Cancers

16 pages, 20571 KiB

Open AccessArticle

Antitumoral Activity of the MEK Inhibitor Trametinib (TMT212) Alone and in Combination with the CDK4/6 Inhibitor Ribociclib (LEE011) in Neuroendocrine Tumor Cells In Vitro

by Xi-Feng Jin, Gerald Spöttl, Julian Maurer, Svenja Nölting and Christoph Josef Auernhammer

Cancers 2021, 13(6), 1485; https://doi.org/10.3390/cancers13061485 - 23 Mar 2021

Cited by 5 | Viewed by 2945

Abstract

Objectives: This study assessed the antitumoral activity of the MEK inhibitor trametinib (TMT212) and the ERK1/2 inhibitor SCH772984, alone and in combination with the CDK4/6 inhibitor ribociclib (LEE011) in human neuroendocrine tumor (NET) cell lines in vitro. Methods: Human NET cell lines BON1, [...] Read more.

Objectives: This study assessed the antitumoral activity of the MEK inhibitor trametinib (TMT212) and the ERK1/2 inhibitor SCH772984, alone and in combination with the CDK4/6 inhibitor ribociclib (LEE011) in human neuroendocrine tumor (NET) cell lines in vitro. Methods: Human NET cell lines BON1, QGP-1, and NCI-H727 were treated with trametinib or SCH772984, alone and in combination with ribociclib, to assess cell proliferation, cell cycle distribution, and protein signaling using cell proliferation, flow cytometry, and Western blot assays, respectively. Results: Trametinib and SCH772984, alone and in combination with ribociclib, significantly reduced NET cell viability and arrested NET cells at the G1 phase of the cell cycle in all three cell lines tested. In addition, trametinib also caused subG1 events and apoptotic PARP cleavage in QGP1 and NCI-H727 cells. A western blot analysis demonstrated the use of trametinib alone and trametinib in combination with ribociclib to decrease the expression of pERK, cMyc, Chk1, pChk2, pCDK1, CyclinD1, and c-myc in a time-dependent manner in NCI-H727 and QGP-1 cells. Conclusions: MEK and ERK inhibition causes antiproliferative effects in human NET cell lines in vitro. The combination of the MEK inhibitor trametinib (TMT212) with the CDK4/6 inhibitor ribociclib (LEE011) causes additive antiproliferative effects. Future preclinical and clinical studies of MEK inhibition in NETs should be performed. Full article

(This article belongs to the Section Cancer Therapy)

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20 pages, 19673 KiB

Open AccessArticle

Immune Checkpoints Inhibitors and Chemotherapy as First-Line Treatment for Metastatic Urothelial Carcinoma: A Network Meta-Analysis of Randomized Phase III Clinical Trials

by Hsiao-Ling Chen, Vinson Wai-Shun Chan, Yu-Kang Tu, Erica On-Ting Chan, Hsiu-Mei Chang, Yung-Shun Juan, Jeremy Yuen-Chun Teoh and Hsiang Ying Lee

Cancers 2021, 13(6), 1484; https://doi.org/10.3390/cancers13061484 - 23 Mar 2021

Cited by 5 | Viewed by 2451

Abstract

Immune checkpoints inhibitors (ICIs) were considered as second-line treatments in metastatic urothelial carcinoma (mUC) based on better survival benefit and safety profile than chemotherapy (CTX). We aimed to assess different ICIs regimens in the efficacy and safety for front-line treatments in mUC patients. [...] Read more.

Immune checkpoints inhibitors (ICIs) were considered as second-line treatments in metastatic urothelial carcinoma (mUC) based on better survival benefit and safety profile than chemotherapy (CTX). We aimed to assess different ICIs regimens in the efficacy and safety for front-line treatments in mUC patients. A comprehensive literature search was performed and Phase II-III randomized controlled trials (RCTs) on ICIs for patients with mUC were included. The outcome was evaluated by overall survival (OS), progression of free survival (PFS), objective response rate (ORR), and grade 3–5 adverse events. Network meta-analysis was used to estimate the effect size. Surface under cumulative ranking curves (SUCRAs) were applied to rank the included treatments for each outcome. Results: The survival benefit of a single ICI was non-inferiority to chemotherapy (CTX). Although no superior effects were indicated, combination therapy (either ICIs plus CTX or ICIs plus ICIs) presented better OS compared with CTX alone. In terms of PFS, combination therapy produced a noticeable benefit over CTX. Regarding the SUCRA ranking, atezolizumab plus CTX was associated with the best ranking for OS and pembrolizumab plus CTX was the best in PFS. In terms of safety, a single ICI had better safety profile than CTX and combination therapy had a similar risk of grade 3–5 adverse events with CTX. Conclusions: Our NMA results revealed that combination therapy has better ranking compared with monotherapy in OS and acceptable AEs. ICIs alone present non-inferior OS but a lower incidence of AEs compared with CTX. Full article

(This article belongs to the Special Issue Advances in Immunotherapy for Genitourinary Malignancies)

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20 pages, 6613 KiB

Open AccessArticle

Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation

by Iris Simon, Sonia Perales, Laura Casado-Medina, Alba Rodríguez-Martínez, Maria del Carmen Garrido-Navas, Ignacio Puche-Sanz, Juan J. Diaz-Mochon, Clara Alaminos, Pablo Lupiañez, Jose A. Lorente, María J. Serrano and Pedro J. Real

Cancers 2021, 13(6), 1483; https://doi.org/10.3390/cancers13061483 - 23 Mar 2021

Cited by 17 | Viewed by 4603

Abstract

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative [...] Read more.

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment. Full article

(This article belongs to the Section Molecular Cancer Biology)

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14 pages, 2452 KiB

Open AccessArticle

A Profound Basic Characterization of eIFs in Gliomas: Identifying eIF3I and 4H as Potential Novel Target Candidates in Glioma Therapy

by Stefanie Krassnig, Christina Wohlrab, Nicole Golob-Schwarzl, Andrea Raicht, Christoph Schatz, Anna Maria Birkl-Toeglhofer, Christina Skofler, Nadine Gantenbein, Marlene Leoni, Martin Asslaber, Stefan L. Leber, Kariem Mahdy-Ali, Gord von Campe, Marlene Mayer, Andrea Borenich, Serge Weis, Martin Benesch and Johannes Haybaeck

Cancers 2021, 13(6), 1482; https://doi.org/10.3390/cancers13061482 - 23 Mar 2021

Cited by 10 | Viewed by 2354

Abstract

Glioblastoma (GBM) is an utterly devastating cerebral neoplasm and current therapies only marginally improve patients’ overall survival (OS). The PI3K/AKT/mTOR pathway participates in gliomagenesis through regulation of cell growth and proliferation. Since it is an upstream regulator of the rate-limiting translation initiation step [...] Read more.

Glioblastoma (GBM) is an utterly devastating cerebral neoplasm and current therapies only marginally improve patients’ overall survival (OS). The PI3K/AKT/mTOR pathway participates in gliomagenesis through regulation of cell growth and proliferation. Since it is an upstream regulator of the rate-limiting translation initiation step of protein synthesis, controlled by eukaryotic initiation factors (eIFs), we aimed for a profound basic characterization of 17 eIFs to identify potential novel therapeutic targets for gliomas. Therefore, we retrospectively analyzed expressions of mTOR-related proteins and eIFs in human astrocytoma samples (WHO grades I–IV) and compared them to non-neoplastic cortical control brain tissue (CCBT) using immunoblot analyses and immunohistochemistry. We examined mRNA expression using qRT-PCR and additionally performed in silico analyses to observe the influence of eIFs on patients’ survival. Protein and mRNA expressions of eIF3B, eIF3I, eIF4A1, eIF4H, eIF5 and eIF6 were significantly increased in high grade gliomas compared to CCBT and partially in low grade gliomas. However, short OS was only associated with high eIF3I gene expression in low grade gliomas, but not in GBM. In GBM, high eIF4H gene expression significantly correlated with shorter patient survival. In conclusion, we identified eIF3I and eIF4H as the most promising targets for future therapy for glioma patients. Full article

(This article belongs to the Section Molecular Cancer Biology)

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24 pages, 2152 KiB

Open AccessReview

Arming Immune Cells for Battle: A Brief Journey through the Advancements of T and NK Cell Immunotherapy

by Philipp Wendel, Lisa Marie Reindl, Tobias Bexte, Leander Künnemeyer, Vinzenz Särchen, Nawid Albinger, Andreas Mackensen, Eva Rettinger, Tobias Bopp and Evelyn Ullrich

Cancers 2021, 13(6), 1481; https://doi.org/10.3390/cancers13061481 - 23 Mar 2021

Cited by 21 | Viewed by 6302

Abstract

The promising development of adoptive immunotherapy over the last four decades has revealed numerous therapeutic approaches in which dedicated immune cells are modified and administered to eliminate malignant cells. Starting in the early 1980s, lymphokine activated killer (LAK) cells were the first ex [...] Read more.

The promising development of adoptive immunotherapy over the last four decades has revealed numerous therapeutic approaches in which dedicated immune cells are modified and administered to eliminate malignant cells. Starting in the early 1980s, lymphokine activated killer (LAK) cells were the first ex vivo generated NK cell-enriched products utilized for adoptive immunotherapy. Over the past decades, various immunotherapies have been developed, including cytokine-induced killer (CIK) cells, as a peripheral blood mononuclear cells (PBMCs)-based therapeutic product, the adoptive transfer of specific T and NK cell products, and the NK cell line NK-92. In addition to allogeneic NK cells, NK-92 cell products represent a possible “off-the-shelf” therapeutic concept. Recent approaches have successfully enhanced the specificity and cytotoxicity of T, NK, CIK or NK-92 cells towards tumor-specific or associated target antigens generated by genetic engineering of the immune cells, e.g., to express a chimeric antigen receptor (CAR). Here, we will look into the history and recent developments of T and NK cell-based immunotherapy. Full article

(This article belongs to the Special Issue The Role of NK and T Cells in Cancer)

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15 pages, 5502 KiB

Open AccessArticle

miRNA Expression Characterizes Histological Subtypes and Metastasis in Penile Squamous Cell Carcinoma

by Hiresh Ayoubian, Joana Heinzelmann, Sebastian Hölters, Oybek Khalmurzaev, Alexey Pryalukhin, Philine Loertzer, Julia Heinzelbecker, Stefan Lohse, Carol Geppert, Hagen Loertzer, Heiko Wunderlich, Rainer M. Bohle, Michael Stöckle, Vsevolod Borisovich Matveev, Arndt Hartmann and Kerstin Junker

Cancers 2021, 13(6), 1480; https://doi.org/10.3390/cancers13061480 - 23 Mar 2021

Cited by 10 | Viewed by 2987

Abstract

Although microRNAs are described as promising biomarkers in many tumor types, little is known about their role in PSCC. Thus, we attempted to identify miRNAs involved in tumor development and metastasis in distinct histological subtypes considering the impact of HPV infection. In a [...] Read more.

Although microRNAs are described as promising biomarkers in many tumor types, little is known about their role in PSCC. Thus, we attempted to identify miRNAs involved in tumor development and metastasis in distinct histological subtypes considering the impact of HPV infection. In a first step, microarray analyses were performed on RNA from formalin-fixed, paraffin-embedded tumor (22), and normal (8) tissue samples. Microarray data were validated for selected miRNAs by qRT-PCR on an enlarged cohort, including 27 tumor and 18 normal tissues. We found 876 significantly differentially expressed miRNAs (p ≤ 0.01) between HPV-positive and HPV-negative tumor samples by microarray analysis. Although no significant differences were detected between normal and tumor tissue in the whole cohort, specific expression patterns occurred in distinct histological subtypes, such as HPV-negative usual PSCC (95 differentially expressed miRNAs, p ≤ 0.05) and HPV-positive basaloid/warty subtypes (247 differentially expressed miRNAs, p ≤ 0.05). Selected miRNAs were confirmed by qRT-PCR. Furthermore, microarray data revealed 118 miRNAs (p ≤ 0.01) that were significantly differentially expressed in metastatic versus non-metastatic usual PSCC. The lower expression levels for miR-137 and miR-328-3p in metastatic usual PSCC were validated by qRT-PCR. The results of this study confirmed that specific miRNAs could serve as potential diagnostic and prognostic markers in single PSCC subtypes and are associated with HPV-dependent pathways. Full article

(This article belongs to the Special Issue Non-Coding RNAs in Urological Malignancies: Relevance for Tumorigenesis and Biomarker Development)

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13 pages, 1524 KiB

Open AccessArticle

Impact of Gastrointestinal Side Effects on Patients’ Reported Quality of Life Trajectories after Radiotherapy for Prostate Cancer: Data from the Prospective, Observational Pros-IT CNR Study

by Marianna Noale, Alessio Bruni, Luca Triggiani, Michela Buglione, Filippo Bertoni, Luca Frassinelli, Rodolfo Montironi, Renzo Corvò, Vittorina Zagonel, Angelo Porreca, Pierfrancesco Bassi, Mauro Gacci, Giario Natale Conti, Stefania Maggi, Stefano Magrini and The Pros-IT CNR Study Group

Cancers 2021, 13(6), 1479; https://doi.org/10.3390/cancers13061479 - 23 Mar 2021

Cited by 5 | Viewed by 2334

Abstract

Radiotherapy (RT) represents an important therapeutic option for the treatment of localized prostate cancer. The aim of the current study is to examine trajectories in patients’ reported quality of life (QoL) aspects related to bowel function and bother, considering data from the PROState [...] Read more.

Radiotherapy (RT) represents an important therapeutic option for the treatment of localized prostate cancer. The aim of the current study is to examine trajectories in patients’ reported quality of life (QoL) aspects related to bowel function and bother, considering data from the PROState cancer monitoring in ITaly from the National Research Council (Pros-IT CNR) study, analyzed with growth mixture models. Data for patients who underwent RT, either associated or not associated with androgen deprivation therapy, were considered. QoL outcomes were assessed over a 2-year period from the diagnosis, using the Italian version of the University of California Los Angeles-Prostate Cancer Index (Italian-UCLA-PCI). Three trajectories were identified for the bowel function; having three or more comorbidities and the use of 3D-CRT technique for RT were associated with the worst trajectory (OR = 3.80, 95% CI 2.04–7.08; OR = 2.17, 95% CI 1.22–3.87, respectively). Two trajectories were identified for the bowel bother scores; diabetes and the non-Image guided RT method were associated with being in the worst bowel bother trajectory group (OR = 1.69, 95% CI 1.06–2.67; OR = 2.57, 95% CI 1.70–3.86, respectively). The findings from this study suggest that the absence of comorbidities and the use of intensity modulated RT techniques with image guidance are related with a better tolerance to RT in terms of bowel side effects. Full article

(This article belongs to the Special Issue Prostate Cancer Radiotherapy: Recent Advances and Challenges)

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11 pages, 1714 KiB

Open AccessReview

The TCGA Molecular Classification of Endometrial Cancer and Its Possible Impact on Adjuvant Treatment Decisions

by Matthias Alexa, Annette Hasenburg and Marco Johannes Battista

Cancers 2021, 13(6), 1478; https://doi.org/10.3390/cancers13061478 - 23 Mar 2021

Cited by 62 | Viewed by 9424

Abstract

Adjuvant treatment decisions for endometrial cancer (EC) are based on stage, the histological grade of differentiation, histological subtype, and few histopathological markers. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identified four risk groups of EC patients using a combination of immunohistochemistry [...] Read more.

Adjuvant treatment decisions for endometrial cancer (EC) are based on stage, the histological grade of differentiation, histological subtype, and few histopathological markers. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identified four risk groups of EC patients using a combination of immunohistochemistry and mutation analysis: Polymerase Epsilon exonuclease domain mutated (POLE EDM), mismatch repair deficient (MMRd), p53 wild-type/copy-number-low (p53 wt), and p53-mutated/copy-number-high (p53 abn). Patients allocated to the POLE or abnormal p53 expression subtype are faced with a significantly altered outcome possibly requiring a modified adjuvant treatment decision. Within this review, we summarize the development of ProMisE, characterize the four molecular subtypes, and finally discuss its value in terms of a patient-tailored therapy in order to prevent significant under or overtreatment. Full article

(This article belongs to the Special Issue Radiotherapy in Endometrial Cancer)

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12 pages, 6858 KiB

Open AccessArticle

Abundance of Microvascular Endothelial Cells Is Associated with Response to Chemotherapy and Prognosis in Colorectal Cancer

by Masanori Oshi, Michelle R. Huyser, Lan Le, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo and Kazuaki Takabe

Cancers 2021, 13(6), 1477; https://doi.org/10.3390/cancers13061477 - 23 Mar 2021

Cited by 22 | Viewed by 2604

Abstract

The generation of pathologic, immature, and dysfunctional vessels by angiogenesis is a mechanism of metastasis that has been a therapeutic target for colorectal cancer (CRC). In this study, we investigated the clinical relevance of intra-tumoral microvascular endothelial (mvE) cells in CRC using the [...] Read more.

The generation of pathologic, immature, and dysfunctional vessels by angiogenesis is a mechanism of metastasis that has been a therapeutic target for colorectal cancer (CRC). In this study, we investigated the clinical relevance of intra-tumoral microvascular endothelial (mvE) cells in CRC using the xCell algorithm on transcriptome. A total of 1244 CRC patients in discovery and validation cohorts were analyzed. We found that an abundance of mvE cells did not mirror angiogenesis but reflected mature blood vessels because it was significantly associated with a high expression of vascular stability-related genes, including sphingosine-1-phosphate receptor genes and pericytes. Epithelial–mesenchymal transition and myogenesis gene sets were enriched in mvE cell abundant CRC, while mvE cell-less CRC enriched cell proliferation, oxidative phosphorylation, and protein secretion gene sets. mvE cell abundant CRC was associated with infiltration of M2 macrophages, dendritic cells, and less gamma-delta T cells (all p < 0.001), but not with the interferon-γ response. mvE cell abundant CRC was significantly associated with worse patient survival in CRC. Interestingly, mvE cell abundant CRC was significantly associated with a high response rate to chemotherapy (p = 0.012) and worse patient survival for those that did not receive chemotherapy. However, there was no survival difference in patients who underwent chemotherapy. In conclusion, we estimated the abundance of mvE cells using the xCell algorithm on tumor transcriptome finding its association with the number of mature blood vessels in a tumor microenvironment and its ability to predict response to chemotherapy, thereby patient survival in CRC. Full article

(This article belongs to the Special Issue Targeting Blood Vessel Components to Treat Cancer)

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13 pages, 922 KiB

Open AccessReview

Immunotherapy for ALK-Rearranged Non-Small Cell Lung Cancer: Challenges Inform Promising Approaches

by Kamya Sankar, Sunitha Nagrath and Nithya Ramnath

Cancers 2021, 13(6), 1476; https://doi.org/10.3390/cancers13061476 - 23 Mar 2021

Cited by 20 | Viewed by 4433

Abstract

Rearrangements in the Anaplastic Lymphoma Kinase (ALK) gene have been implicated in 5–6% of all non-small cell lung cancers. ALK-rearranged non-small cell lung cancers are sensitive to ALK-directed tyrosine kinase inhibitors, but generally resistant to single-agent immune checkpoint inhibitors. [...] Read more.

Rearrangements in the Anaplastic Lymphoma Kinase (ALK) gene have been implicated in 5–6% of all non-small cell lung cancers. ALK-rearranged non-small cell lung cancers are sensitive to ALK-directed tyrosine kinase inhibitors, but generally resistant to single-agent immune checkpoint inhibitors. Here, we aim to describe the mechanisms of ALK aberrations in non-small cell lung cancer by which an immunosuppressed tumor microenvironment is created, leading to host immune evasion. We report pre-clinical and clinical studies evaluating novel immunotherapeutic approaches and describe the promises and challenges of incorporating immune-based treatments for ALK-rearranged non-small cell lung cancer. Full article

(This article belongs to the Special Issue ALK: A Tyrosine Kinase Target for Cancer Therapy)

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16 pages, 2385 KiB

Open AccessArticle

Clinical Features and Multiplatform Molecular Analysis Assist in Understanding Patient Response to Anti-PD-1/PD-L1 in Renal Cell Carcinoma

by Eileen Shiuan, Anupama Reddy, Stephanie O. Dudzinski, Aaron R. Lim, Ayaka Sugiura, Rachel Hongo, Kirsten Young, Xian-De Liu, Christof C. Smith, Jamye O’Neal, Kimberly B. Dahlman, Renee McAlister, Beiru Chen, Kristen Ruma, Nathan Roscoe, Jehovana Bender, Joolz Ward, Ju Young Kim, Christine Vaupel, Jennifer Bordeaux, Shridar Ganesan, Tina M. Mayer, Gregory M. Riedlinger, Benjamin G. Vincent, Nancy B. Davis, Scott M. Haake, Jeffrey C. Rathmell, Eric Jonasch, Brian I. Rini, W. Kimryn Rathmell and Kathryn E. Beckermann Show full author list Hide full author list

Cancers 2021, 13(6), 1475; https://doi.org/10.3390/cancers13061475 - 23 Mar 2021

Cited by 11 | Viewed by 4287

Abstract

Predicting response to ICI therapy among patients with renal cell carcinoma (RCC) has been uniquely challenging. We analyzed patient characteristics and clinical correlates from a retrospective single-site cohort of advanced RCC patients receiving anti-PD-1/PD-L1 monotherapy (N = 97), as well as molecular parameters [...] Read more.

Predicting response to ICI therapy among patients with renal cell carcinoma (RCC) has been uniquely challenging. We analyzed patient characteristics and clinical correlates from a retrospective single-site cohort of advanced RCC patients receiving anti-PD-1/PD-L1 monotherapy (N = 97), as well as molecular parameters in a subset of patients, including multiplexed immunofluorescence (mIF), whole exome sequencing (WES), T cell receptor (TCR) sequencing, and RNA sequencing (RNA-seq). Clinical factors such as the development of immune-related adverse events (odds ratio (OR) = 2.50, 95% confidence interval (CI) = 1.05–5.91) and immunological prognostic parameters, including a higher percentage of circulating lymphocytes (23.4% vs. 17.4%, p = 0.0015) and a lower percentage of circulating neutrophils (61.8% vs. 68.5%, p = 0.0045), correlated with response. Previously identified gene expression signatures representing pathways of angiogenesis, myeloid inflammation, T effector presence, and clear cell signatures also correlated with response. High PD-L1 expression (>10% cells) as well as low TCR diversity (≤644 clonotypes) were associated with improved progression-free survival (PFS). We corroborate previously published findings and provide preliminary evidence of T cell clonality impacting the outcome of RCC patients. To further biomarker development in RCC, future studies will benefit from integrated analysis of multiple molecular platforms and prospective validation. Full article

(This article belongs to the Special Issue Urological Cancer 2021)

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15 pages, 2918 KiB

Open AccessArticle

A New Classification System to Predict Functional Outcome after Laryngectomy and Laryngopharyngectomy

by Stefan Grasl, Elisabeth Schmid, Gregor Heiduschka, Markus Brunner, Blažen Marijić, Matthaeus Ch. Grasl, Muhammad Faisal, Boban M. Erovic and Stefan Janik

Cancers 2021, 13(6), 1474; https://doi.org/10.3390/cancers13061474 - 23 Mar 2021

Cited by 10 | Viewed by 2137

Abstract

(1) Objective: To evaluate long-term functional outcome in patients who underwent primary or salvage total laryngectomy (TL), TL with partial (TLPP), or total pharyngectomy (TLTP), and to establish a new scoring system to predict complication rate and long-term functional outcome; (2) Material and [...] Read more.

(1) Objective: To evaluate long-term functional outcome in patients who underwent primary or salvage total laryngectomy (TL), TL with partial (TLPP), or total pharyngectomy (TLTP), and to establish a new scoring system to predict complication rate and long-term functional outcome; (2) Material and Methods: Between 1993 and 2019, 258 patients underwent TL (n = 85), TLPP (n = 101), or TLTP (n = 72). Based on the extent of tumor resection, all patients were stratified to (i) localization I: TL; II: TLPP; III: TLTP and (ii) surgical treatment (A: primary resection; B: salvage surgery). Type and rate of complication and functional outcome, including oral nutrition, G-tube dependence, pharyngeal stenosis, and voice rehabilitation were evaluated in 163 patients with a follow-up ≥ 12 months and absence of recurrent disease; (3) Results: We found 61 IA, 24 IB, 63 IIA, 38 IIB, 37 IIIA, and 35 IIIA patients. Complications and subsequently revision surgeries occurred most frequently in IIIB cases but rarely in IA patients (57.1% vs. 18%; p = 0.001 and 51.4% vs. 14.8%; p = 0.002), respectively. Pharyngocutaneous fistula (PCF) was the most common complication (33%), although it did not significantly differ among cohorts (p = 0.345). Pharyngeal stenosis was found in 27% of cases, with the highest incidence in IIIA (45.5%) and IIIB (72.7%) patients (p < 0.001). Most (91.1%) IA patients achieved complete oral nutrition compared to only 41.7% in class IIIB patients (p < 0.001). Absence of PCF (odds ratio (OR) 3.29; p = 0.003), presence of complications (OR 3.47; p = 0.004), and no need for pharyngeal reconstruction (OR 4.44; p = 0.042) represented independent favorable factors for oral nutrition. Verbal communication was achieved in 69.3% of patients and was accomplished by the insertion of voice prosthesis in 37.4%. Acquisition of esophageal speech was reached in 31.9% of cases. Based on these data, we stratified patients regarding the extent of surgery and previous treatment into subgroups reflecting risk profiles and expectable functional outcome; (4) Conclusions: The extent of resection accompanied by the need for reconstruction and salvage surgery both carry a higher risk of complications and subsequently worse functional outcome. Both factors are reflected in our classification system that can be helpful to better predict patients’ functional outcome. Full article

(This article belongs to the Special Issue Larynx Cancer: From Diagnosis to Treatment and Rehabilitation)

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18 pages, 2220 KiB

Open AccessReview

Ca²⁺ Signaling as the Untact Mode during Signaling in Metastatic Breast Cancer

by Dongun Lee and Jeong Hee Hong

Cancers 2021, 13(6), 1473; https://doi.org/10.3390/cancers13061473 - 23 Mar 2021

Cited by 8 | Viewed by 2934

Abstract

Metastatic features of breast cancer in the brain are considered a common pathology in female patients with late-stage breast cancer. Ca²⁺ signaling and the overexpression pattern of Ca²⁺ channels have been regarded as oncogenic markers of breast cancer. In other words, [...] Read more.

Metastatic features of breast cancer in the brain are considered a common pathology in female patients with late-stage breast cancer. Ca²⁺ signaling and the overexpression pattern of Ca²⁺ channels have been regarded as oncogenic markers of breast cancer. In other words, breast tumor development can be mediated by inhibiting Ca²⁺ channels. Although the therapeutic potential of inhibiting Ca²⁺ channels against breast cancer has been demonstrated, the relationship between breast cancer metastasis and Ca²⁺ channels is not yet understood. Thus, we focused on the metastatic features of breast cancer and summarized the basic mechanisms of Ca²⁺-related proteins and channels during the stages of metastatic breast cancer by evaluating Ca²⁺ signaling. In particular, we highlighted the metastasis of breast tumors to the brain. Thus, modulating Ca²⁺ channels with Ca²⁺ channel inhibitors and combined applications will advance treatment strategies for breast cancer metastasis to the brain. Full article

(This article belongs to the Special Issue Calcium Signaling Remodeling and Functional Role in Cancer Cells)

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28 pages, 5287 KiB

Open AccessArticle

Persistent Inflammatory Stimulation Drives the Conversion of MSCs to Inflammatory CAFs That Promote Pro-Metastatic Characteristics in Breast Cancer Cells

by Linor Rubinstein-Achiasaf, Dina Morein, Hagar Ben-Yaakov, Yulia Liubomirski, Tsipi Meshel, Eti Elbaz, Orly Dorot, Edward Pichinuk, Michael Gershovits, Miguel Weil and Adit Ben-Baruch

Cancers 2021, 13(6), 1472; https://doi.org/10.3390/cancers13061472 - 23 Mar 2021

Cited by 24 | Viewed by 4602

Abstract

The pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) are expressed simultaneously and have tumor-promoting roles in breast cancer. In parallel, mesenchymal stem cells (MSCs) undergo conversion at the tumor site to cancer-associated fibroblasts (CAFs), which are generally connected to [...] Read more.

The pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) are expressed simultaneously and have tumor-promoting roles in breast cancer. In parallel, mesenchymal stem cells (MSCs) undergo conversion at the tumor site to cancer-associated fibroblasts (CAFs), which are generally connected to enhanced tumor progression. Here, we determined the impact of consistent inflammatory stimulation on stromal cell plasticity. MSCs that were persistently stimulated by TNFα + IL-1β (generally 14–18 days) gained a CAF-like morphology, accompanied by prominent changes in gene expression, including in stroma/fibroblast-related genes. These CAF-like cells expressed elevated levels of vimentin and fibroblast activation protein (FAP) and demonstrated significantly increased abilities to contract collagen gels. Moreover, they gained the phenotype of inflammatory CAFs, as indicated by the reduced expression of α smooth muscle actin (αSMA), increased proliferation, and elevated expression of inflammatory genes and proteins, primarily inflammatory chemokines. These inflammatory CAFs released factors that enhanced tumor cell dispersion, scattering, and migration; the inflammatory CAF-derived factors elevated cancer cell migration by stimulating the chemokine receptors CCR2, CCR5, and CXCR1/2 and Ras-activating receptors, expressed by the cancer cells. Together, these novel findings demonstrate that chronic inflammation can induce MSC-to-CAF conversion, leading to the generation of tumor-promoting inflammatory CAFs. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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18 pages, 3802 KiB

Open AccessArticle

Epithelial Mutant p53 Promotes Resistance to Anti-PD-1-Mediated Oral Cancer Immunoprevention in Carcinogen-Induced Mouse Models

by Jin Wang, Yuan Hu, Vicente Escamilla-Rivera, Cassandra L. Gonzalez, Lin Tang, Bingbing Wang, Adel K. El-Naggar, Jeffrey N. Myers and Carlos Caulin

Cancers 2021, 13(6), 1471; https://doi.org/10.3390/cancers13061471 - 23 Mar 2021

Cited by 6 | Viewed by 3455

Abstract

Oral squamous cell carcinoma (OSCC) develops through the multistep malignant progression of squamous epithelium. This process can be prevented by PD-1 blockade in a mouse model for oral carcinogenesis. OSCCs exhibit a high incidence of p53 mutations that confer oncogenic gain-of-function (GOF) activities [...] Read more.

Oral squamous cell carcinoma (OSCC) develops through the multistep malignant progression of squamous epithelium. This process can be prevented by PD-1 blockade in a mouse model for oral carcinogenesis. OSCCs exhibit a high incidence of p53 mutations that confer oncogenic gain-of-function (GOF) activities that promote resistance to standard therapies and poor clinical outcomes. To determine whether epithelial p53 mutations modulate anti-PD-1-mediated oral cancer immunoprevention, we generated mouse models for oral carcinogenesis by exposing mice carrying epithelial-specific p53 mutations to the carcinogen 4NQO. Consistent with the oncogenic functions of mutant p53, mice with OSCCs expressing the p53^R172H GOF mutation developed higher metastasis rates than mice with loss-of-function (LOF) p53 deletion or with wild-type p53. Throughout oral cancer progression, pre-invasive and invasive lesions showed a gradual increase in T-cell infiltration, recruitment of immunosuppressive regulatory T-cells (Tregs), and induction of PD-1/PD-L1 immune checkpoint proteins. Notably, while PD-1 blockade prevented the development of OSCCs in mice with wild-type p53 or p53 deletion, GOF p53^R172H abrogated the immunopreventive effects of anti-PD-1, associated with upregulation of IL17 signaling and depletion of exhausted CD8 cells in the microenvironment of the p53^R172H tumors. These findings sustain a potential role for p53 profiling in personalized oral cancer immunoprevention. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

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19 pages, 998 KiB

Open AccessArticle

Night Work and Breast Cancer Risk in Nurses: Multifactorial Risk Analysis

by Juan Gómez-Salgado, Javier Fagundo-Rivera, Mónica Ortega-Moreno, Regina Allande-Cussó, Diego Ayuso-Murillo and Carlos Ruiz-Frutos

Cancers 2021, 13(6), 1470; https://doi.org/10.3390/cancers13061470 - 23 Mar 2021

Cited by 10 | Viewed by 3905

Abstract

Night work has been highlighted by the International Agency for Research on Cancer (IARC) as a likely carcinogenic factor for humans, associated with breast cancer and professions that require continuity of work. Knowing the impact that short and long-term night work has on [...] Read more.

Night work has been highlighted by the International Agency for Research on Cancer (IARC) as a likely carcinogenic factor for humans, associated with breast cancer and professions that require continuity of work. Knowing the impact that short and long-term night work has on the nurses’ collective seems a priority, therefore, this study aims to analyse the relationship between night work and the development of breast cancer risk factors in nurses. For this, a cross-sectional study through an online questionnaire on breast cancer risk variables and working life was designed. The study was conducted in Spain and the sample consisted of 966 nurses, of whom 502 were healthy participants and 56 were breast cancer patients. These two groups were compared in the analyses. A descriptive analysis was performed, and the relationship was tested using χ2 independence test and OR calculation. The CHAID (Chi Square Automatic Interaction Detection) data mining method allowed for the creation of a segmentation tree for the main risk variables. The most significant risk variables related to working life have been the number of years worked, nights worked throughout life, and years working more than 3 nights per month. Exceeding 16 years of work has been significant for women and men. When the time worked is less than 16 years, the number of cases increases if there is a family history of cancer and if there have been more than 500 nights of work. High-intensity night work seems more harmful at an early age. The accumulation of years and nights worked increase the risk of breast cancer when factors such as sleep disturbance, physical stress, or family responsibilities come together. Full article

(This article belongs to the Special Issue Environmental Carcinogens and Cancer Risk)

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18 pages, 2556 KiB

Open AccessArticle

The Epithelial–Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA let-7 in Cancer

by Hanmin Wang, Evgeny Chirshev, Nozomi Hojo, Tise Suzuki, Antonella Bertucci, Michael Pierce, Christopher Perry, Ruining Wang, Jeffrey Zink, Carlotta A. Glackin, Yevgeniya J. Ioffe and Juli J. Unternaehrer

Cancers 2021, 13(6), 1469; https://doi.org/10.3390/cancers13061469 - 23 Mar 2021

Cited by 15 | Viewed by 3540

Abstract

We aimed to determine the mechanism of epithelial–mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, [...] Read more.

We aimed to determine the mechanism of epithelial–mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer, and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies. Full article

(This article belongs to the Special Issue Stemness and Differentiation in Cancer)

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29 pages, 1048 KiB

Open AccessReview

Charged Particle and Conventional Radiotherapy: Current Implications as Partner for Immunotherapy

by Damiënne Marcus, Relinde I. Y. Lieverse, Carmen Klein, Amir Abdollahi, Philippe Lambin, Ludwig J. Dubois and Ala Yaromina

Cancers 2021, 13(6), 1468; https://doi.org/10.3390/cancers13061468 - 23 Mar 2021

Cited by 22 | Viewed by 4179

Abstract

Radiotherapy (RT) has been shown to interfere with inflammatory signals and to enhance tumor immunogenicity via, e.g., immunogenic cell death, thereby potentially augmenting the therapeutic efficacy of immunotherapy. Conventional RT consists predominantly of high energy photon beams. Hypofractionated RT regimens administered, e.g., by [...] Read more.

Radiotherapy (RT) has been shown to interfere with inflammatory signals and to enhance tumor immunogenicity via, e.g., immunogenic cell death, thereby potentially augmenting the therapeutic efficacy of immunotherapy. Conventional RT consists predominantly of high energy photon beams. Hypofractionated RT regimens administered, e.g., by stereotactic body radiation therapy (SBRT), are increasingly investigated in combination with cancer immunotherapy within clinical trials. Despite intensive preclinical studies, the optimal dose per fraction and dose schemes for elaboration of RT induced immunogenic potential remain inconclusive. Compared to the scenario of combined immune checkpoint inhibition (ICI) and RT, multimodal therapies utilizing other immunotherapy principles such as adoptive transfer of immune cells, vaccination strategies, targeted immune-cytokines and agonists are underrepresented in both preclinical and clinical settings. Despite the clinical success of ICI and RT combination, e.g., prolonging overall survival in locally advanced lung cancer, curative outcomes are still not achieved for most cancer entities studied. Charged particle RT (PRT) has gained interest as it may enhance tumor immunogenicity compared to conventional RT due to its unique biological and physical properties. However, whether PRT in combination with immune therapy will elicit superior antitumor effects both locally and systemically needs to be further investigated. In this review, the immunological effects of RT in the tumor microenvironment are summarized to understand their implications for immunotherapy combinations. Attention will be given to the various immunotherapeutic interventions that have been co-administered with RT so far. Furthermore, the theoretical basis and first evidences supporting a favorable immunogenicity profile of PRT will be examined. Full article

(This article belongs to the Special Issue Cancer Radiotherapy)

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16 pages, 12906 KiB

Open AccessArticle

Pre-Surgery Cognitive Performance and Voxel-Based Lesion-Symptom Mapping in Patients with Left High-Grade Glioma

by Ilaria Guarracino, Tamara Ius, Cinzia Baiano, Serena D’Agostini, Miran Skrap and Barbara Tomasino

Cancers 2021, 13(6), 1467; https://doi.org/10.3390/cancers13061467 - 23 Mar 2021

Cited by 5 | Viewed by 1968

Abstract

(1) Background: The literature on the effects of high-grade glioma (HGG) growth on cognition is still scarce. (2) Method: A consecutive series of 85 patients with HGG involving the left hemisphere underwent an extended neuropsychological evaluation prior to surgery. Voxel-based lesion-symptom mapping (VLSM) [...] Read more.

(1) Background: The literature on the effects of high-grade glioma (HGG) growth on cognition is still scarce. (2) Method: A consecutive series of 85 patients with HGG involving the left hemisphere underwent an extended neuropsychological evaluation prior to surgery. Voxel-based lesion-symptom mapping (VLSM) was used to identify regions related to cognitive performance. (3) Results: The patients’ mean level of pre-surgery accuracy was overall high. They showed the greatest difficulties in language with tasks such as naming (42.1% of patients impaired on nouns and 61.4% on verbs), reading (36.3% on words and 32.7% on pseudo-words), auditory lexical decisions (43.9%) and writing (41.3%) being most frequently impaired. VLSM analysis revealed anatomically separated areas along the temporal cortex and the white matter related to impairments on the different tasks, with voxels commonly shared by all tasks restricted to a small region in the ventral superior and middle temporal gyrus. (4) Conclusions: High-grade glioma affects cognition; nonetheless, lesions do not cause diffuse deficits but selectively impact the different language sub-domains along the ventral stream and the dorsal stream for language processing. Full article

(This article belongs to the Collection Diagnostic and Therapeutic Challenges in Patients with Primary or Secondary Brain Tumor)

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19 pages, 4521 KiB

Open AccessReview

In-Depth Characterization of Stromal Cells within the Tumor Microenvironment Yields Novel Therapeutic Targets

by Sebastian G. Walter, Sebastian Scheidt, Robert Nißler, Christopher Gaisendrees, Kourosh Zarghooni and Frank A. Schildberg

Cancers 2021, 13(6), 1466; https://doi.org/10.3390/cancers13061466 - 23 Mar 2021

Cited by 9 | Viewed by 4741

Abstract

Cells within the tumor stroma are essential for tumor progression. In particular, cancer-associated fibroblasts (CAF) and CAF precursor cells (resident fibroblasts and mesenchymal stromal cells) are responsible for the formation of the extracellular matrix in tumor tissue. Consequently, CAFs directly and indirectly mediate [...] Read more.

Cells within the tumor stroma are essential for tumor progression. In particular, cancer-associated fibroblasts (CAF) and CAF precursor cells (resident fibroblasts and mesenchymal stromal cells) are responsible for the formation of the extracellular matrix in tumor tissue. Consequently, CAFs directly and indirectly mediate inflammation, metastasis, immunomodulation, angiogenesis, and the development of tumor chemoresistance, which is orchestrated by complex intercellular cytokine-mediated crosstalk. CAFs represent a strategic target in antitumor therapy but their heterogeneity hinders effective treatment regimes. In-depth understanding of CAF subpopulations and knowledge of specific functions in tumor progression will ultimately result in more specific and effective cancer treatments. This review provides a detailed description of CAFs and CAF precursor cells and summarizes possible treatment strategies as well as molecular targets of these cells in antitumor therapies. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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19 pages, 3445 KiB

Open AccessArticle

Three-Dimensional Tumor Spheroids as a Tool for Reliable Investigation of Combined Gold Nanoparticle and Docetaxel Treatment

by Kyle Bromma, Abdulaziz Alhussan, Monica Mesa Perez, Perry Howard, Wayne Beckham and Devika B. Chithrani

Cancers 2021, 13(6), 1465; https://doi.org/10.3390/cancers13061465 - 23 Mar 2021

Cited by 14 | Viewed by 3137

Abstract

Radiotherapy and chemotherapy are the gold standard for treating patients with cancer in the clinic but, despite modern advances, are limited by normal tissue toxicity. The use of nanomaterials, such as gold nanoparticles (GNPs), to improve radiosensitivity and act as drug delivery systems [...] Read more.

Radiotherapy and chemotherapy are the gold standard for treating patients with cancer in the clinic but, despite modern advances, are limited by normal tissue toxicity. The use of nanomaterials, such as gold nanoparticles (GNPs), to improve radiosensitivity and act as drug delivery systems can mitigate toxicity while increasing deposited tumor dose. To expedite a quicker clinical translation, three-dimensional (3D) tumor spheroid models that can better approximate the tumor environment compared to a two-dimensional (2D) monolayer model have been used. We tested the uptake of 15 nm GNPs and 50 nm GNPs on a monolayer and on spheroids of two cancer cell lines, CAL-27 and HeLa, to evaluate the differences between a 2D and 3D model in similar conditions. The anticancer drug docetaxel (DTX) which can act as a radiosensitizer, was also utilized, informing future potential of GNP-mediated combined therapeutics. In the 2D monolayer model, the addition of DTX induced a small, non-significant increase of uptake of GNPs of between 13% and 24%, while in the 3D spheroid model, DTX increased uptake by between 47% and 186%, with CAL-27 having a much larger increase relative to HeLa. Further, the depth of penetration of 15 nm GNPs over 50 nm GNPs increased by 33% for CAL-27 spheroids and 17% for HeLa spheroids. These results highlight the necessity to optimize GNP treatment conditions in a more realistic tumor-life environment. A 3D spheroid model can capture important details, such as different packing densities from different cancer cell lines, which are absent from a simple 2D monolayer model. Full article

(This article belongs to the Special Issue Emerging Technologies and Computation Methods for Precision Medicine in Cancer—Ready for Use in Clinics?)

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15 pages, 977 KiB

Open AccessArticle

Thyroid Dysfunction in Lung Cancer Patients Treated with Immune Checkpoint Inhibitors (ICIs): Outcomes in a Multiethnic Urban Cohort

by Angelica D’Aiello, Juan Lin, Rasim Gucalp, Vafa Tabatabaie, Haiying Cheng, Noah A. Bloomgarden, Yaron Tomer and Balazs Halmos

Cancers 2021, 13(6), 1464; https://doi.org/10.3390/cancers13061464 - 23 Mar 2021

Cited by 12 | Viewed by 2424

Abstract

We sought to characterize thyroid dysfunction and its association with baseline clinical and demographic characteristics, as well as progression-free survival (PFS), in a multiethnic cohort of lung cancer patients treated with ICIs. A retrospective chart review of lung cancer patients receiving an anti-PD1 [...] Read more.

We sought to characterize thyroid dysfunction and its association with baseline clinical and demographic characteristics, as well as progression-free survival (PFS), in a multiethnic cohort of lung cancer patients treated with ICIs. A retrospective chart review of lung cancer patients receiving an anti-PD1 or PD-L1 agent was performed. Multivariate Cox proportional hazards were fitted to compare time to thyroid dysfunction among race subgroups controlling for age, gender, treatment type, and duration. Thyroid dysfunction was based on laboratory testing; clinical symptoms were not required. PFS at a 24-week landmark analysis point among patients with and without thyroid dysfunction was compared using a log-rank test. We identified 205 subjects that received ICIs, including 76 (37.1%) who developed thyroid dysfunction. Rates of thyroid dysfunction by one year occurred at similar frequencies among all races (p = 0.92). Gender and concurrent chemotherapy showed no significant association with thyroid dysfunction (p = 0.81 and p = 0.67, respectively). Thyrotoxicosis occurred at higher rates in Black (25, 31.6%) subjects than in White (7, 16.7%) and Hispanic (8, 12.7%) subjects when employing the log-rank test (p = 0.016) and multivariate Cox regression (HR 0.48, p = 0.09 for White and HR 0.36, p = 0.01 for Hispanic compared to Black subjects). PFS was similar among subjects with and without thyroid dysfunction when applying the log-rank test (p = 0.353). Gender, concurrent treatment with chemotherapy, and PFS were not associated with thyroid dysfunction in patients receiving ICIs; however, Black race was a risk factor for thyrotoxicosis. The mechanisms underlying the role of race in the development of irAEs warrant further study. Full article

(This article belongs to the Special Issue Thoracic Cancers)

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15 pages, 1567 KiB

Open AccessReview

Applications of Melanin and Melanin-Like Nanoparticles in Cancer Therapy: A Review of Recent Advances

by Stefania Cuzzubbo and Antoine F. Carpentier

Cancers 2021, 13(6), 1463; https://doi.org/10.3390/cancers13061463 - 23 Mar 2021

Cited by 22 | Viewed by 3811

Abstract

Thanks to the growing knowledge about cancers and their interactions with the immune system, a huge number of therapeutic cancer vaccines have been developed in the past two decades. Despite encouraging results in pre-clinical models, cancer vaccines have not yet achieved significant clinical [...] Read more.

Thanks to the growing knowledge about cancers and their interactions with the immune system, a huge number of therapeutic cancer vaccines have been developed in the past two decades. Despite encouraging results in pre-clinical models, cancer vaccines have not yet achieved significant clinical efficacy. Several factors may contribute to such poor results, including the difficulty of triggering a strong immune response and the immunosuppressive tumor microenvironment. Many strategies are currently being explored. Different types of adjuvants have been incorporated into vaccine formulations to improve their efficacy, as cancer antigens are usually poorly immunogenic. Nanoparticle systems are promising tools as they act as carriers for antigens and can be surface-modified so that they specifically target antigen-presenting cells in lymph nodes. Bioinspired nanomaterials are ideal candidates thanks to their biocompatibility. Recently, melanin-based nanoparticles were reported to efficiently localize into draining lymphoid tissues and trigger immune responses against loaded antigens. In addition, by virtue of their photochemical properties, melanin-based nanoparticles can also play an immunomodulatory role to promote anti-cancer responses in the context of photothermal therapy. In this review, we discuss the above-mentioned properties of melanin, and summarize the promising results of the melanin-based cancer vaccines recently reported in preclinical models. Full article

(This article belongs to the Special Issue Biomaterials for Cancer Immunotherapy)

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14 pages, 1891 KiB

Open AccessArticle

Tracking the Progression of Triple Negative Mammary Tumors over Time by Chemometric Analysis of Urinary Volatile Organic Compounds

by Mark Woollam, Luqi Wang, Paul Grocki, Shengzhi Liu, Amanda P. Siegel, Maitri Kalra, John V. Goodpaster, Hiroki Yokota and Mangilal Agarwal

Cancers 2021, 13(6), 1462; https://doi.org/10.3390/cancers13061462 - 23 Mar 2021

Cited by 12 | Viewed by 2678

Abstract

Previous studies have shown that volatile organic compounds (VOCs) are potential biomarkers of breast cancer. An unanswered question is how urinary VOCs change over time as tumors progress. To explore this, BALB/c mice were injected with 4T1.2 triple negative murine tumor cells in [...] Read more.

Previous studies have shown that volatile organic compounds (VOCs) are potential biomarkers of breast cancer. An unanswered question is how urinary VOCs change over time as tumors progress. To explore this, BALB/c mice were injected with 4T1.2 triple negative murine tumor cells in the tibia. This typically causes tumor progression and osteolysis in 1–2 weeks. Samples were collected prior to tumor injection and from days 2–19. Samples were analyzed by headspace solid phase microextraction coupled to gas chromatography–mass spectrometry. Univariate analysis identified VOCs that were biomarkers for breast cancer; some of these varied significantly over time and others did not. Principal component analysis was used to distinguish Cancer (all Weeks) from Control and Cancer Week 1 from Cancer Week 3 with over 90% accuracy. Forward feature selection and linear discriminant analysis identified a unique panel that could identify tumor presence with 94% accuracy and distinguish progression (Cancer Week 1 from Cancer Week 3) with 97% accuracy. Principal component regression analysis also demonstrated that a VOC panel could predict number of days since tumor injection (R² = 0.71 and adjusted R² = 0.63). VOC biomarkers identified by these analyses were associated with metabolic pathways relevant to breast cancer. Full article

(This article belongs to the Special Issue Cancer Biomarkers in Body Fluids)

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12 pages, 2172 KiB

Open AccessArticle

Role of Repeat PET/CT Imaging in Head and Neck Cancer Following Initial Incomplete PET/CT Response to Chemoradiation

by Austin J. Iovoli, Mark K. Farrugia, Sung Jun Ma, Jon M. Chan, Michael R. Markiewicz, Ryan McSpadden, Kimberly E. Wooten, Vishal Gupta, Moni A. Kuriakose, Wesley L. Hicks, Jr. and Anurag K. Singh

Cancers 2021, 13(6), 1461; https://doi.org/10.3390/cancers13061461 - 23 Mar 2021

Cited by 9 | Viewed by 2351

Abstract

Despite waiting 13 weeks to perform a PET/CT scan after completion of chemoradiation for head and neck squamous cell carcinoma (HNSCC), equivocal findings are often found that make assessing treatment response difficult. This retrospective study examines the utility of a repeat PET/CT scan [...] Read more.

Despite waiting 13 weeks to perform a PET/CT scan after completion of chemoradiation for head and neck squamous cell carcinoma (HNSCC), equivocal findings are often found that make assessing treatment response difficult. This retrospective study examines the utility of a repeat PET/CT scan in HNSCC patients following an incomplete response on initial post-treatment imaging. For this cohort of 350 patients, initial PET/CT was performed 13 weeks after completion of treatment. For select patients with an incomplete response, repeat PET/CT was performed a median of 91 days later. Primary endpoints were conversion rate to complete response (CR) and the predictive values of repeat PET/CT imaging. Of 179 patients who did not have an initial complete response, 57 (32%) received a repeat PET/CT scan. Among these patients, 26 of 57 (48%) had a CR on repeat PET/CT. In patients with CR conversion, there were no cases of disease relapse. The sensitivity, specificity, PPV, and NPV for the repeat PET/CT for locoregional disease were 100%, 59%, 42%, and 100%. Repeat PET/CT in HNSCC patients with an incomplete post-treatment scan can be valuable in obtaining diagnostic clarity. This can reduce the incidence of unnecessary biopsies and neck dissections. Full article

(This article belongs to the Special Issue Advanced Oncologic Imaging)

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10 pages, 1259 KiB

Open AccessArticle

Three-Dimensional Radiological Assessment of Ablative Margins in Hepatocellular Carcinoma: Pilot Study of Overlay Fused CT/MRI Imaging with Automatic Registration

by Yasunori Minami, Tomohiro Minami, Kazuomi Ueshima, Yukinobu Yagyu, Masakatsu Tsurusaki, Takuya Okada, Masatoshi Hori, Masatoshi Kudo and Takamichi Murakami

Cancers 2021, 13(6), 1460; https://doi.org/10.3390/cancers13061460 - 23 Mar 2021

Cited by 5 | Viewed by 2193

Abstract

Background: We investigate the feasibility of image fusion application for ablative margin assessment in radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) and possible causes for a wrong initial evaluation of technical success through a side-by-side comparison. Methods: A total of 467 patients with [...] Read more.

Background: We investigate the feasibility of image fusion application for ablative margin assessment in radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) and possible causes for a wrong initial evaluation of technical success through a side-by-side comparison. Methods: A total of 467 patients with 1100 HCCs who underwent RFA were reviewed retrospectively. Seventeen patients developed local tumor progressions (LTPs) (median size, 1.0 cm) despite initial judgments of successful ablation referring to contrast-enhanced images obtained in the 24 h after ablation. The ablative margins were reevaluated radiologically by overlaying fused images pre- and post-ablation. Results: The initial categorizations of the 17 LTPs had been grade A (absolutely curative) (n = 5) and grade B (relatively curative) (n = 12); however, the reevaluation altered the response categories to eight grade C (margin-zero ablation) and nine grade D (existence of residual HCC). LTP occurred in eight patients re-graded as C within 4 to 30.3 months (median, 14.3) and in nine patients re-graded as D within 2.4 to 6.7 months (median, 4.2) (p = 0.006). Periablational hyperemia enhancements concealed all nine HCCs reevaluated as grade D. Conclusion: Side-by-side comparisons carry a risk of misleading diagnoses for LTP of HCC. Overlay fused imaging technology can be used to evaluate HCC ablative margin with high accuracy. Full article

(This article belongs to the Collection Advances in the Management of Hepatocellular Carcinoma)

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15 pages, 2325 KiB

Open AccessArticle

Image-Guided Adaptive Brachytherapy (IGABT) for Primary Vaginal Cancer: Results of the International Multicenter RetroEMBRAVE Cohort Study

by Henrike Westerveld, Maximilian P. Schmid, Remi A. Nout, Cyrus Chargari, Bradley R. Pieters, Carien L. Creutzberg, Alina Sturdza, Jacob C. Lindegaard, Zdenko van Kesteren, Renaud Mazeron, Nicole Nesvacil and Lars U. Fokdal

Cancers 2021, 13(6), 1459; https://doi.org/10.3390/cancers13061459 - 23 Mar 2021

Cited by 7 | Viewed by 2842

Abstract

Purpose: This study assessed outcomes following the nowadays standing treatment for primary vaginal cancer with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT) in a multicenter patient cohort. Methods: Patients treated with computer tomography (CT)–MRI-assisted-based IGABT were included. Retrospective data collection included patient, tumor and [...] Read more.

Purpose: This study assessed outcomes following the nowadays standing treatment for primary vaginal cancer with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT) in a multicenter patient cohort. Methods: Patients treated with computer tomography (CT)–MRI-assisted-based IGABT were included. Retrospective data collection included patient, tumor and treatment characteristics. Late morbidity was assessed by using the CTCAE 3.0 scale. Results: Five European centers included 148 consecutive patients, with a median age of 63 years. At a median follow-up of 29 months (IQR 25–57), two- and five-year local control were 86% and 83%; disease-free survival (DFS) was 73% and 66%, and overall survival (OS) was 79% and 68%, respectively. Crude incidences of ≥ grade-three urogenital, gastro-intestinal and vaginal morbidity was 8%, 3% and 8%, respectively. Lymph node metastasis was an independent prognostic factor for disease-free survival (DFS). Univariate analysis showed improved local control in patients with T2–T4 tumors if >80 Gy EQD2_α/β10 was delivered to the clinical target volume (CTV) at the time of brachytherapy. Conclusions: In this large retrospective multicenter study, IGABT for primary vaginal cancer resulted in a high local control with acceptable morbidity. These results compared favorably with two-dimensional (2D) radiograph-based brachytherapy and illustrate that IGABT plays an important role in the treatment of vaginal cancer. Full article

(This article belongs to the Special Issue Cancer Imaging: Current Practice and Future Perspectives)

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21 pages, 1993 KiB

Open AccessSystematic Review

Endocrine-Based Treatments in Clinically-Relevant Subgroups of Hormone Receptor-Positive/HER2-Negative Metastatic Breast Cancer: Systematic Review and Meta-Analysis

by Francesco Schettini, Mario Giuliano, Fabiola Giudici, Benedetta Conte, Pietro De Placido, Sergio Venturini, Carla Rognoni, Angelo Di Leo, Mariavittoria Locci, Guy Jerusalem, Lucia Del Mastro, Fabio Puglisi, PierFranco Conte, Michelino De Laurentiis, Lajos Pusztai, Mothaffar F. Rimawi, Rachel Schiff, Grazia Arpino, Sabino De Placido, Aleix Prat and Daniele Generali Show full author list Hide full author list

Cancers 2021, 13(6), 1458; https://doi.org/10.3390/cancers13061458 - 22 Mar 2021

Cited by 16 | Viewed by 3800

Abstract

A precise assessment of the efficacy of first-/second-line endocrine therapies (ET) ± target therapies (TT) in clinically-relevant subgroups of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision-making, we thus conducted [...] Read more.

A precise assessment of the efficacy of first-/second-line endocrine therapies (ET) ± target therapies (TT) in clinically-relevant subgroups of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision-making, we thus conducted a systematic literature search to identify all first-/second-line phase II/III randomized clinical trials (RCT) of currently approved or most promising ET ± TT. Then, we performed a meta-analysis to assess progression-free (PFS) and/or overall survival (OS) benefit in several clinically-relevant prespecified subgroups. Thirty-five RCT were included (17,595 patients). Pooled results show significant reductions in the risk of relapse or death of 26–41% and 12–27%, respectively, depending on the clinical subgroup. Combination strategies proved to be more effective than single-agent ET (PFS hazard ratio (HR) range for combinations: 0.60–0.65 vs. HR range for single agent ET: 0.59–1.37; OS HR range for combinations: 0.74–0.87 vs. HR range for single agent ET: 0.68–0.98), with CDK4/6-inhibitors(i) + ET being the most effective regimen. Single agent ET showed comparable efficacy with ET+TT combinations in non-visceral (p = 0.63) and endocrine sensitive disease (p = 0.79), while mTORi-based combinations proved to be a valid therapeutic option in endocrine-resistant tumors, as well as PI3Ki + ET in PIK3CA-mutant tumors. These results strengthen international treatment guidelines and can aid therapeutic decision-making. Full article

(This article belongs to the Special Issue The Renaissance of CDK Inhibition in Cancer Therapy)

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7 pages, 209 KiB

Open AccessOpinion

Unintended Regulatory Caused Early Death—A Difficult Endpoint in Cancer Patient Care and Treatment

by Wolfgang E. Berdel

Cancers 2021, 13(6), 1457; https://doi.org/10.3390/cancers13061457 - 22 Mar 2021

Cited by 2 | Viewed by 1419

Abstract

The pharmacological armory against cancer has been growing, with many new drugs approved. The Good Clinical Practice (GCP)-based Clinical Trials Directive was adopted in the EU in 2001, with the important objectives of achieving better patient safety and improved quality of clinical trial [...] Read more.

The pharmacological armory against cancer has been growing, with many new drugs approved. The Good Clinical Practice (GCP)-based Clinical Trials Directive was adopted in the EU in 2001, with the important objectives of achieving better patient safety and improved quality of clinical trial conduct. However, clinical experience with the implementation of the regulation raises the question as to whether aspects of this regulatory framework can cause harm to some patients. This question also arises in daily clinical cancer patient care when the time between the publication of pivotal study results and their approval, and details of post-approval regulations, are scrutinized. Clinical observations, provocatively summarized as “unintended regulatory caused early death”, are discussed. Full article

13 pages, 829 KiB

Open AccessArticle

Low MicroRNA-19b Expression Shows a Promising Clinical Impact in Locally Advanced Rectal Cancer

by Jaime Rubio, Ion Cristóbal, Andrea Santos, Cristina Caramés, Melani Luque, Marta Sanz-Alvarez, Sandra Zazo, Juan Madoz-Gúrpide, Federico Rojo and Jesús García-Foncillas

Cancers 2021, 13(6), 1456; https://doi.org/10.3390/cancers13061456 - 22 Mar 2021

Cited by 12 | Viewed by 1728

Abstract

The standard treatment for patients with locally advanced colorectal cancer (LARC) is neoadjuvant 5-fluorouracil (5-FU) based chemoradiotherapy (CRT) followed by surgical mesorectal excision. However, the lack of response to this preoperative treatment strongly compromises patient outcomes and leads to surgical delays and undesired [...] Read more.

The standard treatment for patients with locally advanced colorectal cancer (LARC) is neoadjuvant 5-fluorouracil (5-FU) based chemoradiotherapy (CRT) followed by surgical mesorectal excision. However, the lack of response to this preoperative treatment strongly compromises patient outcomes and leads to surgical delays and undesired toxicities in those non-responder cases. Thus, the identification of effective and robust biomarkers to predict response to preoperative CRT represents an urgent need in the current clinical management of LARC. The oncomiR microRNA-19b (miR-19b) has been reported to functionally play oncogenic roles in colorectal cancer (CRC) cells as well as regulate 5-FU sensitivity and determine outcome in CRC patients. However, its clinical impact in LARC has not been previously investigated. Here, we show that miR-19b deregulation is a common event in this disease, and its decreased expression significantly associates with lower tumor size after CRT (p = 0.003), early pathological stage (p = 0.003), and absence of recurrence (p = 0.001) in LARC patients. Interestingly, low miR-19b expression shows a predictive value of better response to neoajuvant CRT (p < 0.001), and the subgroup of LARC patients with low miR-19b levels have a markedly longer overall (p = 0.003) and event-free survival (p = 0.023). Finally, multivariate analyses determined that miR-19b independently predicts both patient outcome and response to preoperative CRT, highlighting its potential clinical usefulness in the management of LARC patients. Full article

(This article belongs to the Special Issue microRNAs in Colorectal Cancer)

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Cancers, Volume 13, Issue 6 (March-2 2021) – 299 articles

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