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Cancers, Volume 13, Issue 11 (June-1 2021) – 344 articles

Cover Story (view full-size image): Tumor progression, therapy resistance and metastasis are profoundly controlled by the tumor microenvironment. Endothelial cell contribution to tumor progression was initially only attributed to the formation of new blood vessels (angiogenesis). However, endothelial cells do not only provide conduits for blood transportation but also express numerous membrane-bound and secreted factors. Such angiocrine functions promote aggressiveness of cancer cells, influence the immune response towards cancer cells and thereby contribute to tumor progression and metastasis. Crosstalk between endothelial cells and cancer cells contributes to the cancer stem cell phenotype, epithelial to mesenchymal transition, immunosuppression, remodeling of the extracellular matrix and intravasation of cancer cells into the bloodstream in primary tumor but also at the pre-metastatic niche and metastasis. View this [...] Read more.
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Article
VDAC1 Silencing in Cancer Cells Leads to Metabolic Reprogramming That Modulates Tumor Microenvironment
Cancers 2021, 13(11), 2850; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112850 - 07 Jun 2021
Viewed by 949
Abstract
The tumor microenvironment (TME) plays an important role in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Thus, better insight into tumor–host interactions is required. Most of these processes involve the metabolic reprogramming of cells. Here, we focused on this reprogramming in [...] Read more.
The tumor microenvironment (TME) plays an important role in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Thus, better insight into tumor–host interactions is required. Most of these processes involve the metabolic reprogramming of cells. Here, we focused on this reprogramming in cancerous cells and its effect on the TME. A major limitation in the study of tumor–host interactions is the difficulty in separating cancerous from non-cancerous signaling pathways within a tumor. Our strategy involved specifically silencing the expression of VDAC1 in the mitochondria of human-derived A549 lung cancer xenografts in mice, but not in the mouse-derived cells of the TME. Next-generation sequencing (NGS) analysis allows distinguishing the human or mouse origin of genes, thus enabling the separation of the bidirectional cross-talk between the TME and malignant cells. We demonstrate that depleting VDAC1 in cancer cells led to metabolic reprogramming, tumor regression, and the disruption of tumor–host interactions. This was reflected in the altered expression of a battery of genes associated with TME, including those involved in extracellular matrix organization and structure, matrix-related peptidases, angiogenesis, intercellular interacting proteins, integrins, and growth factors associated with stromal activities. We show that metabolic rewiring upon mitochondrial VDAC1 silencing in cancer cells affected several components of the TME, such as structural protein matrix metalloproteinases and Lox, and elicited a stromal response resembling the reaction to a foreign body in wound healing. As tumor progression requires a cooperative interplay between the host and cancer cells, and the ECM is intensively remodeled during cancer progression, VDAC1 depletion induced metabolic reprogramming that targeted both tumor cells and resulted in the alteration of the whole spectrum of TME-related genes, affecting the reciprocal feedback between ECM molecules, host cells, and cancer cells. Thus, VDAC1 depletion using si-VDAC1 represents therapeutic potential, inhibiting cancer cell proliferation and also inducing the modulation of TME components, which influences cancer progression, migration, and invasion. Full article
(This article belongs to the Special Issue At the Crossroads of Tumor Microenvironment and Metabolism)
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Article
Circulating Levels of the Interferon-γ-Regulated Chemokines CXCL10/CXCL11, IL-6 and HGF Predict Outcome in Metastatic Renal Cell Carcinoma Patients Treated with Antiangiogenic Therapy
Cancers 2021, 13(11), 2849; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112849 - 07 Jun 2021
Viewed by 630
Abstract
Sunitinib and pazopanib are standard first-line treatments for patients with metastatic renal cell carcinoma (mRCC). Nonetheless, as the number of treatment options increases, there is a need to identify biomarkers that can predict drug efficacy and toxicity. In this prospective study we evaluated [...] Read more.
Sunitinib and pazopanib are standard first-line treatments for patients with metastatic renal cell carcinoma (mRCC). Nonetheless, as the number of treatment options increases, there is a need to identify biomarkers that can predict drug efficacy and toxicity. In this prospective study we evaluated a set of biomarkers that had been previously identified within a secretory signature in mRCC patients. This set includes tumor expression of c-Met and serum levels of HGF, IL-6, IL-8, CXCL9, CXCL10 and CXCL11. Our cohort included 60 patients with mRCC from 10 different Spanish hospitals who received sunitinib (n = 51), pazopanib (n = 4) or both (n = 5). Levels of biomarkers were studied in relation to response rate, progression-free survival (PFS) and overall survival (OS). High tumor expression of c-Met and high basal serum levels of HGF, IL-6, CXCL11 and CXCL10 were significantly associated with reduced PFS and/or OS. In multivariable Cox regression analysis, CXCL11 was identified as an independent biomarker predictive of shorter PFS and OS, and HGF was an independent predictor of reduced PFS. Correlation analyses using our cohort of patients and patients from TCGA showed that HGF levels were significantly correlated with those of IL-6, CXCL11 and CXCL10. Bioinformatic protein–protein network analysis revealed a significant interaction between these proteins, all this suggesting a coordinated expression and secretion. We also developed a prognostic index that considers this group of biomarkers, where high values in mRCC patients can predict higher risk of relapse (HR 5.28 [2.32–12.0], p < 0.0001). In conclusion, high plasma HGF, CXCL11, CXCL10 and IL-6 levels are associated with worse outcome in mRCC patients treated with sunitinib or pazopanib. Our findings also suggest that these factors may constitute a secretory cluster that acts coordinately to promote tumor growth and resistance to antiangiogenic therapy. Full article
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Article
Identification of a Two-MicroRNA Signature in Plasma as a Novel Biomarker for Very Early Diagnosis of Breast Cancer
Cancers 2021, 13(11), 2848; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112848 - 07 Jun 2021
Viewed by 621
Abstract
The early diagnosis of breast cancer is essential to improve patients’ survival rate. In this context, microRNAs have been described as potential diagnostic biomarkers for breast cancer. Particularly, circulating microRNAs have a strong value as non-invasive biomarkers. Herein, we assessed the potential of [...] Read more.
The early diagnosis of breast cancer is essential to improve patients’ survival rate. In this context, microRNAs have been described as potential diagnostic biomarkers for breast cancer. Particularly, circulating microRNAs have a strong value as non-invasive biomarkers. Herein, we assessed the potential of a microRNA signature based on miR-30b-5p and miR-99a-5p levels in plasma as a diagnostic biomarker for breast cancer. This two-microRNA signature was constructed by Principal Component Analysis and its prognostic value was assessed in a discovery cohort and blindly validated in a second cohort from an independent institution. ROC curve analysis and biomarker performance parameter evaluation demonstrated that our proposed signature presents a high value as a non-invasive biomarker for very early detection of breast cancer. In addition, pathway enrichment analysis identified three of the well-known pathways involved in cancer as targets of the two microRNAs. Full article
(This article belongs to the Special Issue Circulating miRNAs as Tumor Biomarkers)
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Article
Molecular Classification to Prognosticate Response in Medically Managed Endometrial Cancers and Endometrial Intraepithelial Neoplasia
Cancers 2021, 13(11), 2847; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112847 - 07 Jun 2021
Viewed by 560
Abstract
Background: The aim of this study was to evaluate whether molecular classification prognosticates treatment response in women with endometrial cancers and endometrial intraepithelial neoplasia (EIN) treated with levonorgestrel intrauterine system (LNG-IUS). Methods: Patients treated with LNG-IUS for endometrial cancer or EIN from 2013 [...] Read more.
Background: The aim of this study was to evaluate whether molecular classification prognosticates treatment response in women with endometrial cancers and endometrial intraepithelial neoplasia (EIN) treated with levonorgestrel intrauterine system (LNG-IUS). Methods: Patients treated with LNG-IUS for endometrial cancer or EIN from 2013 to 2018 were evaluated. Using immunohistochemistry and single gene sequencing of POLE, patients were classified into four groups as per the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE): POLE-mutated, mismatch repair-deficient (MMRd), p53 wild type (p53wt), and p53-abnormal (p53abn). Groups were assessed relative to the primary outcome of progression or receipt of definitive treatment. Results: Fifty-eight subjects with endometrioid endometrial cancer or EIN treated with LNG-IUS were included. Of these, 22 subjects (37.9%) had endometrial cancer and 36 subjects (62.1%) had EIN. Per the ProMisE algorithm, 44 patients (75.9%) were classified as p53wt, 6 (10.3%) as MMRd, 4 (6.9%) as p53abn, and 4 (6.9%) as POLE-mutated. Of the 58 patients, 11 (19.0%) progressed or opted for definitive therapy. Median time to progression or definitive therapy was 7.5 months, with p53abn tumors having the shortest time to progression or definitive therapy. Conclusions: Molecular classification of endometrial cancer and EIN prior to management with LNG-IUS is feasible and may predict patients at risk of progression. Full article
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Article
Hyperspectral Imaging (HSI)—A New Tool to Estimate the Perfusion of Upper Abdominal Organs during Pancreatoduodenectomy
Cancers 2021, 13(11), 2846; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112846 - 07 Jun 2021
Viewed by 504
Abstract
Hyperspectral imaging (HSI) in abdominal surgery is a new non-invasive tool for the assessment of the perfusion and oxygenation of various tissues and organs. Its benefit in pancreatic surgery is still unknown. The aim of this study was to evaluate the key impact [...] Read more.
Hyperspectral imaging (HSI) in abdominal surgery is a new non-invasive tool for the assessment of the perfusion and oxygenation of various tissues and organs. Its benefit in pancreatic surgery is still unknown. The aim of this study was to evaluate the key impact of using HSI during pancreatoduodenectomy (PD). In total, 20 consecutive patients were included. HSI was recorded during surgery as part of a pilot study approved by the local Ethics Committee. Data were collected prospectively with the TIVITA® Tissue System. Intraoperative HS images were recorded before and after gastroduodenal artery (GDA) clamping. We detected four patients with celiac artery stenosis (CAS) caused by a median arcuate ligament (MAL). In two of these patients, a reduction in liver oxygenation (StO2) was discovered 15 and 30 min after GDA clamping. The MAL was divided in these patients. HSI showed an improvement of liver StO2 after MAL division (from 61% to 73%) in one of these two patients. There was no obvious decrease in liver StO2 in the other two patients with CAS. HSI, as a non-invasive procedure, could be helpful in evaluating liver and gastric perfusion during PD, which might assist surgeons in choosing the best surgical approach and in improving patients’ outcomes. Full article
(This article belongs to the Special Issue Recent Highly Advanced Surgery for Pancreatic Cancer)
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Article
RAD51D Aberrant Splicing in Breast Cancer: Identification of Splicing Regulatory Elements and Minigene-Based Evaluation of 53 DNA Variants
Cancers 2021, 13(11), 2845; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112845 - 07 Jun 2021
Viewed by 585
Abstract
RAD51D loss-of-function variants increase lifetime risk of breast and ovarian cancer. Splicing disruption is a frequent pathogenic mechanism associated with variants in susceptibility genes. Herein, we have assessed the splicing and clinical impact of splice-site and exonic splicing enhancer (ESE) variants identified through [...] Read more.
RAD51D loss-of-function variants increase lifetime risk of breast and ovarian cancer. Splicing disruption is a frequent pathogenic mechanism associated with variants in susceptibility genes. Herein, we have assessed the splicing and clinical impact of splice-site and exonic splicing enhancer (ESE) variants identified through the study of ~113,000 women of the BRIDGES cohort. A RAD51D minigene with exons 2–9 was constructed in splicing vector pSAD. Eleven BRIDGES splice-site variants (selected by MaxEntScan) were introduced into the minigene by site-directed mutagenesis and tested in MCF-7 cells. The 11 variants disrupted splicing, collectively generating 25 different aberrant transcripts. All variants but one produced negligible levels (<3.4%) of the full-length (FL) transcript. In addition, ESE elements of the alternative exon 3 were mapped by testing four overlapping exonic microdeletions (≥30-bp), revealing an ESE-rich interval (c.202_235del) with critical sequences for exon 3 recognition that might have been affected by germline variants. Next, 26 BRIDGES variants and 16 artificial exon 3 single-nucleotide substitutions were also assayed. Thirty variants impaired splicing with variable amounts (0–65.1%) of the FL transcript, although only c.202G>A demonstrated a complete aberrant splicing pattern without the FL transcript. On the other hand, c.214T>C increased efficiency of exon 3 recognition, so only the FL transcript was detected (100%). In conclusion, 41 RAD51D spliceogenic variants (28 of which were from the BRIDGES cohort) were identified by minigene assays. We show that minigene-based mapping of ESEs is a powerful approach for identifying ESE hotspots and ESE-disrupting variants. Finally, we have classified nine variants as likely pathogenic according to ACMG/AMP-based guidelines, highlighting the complex relationship between splicing alterations and variant interpretation. Full article
(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)
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Article
Prognostic Association between Common Laboratory Tests and Overall Survival in Elderly Men with De Novo Metastatic Castration Sensitive Prostate Cancer: A Population-Based Study in Canada
Cancers 2021, 13(11), 2844; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112844 - 07 Jun 2021
Viewed by 558
Abstract
De novo cases of metastatic prostate cancer (mCSPC) are associated with poorer prognosis. To assist in clinical decision-making, we aimed to determine the prognostic utility of commonly available laboratory-based markers with overall survival (OS). In a retrospective population-based study, a cohort of 3556 [...] Read more.
De novo cases of metastatic prostate cancer (mCSPC) are associated with poorer prognosis. To assist in clinical decision-making, we aimed to determine the prognostic utility of commonly available laboratory-based markers with overall survival (OS). In a retrospective population-based study, a cohort of 3556 men aged ≥66 years diagnosed with de novo mCSPC between 2014 and 2019 was identified in Ontario (Canada) administrative database. OS was assessed by using the Kaplan–Meier method. Multivariate Cox regression analysis was performed to evaluate the association between laboratory markers and OS adjusting for patient and disease characteristics. Laboratory markers that were assessed include neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), albumin, hemoglobin, serum testosterone and PSA kinetics. Among the 3556 older men with de novo mCSPC, their median age was 77 years (IQR: 71–83). The median survival was 18 months (IQR: 10–31). In multivariate analysis, a statistically significant association with OS was observed with all the markers (NLR, PLR, albumin, hemoglobin, PSA decrease, reaching PSA nadir and a 50% PSA decline), except for testosterone levels. Our findings support the use of markers of systemic inflammation (NLR, PLR and albumin), hemoglobin and PSA metrics as prognostic indicators for OS in de novo mCSPC. Full article
Article
Elevated Expression of the RAGE Variant-V in SCLC Mitigates the Effect of Chemotherapeutic Drugs
Cancers 2021, 13(11), 2843; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112843 - 07 Jun 2021
Viewed by 650
Abstract
Small cell lung carcinoma (SCLC) is a highly aggressive malignancy with a very high mortality rate. A prominent part of this is because these carcinomas are refractory to chemotherapies, such as etoposide or cisplatin, making effective treatment almost impossible. Here, we report that [...] Read more.
Small cell lung carcinoma (SCLC) is a highly aggressive malignancy with a very high mortality rate. A prominent part of this is because these carcinomas are refractory to chemotherapies, such as etoposide or cisplatin, making effective treatment almost impossible. Here, we report that elevated expression of the RAGE variant-V in SCLC promotes homology-directed DNA DSBs repair when challenged with anti-cancer drugs. This variant exclusively localizes to the nucleus, interacts with members of the double-strand break (DSB) repair machinery and thus promotes the recruitment of DSBs repair factors at the site of damage. Increased expression of this variant thus, promotes timely DNA repair. Congruently, the tumor cells expressing high levels of variant-V can tolerate chemotherapeutic drug treatment better than the RAGE depleted cells. Our findings reveal a yet undisclosed role of the RAGE variant-V in the homology-directed DNA repair. This variant thus can be a potential target to be considered for future therapeutic approaches in advanced SSLC. Full article
(This article belongs to the Special Issue Functional Genomics of Cancer)
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Article
Identification of Nucleolin as a Novel AEG-1-Interacting Protein in Breast Cancer via Interactome Profiling
Cancers 2021, 13(11), 2842; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112842 - 07 Jun 2021
Viewed by 661
Abstract
Breast cancer is one of the most common malignant diseases worldwide. Astrocyte elevated gene-1 (AEG-1) is upregulated in breast cancer and regulates breast cancer cell proliferation and invasion. However, the molecular mechanisms by which AEG-1 promotes breast cancer have yet to be fully [...] Read more.
Breast cancer is one of the most common malignant diseases worldwide. Astrocyte elevated gene-1 (AEG-1) is upregulated in breast cancer and regulates breast cancer cell proliferation and invasion. However, the molecular mechanisms by which AEG-1 promotes breast cancer have yet to be fully elucidated. In order to delineate the function of AEG-1 in breast cancer development, we mapped the AEG-1 interactome via affinity purification followed by LC-MS/MS. We identified nucleolin (NCL) as a novel AEG-1 interacting protein, and co-immunoprecipitation experiments validated the interaction between AEG-1 and NCL in breast cancer cells. The silencing of NCL markedly reduced not only migration/invasion, but also the proliferation induced by the ectopic expression of AEG-1. Further, we found that the ectopic expression of AEG-1 induced the tyrosine phosphorylation of c-Met, and NCL knockdown markedly reduced this AEG-1 mediated phosphorylation. Taken together, our report identifies NCL as a novel mediator of the oncogenic function of AEG-1, and suggests that c-Met could be associated with the oncogenic function of the AEG-1-NCL complex in the context of breast cancer. Full article
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Review
Targeting Tissue Factor to Tumor Vasculature to Induce Tumor Infarction
Cancers 2021, 13(11), 2841; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112841 - 07 Jun 2021
Viewed by 543
Abstract
Besides its central functional role in coagulation, TF has been described as being operational in the development of malignancies and is currently being studied as a possible therapeutic tool against cancer. One of the avenues being explored is retargeting TF or its truncated [...] Read more.
Besides its central functional role in coagulation, TF has been described as being operational in the development of malignancies and is currently being studied as a possible therapeutic tool against cancer. One of the avenues being explored is retargeting TF or its truncated extracellular part (tTF) to the tumor vasculature to induce tumor vessel occlusion and tumor infarction. To this end, multiple structures on tumor vascular wall cells have been studied at which tTF has been aimed via antibodies, derivatives, or as bifunctional fusion protein through targeting peptides. Among these targets were vascular adhesion molecules, oncofetal variants of fibronectin, prostate-specific membrane antigens, vascular endothelial growth factor receptors and co-receptors, integrins, fibroblast activation proteins, NG2 proteoglycan, microthrombus-associated fibrin-fibronectin, and aminopeptidase N. Targeting was also attempted toward cellular membranes within an acidic milieu or toward necrotic tumor areas. tTF-NGR, targeting tTF primarily at aminopeptidase N on angiogenic endothelial cells, was the first drug candidate from this emerging class of coaguligands translated to clinical studies in cancer patients. Upon completion of a phase I study, tTF-NGR entered randomized studies in oncology to test the therapeutic impact of this novel therapeutic modality. Full article
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Article
A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways
Cancers 2021, 13(11), 2840; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112840 - 07 Jun 2021
Viewed by 785
Abstract
(1) Background: Today, the discovery of novel anticancer agents with multitarget effects and high safety margins represents a high challenge. Drug discovery efforts indicated that benzopyrane scaffolds possess a wide range of pharmacological activities. This spurs on building a skeletally diverse library of [...] Read more.
(1) Background: Today, the discovery of novel anticancer agents with multitarget effects and high safety margins represents a high challenge. Drug discovery efforts indicated that benzopyrane scaffolds possess a wide range of pharmacological activities. This spurs on building a skeletally diverse library of benzopyranes to identify an anticancer lead drug candidate. Here, we aim to characterize the anticancer effect of a novel benzopyrane derivative, aiming to develop a promising clinical anticancer candidate. (2) Methods: The anticancer effect of SIMR1281 against a panel of cancer cell lines was tested. In vitro assays were performed to determine the effect of SIMR1281 on GSHR, TrxR, mitochondrial metabolism, DNA damage, cell cycle progression, and the induction of apoptosis. Additionally, SIMR1281 was evaluated in vivo for its safety and in a xenograft mice model. (3) Results: SIMR1281 strongly inhibits GSHR while it moderately inhibits TrxR and modulates the mitochondrial metabolism. SIMR1281 inhibits the cell proliferation of various cancers. The antiproliferative activity of SIMR1281 was mediated through the induction of DNA damage, perturbations in the cell cycle, and the inactivation of Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281 induced apoptosis and attenuated cell survival machinery. In addition, SIMR1281 reduced the tumor volume in a xenograft model while maintaining a high in vivo safety profile at a high dose. (4) Conclusions: Our findings demonstrate the anticancer multitarget effect of SIMR1281, including the dual inhibition of glutathione and thioredoxin reductases. These findings support the development of SIMR1281 in preclinical and clinical settings, as it represents a potential lead compound for the treatment of cancer. Full article
(This article belongs to the Section Cancer Therapy)
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Study Protocol
TremelImumab and Durvalumab Combination for the Non-OperatIve Management (NOM) of Microsatellite InstabiliTY (MSI)-High Resectable Gastric or Gastroesophageal Junction Cancer: The Multicentre, Single-Arm, Multi-Cohort, Phase II INFINITY Study
Cancers 2021, 13(11), 2839; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112839 - 07 Jun 2021
Viewed by 620
Abstract
In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for [...] Read more.
In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection. Full article
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Article
Trend Shifts in Age-Specific Incidence for In Situ and Invasive Cutaneous Melanoma in Sweden
Cancers 2021, 13(11), 2838; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112838 - 07 Jun 2021
Viewed by 559
Abstract
Background: The incidence of invasive cutaneous melanoma (CM) is increasing in Sweden. The aim was to present age- and sex-specific trends of the age-standardised incidence and the average annual percentage change (AAPC) for in situ and invasive CM. Methods: Joinpoint regression models were [...] Read more.
Background: The incidence of invasive cutaneous melanoma (CM) is increasing in Sweden. The aim was to present age- and sex-specific trends of the age-standardised incidence and the average annual percentage change (AAPC) for in situ and invasive CM. Methods: Joinpoint regression models were used to analyse data from the Swedish Cancer Register and the Swedish Melanoma Registry 1997–2018 (N = 35,350 in situ CM; 59,932 CM). Results: The AAPC of CM for women was 4.5 (4.1–5.0; p < 0.001) for the period 1997–2018. For men, the APCC was 4.2 (3.0–5.4; p < 0.001), with a significantly higher annual percentage change (APC) for the period 2000–2018 (5.0; 4.6–5.4; p < 0.001) compared to 1997–1999. An increasing annual incidence of CM ≤ 0.6 mm and 0.7 mm Breslow tumour thickness was found for men with a significant incidence shift for the period 2006–2015, respectively. Similarly for women, with a significantly higher APC for CM ≤ 0.6 mm from 2005. The incidence of intermediate thick CM (2.1–4.0 mm) has not increased since 2011. The incidence of CM > 4.0 mm has been increasing among both sexes, with a significantly lower APC among women from 2005. Conclusions: The incidence of in situ and low-risk CM ≤ 1.0 mm in tumour thickness has been rising among both sexes since the 2000s. Full article
(This article belongs to the Section Cancer Epidemiology and Prevention)
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Review
Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies
Cancers 2021, 13(11), 2837; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112837 - 07 Jun 2021
Viewed by 746
Abstract
Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment of pediatric and adult malignancies, such as acute lymphoblastic leukemia, osteosarcoma, and lymphoma. Despite the vast evidence for clinical efficacy, high-dose MTX displays significant inter-individual pharmacokinetic variability. Delayed MTX [...] Read more.
Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment of pediatric and adult malignancies, such as acute lymphoblastic leukemia, osteosarcoma, and lymphoma. Despite the vast evidence for clinical efficacy, high-dose MTX displays significant inter-individual pharmacokinetic variability. Delayed MTX clearance can lead to prolonged, elevated exposure, causing increased risks for nephrotoxicity, mucositis, seizures, and neutropenia. Numerous pharmacogenetic studies have investigated the effects of several genes and polymorphisms on MTX clearance in an attempt to better understand the pharmacokinetic variability and improve patient outcomes. To date, several genes and polymorphisms that affect MTX clearance have been identified. However, evidence for select genes have conflicting results or lack the necessary replication and validation needed to confirm their effects on MTX clearance. Therefore, we performed a systematic review to identify and then summarize the pharmacogenetic factors that influence high-dose MTX pharmacokinetics in pediatric malignancies. Using the PRISMA guidelines, we analyzed 58 articles and 24 different genes that were associated with transporter pharmacology or the folate transport pathway. We conclude that there is only one gene that reliably demonstrates an effect on MTX pharmacokinetics: SLCO1B1. Full article
(This article belongs to the Special Issue Germline Pharmacogenetics of Cancer Treatment)
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Review
Two Complementarity Immunotherapeutics in Non-Small-Cell Lung Cancer Patients—Mechanism of Action and Future Concepts
Cancers 2021, 13(11), 2836; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112836 - 07 Jun 2021
Viewed by 706
Abstract
Due to the limited effectiveness of immunotherapy used as first-line monotherapy in patients with non-small-cell lung cancer (NSCLC), the concepts of combining classical immunotherapy based on immune checkpoint antibodies with other treatment methods have been developed. Pembrolizumab and atezolizumab were registered in combination [...] Read more.
Due to the limited effectiveness of immunotherapy used as first-line monotherapy in patients with non-small-cell lung cancer (NSCLC), the concepts of combining classical immunotherapy based on immune checkpoint antibodies with other treatment methods have been developed. Pembrolizumab and atezolizumab were registered in combination with chemotherapy for the treatment of metastatic NSCLC, while durvalumab found its application in consolidation therapy after successful chemoradiotherapy in patients with locally advanced NSCLC. Exceptionally attractive, due to their relatively low toxicity and high effectiveness, are treatment approaches in which a combination of two different immunotherapy methods is applied. This method is based on observations from clinical trials in which nivolumab and ipilimumab were used as first-line therapy for advanced NSCLC. It turned out that the dual blockade of immune checkpoints activated T lymphocytes in different compartments of the immune response, at the same time affecting the downregulation of immune suppressor cells (regulatory T cells). These experiments not only resulted in the registration of combination therapy with nivolumab and ipilimumab, but also initiated other clinical trials using immune checkpoint inhibitors (ICIs) in combination with other ICIs or activators of costimulatory molecules found on immune cells. There are also studies in which ICIs are associated with molecules that modify the tumour environment. This paper describes the mechanism of the synergistic effect of a combination of different immunotherapy methods in NSCLC patients. Full article
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Review
Sinonasal Squamous Cell Carcinoma, a Narrative Reappraisal of the Current Evidence
Cancers 2021, 13(11), 2835; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112835 - 07 Jun 2021
Viewed by 628
Abstract
Sinonasal squamous cell carcinoma is a rare tumor affecting the nasal cavity and paranasal sinuses. Several aspects of this disease, ranging from epidemiology to biology, pathology, diagnosis, staging, treatment, and post-treatment surveillance are controversial, and consensus on how to manage this sinonasal cancer [...] Read more.
Sinonasal squamous cell carcinoma is a rare tumor affecting the nasal cavity and paranasal sinuses. Several aspects of this disease, ranging from epidemiology to biology, pathology, diagnosis, staging, treatment, and post-treatment surveillance are controversial, and consensus on how to manage this sinonasal cancer is lacking. A narrative literature review was performed to summarize the current evidence and provide the reader with available data supporting the decision-making process in patients affected by sinonasal squamous cell carcinoma, alongside the authors’ personal opinion on the unsolved issues of this tumor. The review has highlighted several advances in molecular definition of epithelial cancers of the sinonasal tract. Surgery represents the pivot of treatment and is performed through an endoscopic transnasal approach whenever feasible. Open surgery is required for a large proportion of cases. Reconstruction of the defect follows principles of skull base and cranio-maxillo-facial reconstruction. Chemotherapy is given as neoadjuvant treatment or concomitantly to radiotherapy. Photon-based radiation therapy has a crucial role in the adjuvant setting. Particle therapy is providing promising results. Management of the neck should be planned based on the presence of clinically appreciable metastases, primary tumor extension, and need for recipient vessels. Biotherapy and immunotherapy are still underexplored therapeutical modalities. Full article
(This article belongs to the Special Issue Surgical Treatment of Head and Neck Squamous Cell Carcinomas (HNSCC))
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Article
Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential
Cancers 2021, 13(11), 2834; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112834 - 07 Jun 2021
Viewed by 666
Abstract
The heterogeneity of triple negative breast cancer (TNBC) has led to efforts to further subtype this disease with the hope of identifying new molecular liabilities and drug targets. Furthermore, the finding that TNBC is the most inherently immunogenic type of breast cancer provides [...] Read more.
The heterogeneity of triple negative breast cancer (TNBC) has led to efforts to further subtype this disease with the hope of identifying new molecular liabilities and drug targets. Furthermore, the finding that TNBC is the most inherently immunogenic type of breast cancer provides the potential for effective treatment with immune checkpoint inhibitors and immune adjuvants. Thus, we devised a dual screen to identify compounds from natural product extracts with TNBC subtype selectivity that also promote the expression of cytokines associated with antitumor immunity. These efforts led to the identification of yuanhuacine (1) as a potent and highly selective inhibitor of the basal-like 2 (BL2) subtype of TNBC that also promoted an antitumor associated cytokine signature in immune cells. The mechanism of action of yuanhuacine for both phenotypes depends on activation of protein kinase C (PKC), defining a novel target for the treatment of this clinical TNBC subtype. Yuanhuacine showed potent antitumor efficacy in animals bearing BL2 tumors further demonstrating that PKC could function as a potential pharmacological target for the treatment of the BL2 subtype of TNBC. Full article
(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)
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Article
Pretreatment Plasma IL-6 and YKL-40 and Overall Survival after Surgery for Metastatic Bone Disease of the Extremities
Cancers 2021, 13(11), 2833; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112833 - 07 Jun 2021
Viewed by 466
Abstract
Background: Plasma IL-6 and YKL-40 are prognostic biomarkers for OS in patients with different types of solid tumors, but they have not been studied in patients before surgery of metastatic bone disease (MBD) of the extremities. The aim was to evaluate the prognostic [...] Read more.
Background: Plasma IL-6 and YKL-40 are prognostic biomarkers for OS in patients with different types of solid tumors, but they have not been studied in patients before surgery of metastatic bone disease (MBD) of the extremities. The aim was to evaluate the prognostic value of plasma IL-6 and YKL-40 in patients undergoing surgery for MBD of the extremities. Patients and Methods: A prospective study included all patients undergoing surgery for MBD in the extremities at a tertiary referral center during the period 2014–2018. Preoperative blood samples from index surgery were included. IL-6 and YKL-40 concentrations in plasma were determined by commercial ELISA. A total of 232 patients (median age 66 years, IQR 58–74; female 51%) were included. Results: Cox regression analysis was performed to identify independent prognostic factors for OS. IL-6 correlated with YKL-40 (rho = 0.46, p < 0.01). In univariate analysis (log2 continuous variable) IL-6 (HR = 1.26, 95% CI 1.16–1.37), CRP (HR = 1.20, 95% CI 1.12–1.29) and YKL-40 (HR = 1.25, 95% CI 1.15–1.37) were associated with short OS. In multivariable analysis, adjusted for known risk factors for survival, only log2(IL-6) was independently associated with OS (HR = 1.24, 95% CI 1.08–1.43), whereas CRP and YKL-40 were not. Conclusion: High preoperative plasma IL-6 is an independent biomarker of short OS in patients undergoing surgery for MBD. Full article
(This article belongs to the Special Issue Surgical Treatment of Bone Metastases)
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Review
Neutrophil Extracellular Traps in Tumor Metastasis: Pathological Functions and Clinical Applications
Cancers 2021, 13(11), 2832; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112832 - 06 Jun 2021
Viewed by 705
Abstract
Neutrophil extracellular trap (NET) formation is an ability of neutrophils to capture and kill pathogens by releasing chromatin scaffolds, along with associated cytotoxic enzymes and proteases, into the extracellular space. NETs are usually stimulated by pathogenic microorganisms and their products, surgical pressure or [...] Read more.
Neutrophil extracellular trap (NET) formation is an ability of neutrophils to capture and kill pathogens by releasing chromatin scaffolds, along with associated cytotoxic enzymes and proteases, into the extracellular space. NETs are usually stimulated by pathogenic microorganisms and their products, surgical pressure or hypoxia. Interestingly, a number of recent studies suggest that tumor cells can induce NET formation, which in turn confers tumor cell malignancy. Notably, emerging studies indicate that NETs are involved in enhancing local invasion, increasing vascular permeability and facilitating immune escape and colonization, thus promoting tumor metastasis. In this article, we review the pivotal roles of NETs in the tumor metastasis cascade. We also recapitulate the potential of NETs as a cancer prognostic biomarker and therapeutic target. Full article
(This article belongs to the Special Issue Emerging Roles of Immune Cells in Cancer Development and Progression)
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Article
Indications and Clinical Outcomes of Transoral Robotic Surgery and Free Flap Reconstruction
Cancers 2021, 13(11), 2831; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112831 - 06 Jun 2021
Viewed by 926
Abstract
We reviewed the indications, peroperative feasibility, and postoperative clinical outcomes of our first 50 consecutive patients who underwent free flap reconstruction after TORS for complex pharyngeal defects at our institution. We analyzed indications according to previous radiotherapy, the size of the resection, and [...] Read more.
We reviewed the indications, peroperative feasibility, and postoperative clinical outcomes of our first 50 consecutive patients who underwent free flap reconstruction after TORS for complex pharyngeal defects at our institution. We analyzed indications according to previous radiotherapy, the size of the resection, and the transoral exposure of critical structures. We reviewed surgical data, postoperative complications, and functional outcomes comprising tracheostomy and alimentation management. Indications were upfront surgery (34%), a second primary surgery after radiotherapy (28%), or salvage surgery after chemoradiotherapy failure (38%). Localizations were the tongue base (44%), tonsillar fossa (28%), pharyngeal wall (22%), and soft palate (6%). T-classifications were T1 (6%), T2 (52%), T3 (20%), and T4 (22%). The mean length of the surgery was 574 min. Two patients were intraoperatively converted to a conventional approach at the beginning of the learning curve. In conclusion, TORS and free flap reconstruction in complex situations were associated with low rates of postoperative complications and satisfactory functional outcomes. They were, however, associated with a renewed learning curve. Full article
(This article belongs to the Special Issue Surgical Treatment of Head and Neck Squamous Cell Carcinomas (HNSCC))
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Article
Neutrophil-to-Lymphocyte Ratio as a Biomarker Predicting Overall Survival after Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma
Cancers 2021, 13(11), 2830; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112830 - 06 Jun 2021
Viewed by 707
Abstract
The clinical impact of neutrophil-to-lymphocyte ratio (NLR) in predicting outcomes in hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) remain unclear, and additional large-scale studies are required. This retrospective study evaluated outcomes in treatment-naïve patients who received TACE as first-line treatment for [...] Read more.
The clinical impact of neutrophil-to-lymphocyte ratio (NLR) in predicting outcomes in hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) remain unclear, and additional large-scale studies are required. This retrospective study evaluated outcomes in treatment-naïve patients who received TACE as first-line treatment for intermediate-stage HCC between 2008 and 2017. Patients who underwent TACE before and after 2013 were assigned to the development (n = 495) and validation (n = 436) cohorts, respectively. Multivariable Cox analysis identified six factors predictive of outcome, including NLR, which were used to create models predictive of overall survival (OS) in the development cohort. Risk scores of 0–3, 4–7, and 8–12 were defined as low, intermediate, and high risk, respectively. Median OS times in the low-, medium-, and high-risk groups in the validation cohort were 48.1, 24.3, and 9.7 months, respectively (p < 0.001). Application to the validation cohort of time-dependent ROC curves for models predictive of OS showed AUC values of 0.72 and 0.70 at 3 and 5 years, respectively. Multivariable logistic regression analysis found that NLR ≥ 3 was a significant predictor (odds ratio, 3.4; p < 0.001) of disease progression 6 months after TACE. Higher baseline NLR was predictive of poor prognosis in patients who underwent TACE for intermediate-stage HCC. Full article
(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)
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Article
Small Proline-Rich Protein 2A and 2D Are Regulated by the RBM38-p73 Axis and Associated with p73-Dependent Suppression of Chronic Inflammation
Cancers 2021, 13(11), 2829; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112829 - 06 Jun 2021
Viewed by 585
Abstract
Small proline-rich protein 2A and 2D (SPRR2A and SPRR2D) provide barrier function in terminally differentiated stratified squamous epithelia through the epidermal differentiation complex. However, little is known how SPRR2A/2D expression is controlled and their role in chronic inflammation. Here, we showed that that [...] Read more.
Small proline-rich protein 2A and 2D (SPRR2A and SPRR2D) provide barrier function in terminally differentiated stratified squamous epithelia through the epidermal differentiation complex. However, little is known how SPRR2A/2D expression is controlled and their role in chronic inflammation. Here, we showed that that SPRR2A/2D expression is controlled by a regulatory loop formed by RNA-binding protein RBM38 and tumor suppressor p73. Specifically, we found that SPRR2A/2D expression was induced by ectopic expression of RBM38 or p73 but suppressed by knockout of Rbm38 or p73. We also found that RBM38-mediated expression of SPRR2A/2D was p73-dependent and that induction of SPRR2A/2D during keratinocyte differentiation was dependent on both p73 and Rbm38. Additionally, we found that SPRR2A/2D expression was closely associated with p73 expression in normal and cancerous tissues. To determine the biological function of the RBM38-p73 loop potentially via SPRR2A/2D, we generated a cohort of wild-type, Rbm38−/−, Trp73+/−, and Rbm38−/−;Trp73+/− mice. We found that Rbm38−/−;Trp73+/− mice had a much shorter lifespan than that for Rbm38−/−—and to a lesser extent for Trp73+/− mice—but were less prone to spontaneous tumors than Trp73+/− or Rbm38−/− mice. We also found that Rbm38−/−;Trp73+/− mice exhibited weak expression of SPRR2A/2D in multiple tissues and were susceptible to systemic chronic inflammation, suggesting that decreased SPRR2A/2D expression is likely responsible for chronic inflammation in Rbm38−/−;Trp73+/− mice, leading to a shortened lifespan. Together, our data reveal that SPRR2A/2D are novel targets of the RBM38-p73 loop and contribute to p73-dependent suppression of chronic inflammation. Full article
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Article
Prospective SPECT-CT Organ Dosimetry-Driven Radiation-Absorbed Dose Escalation Using the In-111 (111In)/Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) Theranostic Pair in Patients with Lymphoma at Myeloablative Dose Levels
Cancers 2021, 13(11), 2828; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112828 - 06 Jun 2021
Viewed by 662
Abstract
Purpose: We prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin’s lymphoma using the theranostic pair of 111In and 90Y anti-CD20 ibritumomab tiuxetan (Zevalin®) at myeloablative radiation-absorbed doses with autologous stem [...] Read more.
Purpose: We prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin’s lymphoma using the theranostic pair of 111In and 90Y anti-CD20 ibritumomab tiuxetan (Zevalin®) at myeloablative radiation-absorbed doses with autologous stem cell support. We also assessed acute non-hematopoietic toxicity and early tumor response in this two-center outpatient study. Methods: 24 patients with CD20-positive relapsed or refractory rituximab-sensitive, low-grade, mantle cell, or diffuse large-cell NHL, with normal organ function, platelet counts > 75,000/mm3, and <35% tumor involvement in the marrow were treated with Rituximab (375 mg/m2) weekly for 4 consecutive weeks, then one dose of cyclophosphamide 2.5 g/m2 with filgrastim 10 mcg/kg/day until stem cell collection. Of these, 18 patients with successful stem cell collection (at least 2 × 106 CD34 cells/kg) proceeded to RIT. A dosimetric administration of 111In ibritumomab tiuxetan (185 MBq) followed by five sequential quantitative planar and one SPECT/CT scan was used to determine predicted organ radiation-absorbed dose. Two weeks later, 90Y ibritumomab tiuxetan was administered in an outpatient setting at a cohort- and patient-specific predicted organ radiation-absorbed dose guided by a Continuous Response Assessment (CRM) methodology with the following cohorts for dose escalation: 14.8 MBq/kg, and targeted 18, 24, 28, and 30.5 Gy to the liver. Autologous stem cell infusion occurred when the estimated marrow radiation-absorbed dose rate was predicted to be <1 cGy/h. Feasibility, short-term toxicities, and tumor response were assessed. Results: Patient-specific hybrid SPECT/CT + planar organ dosimetry was feasible in all 18 cases and used to determine the patient-specific therapeutic dose and guide dose escalation (26.8 ± 7.3 MBq/kg (mean), 26.3 MBq/kg (median) of 90Y (range: 12.1–41.4 MBq/kg)) of ibritumomab tiuxetan that was required to deliver 10 Gy to the liver. Infused stem cells engrafted rapidly. The most common treatment-related toxicities were hematological and were reversible following stem cell infusion. No significant hepatotoxicity was seen. One patient died from probable treatment-related causes—pneumonia at day 27 post-transplant. One patient at dose level 18 Gy developed myelodysplastic syndrome (MDS), 4 patients required admission post-90Y RIT for febrile neutropenia, 16/18 patients receiving 90Y ibritumomab tiuxetan (89%) responded to the therapy, with 13 CR (72%) and 3/18 PR (17%), at 60 days post-treatment. Two patients had progressive disease at sixty days. One patient was lost to follow-up. Median time to progression was estimated to be at least 13 months. MTD to the liver is greater than 28 Gy, but the MTD was not reached as the study was terminated due to unexpected discontinuation of availability of the therapeutic agent. Conclusions: Patient-specific outpatient 90Y ibritumomab tiuxetan RIT with myeloablative doses of RIT up to a targeted 30.5 Gy to the liver is feasible, guided by prospective SPECT/CT + planar imaging with the theranostic pair of 111In and 90Y anti-CD20, with outpatient autologous stem cell transplant support. Administered activity over 5 times the standard FDA-approved activity was well-tolerated. The non-hematopoietic MTD in this study exceeds 28 Gy to the liver. Initial tumor responses were common at all dose levels. This study supports the feasibility of organ dosimetry-driven patient-specific dose escalation in the treatment of NHL with stem cell transplant and provides additional information on the radiation tolerance of the normal liver to radiopharmaceutical therapy. Full article
(This article belongs to the Special Issue Antibodies in Cancer Treatment)
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Systematic Review
Do Salivary Bypass Tubes Reduce the Risk of Pharyngocutaneous Fistula after Laryngopharyngectomy—A Systematic Review and Meta-Analysis
Cancers 2021, 13(11), 2827; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112827 - 06 Jun 2021
Viewed by 498
Abstract
To evaluate the effect of salivary bypass tube (SBT) usage on the occurrence of pharyngocutaneous fistula (PCF) in patients after a laryngopharyngectomy, a total of 20 studies, published between 1988 and 2021, were identified including 2946 patients. We performed a meta-analysis assessing the [...] Read more.
To evaluate the effect of salivary bypass tube (SBT) usage on the occurrence of pharyngocutaneous fistula (PCF) in patients after a laryngopharyngectomy, a total of 20 studies, published between 1988 and 2021, were identified including 2946 patients. We performed a meta-analysis assessing the risk of PCF occurrence in patients after SBT application compared to those without. PCF occurred in 26.8% of cases (669/2496) and SBT was applied in 33.0% of patients (820/2483). There was an overall trend towards lower PCF rates when using SBTs (22.2% vs. 35.3%; p = 0.057). We further selected five studies, comprising 580 patients who underwent laryngopharyngectomies, for meta-analysis showing that application of SBT reduced the risk of PCF formation (OR 0.46; 95% CI 0.18–1.18; p = 0.11). The meta-analysis demonstrates a beneficial effect of SBT insertion on PCF formation in patients after laryngopharyngectomy. Full article
(This article belongs to the Special Issue Larynx Cancer: From Diagnosis to Treatment and Rehabilitation)
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Article
Toxicity, Response and Survival in Older Patients with Metastatic Melanoma Treated with Checkpoint Inhibitors
Cancers 2021, 13(11), 2826; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112826 - 05 Jun 2021
Viewed by 653
Abstract
Background: Previous trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included. The aim of this study was to describe the treatment patterns and outcomes of “real-world” older patients with [...] Read more.
Background: Previous trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included. The aim of this study was to describe the treatment patterns and outcomes of “real-world” older patients with metastatic melanoma and to identify predictors of outcome. Methods: We included patients aged ≥65 years with metastatic melanoma from the Dutch Melanoma Treatment Registry. We described the reasons for hospital admissions and treatment discontinuation. Additionally, we assessed predictors of toxicity and response using logistic regression models and survival using Cox regression models. Results: We included 2216 patients. Grade ≥3 toxicity was not associated with age, comorbidities or WHO status. Patients aged ≥75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. Response rates were similar to previous trials (40.3% and 43.6% in patients aged 65–75 and ≥75, respectively, for anti-PD1 treatment) and did not decrease with age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity. Conclusion: Response rates and toxicity outcomes of checkpoint inhibitors did not change with increasing age or comorbidity. However, the impact of grade I-II toxicity on quality of life deserves further study as older patients discontinue treatment more frequently. Full article
(This article belongs to the Special Issue Geriatric Oncology: From Research to Clinical Practice)
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Review
Tribbles Pseudokinases in Colorectal Cancer
Cancers 2021, 13(11), 2825; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112825 - 05 Jun 2021
Viewed by 554
Abstract
The Tribbles family of pseudokinases controls a wide number of processes during cancer on-set and progression. However, the exact contribution of each of the three family members is still to be defined. Their function appears to be context-dependent as they can act as [...] Read more.
The Tribbles family of pseudokinases controls a wide number of processes during cancer on-set and progression. However, the exact contribution of each of the three family members is still to be defined. Their function appears to be context-dependent as they can act as oncogenes or tumor suppressor genes. They act as scaffolds modulating the activity of several signaling pathways involved in different cellular processes. In this review, we discuss the state-of-knowledge for TRIB1, TRIB2 and TRIB3 in the development and progression of colorectal cancer. We take a perspective look at the role of Tribbles proteins as potential biomarkers and therapeutic targets. Specifically, we chronologically systematized all available articles since 2003 until 2020, for which Tribbles were associated with colorectal cancer human samples or cell lines. Herein, we discuss: (1) Tribbles amplification and overexpression; (2) the clinical significance of Tribbles overexpression; (3) upstream Tribbles gene and protein expression regulation; (4) Tribbles pharmacological modulation; (5) genetic modulation of Tribbles; and (6) downstream mechanisms regulated by Tribbles; establishing a comprehensive timeline, essential to better consolidate the current knowledge of Tribbles’ role in colorectal cancer. Full article
(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)
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Article
HER2-Low Breast Cancer: Molecular Characteristics and Prognosis
Cancers 2021, 13(11), 2824; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112824 - 05 Jun 2021
Viewed by 931
Abstract
Background: We aimed to determine the distribution of intrinsic subtypes within HER2-low breast cancer (BC), and to describe the prognostic impact of HER2-low status on survival outcomes. Methods: This is a retrospective, observational study of primary BC extracted from The Cancer Genome Atlas [...] Read more.
Background: We aimed to determine the distribution of intrinsic subtypes within HER2-low breast cancer (BC), and to describe the prognostic impact of HER2-low status on survival outcomes. Methods: This is a retrospective, observational study of primary BC extracted from The Cancer Genome Atlas dataset. We described the distribution of PAM50 intrinsic subtypes within HER2-low BC subtype according to hormonal receptor status (positive (HR+) and negative (HR−)). Secondly, we assessed the impact of HER2-low on survival outcomes (progression-free interval (PFI), disease-free interval (DFI), and overall survival (OS)). Results: We analyzed 804 primary BCs, including 410 (51%) HER2-low BCs (336 HR+ and 74 HR−). The proportion of HER2-enriched tumors was higher in the HER2-low/HR− group compared to HER2-low/HR+ (13.7% versus 1.2%, respectively). HER2-enriched tumors were more frequent in HER2-low/HR− and HER2-low/HR+ subtypes, compared to HER2-negative/HR− and HER2-negative/HR+ subtypes, respectively (13.7% versus 1.6% and 1.2% versus 0.5%, respectively). We observed no significant differences in PFI, DFI, and OS between HER2-low subtypes and each non-HER2-low subtype paired by HR status. Conclusions: Our characterization of PAM50 intrinsic subtypes within HER2-low breast cancer may explain the different clinical behaviors and responses to treatment, and ultimately support further investigation of new treatment strategies in the HER2-low category. Moreover, it highlights the importance of considering HR status in the HER2-low category. Full article
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Review
Cadmium-Associated Molecular Signatures in Cancer Cell Models
Cancers 2021, 13(11), 2823; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112823 - 05 Jun 2021
Viewed by 527
Abstract
The exposure of cancer cells to cadmium and its compounds is often associated with the development of more malignant phenotypes, thereby contributing to the acceleration of tumor progression. It is known that cadmium is a transcriptional regulator that induces molecular reprogramming, and therefore [...] Read more.
The exposure of cancer cells to cadmium and its compounds is often associated with the development of more malignant phenotypes, thereby contributing to the acceleration of tumor progression. It is known that cadmium is a transcriptional regulator that induces molecular reprogramming, and therefore the study of differentially expressed genes has enabled the identification and classification of molecular signatures inherent in human neoplastic cells upon cadmium exposure as useful biomarkers that are potentially transferable to clinical research. This review recapitulates selected studies that report the detection of cadmium-associated signatures in breast, gastric, colon, liver, lung, and nasopharyngeal tumor cell models, as specifically demonstrated by individual gene or whole genome expression profiling. Where available, the molecular, biochemical, and/or physiological aspects associated with the targeted gene activation or silencing in the discussed cell models are also outlined. Full article
(This article belongs to the Collection Occupational and Environmental Carcinogenesis)
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Review
New Targeted Therapies and Immunotherapies for Locally Advanced Periocular Malignant Tumours: Towards a New ‘Eye-Sparing’ Paradigm?
Cancers 2021, 13(11), 2822; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112822 - 05 Jun 2021
Viewed by 515
Abstract
The management of periocular skin malignant tumours is challenging. Surgery remains the mainstay of treatment for localised eyelid cancers. For more locally advanced cancers, especially those invading the orbit, orbital exenteration has long been considered the gold standard; however, it is a highly [...] Read more.
The management of periocular skin malignant tumours is challenging. Surgery remains the mainstay of treatment for localised eyelid cancers. For more locally advanced cancers, especially those invading the orbit, orbital exenteration has long been considered the gold standard; however, it is a highly disfiguring and traumatic surgery. The last two decades have been marked by the emergence of a new paradigm shift towards the use of ‘eye-sparing’ strategies. In the early 2000s, the first step consisted of performing wide conservative eyelid and orbital excisions. Multiple flaps and grafts were needed, as well as adjuvant radiotherapy in selected cases. Although being incredibly attractive, several limitations such as the inability to treat the more posteriorly located orbital lesions, as well as unbearable diplopia, eye pain and even secondary eye loss were identified. Therefore, surgeons should distinguish ‘eye-sparing’ from ‘sight-sparing’ strategies. The second step emerged over the last decade and was based on the development of targeted therapies and immunotherapies. Their advantages include their potential ability to treat almost all tumours, regardless of their locations, without performing complex surgeries. However, several limitations have been reported, including their side effects, the appearance of primary or secondary resistances, their price and the lack of consensus on treatment regimen and exact duration. The aim of this article was to review the evolution of the management of locally advanced periocular malignant tumours over the last three decades and highlight the new paradigm shift towards the use of ‘eye-sparing’ strategies. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Cancer)
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Review
Restoring the Immunity in the Tumor Microenvironment: Insights into Immunogenic Cell Death in Onco-Therapies
Cancers 2021, 13(11), 2821; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112821 - 05 Jun 2021
Viewed by 774
Abstract
Immunogenic cell death (ICD) elicited by cancer therapy reshapes the tumor immune microenvironment. A long-term adaptative immune response can be initiated by modulating cell death by therapeutic approaches. Here, the major hallmarks of ICD, endoplasmic reticulum (ER) stress, and damage-associated molecular patterns (DAMPs) [...] Read more.
Immunogenic cell death (ICD) elicited by cancer therapy reshapes the tumor immune microenvironment. A long-term adaptative immune response can be initiated by modulating cell death by therapeutic approaches. Here, the major hallmarks of ICD, endoplasmic reticulum (ER) stress, and damage-associated molecular patterns (DAMPs) are correlated with ICD inducers used in clinical practice to enhance antitumoral activity by suppressing tumor immune evasion. Approaches to monitoring the ICD triggered by antitumoral therapeutics in the tumor microenvironment (TME) and novel perspective in this immune system strategy are also reviewed to give an overview of the relevance of ICD in cancer treatment. Full article
(This article belongs to the Special Issue Immunogenic Cell Death and Immunotherapy in Cancers)
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