require up to 10% compensation dose if the sublethal DNA repair half-time, T1/2, spans over 10 h. We show that the contribution of the fast DNA repair mechanisms to the total dose is negligible. Instead, any compensation to the total dose stems from the tumor cell repopulation that may go up to a significant fraction of the original dose for a time gap of up to one week. Conclusions: We recommend implementation of time irregularities in treatment scheduling in the clinic settings to be taken into account. To achieve a clinical endpoint, corrections to the prescription dose must be assessed, in particular, if modern external beam therapy techniques such as IMRT/VMAT are used for the treatment of cancer.
]]>Authors: Sanjive Qazi Fatih M. Uckun
Here, we evaluated transcript-level IL3RA/CD123 expression in mixed lineage leukemia 1 (MLL) gene/KMT2A-rearranged (MLL-R+) vs. MLL-R− pediatric AML as well as infant ALL by comparing the archived datasets of the transcriptomes of primary leukemic cells from the corresponding patient populations. Our studies provide unprecedented evidence that IL3RA/CD123 expression exhibits transcript-level amplification in MLL-R+ pediatric AML and infant ALL cells. IL3RA was differentially upregulated in MLL-AF10+ (2.41-fold higher, p-value = 4.4 × 10−6) and MLL-AF6+ (1.83-fold higher, p-value = 9.9 × 10−4) but not in MLL-AF9+ cases compared to other pediatric AML cases. We also show that IL3RA/CD123 expression is differentially amplified in MLL-AF4+ (1.76-fold higher, p-value = 2.1 × 10−4) as well as MLL-ENL+ infant ALL (1.43-fold higher, p-value = 0.055). The upregulated expression of IL3RA/CD123 in MLL-R+ pediatric AML and infant ALL suggests that CD123 may be a suitable target for biotherapy in these high-risk leukemias.
]]>Authors: Ugo Testa Elvira Pelosi Germana Castelli
Small-cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma, corresponding to about 15% of lung cancers, occurring predominantly in smokers and associated with a very poor prognosis. Key genetic alterations very frequently observed in SCLC are represented by the loss of TP53 and RB1, due to mutational events or deletions; frequent amplification or overexpression of MYC family genes (MYC, MYCL and MYCN); frequent genetic alterations by mutation/deletion of KMT2D, RB family members p107 (RBL1) and p130 (RBL2), PTEN, NOTCH receptors and CREBBP. The profile of expression of specific transcription factors allowed to differentiate four subtypes of SCLC defined according to levels of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POUF23 (SCLC-P) or YAP1 (SCLC-Y). A recent study identified the subgroup SCLC-I, characterized by the expression of inflammatory/immune-related genes. Recent studies have characterized at molecular level other lung neuroendocrine tumors, including large cell neuroendocrine cancers (LCNECs) and lung carcinoids. These molecular studies have identified some therapeutic vulnerabilities that can be targeted using specific drugs and some promising biomarkers that can predict the response to this treatment. Furthermore, the introduction of immunotherapy (immune checkpoint blockade) into standard first-line treatment has led to a significant clinical benefit in a limited subset of patients.
]]>Authors: Aaron C. Tan
The discovery of therapeutically targetable oncogenic driver alterations has led to marked improvements in NSCLC outcomes. Targeted agents have been approved for an expanding list of biomarkers. Consequently, the accurate and timely identification of targetable alterations with diagnostic molecular profiling is crucial. The use of multiplexed tissue assays, such as next-generation sequencing (NGS), has increased significantly. However, significant limitations with tissue NGS remain, such as insufficient tissue, scheduling limitations, the need for repeat biopsies, and long turnaround times. Liquid biopsies, using plasma circulating tumor DNA (ctDNA), have the potential to overcome these issues, with simpler sample processing requirements, greater convenience, and better patient acceptability. In particular, an early liquid biopsy may allow patients access to highly effective therapies faster, allow better symptom control and quality of life, prevent rapid clinical deterioration, and reduce patient anxiety at diagnosis. More broadly, it may also allow for the more cost-effective delivery of healthcare to patients.
]]>Authors: Margarida Silva Diana Martins Fernando Mendes
Immune checkpoint inhibition (ICI) has emerged as a therapeutic option for acute myeloid leukemia (AML) for patients that suffer from relapsed or high-risk disease, or patients ineligible for standard therapy. We aimed to study ICI as monotherapy and/or combined therapy (with chemotherapy (QT), for AML patients. The PRISMA statement was used. The literature used comprised clinical trials, randomized controlled trials, and systematic reviews published within the last 7 years. The blockade of CTLA-4 presented a 42% of complete remission within AML. Nivolumab in high-risk AML showed a median recurrence-free survival (RFS) of 8.48 months. The same drug on relapsed hematologic malignancies after allogenic transplantation shows a 1-year OS of 56%. The use of prophylaxis post allogenic transplantation cyclophosphamide (PTCy), following checkpoint inhibition, demonstrated different baseline disease and transplantation characteristics when compared to no-PCTy patients, being 32% and 10%, respectively. CTLA-4 blockage was a worthy therapeutic approach in relapsed hematologic malignancies, presenting long-lasting responses. The approach to AML and myelodysplastic syndrome patients with ICI before allogenic hematopoietic stem cell transplantation and the use of a graft-versus-host disease prophylaxis have shown improvement in the transplantation outcomes, and therefore AML treatment.
]]>Authors: Ayaka Yasuda Momoka Wagatsuma Wataru Murase Atsuhito Kubota Hiroyuki Kojima Tohru Ohta Junichi Hamada Hayato Maeda Masaru Terasaki
Fucoxanthinol (FxOH), the main metabolite of the marine carotenoid fucoxanthin, exerts anti-cancer effects. However, fragmentary information is available on the growth-inhibiting effects of FxOH on breast cancer (BC). We investigated the growth-inhibiting effects of FxOH on human BC cells (MCF-7 and MDA-MB-231 cells), and the underlying mechanisms, differently from previous studies, by using comprehensive transcriptome analysis. The molecular mechanisms of FxOH were evaluated using flow cytometry, microarray, Western blotting, and gene knockdown analyses. FxOH (20 μM) significantly induced apoptosis in MCF-7 and MDA-MB-231 cells. Transcriptome analysis revealed that FxOH modulated the following 12 signaling pathways: extracellular matrix (ECM), adhesion, cell cycle, chemokine and cytokine, PI3K/AKT, STAT, TGF-β, MAPK, NF-κB, RAS/Rho, DNA repair, and apoptosis signals. FxOH downregulated the levels of laminin β1, integrin α5, integrin β1, integrin β4, cyclin D1, Rho A, phosphorylated (p)paxillin (Tyr31), pSTAT3(Ser727), and pSmad2(Ser465/467), which play critical roles in the 12 signaling pathways mentioned above. Additionally, FxOH upregulated the levels of pERK1/2(Thr202/Tyr204) and active form of caspase-3. Integrin β1 or β4 knockdown significantly inhibited the growth of MCF7 and MDA-MB-231 cells. These results suggest that FxOH induces apoptosis in human BC cells through some core signals, especially the ECM–integrins axis, and the downstream of cell cycle, STAT, TGF-β, RAS/Rho, MAPK, and/or DNA repair signals.
]]>Authors: John Torcivia Kawther Abdilleh Fabian Seidl Owais Shahzada Rebecca Rodriguez David Pot Raja Mazumder
Whole genome sequencing (WGS) has helped to revolutionize biology, but the computational challenge remains for extracting valuable inferences from this information. Here, we present the cancer-associated variants from the Cancer Genome Atlas (TCGA) WGS dataset. This set of data will allow cancer researchers to further expand their analysis beyond the exomic regions of the genome to the entire genome. A total of 1342 WGS alignments available from the consortium were processed with VarScan2 and deposited to the NCI Cancer Cloud. The sample set covers 18 different cancers and reveals 157,313,519 pooled (non-unique) cancer-associated single-nucleotide variations (SNVs) across all samples. There was an average of 117,223 SNVs per sample, with a range from 1111 to 775,470 and a standard deviation of 163,273. The dataset was incorporated into BigQuery, which allows for fast access and cross-mapping, which will allow researchers to enrich their current studies with a plethora of newly available genomic data.
]]>Authors: Lucy Macharia Wanjiru Muriithi Dennis Nyaga Juliana de Mattos Coelho-Aguiar Tania de Sampaio e Spohr Vivaldo Moura-Neto
Purpose: Glioblastoma is an aggressive and incurable brain tumor whose progression is driven in part by glioblastoma stem cells, which are also responsible for the tumor’s low therapy efficacy. The maintenance and expansion of the stem cell population is promoted by the hypoxic microenvironment, where miRNAs play fundamental roles in their survival. Methods: GBM stem-like cells were isolated from three GBM parental cell lines. The stem-like cells were then cultured under normoxic and hypoxic microenvironments followed by investigation of the in vitro “stemness” of the cells. Results: We found miR-128a-3p, 34-5p and 181a-3p to be downregulated and miR-17-5p and miR-221-3p to be upregulated in our stem-like cells compared to the GBMs. When a comparison was made between normoxia and hypoxia, a further fold downregulation was observed for miR-34-5p, miR-128a-3p and miR-181a-3p and a further upregulation was observed for miR-221-3p and 17-5p. There was an increased expression of HIF-1/2, SOX2, OCT4, VEGF, GLUT-1, BCL2 and survivin under hypoxia. Conclusion: Our data suggest that our GBMs were able to grow as stem-like cells and as spheroids. There was a differential expression of miRNAs between the stems and the GBMs and the hypoxia microenvironment influenced further dysregulation of the miRNAs and some selected genes.
]]>Authors: Leila Jahangiri
A complex interaction occurs between cancer cells and the extracellular matrix (ECM) in the tumour microenvironment (TME). In this study, the expressions and mutational profiles of 964 ECM-related genes and their correlations with patient overall survival (OS) in neuroblastoma, an aggressive paediatric malignancy, were investigated using cBioPortal and PCAT databases. Furthermore, extended networks comprising protein-protein, protein-long non-coding RNA (lncRNA), and protein-miRNA of 12 selected ECM-related genes were established. The higher expressions of 12 ECM-related genes, AMBN, COLQ, ELFN1, HAS3, HSPE1, LMAN1, LRP5, MUC6, RAMP2, RUVBL2, SSBP1 and UMOD in neuroblastoma patients displayed a significant correlation with patient OS, while similar associations with neuroblastoma patient risk groups, histology and MYCN amplification were obtained. Furthermore, extended gene networks formed by these 12 ECM-related genes were established using Cytoscape, STRING, MSigDB/BioGRID, GeneMANIA and Omicsnet. Finally, the implications of the 12 ECM-related genes in other cancers were revealed using GEPIA2 and the Human Pathology Atlas databases. This meta-analysis showed the significance of these 12 ECM-related genes as putative prognostic predictors in neuroblastoma and other cancers.
]]>Authors: Emmanouil George Moursellas Andrew Tzardi Maria Voumvouraki Argyro Kouroumalis Elias
Purpose: To study the production of angiodrastic chemokines by colonic cancer cell lines. Methods: A pro-angiogenic factor (VEGF), two angiogenic chemokines (CXCL8, CXCL6), and one angiostatic (CXCL4) chemokine were measured by ELISA in the supernatants of the colon cancer cell lines HT-29 and Caco-2. Cells were cultured for 24 h in the presence of serum from cancer patients or healthy individuals. Results were analyzed by one-way ANOVA and the General Linear Model for repeated measures. Results: Colonic epithelial cells are potent producers of angiodrastic chemokines. HT-29 and Caco-2 cells produce all four chemokines under basal conditions and 24 h after incubation with human serum. The secretion response, however, was completely different. HT-29 cells produce more CXCL8 and VEGF irrespective of culture conditions, while Caco-2 cells seem unresponsive with respect to CXCL6 and CXCL4. Moreover, HT-29 cells produce more CXCL8 and VEGF when incubated with cancer serum, contrary to Caco-2 cells which produce more CXCL4 under the same conditions. Conclusions: The two colon cancer cell lines were producers of all chemokines studied, but their responses were not uniform under similar culture conditions. CXCL8 and VEGF are differently regulated compared to CXCL4 and CXCL6 in these two cell lines
]]>Authors: Nikolaos Dikaios
Background and Objective: This paper aimed to differentiate primary cancer types from primary tumor samples on the basis of somatic point mutations (SPMs). Primary cancer site identification is necessary to perform site-specific and potentially targeted treatment. Current methods such as histopathology and lab tests cannot accurately determine cancer origin, which results in empirical patient treatment and poor survival rates. The availability of large deoxyribonucleic acid sequencing datasets has allowed scientists to examine the ability of somatic mutations to classify primary cancer sites. These datasets are highly sparse since most genes will not be mutated, have a low signal-to-noise ratio, and are often imbalanced since rare cancers have fewer samples. Methods: To overcome these limitations a sparse-input neural network (SPINN) is suggested that projects the input data in a lower-dimensional space, where the more informative genes are used for learning. To train and evaluate SPINN, an extensive dataset for SPM was collected from the cancer genome atlas containing 7624 samples spanning 32 cancer types. Different sampling strategies were performed to balance the dataset. SPINN was further validated on an independent ICGC dataset that contained 226 samples spanning four cancer types. Results and Conclusions: SPINN consistently outperformed classification algorithms such as extreme gradient boosting, deep neural networks, and support vector machines, achieving an accuracy up to 73% on independent testing data. Certain primary cancer types/subtypes (e.g., lung, brain, colon, esophagus, skin, and thyroid) were classified with an F-score > 0.80.
]]>Authors: Carolina Sousa Beatriz Silva-Lima Mafalda Videira
The high incidence and modest therapeutic outcomes of lung cancer have prompted the identification of cell molecular targets/biomarkers within the complex networks of interactions involved in cell malignancy. Most of the EMT-related regulatory mediators underline patients’ biologic variations, therapeutic refractory events, and tumor cell heterogeneity. Patient stratification based on the understanding of the relevant pathways, such as the PI3K/Akt axis crucial in EMT initiation, could favorably alter disease management. Significant clinical advantage could be expected when overexpressed Akt tyrosine kinase (Akt2) is addressed as a malignant biomarker to guide clinical management decisions, improving prognosis in lung cancer patients. Moreover, one should not miss the opportunity of using it as a druggable target aiming at the inhibition of the downstream complexity that underlies cell proliferation and survival, expression of stemness markers and drug resistance. The value of mTOR, as a downstream target of Akt, and the further activation of EMT transcription factors Twist, Snail and Zeb1 are revisited in this review. An in-depth state-of-the-art assessment provides evidence of its role in the mechanistic inhibition of epithelial markers, such as E-cadherin and miR-200, while inducing the expression of the mesenchymal ones, such as vimentin, N-cadherin, and miR-21. Lastly, evidence suggesting another transcription factor, FOXM1, as the link between the PI3K/Akt and Wnt/β-catenin pathways, prompting cell metabolism through the regulation of p70S6K, is analyzed. A more realistic approach is advised to address unmet clinical needs and support decision making at a clinical level. Taking into consideration several complex intracellular interactions might further improve patient stratification and result in better outcomes.
]]>Authors: Chiaki Takahashi Jun-ya Kato
The accelerated cell cycle progression is one of the hallmarks of human cancer [...]
]]>Authors: Tristan Le Clainche Nazareth Milagros Carigga Gutierrez Núria Pujol-Solé Jean-Luc Coll Mans Broekgaarden
Photodynamic therapy (PDT) is a cancer treatment that relies on the remote-controlled activation of photocatalytic dyes (photosensitizers) in cancer tissues. To effectively treat cancer, a variety of pharmacological and optical parameters require optimization, which are dependent on the photosensitizer type. As most photosensitizers are hydrophobic molecules, nanoliposomes are frequently used to increase the biocompatibility of these therapeutics. However, as nanoliposomes can influence the therapeutic performance of photosensitizers, the most suitable treatment parameters need to be elucidated. Here, we evaluate the efficacy of PDT on spheroid cultures of PANC-1 and MIA PaCa-2 pancreatic cancer cells. Two strategies to photosensitize the pancreatic microtumors were selected, based on either nanoliposomal benzoporphyrin derivative (BPD), or non-liposomal methylene blue (MB). Using a comprehensive image-based assay, our findings show that the PDT efficacy manifests in distinct manners for each photosensitizer. Moreover, the efficacy of each photosensitizer is differentially influenced by the photosensitizer dose, the light dose (radiant exposure or fluence in J/cm2), and the dose rate (fluence rate in mW/cm2). Taken together, our findings illustrate that the most suitable light dosimetry for PDT strongly depends on the selected photosensitization strategy. The PDT dose parameters should therefore always be carefully optimized for different models of cancer.
]]>Authors: Marja Heiskala Kristiina Joensuu Päivi Heikkilä
The use of core needle biopsy (CNB) as a means to verify malignancy preoperatively is a paradigm in current breast cancer care, and the risk of enhancing tumor development by this procedure has been considered insignificant. Experimental work in mice has shown preoperative biopsies to increase tumor supportive elements in the microenvironment, whereas, in humans, the impact of CNB on the host’s immunologic response has not been investigated. In this pilot study, we compared the expression of CCL2/CCR2 pathway components at the protein level in samples from CNBs to those from the corresponding resected tumors from 52 patients with primary breast cancer. We found an increased expression of CD163, CD14 and CCR2 in monocytes/macrophages and a slight decrease of CCL2 in the malignant epithelium in the tumors after the biopsy. The increased infiltration of immunosuppressive monocytes/macrophages and the decreased tumor cell CCL2 expression, presumably due to the CCR2 availability-dependent CCL2 internalization, suggest that CNB enhances the activity of the CCL2/CCR2 pathway, and this finding warrants confirmatory examination. The switch in the context-dependent role of CCL2 on the polarization of macrophages may lead to increased tumor supportive function both locally and in the peripheral immune machinery. The future directions in breast cancer should include early interventions to support the tumor surveillance of the host.
]]>Authors: Fleur Jeanquartier Claire Jean-Quartier Sarah Stryeck Andreas Holzinger
Supporting data sharing is paramount to making progress in cancer research. This includes the search for more precise targeted therapies and the search for novel biomarkers, through cluster and classification analysis, and extends to learning details in signal transduction pathways or intra- and intercellular interactions in cancer, through network analysis and network simulation. Our work aims to support and promote the use of publicly available resources in cancer research and demonstrates artificial intelligence (AI) methods to find answers to detailed questions. For example, how targeted therapies can be developed based on precision medicine or how to investigate cell-level phenomena with the help of bioinformatical methods. In our paper, we illustrate the current state of the art with examples from glioma research, in particular, how open data can be used for cancer research in general, and point out several resources and tools that are readily available. Presently, cancer researchers are often not aware of these important resources.
]]>Authors: Michael P. Del Rosario Nadine Abi-Jaoudeh May T. Cho Zeljka Jutric Farshid Dayyani
About 70% of patients with metastatic colorectal carcinoma (mCRC) have liver metastases. Hepatic failure accounts for most mCRC-related deaths. Therefore, controlling liver metastases may improve outcomes. A data overview of liver-directed treatment using yttrium-90 selective internal radiation therapy (SIRT) is provided as part of a multimodality treatment. SIRT in mCRC is discussed, and the prognostic factors for patient selection are defined. Pooled analyses of three recent trials incorporating SIRT plus chemotherapy revealed subsets of patients with mCRC who might benefit from SIRT. A multidisciplinary treatment for most mCRC patients is proposed to achieve long-term survival in this cohort of patients.
]]>Authors: Revathy Nadhan Danny N. Dhanasekaran
Cancer is one of the leading causes of death worldwide. Multifactorial etiology of cancer and tumor heterogeneity are the two most acute challenges in existing diagnostic and therapeutic strategies for cancer. An effective precision cancer medicine strategy to overcome these challenges requires a clear understanding of the transcriptomic landscape of cancer cells. Recent innovative breakthroughs in high-throughput sequencing technologies have identified the oncogenic or tumor-suppressor role of several long non-coding RNAs (lncRNAs). LncRNAs have been characterized as regulating various signaling cascades which are involved in the pathobiology of cancer. They modulate cancer cell survival, proliferation, metabolism, invasive metastasis, stemness, and therapy-resistance through their interactions with specific sets of proteins, miRNAs and other non-coding RNAs, mRNAs, or DNAs in cells. By virtue of their ability to regulate multiple sets of genes and their cognate signaling pathways, lncRNAs are emerging as potential candidates for diagnostic, prognostic, and therapeutic targets. This review is focused on providing insight into the mechanisms by which different lncRNAs play a critical role in cancer growth, and their potential role in cancer diagnosis, prognosis, and therapy.
]]>Authors: Paresh Vishwasrao Susanta K. Hui D. Lynne Smith Vishal Khairnar
Increasing knowledge of cancer immunology has led to the design of therapies using immune cells directly or manipulating their activity, collectively termed immunotherapy. In the field of immuno-oncology, research on adaptive immune T cells has led to the development of CAR-T cells. Innate immune cells such as NK cells can also eliminate oncogenically transformed cells and regulate cells of the immune system. Considering NK cells as a live drug, numerous methods for the isolation and activation of NK cells have been shown to be clinically and therapeutically relevant. In such processes, various cytokines and antibodies present a source of stimulation of NK cells and enhance the efficacy of such treatments. The ex vivo expansion and activation of NK cells, along with genetic modification with CAR, enhance their antitumor activity. Recent preclinical studies have shown an antitumor effect through extracellular vesicles (EVs) derived from NK cells. Work with autologous NK cells has provided insights for clinical applications. In this review, we outline the recent advances of NK-cell-based immunotherapies, summarizing CAR-NK cells, BiKEs, and TriKEs as treatment options against cancer. This review also discusses the challenges of NK cell immunotherapy.
]]>Authors: Bruno Takao Real Karia Camila Albuquerque Pinto Carolina Oliveira Gigek Fernanda Wisnieski Marilia Arruda Cardoso Smith
Gastric cancer is one of the most common cancers and the third cause of cancer-related death worldwide. The treatment of GC patients improved due to advancements in surgery, radiotherapy and chemotherapy. However, the long-term survival rate of patients with gastric cancer remains around 20%. Thus, development of novel therapeutic approaches is of great interest, in order to reduce the need for mutilating surgeries and morbid adjuvant therapies. For many years, it was believed that the RNA was a mere intermediate molecule in the genetic information flow. However, during the past decades, with the advent of new sequencing technologies, it was revealed that non-coding RNAs play important roles in many different biological processes. The Wnt/β-catenin signaling pathway has been reported to regulate crucial events during neoplasic development, such as cell differentiation, proliferation, invasion, migration, apoptosis, and angiogenesis. In this review, we will focus on microRNAs and long non-coding RNAs that have been implicated in gastric cancer tumorigenesis via modulation of the Wnt/β-catenin signaling pathway, which provided some biomarkers to prognosis, diagnosis, and therapy.
]]>Authors: Luca Filippi Viviana Frantellizzi Marko Magdi Abdou Sidrak Joana Gorica Stefano Scippa Agostino Chiaravalloti Orazio Schillaci Oreste Bagni Giuseppe De Vincentis
Neuroblastoma (NB) represents the most common extracranial tumor of childhood. Prognosis is quite variable, ranging from spontaneous regression to aggressive behavior with wide metastatization, high mortality, and limited therapeutic options. Radiotheranostics combines a radiopharmaceutical pair in a unique approach, suitable both for diagnosis and therapy. For many years, metaiodobenzylguanidine (MIBG), labeled with 123I for imaging or 131I for therapy, has represented the main theranostic agent in NB, since up to 90% of NB incorporates the aforementioned radiopharmaceutical. In recent years, novel theranostic agents hold promise in moving the field of NB radiotheranostics forward. In particular, SarTATE, consisting of octreotate targeting somatostatin receptors, has been applied with encouraging results, with 64Cu-SARTATE being used for disease detection and with 67Cu-SARTATE being used for therapy. Furthermore, recent evidence has highlighted the potential of targeted alpha therapy (TAT) for treating cancer by virtue of alpha particles’ high ionizing density and high probability of killing cells along their track. On this path, 211At-astatobenzylguanidine (MABG) has been developed as a potential agent for TAT and is actually under evaluation in preclinical NB models. In this review, we performed a web-based and desktop literature research concerning radiotheranostic approaches in NB, covering both the radiopharmaceuticals already implemented in clinical practice (i.e.,123/1311-MIBG) and those still in a preliminary or preclinical phase.
]]>Authors: Anne Marie Stensvold Ninna Aggerholm-Pedersen Anne Winther-Larsen Birgitte Sandfeld-Paulsen
Improved prognostication of small cell lung cancer (SCLC) patients could strengthen the treatment strategy and, thereby, potentially improve the overall survival (OS) of these patients. C-reactive protein (CRP) has been proposed as a prognostic indicator of inferior survival, although so far, only based on data from smaller studies. Data on SCLC patients diagnosed from January 2009 to June 2018 were extracted from the Danish Lung Cancer Registry and the clinical laboratory information system. CRP measurements were divided at the clinical cut-off value of 8 mg/L or 75 nmol/L) and stratified into quartiles. Cox proportional hazards model assessed the prognostic value of the CRP level. C-statistics further evaluated the biomarker’s prognostic value. In total, 923 patients were included. A pre-treatment CRP level above the clinical cut-off significantly correlated to inferior OS (adjusted hazard ratio (HR) = 1.25 (95% confidence interval (CI): 1.08–1.46). When divided into quartiles, a level-dependent correlation was observed with only the highest quartiles significantly associated with OS (3rd quartile: adjusted HR = 1.26 (95% CI: 1.03–1.55) 4th quartile: adjusted HR = 1.44 (95% CI: 1.17–1.77)). Adding CRP level to already well-established prognostic factors improved the prognostication of SCLC patients. In conclusion, high pre-treatment CRP level is an independent prognostic factor in SCLC patients.
]]>Authors: Sheng-Zhi Liu Xun Sun Ke-Xin Li Chien-Chi Lin Sungsoo Na Bai-Yan Li Hiroki Yokota
Tumor cells regulate their progression not only by the factors within their cell bodies but also by the secretome they produce and secrete. While their secretome significantly alters the fate of tumor cells themselves, they also regulate the growth of surrounding cells including both companion cancer and non-cancer cells. Tumor cell secretome consists of varying molecules that have been reported mostly tumor-promotive. Furthermore, their pro-tumor capability is enhanced by the application of chemotherapeutic agents. However, multiple lines of emerging evidence suggest that the tumor cell secretome can be tumor-suppressive in response to paracrine and endocrine signaling. This review introduces both tumor-promotive and tumor-suppressive secretomes, focusing on multi-tasking proteins in the intracellular and extracellular domains. We describe tumorigenic signaling that governs the nature of the tumor cell secretome and discuss the possibility of inducing tumor-suppressive proteomes as a novel option for cancer treatment. We evaluated the counterintuitive procedure to generate tumor-suppressive proteomes from a unique type of tumor-modifying cells, which are named “induced tumor-suppressing cells” (iTSCs).
]]>Authors: Aaron C. Tan
Since the very beginnings of cancer therapy with chemotherapy, tumors have been treated according to the organ or tissue of origin. The advent of precision medicine however, has recently led to growing promise for tumor-agnostic biomarkers for targeted therapies and immunotherapies, such as NTRK fusions. Despite this, prominent examples such as BRAF V600E mutations in melanoma compared to colorectal cancer, in which the site of tumor origin dramatically influences the efficacy of targeted therapies, heeds caution against disregarding the importance of cell of origin. Indeed, another illustrative example, is the almost complete absence outside of cancers originating from the lung of the classical activating EGFR mutations—exon 19 deletions and exon 21 L858R mutations. Consequently, an understanding of lineage dependency and lineage-survival oncogenes may still offer significant mechanistic insights into the malignant transformation of tumors to ultimately identify further therapeutic vulnerabilities.
]]>Authors: Gee Young Lee Mohamed Mubasher Tamra S. McKenzie Nicole C. Schmitt Merry E. Sebelik Carrie E. Flanagan Badi El Osta Maya B. Cothran Hadiyah-Nicole Green
Objective: The combination of docetaxel (DTX) with Laser-Activated NanoTherapy (LANT), as a treatment for head and neck cancer (HNC), may enhance the therapeutic efficacy of lower doses of DTX, thereby minimizing the effective dosage, side effects and treatment times. Material and methods: Three HNSCC cell lines, Detroit 562, FaDu, and CAL 27, were treated with four combinations of DTX + LANT to evaluate DTX dose reduction and cell viability. Results: The 1 nM DTX + 5 nM LANT combination was the most effective treatment, increasing cell death over its corresponding DTX monotreatment with approximately 86.6%, 80.7%, and 92.1% cell death for Detroit 562, FaDu, and CAL 27, respectively. In Detroit 562, the 1 nM DTX + 5 nM LANT combination treatment resulted in the highest percentage of DTX dose reduction at 84.6%; in FaDu and CAL 27, the 0.5 nM DTX + 5 nM LANT combination treatment resulted in the highest percentage of DTX dose reduction at 78.2% and 82.4%, respectively. Conclusion: LANT may increase the therapeutic efficacy of DTX at significantly lower doses, which could improve patient outcomes.
]]>Authors: Ben Johnson Kenneth Lee Yuen Yee Cheng
Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the lung lining that is predominantly associated with occupational exposure to asbestos. MPM is responsible for thousands of deaths worldwide every year, with the median survival of MPM of 8–14 months. There are limited biomarkers available in the clinic to effectively diagnose MPM, an invasive biopsy procedure is usually required to provide a definitive diagnosis. Due to the long latency period associated with MPM disease presentation, the cancer is usually at an advanced stage at the time of diagnosis where treatment options are largely ineffective at controlling disease progression. Previous MPM-based pre-clinical studies have made significant strides in determining the exact molecular mechanisms associated with asbestos carcinogenesis. Exploring less invasive blood-based biomarkers and treatment strategies involving targeted therapy, immunotherapy, and virotherapy is particularly important. Research in these areas is of crucial importance in relation to improving the rate of novel diagnostic biomarkers and treatment strategies progressing through to clinical trials and ultimately into the clinical setting. This review comprehensively summarises both previous and current pre-clinical research developments that have specifically contributed to an improved understanding of MPM disease biology, and the development of novel diagnostic biomarkers and treatment strategies.
]]>Authors: Daniel Zeitouni Michael P. Catalino Jordan Wise Sean McCabe Kathryn Pietrosimone Naim Rashid Simon Khagi
BACKGROUND: Glioblastoma (GBM) is driven by various genomic alterations. Next-generation sequencing (NGS) could yield targetable alterations that might impact outcomes. The goal of this study was to describe how NGS can inform targeted therapy (TT) in this patient population. METHODS: The medical records of patients with a diagnosis of GBM from 2017 to 2019 were reviewed. Records of patients with recurrent GBM and genomic alterations were evaluated. Objective response rates and disease control rates were determined. RESULTS: A total of 87 patients with GBM underwent NGS. Forty percent (n = 35) were considered to have actionable alterations. Of these 35, 40% (n = 14) had their treatment changed due to the alteration. The objective response rate (ORR) of this population was 43%. The disease control rate (DCR) was 100%. The absolute mean decrease in contrast-enhancing disease was 50.7% (95% CI 34.8–66.6). CONCLUSION: NGS for GBM, particularly in the recurrent setting, yields a high rate of actionable alterations. We observed a high ORR and DCR, reflecting the value of NGS when deciding on therapies to match genomic alterations. In conclusion, patient selection and the availability of NGS might impact outcomes in select patients with recurrent GBM.
]]>Authors: Brady Anderson Mary Vue Nya Gayluak Sarah Jane Brown Lynne T. Bemis Glenn E. Simmons
Evidence of immunogenic cell death as a predictor of response to cancer therapy has increased interest in the high molecular group box 1 protein (HMGB1). HMGB1 is a nuclear protein associated with chromatin organization and DNA damage repair. HMGB1 is also a damage-associated molecular pattern (DAMP) protein and promotes proinflammatory signaling in a paracrine and autocrine manner. Extracellular HMGB1 can promote activation of NF-kB and is associated with several chronic inflammatory and autoimmune diseases, including sepsis, rheumatoid arthritis, atherosclerosis, chronic kidney disease, systemic lupus erythematosus (SLE), as well as cancer. In this review, we describe studies that demonstrate the use of deacetylase inhibitors and HMGB1 inhibitors to alter the expression and localization of HMGB1 in cancer cells, with a focus on lung cancer. The drugs described herein are well established and frequently used in human and small mammal studies. The main objective of this review is to summarize the potential benefit of targeting posttranslational modification of HMGB1 to decrease inflammatory signaling in the tumor microenvironment, and perhaps lead to improved response to current immunotherapeutic approaches.
]]>Authors: Fred Saad
As the inaugural editor in chief of the journal Onco I am very proud to take on the challenge of bringing to life a new journal dedicated to promoting the new developments and management of this challenging disease [...]
]]>Authors: Ana Lúcia Silva Pedro Abreu-Mendes Diana Martins Fernando Mendes
Bladder cancer (BC) is one of the most common cancers in the world. From an early age, it was observed that chronic inflammation is associated with conditions favorable to the development of tumors, as well as the tumor microenvironment. Moreover, regulating tumor progression also interferes with the therapy’s response. The interaction between the tumor and the immune system led to the development of new immune therapies, the immune checkpoint inhibitors. Immunotherapy has shown a better safety profile, survival, and tolerance compared to standard chemotherapy. This therapy offers an effective alternative to patients who are ineligible for cisplatin and patients with advanced disease progression after platinum-based therapy. The first immunotherapy approved for BC was intravesical instillation with Bacillus Calmette–Guérin, for tumors at early stages. Later, immunotherapy focused on immune checkpoint inhibitors, namely, anti-programmed cell death protein 1 (PD1), anti-programmed cell death protein ligand 1(PD-L1), and anti-antigen 4 associated with cytotoxic T cells (CTLA-4). Currently, five immune checkpoint inhibitors for advanced BC are approved by the Food and Drug Administration (FDA): Atezolizumab, Durvalumab, Avelumab, Pembrolizumab, and Nivolumab. This review addresses the correlation between inflammation, tumor microenvironment, and cancer; various studies regarding immune checkpoint inhibitors, either in monotherapy or in combination therapy, are also addressed.
]]>Authors: Chiaki Takahashi Jun-ya Kato
The status of RB1 in cancer may help us determine the optimal therapeutic approach to patients [...]
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