Cancers

15 pages, 1055 KiB

Open AccessArticle

Characteristics and Outcomes of Adult Patients in the PETHEMA Registry with Relapsed or Refractory FLT3-ITD Mutation-Positive Acute Myeloid Leukemia

by David Martínez-Cuadrón, Josefina Serrano, José Mariz, Cristina Gil, Mar Tormo, Pilar Martínez-Sánchez, Eduardo Rodríguez-Arbolí, Raimundo García-Boyero, Carlos Rodríguez-Medina, Carmen Martínez-Chamorro, Marta Polo, Juan Bergua, Eliana Aguiar, María L. Amigo, Pilar Herrera, Juan M. Alonso-Domínguez, Teresa Bernal, Ana Espadana, María J. Sayas, Lorenzo Algarra, María B. Vidriales, Graça Vasconcelos, Susana Vives, Manuel M. Pérez-Encinas, Aurelio López, Víctor Noriega, María García-Fortes, María C. Chillón, Juan I. Rodríguez-Gutiérrez, María J. Calasanz, Jorge Labrador, Juan A. López, Blanca Boluda, Rebeca Rodríguez-Veiga, Joaquín Martínez-López, Eva Barragán, Miguel A. Sanz, Pau Montesinos and on behalf of the PETHEMA Group Show full author list Hide full author list

Cancers 2022, 14(11), 2817; https://doi.org/10.3390/cancers14112817 - 06 Jun 2022

Cited by 1 | Viewed by 2300

Abstract

This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 [...] Read more.

This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p < 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant. Full article

(This article belongs to the Collection Acute Myeloid Leukemia (AML))

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16 pages, 4943 KiB

Open AccessArticle

Mutations in KMT2C, BCOR and KDM5C Predict Response to Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer

by Dingxie Liu, Jonathan Benzaquen, Luc G. T. Morris, Marius Ilié and Paul Hofman

Cancers 2022, 14(11), 2816; https://doi.org/10.3390/cancers14112816 - 06 Jun 2022

Cited by 5 | Viewed by 2975

Abstract

Efficient predictive biomarkers are urgently needed to identify non-small cell lung cancer (NSCLC) patients who could benefit from immune checkpoint blockade (ICB) therapy. Since chromatin remodeling is required for DNA repair process, we asked whether mutations in chromatin remodeling genes could increase tumor [...] Read more.

Efficient predictive biomarkers are urgently needed to identify non-small cell lung cancer (NSCLC) patients who could benefit from immune checkpoint blockade (ICB) therapy. Since chromatin remodeling is required for DNA repair process, we asked whether mutations in chromatin remodeling genes could increase tumor mutational burden (TMB) and predict response to ICB therapy in NSCLC. Analysis of seven ICB-treated NSCLC cohorts revealed that mutations of three chromatin remodeling-related genes, including KMT2C, BCOR and KDM5C, were significantly associated with ICB response, and combined mutations of these three genes further enhance this association. NSCLC patients with KMT2C/BCOR/KDM5C mutations had comparable clinical outcomes to TMB-high patients in terms of objective response rate, durable clinical benefit and overall survival. Although KMT2C/BCOR/KDM5C mutations were positively correlated with TMB levels in NSCLC, the association of this mutation with better ICB response was independent of tumor TMB and programmed death-ligand 1 (PD-L1) level, and combination of KMT2C/BCOR/KDM5C mutations with TMB or PD-L1 further improve the prediction of ICB response in NSCLC patients. Cancer Genome Atlas (TCGA) pan-cancer analysis suggested that the association of KMT2C/BCOR/KDM5C mutations with ICB response observed here might not result from DNA repair defects. In conclusion, our data indicate that KMT2C/BCOR/KDM5C mutation has the potential to serve as a predictive biomarker, alone or combined with PD-L1 expression or TMB, for ICB therapy in NSCLC. Full article

(This article belongs to the Special Issue Understanding New Therapeutic Options and Promising Predictive Biomarkers for Lung Cancer Patients. A Selection of Papers from the Third Joint Meeting on Lung Cancer of the FHU OncoAge (Nice, France) and the MD Anderson Cancer Center (Houston, TX, USA))

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14 pages, 1742 KiB

Open AccessArticle

Simultaneous and Spatially-Resolved Analysis of T-Lymphocytes, Macrophages and PD-L1 Immune Checkpoint in Rare Cancers

by Karina Cereceda, Nicolas Bravo, Roddy Jorquera, Roxana González-Stegmaier and Franz Villarroel-Espíndola

Cancers 2022, 14(11), 2815; https://doi.org/10.3390/cancers14112815 - 06 Jun 2022

Cited by 2 | Viewed by 2085

Abstract

Penile, vulvar and anal neoplasms show an incidence lower than 0.5% of the population per year and therefore can be considered as rare cancers but with a dramatic impact on quality of life and survival. This work describes the experience of a Chilean [...] Read more.

Penile, vulvar and anal neoplasms show an incidence lower than 0.5% of the population per year and therefore can be considered as rare cancers but with a dramatic impact on quality of life and survival. This work describes the experience of a Chilean cancer center using multiplexed immunofluorescence to study a case series of four penile cancers, two anal cancers and one vulvar cancer and simultaneous detection of CD8, CD68, PD-L1, Cytokeratin and Ki-67 in FFPE samples. Fluorescent image analyses were performed using open sources for automated tissue segmentation and cell phenotyping. Our results showed an objective and reliable counting of objects with a single or combined labeling or within a specific tissue compartment. The variability was below 10%, and the correlation between analytical events was 0.92–0.97. Critical cell phenotypes, such as TILs, PD-L1+ or proliferative tumor cells were detected in a supervised and unsupervised manner with a limit of detection of less than 1% of relative abundance. Finally, the observed diversity and abundance of the different cell phenotypes within the tumor microenvironment for the three studied tumor types confirmed that our methodology is useful and robust to be applicable for many other solid tumors. Full article

(This article belongs to the Collection Imaging Biomarker in Oncology)

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Graphical abstract

16 pages, 1203 KiB

Open AccessSystematic Review

Novel Pharmacological Treatment Options in Pediatric Glioblastoma—A Systematic Review

by Johanna Wyss, Nicole Alexandra Frank, Jehuda Soleman and Katrin Scheinemann

Cancers 2022, 14(11), 2814; https://doi.org/10.3390/cancers14112814 - 06 Jun 2022

Cited by 5 | Viewed by 2526

Abstract

Background: Pediatric glioblastoma (GBM) is an aggressive central nervous system tumor in children that has dismal prognosis. Standard of care is surgery with subsequent irradiation and temozolomide. We aimed to outline currently available data on novel pharmacological treatments for pediatric GBM. Methods: We [...] Read more.

Background: Pediatric glioblastoma (GBM) is an aggressive central nervous system tumor in children that has dismal prognosis. Standard of care is surgery with subsequent irradiation and temozolomide. We aimed to outline currently available data on novel pharmacological treatments for pediatric GBM. Methods: We conducted a systematic literature search in PubMed and Embase, including reports published in English from 2010 to 2021. We included randomized trials, cohort studies and case series. Phase I trials were not analyzed. We followed PRISMA guidelines, assessed the quality of the eligible reports using the Newcastle-Ottawa scale (NOS) and the RoB-2 tool and registered the protocol on PROSPERO. Results: We included 6 out of 1122 screened reports. All six selected reports were prospective, multicenter phase II trials (five single-arm and one randomized controlled trial). None of the investigated novel treatment modalities showed any benefit regarding overall or progression free survival. Conclusions: To date, the role of pharmacological approaches regarding pediatric GBM remains unclear, since no novel treatment approach could provide a significant impact on overall or progression free survival. Further research should aim to combine different treatment strategies in large international multicenter trials with central comprehensive diagnostics regarding subgrouping. These novel treatment approaches should include targeted and immunotherapeutic treatments, potentially leading to a more successful outcome. Full article

(This article belongs to the Special Issue Recent Advances in Drug Therapy for Glioblastoma)

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12 pages, 3978 KiB

Open AccessCommunication

EPA Modulates KLK Genes via miR-378: A Potential Therapy in Prostate Cancer

by Kai-Jie Yu, De-Yi Ji, Ming-Li Hsieh, Cheng-Keng Chuang, See-Tong Pang and Wen-Hui Weng

Cancers 2022, 14(11), 2813; https://doi.org/10.3390/cancers14112813 - 06 Jun 2022

Viewed by 1811

Abstract

It is known that miRNA-378a-3p (miR-378) could be induced by eicosapentaenoic acid (EPA), an omega-3 fatty acid. Herein, we first demonstrated how miR-378 exerts anti-prostate cancer (PCa) actions by influencing multiple target genes, including KLK2, KLK4, KLK6, and KLK14, which are implicated in [...] Read more.

It is known that miRNA-378a-3p (miR-378) could be induced by eicosapentaenoic acid (EPA), an omega-3 fatty acid. Herein, we first demonstrated how miR-378 exerts anti-prostate cancer (PCa) actions by influencing multiple target genes, including KLK2, KLK4, KLK6, and KLK14, which are implicated in PCa development, cell proliferation, and cell survival. Furthermore, these genes also correlate with androgen and mTOR signaling transduction, and are considered pivotal pathways for the onset and progression of PCa. In total, four PCa cell lines and eight pairing tissues (tumor vs. normal) from clinical PCa patients were included in the current study. The results showed high significance after EPA induced tumor cells containing higher expression levels of miR-378, and led the PCa cells having low cell viabilities, and they progressed to apoptosis when compared with normal prostate cells (p < 0.001). The findings indicated that EPA might become a potential therapy for PCa, especially because it is derived from the components of natural fish oil; it may prove to be a great help for solving the problem of castration-resistant prostate cancer (CRPC). Full article

(This article belongs to the Special Issue Actual Aspects of Prostate Cancer Treatment—an Interdisciplinary Approach)

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13 pages, 1833 KiB

Open AccessArticle

Cancer-Associated Fibroblasts Confer Gemcitabine Resistance to Pancreatic Cancer Cells through PTEN-Targeting miRNAs in Exosomes

by Katherine E. Richards, Weikun Xiao, Reginald Hill and on behalf of the USC Pancreas Research Team

Cancers 2022, 14(11), 2812; https://doi.org/10.3390/cancers14112812 - 06 Jun 2022

Cited by 22 | Viewed by 2708

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-related death in the United States. Even though the poor prognosis of PDAC is often attributed to late diagnosis, patients with an early diagnosis who undergo tumor resection and adjuvant chemotherapy still [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-related death in the United States. Even though the poor prognosis of PDAC is often attributed to late diagnosis, patients with an early diagnosis who undergo tumor resection and adjuvant chemotherapy still show tumor recurrence, highlighting a need to develop therapies which can overcome chemoresistance. Chemoresistance has been linked to the high expression of microRNAs (miRs), such as miR-21, within tumor cells. Tumor cells can collect miRs through the uptake of miR-containing lipid extracellular vesicles called exosomes. These exosomes are secreted in high numbers from cancer-associated fibroblasts (CAFs) within the tumor microenvironment during gemcitabine treatment and can contribute to cell proliferation and chemoresistance. Here, we show a novel mechanism in which CAF-derived exosomes may promote proliferation and chemoresistance, in part, through suppression of the tumor suppressor PTEN. We identified five microRNAs: miR-21, miR-181a, miR-221, miR-222, and miR-92a, that significantly increased in number within the CAF exosomes secreted during gemcitabine treatment which target PTEN. Furthermore, we found that CAF exosomes suppressed PTEN expression in vitro and that treatment with the exosome inhibitor GW4869 blocked PTEN suppression in vivo. Collectively, these findings highlight a mechanism through which the PTEN expression loss, often seen in PDAC, may be attained and lend support to investigations into the use of exosome inhibitors as potential therapeutics to improve the effectiveness of chemotherapy. Full article

(This article belongs to the Section Molecular Cancer Biology)

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19 pages, 793 KiB

Open AccessReview

Cellular Carcinogenesis: Role of Polarized Macrophages in Cancer Initiation

by Ram Babu Undi, Adrian Filiberti, Naushad Ali and Mark M. Huycke

Cancers 2022, 14(11), 2811; https://doi.org/10.3390/cancers14112811 - 06 Jun 2022

Cited by 4 | Viewed by 2658

Abstract

Inflammation is an essential hallmark of cancer. Macrophages are key innate immune effector cells in chronic inflammation, parainflammation, and inflammaging. Parainflammation is a form of subclinical inflammation associated with a persistent DNA damage response. Inflammaging represents low-grade inflammation due to the dysregulation of [...] Read more.

Inflammation is an essential hallmark of cancer. Macrophages are key innate immune effector cells in chronic inflammation, parainflammation, and inflammaging. Parainflammation is a form of subclinical inflammation associated with a persistent DNA damage response. Inflammaging represents low-grade inflammation due to the dysregulation of innate and adaptive immune responses that occur with aging. Whether induced by infection, injury, or aging, immune dysregulation and chronic macrophage polarization contributes to cancer initiation through the production of proinflammatory chemokines/cytokines and genotoxins and by modulating immune surveillance. This review presents pre-clinical and clinical evidence for polarized macrophages as endogenous cellular carcinogens in the context of chronic inflammation, parainflammation, and inflammaging. Emerging strategies for cancer prevention, including small molecule inhibitors and probiotic approaches, that target macrophage function and phenotype are also discussed. Full article

(This article belongs to the Special Issue Tumor, Tumor-Associated Macrophages, and Therapy)

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13 pages, 2559 KiB

Open AccessArticle

Multiparametric Phenotyping of Circulating Tumor Cells for Analysis of Therapeutic Targets, Oncogenic Signaling Pathways and DNA Repair Markers

by Stephanie Staudte, Konrad Klinghammer, Philipp Sebastian Jurmeister, Paul Jank, Jens-Uwe Blohmer, Sandra Liebs, Peter Rhein, Anja E. Hauser and Ingeborg Tinhofer

Cancers 2022, 14(11), 2810; https://doi.org/10.3390/cancers14112810 - 06 Jun 2022

Cited by 5 | Viewed by 2437

Abstract

Detection of circulating tumor cells (CTCs) has been established as an independent prognostic marker in solid cancer. Multiparametric phenotyping of CTCs could expand the area of application for this liquid biomarker. We evaluated the Amnis^® brand ImageStream^®X MkII (ISX) (Luminex, [...] Read more.

Detection of circulating tumor cells (CTCs) has been established as an independent prognostic marker in solid cancer. Multiparametric phenotyping of CTCs could expand the area of application for this liquid biomarker. We evaluated the Amnis^® brand ImageStream^®X MkII (ISX) (Luminex, Austin, TX, USA) imaging flow cytometer for its suitability for protein expression analysis and monitoring of treatment effects in CTCs. This was carried out using blood samples from patients with head and neck squamous cell carcinoma (n = 16) and breast cancer (n = 8). A protocol for negative enrichment and staining of CTCs was established, allowing quantitative analysis of the therapeutic targets PD–L1 and phosphorylated EGFR (phospho–EGFR), and the treatment response marker γH2AX as an indicator of radiation–induced DNA damage. Spiking experiments revealed a sensitivity of 73% and a specificity of 100% at a cut–off value of ≥3 CTCs, and thus confirmed the suitability of the ISX-based protocol to detect phospho–EGFR and γH2AX foci in CTCs. Analysis of PD–L1/–L2 in both spiked and patient blood samples further showed that assessment of heterogeneity in protein expression within the CTC population was possible. Further validation of the diagnostic potential of this ISX protocol for multiparametric CTC analysis in larger clinical cohorts is warranted. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)

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Graphical abstract

16 pages, 613 KiB

Open AccessReview

Management of Older Adults with Locally Advanced Head and Neck Cancer

by Daniel R. Dickstein, Eric J. Lehrer, Kristin Hsieh, Alexandra Hotca, Brianna M. Jones, Ann Powers, Sonam Sharma, Jerry Liu, Vishal Gupta, Loren Mell, Zain Husain, Diana Kirke, Krzysztof Misiukiewicz, Marshall Posner, Eric Genden and Richard L. Bakst

Cancers 2022, 14(11), 2809; https://doi.org/10.3390/cancers14112809 - 05 Jun 2022

Cited by 8 | Viewed by 2462

Abstract

Thirty percent of patients with head and neck squamous cell carcinoma (HNSCC) are at least 70 years of age. This number continues to rise as life expectancy continues to increase. Still, older adults with HNSCC remain underrepresented in clinical trials, resulting in ambiguity [...] Read more.

Thirty percent of patients with head and neck squamous cell carcinoma (HNSCC) are at least 70 years of age. This number continues to rise as life expectancy continues to increase. Still, older adults with HNSCC remain underrepresented in clinical trials, resulting in ambiguity on optimal management. Older adults are a complex patient population, often requiring increased support due to issues relating to functional and performance status, medical comorbidities, and medication management. Furthermore, in older adults with HNSCC, many of these conditions are independently associated with increased toxicity and worse outcomes. Toxicity in the older adult remains difficult to predict and to understand, and as treatment decisions are based on treatment tolerability, it is essential to understand the toxicities and how to minimize them. Novel predictive scores are being developed specifically for older adults with HNSCC to understand toxicity and to assist in personalized treatment decisions. There are clinical trials presently underway that are investigating shortened radiation courses and novel, less toxic systemic treatments in this population. In the forthcoming sections, we provide a detailed overview of the clinical data, treatment paradigms, and considerations in this population. This review provides a comprehensive overview of existing clinical data and clinical considerations in the older adult head and neck cancer population. Additionally, we provide a detailed overview of pertinent current and ongoing clinical trials, as well as future areas for investigation. Full article

(This article belongs to the Special Issue Chemoradiotherapy for Head-and-Neck Cancer in the Elderly)

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20 pages, 3418 KiB

Open AccessArticle

Immunoprotecting Effects of Exercise Program against Ovarian Cancer: A Single-Blind, Randomized Controlled Trial

by Jong-Kyun Lee, Sihwa Park and Yong-Seok Jee

Cancers 2022, 14(11), 2808; https://doi.org/10.3390/cancers14112808 - 05 Jun 2022

Cited by 3 | Viewed by 2380

Abstract

Exercise is known to help the immune function of cancer survivors after cancer cell removal, but there is little information about the effect of exercise on ovarian cancer survivors. We conducted this study to investigate the effects of exercise training on the physical [...] Read more.

Exercise is known to help the immune function of cancer survivors after cancer cell removal, but there is little information about the effect of exercise on ovarian cancer survivors. We conducted this study to investigate the effects of exercise training on the physical fitness and innate immunity of ovarian cancer survivors (OCS). Twenty-seven OCS between forty-two and sixty-one years of age volunteered for this study. The participants were divided into a control group (COG, n = 15) and an exercise group (EXG, n = 12). The mean (SD) age was 51.07 (5.67) years, and the mean post-operation period was 45.96 (5.88) months. EXG participated in regular exercise training 6 days a week for 12 weeks. Body weight, fat mass, and body mass index of EXE were significantly decreased compared with those of COG. The muscle mass in EXE was increased compared to that of COG. Physical fitness factors showed positive changes in EXG compared to COG. We found that exercise training enhanced lymphocyte and neutrophil counts of leucocytes and total natural killer (NK) and natural killer T (NKT) cell counts of lymphocytes through improved body composition and physical fitness after 12 weeks. Moreover, we found that improved innate immune cells through the exercise program were achieved through an increase in NKG₂D+NK receptors and a decrease in KIR₂DL₃+NK receptors in OCS. Full article

(This article belongs to the Special Issue Lifestyle Modifications and Survival of Cancer Patients)

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24 pages, 4934 KiB

Open AccessArticle

SCAMP3 Regulates EGFR and Promotes Proliferation and Migration of Triple-Negative Breast Cancer Cells through the Modulation of AKT, ERK, and STAT3 Signaling Pathways

by Ariana Acevedo-Díaz, Beatriz M. Morales-Cabán, Astrid Zayas-Santiago, Michelle M. Martínez-Montemayor and Ivette J. Suárez-Arroyo

Cancers 2022, 14(11), 2807; https://doi.org/10.3390/cancers14112807 - 05 Jun 2022

Cited by 6 | Viewed by 2824

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive, metastatic, and lethal breast cancer subtype. To improve the survival of TNBC patients, it is essential to explore new signaling pathways for the further development of effective drugs. This study aims to investigate the role [...] Read more.

Triple-negative breast cancer (TNBC) is the most aggressive, metastatic, and lethal breast cancer subtype. To improve the survival of TNBC patients, it is essential to explore new signaling pathways for the further development of effective drugs. This study aims to investigate the role of the secretory carrier membrane protein 3 (SCAMP3) in TNBC and its association with the epidermal growth factor receptor (EGFR). Through an internalization assay, we demonstrated that SCAMP3 colocalizes and redistributes EGFR from the cytoplasm to the perinucleus. Furthermore, SCAMP3 knockout decreased proliferation, colony and tumorsphere formation, cell migration, and invasion of TNBC cells. Immunoblots and degradation assays showed that SCAMP3 regulates EGFR through its degradation. In addition, SCAMP3 modulates AKT, ERK, and STAT3 signaling pathways. TNBC xenograft models showed that SCAMP3 depletion delayed tumor cell proliferation at the beginning of tumor development and modulated the expression of genes from the PDGF pathway. Additionally, analysis of TCGA data revealed elevated SCAMP3 expression in breast cancer tumors. Finally, patients with TNBC with high expression of SCAMP3 showed decreased RFS and DMFS. Our findings indicate that SCAMP3 could contribute to TNBC development through the regulation of multiple pathways and has the potential to be a target for breast cancer therapy. Full article

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24 pages, 967 KiB

Open AccessEditor’s ChoiceReview

New Therapeutic Strategies for Adult Acute Myeloid Leukemia

by Hiroto Ishii and Shingo Yano

Cancers 2022, 14(11), 2806; https://doi.org/10.3390/cancers14112806 - 05 Jun 2022

Cited by 15 | Viewed by 5288

Abstract

Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy. Chromosomal and genetic analyses are important for the diagnosis and prognosis of AML. Some patients experience relapse or have refractory disease, despite conventional cytotoxic chemotherapies and allogeneic transplantation, and a variety of new [...] Read more.

Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy. Chromosomal and genetic analyses are important for the diagnosis and prognosis of AML. Some patients experience relapse or have refractory disease, despite conventional cytotoxic chemotherapies and allogeneic transplantation, and a variety of new agents and treatment strategies have emerged. After over 20 years during which no new drugs became available for the treatment of AML, the CD33-targeting antibody–drug conjugate gemtuzumab ozogamicin was developed. This is currently used in combination with standard chemotherapy or as a single agent. CPX-351, a liposomal formulation containing daunorubicin and cytarabine, has become one of the standard treatments for secondary AML in the elderly. FMS-like tyrosine kinase 3 (FLT3) inhibitors and isocitrate dehydrogenase 1/2 (IDH 1/2) inhibitors are mainly used for AML patients with actionable mutations. In addition to hypomethylating agents and venetoclax, a B-cell lymphoma-2 inhibitor is used in frail patients with newly diagnosed AML. Recently, tumor protein p53 inhibitors, cyclin-dependent kinase inhibitors, and NEDD8 E1-activating enzyme inhibitors have been gaining attention, and a suitable strategy for the use of these drugs is required. Antibody drugs targeting cell-surface markers and immunotherapies, such as antibody–drug conjugates and chimeric antigen receptor T-cell therapy, have also been developed for AML. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)

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28 pages, 7042 KiB

Open AccessArticle

Prediction of Adrenocortical Carcinoma Relapse and Prognosis with a Set of Novel Multigene Panels

by Xiaozeng Lin, Yan Gu, Yingying Su, Ying Dong, Pierre Major, Anil Kapoor and Damu Tang

Cancers 2022, 14(11), 2805; https://doi.org/10.3390/cancers14112805 - 05 Jun 2022

Cited by 4 | Viewed by 2108

Abstract

Effective assessment of adrenocortical carcinoma (ACC) prognosis is critical in patient management. We report four novel and robust prognostic multigene panels. Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B predict ACC relapse at area under the curve (AUC) of 0.89, 0.79, 0.78, and 0.80, respectively, and [...] Read more.

Effective assessment of adrenocortical carcinoma (ACC) prognosis is critical in patient management. We report four novel and robust prognostic multigene panels. Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B predict ACC relapse at area under the curve (AUC) of 0.89, 0.79, 0.78, and 0.80, respectively, and fatality at AUC of 0.91, 0.88, 0.85, and 0.87, respectively. Among their 33 component genes, 31 are novel. They could be differentially expressed in ACCs from normal tissues, tumors with different severity (stages and lymph node metastasis), ACCs with TP53 mutations, and tumors with differentially expressed immune checkpoints (CTLA4, PD1, TGFBR1, and others). All panels correlate with reductions of ACC-associated CD8+ and/or NK cells. Furthermore, we provide the first evidence for the association of mesenchymal stem cells (MSCs) with ACC relapse (p = 2 × 10⁻⁶) and prognosis (p = 2 × 10⁻⁸). Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B correlate with MSC (spearman r ≥ 0.53, p ≤ 1.38 × 10⁻⁵). Sig27var25 and SigIQvar8 were derived from a prostate cancer (PC) and clear cell renal cell carcinoma (ccRCC) multigene signature, respectively; SigCmbnvar5 and SigCmbn_B are combinations of both panels, revealing close relationships of ACC with PC and ccRCC. The origin of these four panels from PC and ccRCC favors their prognostic potential towards ACC. Full article

(This article belongs to the Special Issue Innovations in Cancer Diagnostic Evaluation and Biomarker Detection)

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18 pages, 1354 KiB

Open AccessReview

Insights into the Possible Molecular Mechanisms of Resistance to PARP Inhibitors

by Claudia Piombino and Laura Cortesi

Cancers 2022, 14(11), 2804; https://doi.org/10.3390/cancers14112804 - 05 Jun 2022

Cited by 5 | Viewed by 3264

Abstract

PARP1 enzyme plays an important role in DNA damage recognition and signalling. PARP inhibitors are approved in breast, ovarian, pancreatic, and prostate cancers harbouring a pathogenic variant in BRCA1 or BRCA2, where PARP1 inhibition results mainly in synthetic lethality in cells with [...] Read more.

PARP1 enzyme plays an important role in DNA damage recognition and signalling. PARP inhibitors are approved in breast, ovarian, pancreatic, and prostate cancers harbouring a pathogenic variant in BRCA1 or BRCA2, where PARP1 inhibition results mainly in synthetic lethality in cells with impaired homologous recombination. However, the increasingly wide use of PARP inhibitors in clinical practice has highlighted the problem of resistance to therapy. Several different mechanisms of resistance have been proposed, although only the acquisition of secondary mutations in BRCA1/2 has been clinically proved. The aim of this review is to outline the key molecular findings that could explain the development of primary or secondary resistance to PARP inhibitors, analysing the complex interactions between PARP1, cell cycle regulation, PI3K/AKT signalling, response to stress replication, homologous recombination, and other DNA damage repair pathways in the setting of BRCA1/2 mutated cancers. Full article

(This article belongs to the Special Issue A Deeper Dive into Signaling Pathways in Cancers)

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11 pages, 7693 KiB

Open AccessArticle

Glioblastoma Stem-like Cell Detection Using Perfusion and Diffusion MRI

by Tanguy Duval, Jean-Albert Lotterie, Anthony Lemarie, Caroline Delmas, Fatima Tensaouti, Elizabeth Cohen-Jonathan Moyal and Vincent Lubrano

Cancers 2022, 14(11), 2803; https://doi.org/10.3390/cancers14112803 - 04 Jun 2022

Cited by 3 | Viewed by 2030

Abstract

Purpose: With current gold standard treatment, which associates maximum safe surgery and chemo-radiation, the large majority of glioblastoma patients relapse within a year in the peritumoral non contrast-enhanced region (NCE). A subpopulation of glioblastoma stem-like cells (GSC) are known to be particularly radio-resistant [...] Read more.

Purpose: With current gold standard treatment, which associates maximum safe surgery and chemo-radiation, the large majority of glioblastoma patients relapse within a year in the peritumoral non contrast-enhanced region (NCE). A subpopulation of glioblastoma stem-like cells (GSC) are known to be particularly radio-resistant and aggressive, and are thus suspected to be the cause of these relapses. Previous studies have shown that their distribution is heterogeneous in the NCE compartment, but no study exists on the sensitivity of medical imaging for localizing these cells. In this work, we propose to study the magnetic resonance (MR) signature of these infiltrative cells. Methods: In the context of a clinical trial on 16 glioblastoma patients, relative Cerebral Blood Volume (rCBV) and Apparent Diffusion Coefficient (ADC) were measured in a preoperative diffusion and perfusion MRI examination. During surgery, two biopsies were extracted using image-guidance in the hyperintensities-FLAIR region. GSC subpopulation was quantified within the biopsies and then cultivated in selective conditions to determine their density and aggressiveness. Results: Low ADC was found to be a good predictor of the time to GSC neurospheres formation in vitro. In addition, GSCs were found in higher concentrations in areas with high rCBV. Conclusions: This study confirms that GSCs have a critical role for glioblastoma aggressiveness and supports the idea that peritumoral sites with low ADC or high rCBV should be preferably removed when possible during surgery and targeted by radiotherapy. Full article

(This article belongs to the Section Cancer Biomarkers)

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7 pages, 815 KiB

Open AccessArticle

Interobserver Reliability and the Sigmoid Takeoff—An Interobserver Study

by Malene Roland Vils Pedersen, Peter Obel Otto, Chris Vagn-Hansen, Torben Sørensen and Søren Rafael Rafaelsen

Cancers 2022, 14(11), 2802; https://doi.org/10.3390/cancers14112802 - 04 Jun 2022

Cited by 1 | Viewed by 1768

Abstract

Background: Colorectal cancer is the second most common cancer worldwide. The sigmoid takeoff is the landmark where the colon sigmoid curves toward the sacrum viewed from sagittal magnetic resonance imaging (MRI). The purpose of this study was to assess interobserver variability in the [...] Read more.

Background: Colorectal cancer is the second most common cancer worldwide. The sigmoid takeoff is the landmark where the colon sigmoid curves toward the sacrum viewed from sagittal magnetic resonance imaging (MRI). The purpose of this study was to assess interobserver variability in the assessment of the anal verge and anorectal junction in patients diagnosed with rectal cancer on magnetic resonance imaging (MRI). Materials and Methods: The rectal MRI examinations were performed using a 1.5- or 3.0-tesla unit using an anterior coil and a standard scan protocol. Two senior radiologists assessed MRI scans from patients under investigation for rectal cancer. The two observers assessed the anal verge and takeoff in cm independently. Difference in agreement between the observers were evaluated using intraclass correlation (ICC) and graphically by Bland–Altman plots. Results: The study population (n = 122) included 68 (55.7%) female and 54 (44.3%) male subjects. The overall median age was 69.5 years (range 39–95 years). There was perfect agreement between the two observers when defining rectal tumor above or below the takeoff landmark. The reliability of measuring the distance from the anal verge to the sigmoid takeoff was 0.712. Conclusion: Overall, the study found a moderate reliability in assessing the location of the sigmoid takeoff, with a low difference in the distance measuring, as well as a good consensus concerning the determination of tumors in relation to the sigmoid takeoff. Routine implementation of this information within the report seems reasonable. Full article

(This article belongs to the Special Issue A Model for Improved Care of Patients with Colorectal Cancer – Experience from a Center of Clinical Excellence)

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11 pages, 272 KiB

Open AccessArticle

In-Depth Characterisation of Real-World Advanced Melanoma Patients Receiving Immunotherapies and/or Targeted Therapies: A Case Series

by Saira Sanjida, Brigid Betz-Stablein, Victoria Atkinson, Monika Janda, Ramez Barsoum, Harrison Aljian Edwards, Frank Chiu, My Co Tran, H Peter Soyer and Helmut Schaider

Cancers 2022, 14(11), 2801; https://doi.org/10.3390/cancers14112801 - 04 Jun 2022

Viewed by 2107

Abstract

Immunotherapies and targeted therapies have shown significant benefits for melanoma survival in the clinical trial setting. Much less is known about the characteristics and associated outcomes of those receiving such therapies in real-world settings. This study describes the characteristics of patients with advanced [...] Read more.

Immunotherapies and targeted therapies have shown significant benefits for melanoma survival in the clinical trial setting. Much less is known about the characteristics and associated outcomes of those receiving such therapies in real-world settings. This study describes the characteristics of patients with advanced melanoma receiving immuno- and/or targeted therapies in a real-world setting. This prospective cohort study enrolled participants aged >18 years, diagnosed with advanced melanoma and currently undergoing immuno- and/or targeted therapies outside a clinical trial for follow-up with three-dimensional (3D) total-body imaging. Participants (n = 41) had a mean age of 62 years (range 29–86), 26 (63%) were male and the majority (n = 26, 63%) had ≥2 comorbidities. After a median of 39 months (range 1–52) follow-up, 59% (n = 24/41) of participants were alive. Despite multiple co-morbidities, the survival of participants with advanced melanoma treated using immuno- and/or targeted therapies was similar or better in our real-world setting compared to those treated in clinical trials using similar therapies. Larger studies powered to evaluate phenotypic and socio-economic characteristics, as well as specific comorbidities associated with survival in a real-world setting, are required to help determine those who will most benefit from immuno- and/or targeted therapies. Full article

(This article belongs to the Special Issue Prevention, Diagnosis and Treatment of Skin Cancer)

20 pages, 340 KiB

Open AccessArticle

Process Evaluation of a Sport-Based Supportive Care Intervention for Testicular Cancer Survivors: A Mixed Methods Study

by Anika R. Petrella, Catherine M. Sabiston, Roxy H. O’Rourke, Daniel Santa Mina, Robert J. Hamilton and Andrew G. Matthew

Cancers 2022, 14(11), 2800; https://doi.org/10.3390/cancers14112800 - 04 Jun 2022

Cited by 2 | Viewed by 2220

Abstract

Testicular cancer survivors report unmet supportive care needs that are associated with poorer physical and mental health, yet engagement in traditional supportive care is low. The Ball’s in Your Court intervention was designed to engage testicular cancer survivors in supportive care by leveraging [...] Read more.

Testicular cancer survivors report unmet supportive care needs that are associated with poorer physical and mental health, yet engagement in traditional supportive care is low. The Ball’s in Your Court intervention was designed to engage testicular cancer survivors in supportive care by leveraging a community-based sport and exercise model. Age-appropriate, gender-sensitized, and disease specific elements were reflected in the intervention design, setting, content, and delivery. The intervention included five weekly health promotion sessions among a group of testicular cancer survivors. The purpose of this study was to explore the intervention’s (i) feasibility and acceptability, (ii) effects on testicular cancer survivors’ perceived health, and (iii) gain feedback for intervention refinement. A total of 10 testicular cancer survivors participated in the pilot and completed questionnaires on demographics, cancer history, perceived health, and physical activity behavior at baseline (pre-intervention) and perceived health and satisfaction with intervention components (post-intervention). Open-ended feedback surveys were collected after each weekly session and researcher field notes were recorded by three members of the study team. One month following the intervention, a focus group was conducted with intervention participants. All participants were satisfied with the intervention. Content analysis of the qualitative data supported intervention acceptability. Visual analysis conducted at the individual level indicated that perceived health either remained stable or improved from pre- to post-intervention. The Ball’s in Your Court intervention provides a feasible and acceptable approach for the delivery of supportive care aimed at improving testicular cancer survivors’ health and wellness. Recommendations for intervention refinement were provided and require future examination. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric, Adolescent and Young Adult (AYA) Psycho-Oncology)

21 pages, 2513 KiB

Open AccessReview

The Role of NOTCH1, GATA3, and c-MYC in T Cell Non-Hodgkin Lymphomas

by Mutaz Jamal Al-Khreisat, Faezahtul Arbaeyah Hussain, Ali Mahmoud Abdelfattah, Alhomidi Almotiri, Ola Mohammed Al-Sanabra and Muhammad Farid Johan

Cancers 2022, 14(11), 2799; https://doi.org/10.3390/cancers14112799 - 04 Jun 2022

Cited by 4 | Viewed by 2796

Abstract

Lymphomas are heterogeneous malignant tumours of white blood cells characterised by the aberrant proliferation of mature lymphoid cells or their precursors. Lymphomas are classified into main types depending on the histopathologic evidence of biopsy taken from an enlarged lymph node, progress stages, treatment [...] Read more.

Lymphomas are heterogeneous malignant tumours of white blood cells characterised by the aberrant proliferation of mature lymphoid cells or their precursors. Lymphomas are classified into main types depending on the histopathologic evidence of biopsy taken from an enlarged lymph node, progress stages, treatment strategies, and outcomes: Hodgkin and non-Hodgkin lymphoma (NHL). Moreover, lymphomas can be further divided into subtypes depending on the cell origin, and immunophenotypic and genetic aberrations. Many factors play vital roles in the progression, pathogenicity, incidence, and mortality rate of lymphomas. Among NHLs, peripheral T cell lymphomas (PTCLs) are rare lymphoid malignancies, that have various cellular morphology and genetic mutations. The clinical presentations are usually observed at the advanced stage of the disease. Many recent studies have reported that the expressions of NOTCH1, GATA3, and c-MYC are associated with poorer prognosis in PTCL and are involved in downstream activities. However, questions have been raised about the pathological relationship between these factors in PTCLs. Therefore, in this review, we investigate the role and relationship of the NOTCH1 pathway, transcriptional factor GATA3 and proto-oncogene c-MYC in normal T cell development and malignant PTCL subtypes. Full article

(This article belongs to the Special Issue Peripheral T-cell Lymphoma: From Biological Research to New Therapies)

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23 pages, 975 KiB

Open AccessReview

Emerging Therapies for Hepatocellular Carcinoma (HCC)

by Eesha Chakraborty and Devanand Sarkar

Cancers 2022, 14(11), 2798; https://doi.org/10.3390/cancers14112798 - 04 Jun 2022

Cited by 82 | Viewed by 9843

Abstract

Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for [...] Read more.

Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for HCC prognosis remaining dismal are that HCC is asymptomatic in its early stages, leading to late diagnosis, and it is markedly resistant to conventional chemo- and radiotherapy. Liver transplantation is the treatment of choice in early stages, while surgical resection, radiofrequency ablation (RFA) and trans arterial chemoembolization (TACE) are Food and Drug Administration (FDA)-approved treatments for advanced HCC. Additional first line therapy for advanced HCC includes broad-spectrum tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, as well as a combination of immunotherapy and anti-angiogenesis therapy, namely atezolizumab and bevacizumab. However, these strategies provide nominal extension in the survival curve, cause broad spectrum toxic side effects, and patients eventually develop therapy resistance. Some common mutations in HCC, such as in telomerase reverse transcriptase (TERT), catenin beta 1 (CTNNB1) and tumor protein p53 (TP53) genes, are still considered to be undruggable. In this context, identification of appropriate gene targets and specific gene delivery approaches create the potential of gene- and immune-based therapies for the safe and effective treatment of HCC. This review elaborates on the current status of HCC treatment by focusing on potential gene targets and advanced techniques, such as oncolytic viral vectors, nanoparticles, chimeric antigen receptor (CAR)-T cells, immunotherapy, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), and describes future prospects in HCC treatment. Full article

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

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30 pages, 7362 KiB

Open AccessArticle

Integrated Multi-Omics Maps of Lower-Grade Gliomas

by Hans Binder, Maria Schmidt, Lydia Hopp, Suren Davitavyan, Arsen Arakelyan and Henry Loeffler-Wirth

Cancers 2022, 14(11), 2797; https://doi.org/10.3390/cancers14112797 - 04 Jun 2022

Cited by 7 | Viewed by 3015

Abstract

Multi-omics high-throughput technologies produce data sets which are not restricted to only one but consist of multiple omics modalities, often as patient-matched tumour specimens. The integrative analysis of these omics modalities is essential to obtain a holistic view on the otherwise fragmented information [...] Read more.

Multi-omics high-throughput technologies produce data sets which are not restricted to only one but consist of multiple omics modalities, often as patient-matched tumour specimens. The integrative analysis of these omics modalities is essential to obtain a holistic view on the otherwise fragmented information hidden in this data. We present an intuitive method enabling the combined analysis of multi-omics data based on self-organizing maps machine learning. It “portrays” the expression, methylation and copy number variations (CNV) landscapes of each tumour using the same gene-centred coordinate system. It enables the visual evaluation and direct comparison of the different omics layers on a personalized basis. We applied this combined molecular portrayal to lower grade gliomas, a heterogeneous brain tumour entity. It classifies into a series of molecular subtypes defined by genetic key lesions, which associate with large-scale effects on DNA methylation and gene expression, and in final consequence, drive with cell fate decisions towards oligodendroglioma-, astrocytoma- and glioblastoma-like cancer cell lineages with different prognoses. Consensus modes of concerted changes of expression, methylation and CNV are governed by the degree of co-regulation within and between the omics layers. The method is not restricted to the triple-omics data used here. The similarity landscapes reflect partly independent effects of genetic lesions and DNA methylation with consequences for cancer hallmark characteristics such as proliferation, inflammation and blocked differentiation in a subtype specific fashion. It can be extended to integrate other omics features such as genetic mutation, protein expression data as well as extracting prognostic markers. Full article

(This article belongs to the Special Issue Multi-Omics Approaches in Oncology)

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10 pages, 548 KiB

Open AccessArticle

SARS-CoV-2 Neutralizing Antibodies Kinetics Postvaccination in Cancer Patients under Treatment with Immune Checkpoint Inhibition

by Evangelos Terpos, Michalis Liontos, Oraianthi Fiste, Flora Zagouri, Alexandros Briasoulis, Aimilia D. Sklirou, Christos Markellos, Efthymia Skafida, Alkistis Papatheodoridi, Angeliki Andrikopoulou, Konstantinos Koutsoukos, Maria Kaparelou, Vassiliki A. Iconomidou, Ioannis P. Trougakos and Meletios-Athanasios Dimopoulos

Cancers 2022, 14(11), 2796; https://doi.org/10.3390/cancers14112796 - 04 Jun 2022

Cited by 9 | Viewed by 2156

Abstract

Considering that COVID-19 could adversely affect cancer patients, several countries have prioritized this highly susceptible population for vaccination. Thus, rapidly generating evidence on the efficacy of SARS-CoV-2 vaccination in the subset of patients with cancer under active therapy is of paramount importance. From [...] Read more.

Considering that COVID-19 could adversely affect cancer patients, several countries have prioritized this highly susceptible population for vaccination. Thus, rapidly generating evidence on the efficacy of SARS-CoV-2 vaccination in the subset of patients with cancer under active therapy is of paramount importance. From this perspective, we launched the present prospective observational study to comprehensively address the longitudinal dynamics of immunogenicity of both messenger RNA (mRNA) and viral vector-based vaccines in 85 patients treated with immune checkpoint inhibitors (ICIs) for a broad range of solid tumors. Despite the relatively poor humoral responses following the priming vaccine inoculum, the seroconversion rates significantly increased after the second dose. Waning vaccine-based immunity was observed over the following six months, yet the administration of a third booster dose remarkably optimized antibody responses. Larger cohort studies providing real-world data with regard to vaccines effectiveness and durability of their protection among cancer patients receiving immunotherapy are an increasing priority. Full article

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20 pages, 2207 KiB

Open AccessArticle

Molecular Assessment of HER2 to Identify Signatures Associated with Therapy Response in HER2-Positive Breast Cancer

by Adam L. Maddox, Matthew S. Brehove, Kiarash R. Eliato, Andras Saftics, Eugenia Romano, Michael F. Press, Joanne Mortimer, Veronica Jones, Daniel Schmolze, Victoria L. Seewaldt and Tijana Jovanovic-Talisman

Cancers 2022, 14(11), 2795; https://doi.org/10.3390/cancers14112795 - 04 Jun 2022

Cited by 5 | Viewed by 2817

Abstract

Trastuzumab, the prototype HER2-directed therapy, has markedly improved survival for women with HER2-positive breast cancers. However, only 40–60% of women with HER2-positive breast cancers achieve a complete pathological response to chemotherapy combined with HER2-directed therapy. The current diagnostic assays have poor positive-predictive accuracy [...] Read more.

Trastuzumab, the prototype HER2-directed therapy, has markedly improved survival for women with HER2-positive breast cancers. However, only 40–60% of women with HER2-positive breast cancers achieve a complete pathological response to chemotherapy combined with HER2-directed therapy. The current diagnostic assays have poor positive-predictive accuracy in identifying therapy-responsive breast cancers. Here, we deployed quantitative single molecule localization microscopy to assess the molecular features of HER2 in a therapy-responsive setting. Using fluorescently labeled trastuzumab as a probe, we first compared the molecular features of HER2 in trastuzumab-sensitive (BT-474 and SK-BR-3) and trastuzumab-resistant (BT-474^R and JIMT-1) cultured cell lines. Trastuzumab-sensitive cells had significantly higher detected HER2 densities and clustering. We then evaluated HER2 in pre-treatment core biopsies from women with breast cancer undergoing neoadjuvant therapy. A complete pathological response was associated with a high detected HER2 density and significant HER2 clustering. These results established the nano-organization of HER2 as a potential signature of therapy-responsive disease. Full article

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19 pages, 1860 KiB

Open AccessArticle

Unraveling the Role of Guanylate-Binding Proteins (GBPs) in Breast Cancer: A Comprehensive Literature Review and New Data on Prognosis in Breast Cancer Subtypes

by Erin N. Hunt, Jonathan P. Kopacz and Deborah J. Vestal

Cancers 2022, 14(11), 2794; https://doi.org/10.3390/cancers14112794 - 04 Jun 2022

Cited by 4 | Viewed by 2455

Abstract

At least one member of the Guanylate-Binding Protein (GBP) family of large interferon-induced GTPases has been classified as both a marker of good prognosis and as a potential drug target to treat breast cancers. However, the activity of individual GBPs appears to not [...] Read more.

At least one member of the Guanylate-Binding Protein (GBP) family of large interferon-induced GTPases has been classified as both a marker of good prognosis and as a potential drug target to treat breast cancers. However, the activity of individual GBPs appears to not just be tumor cell type–specific but dependent on the growth factor and/or cytokine environment in which the tumor cells reside. To clarify what we do and do not know about GBPs in breast cancer, the current literature on GBP-1, GBP-2, and GBP-5 in breast cancer has been assembled. In addition, we have analyzed the role of each of these GBPs in predicting recurrence-free survival (RFS), overall survival (OS), and distance metastasis-free survival (DMFS) as single gene products in different subtypes of breast cancers. When a large cohort of breast cancers of all types and stages were examined, GBP-1 correlated with poor RFS. However, it was the only GBP to do so. When smaller cohorts of breast cancer subtypes grouped into ER+, ER+/HER2−, and HER2+ tumors were analyzed, none of the GBPs influenced RFS, OS, or DMSF as single agents. The exception is GBP-5, which correlated with improved RFS in HER2+ breast cancers. All three GBPs individually predicted improved RFS, OS, and DMSF in ER− breast cancers, regardless of the PR or HER2 status, and TNBCs. Full article

(This article belongs to the Special Issue Triple Negative Breast Cancer: From Biology to Treatment)

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15 pages, 1164 KiB

Open AccessEditor’s ChoiceReview

The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated

by Roumaïssa Gouasmi, Carole Ferraro-Peyret, Stéphane Nancey, Isabelle Coste, Toufic Renno, Cédric Chaveroux, Nicolas Aznar and Stéphane Ansieau

Cancers 2022, 14(11), 2793; https://doi.org/10.3390/cancers14112793 - 04 Jun 2022

Cited by 23 | Viewed by 4810

Abstract

The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD⁺ for the organism. Hijacking of its immunosuppressive functions, [...] Read more.

The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD⁺ for the organism. Hijacking of its immunosuppressive functions, as recurrently observed in multiple cancers, facilitates immune evasion and promotes tumor development. Based on these observations, researchers have focused on characterizing indoleamine 2,3-dioxygenase (IDO1), the main enzyme catalyzing the first and limiting step of the pathway, and on developing therapies targeting it. Unfortunately, clinical trials studying IDO1 inhibitors have thus far not met expectations, highlighting the need to unravel this complex signaling pathway further. Recent advances demonstrate that these metabolites additionally promote tumor growth, metastatic dissemination and chemoresistance by a combination of paracrine and autocrine effects. Production of NAD⁺ also contributes to cancer progression by providing cancer cells with enhanced plasticity, invasive properties and chemoresistance. A comprehensive survey of this complexity is challenging but necessary to achieve medical success. Full article

(This article belongs to the Special Issue Targeting Amino Acid Signaling and Metabolism in Cancer)

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20 pages, 2187 KiB

Open AccessArticle

Multivariate Risk Analysis of RAS, BRAF and EGFR Mutations Allelic Frequency and Coexistence as Colorectal Cancer Predictive Biomarkers

by Adriana Ionescu, Liviu Bilteanu, Ovidiu Ionut Geicu, Florin Iordache, Loredana Stanca, Aurelia Magdalena Pisoschi, Adrian Miron, Andreea Iren Serban and Valentin Calu

Cancers 2022, 14(11), 2792; https://doi.org/10.3390/cancers14112792 - 04 Jun 2022

Cited by 3 | Viewed by 1873

Abstract

Background: Biomarker profiles should represent a coherent description of the colorectal cancer (CRC) stage and its predicted evolution. Methods: Using droplet digital PCR, we detected the allelic frequencies (AF) of KRAS, NRAS, BRAF, and EGFR mutations from 60 tumors. We employed a pair-wise [...] Read more.

Background: Biomarker profiles should represent a coherent description of the colorectal cancer (CRC) stage and its predicted evolution. Methods: Using droplet digital PCR, we detected the allelic frequencies (AF) of KRAS, NRAS, BRAF, and EGFR mutations from 60 tumors. We employed a pair-wise association approach to estimate the risk involving AF mutations as outcome variables for clinical data and as predicting variables for tumor-staging. We evaluated correlations between mutations of AFs and also between the mutations and histopathology features (tumor staging, inflammation, differentiation, and invasiveness). Results: KRAS G12/G13 mutations were present in all patients. KRAS Q61 was significantly associated with poor differentiation, high desmoplastic reaction, invasiveness (ypT4), and metastasis (ypM1). NRAS and BRAF were associated with the right-side localization of tumors. Diabetic patients had a higher risk to exhibit NRAS G12/G13 mutations. BRAF and NRAS G12/G13 mutations co-existed in tumors with invasiveness limited to the submucosa. Conclusions: The associations we found and the mutational AF we reported may help to understand disease processes and may be considered as potential CCR biomarker candidates. In addition, we propose representative mutation panels associated with specific clinical and histopathological features of CRC, as a unique opportunity to refine the degree of personalization of CRC treatment. Full article

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11 pages, 513 KiB

Open AccessArticle

Liver Resection for Type IV Perihilar Cholangiocarcinoma: Left or Right Trisectionectomy?

by Heithem Jeddou, Stylianos Tzedakis, Francesco Orlando, Antoine Robert, Eric Meneyrol, Damien Bergeat, Fabien Robin, Laurent Sulpice and Karim Boudjema

Cancers 2022, 14(11), 2791; https://doi.org/10.3390/cancers14112791 - 04 Jun 2022

Cited by 3 | Viewed by 1706

Abstract

How the side of an extended liver resection impacts the postoperative prognosis of advanced perihilar cholangiocarcinoma (PHC) is still controversial. We compared the outcomes of right (RTS) and left trisectionectomies (LTS) in Bismuth-Corlette (BC) type IV PHC resection. All patients undergoing RTS or [...] Read more.

How the side of an extended liver resection impacts the postoperative prognosis of advanced perihilar cholangiocarcinoma (PHC) is still controversial. We compared the outcomes of right (RTS) and left trisectionectomies (LTS) in Bismuth-Corlette (BC) type IV PHC resection. All patients undergoing RTS or LTS for BC type IV PHC in a single tertiary center between January 2012 and December 2019 were compared retrospectively. The endpoints were perioperative outcomes, long-term overall (OS), and disease-free survival (DFS). Among 67 hepatic resections for BC type IV PHC, 25 (37.3%) were LTS and 42 (63.7%) were RTS. Portal vein and artery resection rates were 40% and 52.4% (p = 0.29), and 24% and 0% (p < 0.001) in the LTS and RTS groups, respectively. The severe complication (Clavien–Dindo > IIIa) rate was comparable (36% vs. 21.5%, p = 0.357) while the postoperative liver failure (POLF) rate was lower in the LTS group (16% vs. 38%, p = 0.048). The R0 resection rate was similar between groups (81% vs. 92%; p = 0.154). The five-year OS rate was higher in the LTS group (66% vs. 30%, p = 0.009) while DFS was comparable (43% vs. 18%, p = 0.11). Based on multivariable analysis, the side of the trisectionectomy was an independent predictor of OS. Compared with RTS, LTS is associated with lower POLF and higher overall survival despite more frequent arterial reconstructions in type IV PHC. Although technically more demanding, LTS may be preferred in the treatment of advanced PHC. Full article

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15 pages, 3683 KiB

Open AccessArticle

High Levels of MFG-E8 Confer a Good Prognosis in Prostate and Renal Cancer Patients

by Karen Geoffroy, Patrick Laplante, Sylvie Clairefond, Feryel Azzi, Dominique Trudel, Jean-Baptiste Lattouf, John Stagg, Fred Saad, Anne-Marie Mes-Masson, Marie-Claude Bourgeois-Daigneault and Jean-François Cailhier

Cancers 2022, 14(11), 2790; https://doi.org/10.3390/cancers14112790 - 04 Jun 2022

Cited by 3 | Viewed by 1819

Abstract

Milk fat globule-epidermal growth factor-8 (MFG-E8) is a glycoprotein secreted by different cell types, including apoptotic cells and activated macrophages. MFG-E8 is highly expressed in a variety of cancers and is classically associated with tumor growth and poor patient prognosis through reprogramming of [...] Read more.

Milk fat globule-epidermal growth factor-8 (MFG-E8) is a glycoprotein secreted by different cell types, including apoptotic cells and activated macrophages. MFG-E8 is highly expressed in a variety of cancers and is classically associated with tumor growth and poor patient prognosis through reprogramming of macrophages into the pro-tumoral/pro-angiogenic M2 phenotype. To date, correlations between levels of MFG-E8 and patient survival in prostate and renal cancers remain unclear. Here, we quantified MFG-E8 and CD68/CD206 expression by immunofluorescence staining in tissue microarrays constructed from renal (n = 190) and prostate (n = 274) cancer patient specimens. Percentages of MFG-E8-positive surface area were assessed in each patient core and Kaplan–Meier analyses were performed accordingly. We found that MFG-E8 was expressed more abundantly in malignant regions of prostate tissue and papillary renal cell carcinoma but was also increased in the normal adjacent regions in clear cell renal carcinoma. In addition, M2 tumor-associated macrophage staining was increased in the normal adjacent tissues compared to the malignant areas in renal cancer patients. Overall, high tissue expression of MFG-E8 was associated with less disease progression and better survival in prostate and renal cancer patients. Our observations provide new insights into tumoral MFG-E8 content and macrophage reprogramming in cancer. Full article

(This article belongs to the Section Cancer Biomarkers)

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14 pages, 1057 KiB

Open AccessReview

Proton Therapy in the Management of Pancreatic Cancer

by Jana M. Kobeissi, Charles B. Simone II, Haibo Lin, Lara Hilal and Carla Hajj

Cancers 2022, 14(11), 2789; https://doi.org/10.3390/cancers14112789 - 04 Jun 2022

Cited by 4 | Viewed by 2659

Abstract

Radiation therapy plays a central role in the treatment of pancreatic cancer. While generally shown to be feasible, proton irradiation, particularly when an ablative dose is planned, remains a challenge, especially due to tumor motion and the proximity to organs at risk, like [...] Read more.

Radiation therapy plays a central role in the treatment of pancreatic cancer. While generally shown to be feasible, proton irradiation, particularly when an ablative dose is planned, remains a challenge, especially due to tumor motion and the proximity to organs at risk, like the stomach, duodenum, and bowel. Clinically, standard doses of proton radiation treatment have not been shown to be statistically different from photon radiation treatment in terms of oncologic outcomes and toxicity rates as per non-randomized comparative studies. Fractionation schedules and concurrent chemotherapy combinations are yet to be optimized for proton therapy and are the subject of ongoing trials. Full article

(This article belongs to the Special Issue Application of Proton Beam Therapy in Cancer Treatment)

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17 pages, 2758 KiB

Open AccessArticle

LncRNA ZNF582-AS1 Expression and Methylation in Breast Cancer and Its Biological and Clinical Implications

by Junlong Wang, Dionyssios Katsaros, Nicoletta Biglia, Yuanyuan Fu, Chiara Benedetto, Lenora Loo, Zhanwei Wang and Herbert Yu

Cancers 2022, 14(11), 2788; https://doi.org/10.3390/cancers14112788 - 04 Jun 2022

Cited by 4 | Viewed by 2020

Abstract

Background: Long non-coding RNAs (lncRNAs) play an important role in cellular activities and functions, but our understanding of their involvement in cancer is limited. Methods: TCGA data on RNA expression and DNA methylation were analyzed for lncRNAs’ association with breast cancer survival, using [...] Read more.

Background: Long non-coding RNAs (lncRNAs) play an important role in cellular activities and functions, but our understanding of their involvement in cancer is limited. Methods: TCGA data on RNA expression and DNA methylation were analyzed for lncRNAs’ association with breast cancer survival, using the Cox proportional hazard regression model. Fresh tumor samples and clinical information from 361 breast cancer patients in our study were used to confirm the TCGA finding on ZNF582-AS1. A RT-qPCR method was developed to measure ZNF582-AS1 expression. Survival associations with ZNF582-AS1 were verified with a meta-analysis. In silico predictions of molecular targets and cellular functions of ZNF582-AS1 were performed based on its molecular signatures and nucleotide sequences. Results:ZNF582-AS1 expression was lower in breast tumors than adjacent normal tissues. Low ZNF582-AS1 was associated with high-grade or ER-negative tumors. Patients with high ZNF582-AS1 had a lower risk of relapse and death. These survival associations were confirmed in a meta-analysis and remained significant after adjustment for tumor grade, disease stage, patient age, and hormone receptor status. Correlation analysis indicated the possible suppression of ZNF582-AS1 expression by promoter methylation. Bioinformatics interrogation of molecular signatures suggested that ZNF582-AS1 could suppress tumor cell proliferation via downregulating the HER2-mediated signaling pathway. Analysis of online data also suggested that HIF-1-related transcription factors could suppress ZNF582-AS1 expression, and the lncRNA might bind to hsa-miR-940, a known oncogenic miRNA in breast cancer. Conclusions: ZNF582-AS1 may play a role in suppressing breast cancer progression. Elucidating the lncRNA’s function and regulation may improve our understanding of the disease. Full article

(This article belongs to the Special Issue Targeting the Vulnerabilities of Oncogene Activation)

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