Cancers

12 pages, 1555 KiB

Open AccessArticle

Late Local Recurrence of Bone Giant Cell Tumors Associated with an Increased Risk for Malignant Transformation

by Shinji Tsukamoto, Alberto Righi, Andreas F. Mavrogenis, Manabu Akahane, Kanya Honoki, Yasuhito Tanaka, Davide Maria Donati and Costantino Errani

Cancers 2021, 13(14), 3644; https://doi.org/10.3390/cancers13143644 - 20 Jul 2021

Cited by 10 | Viewed by 2330

Abstract

In giant cell tumor of bone (GCTB), an intermediate malignant bone tumor, approximately 4% of all cases undergo malignant transformation. Accordingly, we analyzed risk factors for malignant transformation of GCTB treated without radiotherapy. We retrospectively reviewed medical records of 530 patients with GCTB [...] Read more.

In giant cell tumor of bone (GCTB), an intermediate malignant bone tumor, approximately 4% of all cases undergo malignant transformation. Accordingly, we analyzed risk factors for malignant transformation of GCTB treated without radiotherapy. We retrospectively reviewed medical records of 530 patients with GCTB of the extremities, admitted and treated at two institutions between January 1980 and December 2019. Overall, 4 patients with primary malignant GCTB, 4 patients with missing data, 3 patients with a history of radiotherapy, 22 patients with a follow-up of less than 6 months, and 36 patients who received denosumab were excluded. Accordingly, 461 patients were included for further analysis. Malignant transformation was observed in 15 of 461 patients (3.3%) at a median follow-up period of 192 months. The median follow-up duration was 89.4 months. Multivariate analysis revealed that local recurrence was an independent prognostic factor for unfavorable malignant transformation (Hazard ratio [HR], 11.33; 95% confidence interval [CI] 2.33–55.13; p = 0.003 for once versus none and HR, 11.24; 95% CI, 1.76–71.96; and p = 0.011 for twice or more versus none). The interval between the last surgery to local recurrence and malignant transformation was longer than that to local recurrence of benign GCTB, with a median of 15.2 years (interquartile range [IQR], 5.2–25.4) versus 1.3 months (IQR, 0.8–2.6), respectively (p < 0.001). Late local recurrence of GCTB is associated with a higher risk of malignant transformation. Full article

(This article belongs to the Special Issue Research Advances in Giant Cell Tumor of Bone)

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16 pages, 7575 KiB

Open AccessArticle

FORGE: A Novel Scoring System to Predict the MIB-1 Labeling Index in Intracranial Meningiomas

by Johannes Wach, Tim Lampmann, Ági Güresir, Patrick Schuss, Hartmut Vatter, Ulrich Herrlinger, Albert Becker, Michael Hölzel, Marieta Toma and Erdem Güresir

Cancers 2021, 13(14), 3643; https://doi.org/10.3390/cancers13143643 - 20 Jul 2021

Cited by 10 | Viewed by 2395

Abstract

The MIB-1 index is an essential predictor of progression-free-survival (PFS) in meningioma. To date, the MIB-1 index is not available in preoperative treatment planning. A preoperative score estimating the MIB-1 index in patients with intracranial meningiomas has not been investigated so far. Between [...] Read more.

The MIB-1 index is an essential predictor of progression-free-survival (PFS) in meningioma. To date, the MIB-1 index is not available in preoperative treatment planning. A preoperative score estimating the MIB-1 index in patients with intracranial meningiomas has not been investigated so far. Between 2013 and 2019, 208 patients with tumor morphology data, MIB-1 index data, and plasma fibrinogen and serum C-reactive protein (CRP) data underwent surgery for intracranial WHO grade I and II meningioma. An optimal MIB-1 index cut-off value (≥6/<6) in the prediction of recurrence was determined by ROC curve analysis (AUC: 0.71; 95% CI: 0.55–0.87). A high MIB-1 index (≥6%) was present in 50 cases (24.0%) and was significantly associated with male sex, peritumoral edema, low baseline CRP, and low fibrinogen level in the multivariate analysis. A scoring system (“FORGE”) based on sex, peritumoral edema, preoperative CRP value, and plasma fibrinogen level supports prediction of the MIB-1 index (sensitivity 62%, specificity 79%). The MIB-1 labeling index and the FORGE score are significantly associated with an increased risk of poor PFS time. We suggest a novel score (“FORGE”) to preoperatively estimate the risk of an increased MIB-1 index (≥6%), which might help in surgical decision making and follow-up interval determination and inform future trials investigating inflammatory burden and proliferative activity. Full article

(This article belongs to the Special Issue Advances in Research on Human Meningiomas)

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14 pages, 2804 KiB

Open AccessArticle

Identification of Blood-Based Biomarkers for the Prediction of the Response to Neoadjuvant Chemoradiation in Rectal Cancer

by Delphine Dayde, Jillian Gunther, Yutaka Hirayama, David C. Weksberg, Adam Boutin, Gargy Parhy, Clemente Aguilar-Bonavides, Hong Wang, Hiroyuki Katayama, Yuichi Abe, Kim-Anh Do, Kazuo Hara, Takashi Kinoshita, Koji Komori, Yasuhiro Shimizu, Masahiro Tajika, Yasumasa Niwa, Y. Alan Wang, Ronald DePinho, Samir Hanash, Sunil Krishnan and Ayumu Taguchi Show full author list Hide full author list

Cancers 2021, 13(14), 3642; https://doi.org/10.3390/cancers13143642 - 20 Jul 2021

Cited by 7 | Viewed by 2492

Abstract

The current standard of care for patients with locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation (nCRT) followed by total mesorectal excision surgery. However, the response to nCRT varies among patients and only about 20% of LARC patients achieve a pathologic complete response [...] Read more.

The current standard of care for patients with locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation (nCRT) followed by total mesorectal excision surgery. However, the response to nCRT varies among patients and only about 20% of LARC patients achieve a pathologic complete response (pCR) at the time of surgery. Therefore, there is an unmet need for biomarkers that could predict the response to nCRT at an early time point, allowing for the selection of LARC patients who would or would not benefit from nCRT. To identify blood-based biomarkers for prediction of nCRT response, we performed in-depth quantitative proteomic analysis of pretreatment plasma from mice bearing rectal tumors treated with concurrent chemoradiation, resulting in the quantification of 567 proteins. Among the plasma proteins that increased in mice with residual rectal tumor after chemoradiation compared to mice that achieved regression, we selected three proteins (Vascular endothelial growth factor receptor 3 [VEGFR3], Insulin like growth factor binding protein 4 [IGFBP4], and Cathepsin B [CTSB]) for validation in human plasma samples. In addition, we explored whether four tissue protein biomarkers previously shown to predict response to nCRT (Epidermal growth factor receptor [EGFR], Ki-67, E-cadherin, and Prostaglandin G/H synthase 2 [COX2]) also act as potential blood biomarkers. Using immunoassays for these seven biomarker candidates as well as Carcinoembryonic antigen [CEA] levels on plasma collected before nCRT from 34 patients with LARC (6 pCR and 28 non-pCR), we observed that levels of VEGFR3 (p = 0.0451, AUC = 0.720), EGFR (p = 0.0128, AUC = 0.679), and COX2 (p = 0.0397, AUC = 0.679) were significantly increased in the plasma of non-pCR LARC patients compared to those of pCR LARC patients. The performance of the logistic regression model combining VEGFR3, EGFR, and COX2 was significantly improved compared with the performance of each biomarker, yielding an AUC of 0.869 (sensitivity 43% at 95% specificity). Levels of VEGFR3 and EGFR were significantly decreased 5 to 7 months after tumor resection in plasma from 18 surgically resected rectal cancer patients, suggesting that VEGFR3 and EGFR may emanate from tumors. These findings suggest that circulating VEGFR3 can contribute to the prediction of the nCRT response in LARC patients together with circulating EGFR and COX2. Full article

(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)

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27 pages, 3570 KiB

Open AccessArticle

A Nationwide Study on the Impact of Routine Testing for EGFR Mutations in Advanced NSCLC Reveals Distinct Survival Patterns Based on EGFR Mutation Subclasses

by Bart Koopman, Betzabel N. Cajiao Garcia, Chantal C. H. J. Kuijpers, Ronald A. M. Damhuis, Anthonie J. van der Wekken, Harry J. M. Groen, Ed Schuuring, Stefan M. Willems and Léon C. van Kempen

Cancers 2021, 13(14), 3641; https://doi.org/10.3390/cancers13143641 - 20 Jul 2021

Cited by 12 | Viewed by 4113

Abstract

EGFR mutation analysis in non-small-cell lung cancer (NSCLC) patients is currently standard-of-care. We determined the uptake of EGFR testing, test results and survival of EGFR-mutant NSCLC patients in the Netherlands, with the overall objective to characterize the landscape of clinically actionable EGFR [...] Read more.

EGFR mutation analysis in non-small-cell lung cancer (NSCLC) patients is currently standard-of-care. We determined the uptake of EGFR testing, test results and survival of EGFR-mutant NSCLC patients in the Netherlands, with the overall objective to characterize the landscape of clinically actionable EGFR mutations and determine the role and clinical relevance of uncommon and composite EGFR mutations. Non-squamous NSCLC patients diagnosed in 2013, 2015 and 2017 were identified in the Netherlands Cancer Registry (NCR) and matched to the Dutch Pathology Registry (PALGA). Overall, 10,254 patients were included. Between 2013–2017, the uptake of EGFR testing gradually increased from 72.7% to 80.9% (p < 0.001). Multi-gene testing via next-generation sequencing (increased from 7.8% to 78.7% (p < 0.001), but did not affect the number of detected EGFR mutations (n = 925; 11.7%; 95% confidence interval (CI), 11.0–12.4) nor the distribution of variants. For patients treated with first-line EGFR inhibitors (n = 651), exon 19 deletions were associated with longer OS than L858R (HR 1.58; 95% CI, 1.30–1.92; p < 0.001) or uncommon, actionable variants (HR 2.13; 95% CI, 1.60–2.84; p < 0.001). Interestingly, OS for patients with L858R was similar to those with uncommon, actionable variants (HR 1.31; 95% CI, 0.98–1.75; p = 0.069). Our analysis indicates that grouping exon 19 deletions and L858R into one class of ‘common’ EGFR mutations in a clinical trial may mask the true activity of an EGFR inhibitor towards specific mutations. Full article

(This article belongs to the Section Cancer Therapy)

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17 pages, 872 KiB

Open AccessArticle

Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors

by Deirdre Kelly, April A. N. Rose, Thiago Pimentel Muniz, David Hogg, Marcus O. Butler, Samuel D. Saibil, Ian King, Zaid Saeed Kamil, Danny Ghazarian, Kendra Ross, Marco Iafolla, Daniel V. Araujo, John Waldron, Normand Laperriere, Hatem Krema and Anna Spreafico

Cancers 2021, 13(14), 3640; https://doi.org/10.3390/cancers13143640 - 20 Jul 2021

Cited by 5 | Viewed by 2841

Abstract

Metastatic uveal melanoma (mUM) is a rare disease. There are limited data on prognostic clinical factors for overall survival (OS) in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0–17% for anti-PD1/L1 [...] Read more.

Metastatic uveal melanoma (mUM) is a rare disease. There are limited data on prognostic clinical factors for overall survival (OS) in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0–17% for anti-PD1/L1 ± anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients. This study evaluates the characteristics associated with ICI benefit in patients with mUM. We performed a single-center retrospective cohort study of patients with mUM who received anti-PD1/L1 ± anti-CTLA4 ICI between 2014–2019. Clinical and genomic characteristics were collected from a chart review. Treatment response and clinical progression were determined by physician assessment. Multivariable Cox regression models and Kaplan–Meier log-rank tests were used to assess differences in clinical progression-free survival (cPFS) and OS between groups and identify clinical variables associated with ICI outcomes. We identified 71 mUM patients who received 75 lines of ICI therapy. Of these, 54 received anti-PD1/L1 alone, and 21 received anti-PD1/L1 + anti-CTLA4. Patient characteristics were: 53% female, 48% were 65 or older, 72% received one or fewer lines of prior therapy. Within our cohort, 53% of patients had developed metastatic disease <2 years after their initial diagnosis. Bone metastases were present in 12% of patients. The median cPFS was 2.7 months, and the median OS was 10.0 months. In multivariable analyses for both cPFS and OS, the following variables were associated with a good prognosis: ≥2 years from the initial diagnosis to metastatic disease (n = 25), LDH < 1.5 × ULN (n = 45), and absence of bone metastases (n = 66). We developed a Metastatic Uveal Melanoma Prognostic Score (MUMPS). Patients were divided into 3 MUMPS groups based on the number of the above-mentioned prognostic variables: Poor prognosis (0–1), Intermediate prognosis (2) and Good prognosis (3). Good prognosis patients experienced longer cPFS (6.0 months) and OS (34.5 months) than patients with intermediate (2.3 months cPFS, 9.4 months OS) and poor prognosis disease (1.8 months cPFS, 3.9 months OS); p < 0.0001. We developed MUMPS—a prognostic score based on retrospective data that is comprised of 3 readily available clinical variables (time to metastatic diagnosis, presence of bone metastases, and LDH). This MUMPS score has a potential prognostic value. Further validation in independent datasets is warranted to determine the role of this MUMPS score in selecting ICI treatment management for mUM. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

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15 pages, 4133 KiB

Open AccessArticle

Two Dimensional-Difference in Gel Electrophoresis (2D-DIGE) Proteomic Approach for the Identification of Biomarkers in Endometrial Cancer Serum

by Blendi Ura, Stefania Biffi, Lorenzo Monasta, Giorgio Arrigoni, Ilaria Battisti, Giovanni Di Lorenzo, Federico Romano, Michelangelo Aloisio, Fulvio Celsi, Riccardo Addobbati, Francesco Valle, Enrico Rampazzo, Marco Brucale, Andrea Ridolfi, Danilo Licastro and Giuseppe Ricci

Cancers 2021, 13(14), 3639; https://doi.org/10.3390/cancers13143639 - 20 Jul 2021

Cited by 13 | Viewed by 4383

Abstract

Endometrial cancer is the most common gynecologic malignancy arising from the endometrium. Identification of serum biomarkers could be beneficial for its early diagnosis. We have used 2D-Difference In Gel Electrophoresis (2D-DIGE) coupled with Mass Spectrometry (MS) procedures to investigate the serum proteome of [...] Read more.

Endometrial cancer is the most common gynecologic malignancy arising from the endometrium. Identification of serum biomarkers could be beneficial for its early diagnosis. We have used 2D-Difference In Gel Electrophoresis (2D-DIGE) coupled with Mass Spectrometry (MS) procedures to investigate the serum proteome of 15 patients with endometrial cancer and 15 non-cancer subjects. We have identified 16 proteins with diagnostic potential, considering only spots with a fold change in %V ≥ 1.5 or ≤0.6 in intensity, which were statistically significant (p < 0.05). Western blotting data analysis confirmed the upregulation of CLU, ITIH4, SERPINC1, and C1RL in endometrial and exosome cancer sera compared to those of control subjects. The application of the logistic regression constructed based on the abundance of these four proteins separated the controls from the cancers with excellent levels of sensitivity and specificity. After a validation phase, our findings support the potential of using the proposed algorithm as a diagnostic tool in the clinical stage. Full article

(This article belongs to the Special Issue Proteomics in Cancer)

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19 pages, 10351 KiB

Open AccessArticle

SPTAN1 Expression Predicts Treatment and Survival Outcomes in Colorectal Cancer

by Christopher Schrecker, Sophia Behrens, Rebecca Schönherr, Anne Ackermann, Daniel Pauli, Guido Plotz, Stefan Zeuzem and Angela Brieger

Cancers 2021, 13(14), 3638; https://doi.org/10.3390/cancers13143638 - 20 Jul 2021

Cited by 2 | Viewed by 2676

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality. In a cohort of 189 patients with CRC, we recently showed that expression of the cytoskeletal scaffolding protein non-erythroid spectrin αII (SPTAN1) was lower in advanced metastatic tumours. The aim of [...] Read more.

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality. In a cohort of 189 patients with CRC, we recently showed that expression of the cytoskeletal scaffolding protein non-erythroid spectrin αII (SPTAN1) was lower in advanced metastatic tumours. The aim of the present study was to clarify the association of intratumoural SPTAN1 expression levels with treatment and survival outcomes in patients with CRC. The analysis was based on histologic assessment of SPTAN1 protein levels in our own CRC cohort, and transcriptome data of 573 CRC cases from The Cancer Genome Atlas (TCGA). We first establish that high intratumoural levels of SPTAN1 protein and mRNA associate with favourable survival outcomes in patients with CRC. Next, a response prediction signature applied to the TCGA data reveals a possible link between high SPTAN1 transcript levels and improved patient responses to FOLFOX chemotherapy. Complementary in vitro experiments confirm that SPTAN1 knockdown strains of the colon cancer cell lines HT-29, HCT116 mlh1-2 and Caco-2 are less responsive to FOLFOX chemotherapy compared with SPTAN1-proficient control strains. Taken together, we identify SPTAN1 as a novel prognostic biomarker in CRC and show that SPTAN1 expression levels may predict patient responses to chemotherapy. These investigations illustrate how an affordable, histology-based diagnostic test could directly impact therapeutic decision-making at the bedside. Full article

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11 pages, 1232 KiB

Open AccessSystematic Review

Hyperthermic Intrathoracic Chemoperfusion for Malignant Pleural Mesothelioma: Systematic Review and Meta-Analysis

by Tommi Järvinen, Juuso Paajanen, Ilkka Ilonen and Jari Räsänen

Cancers 2021, 13(14), 3637; https://doi.org/10.3390/cancers13143637 - 20 Jul 2021

Cited by 9 | Viewed by 3768

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleural lining with exceptionally poor survival. Hyperthermic intrathoracic chemoperfusion (HITHOC) is commonly used with surgery in limited disease. However, data on its effect on survival are limited. In this systematic review and meta-analysis, [...] Read more.

Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleural lining with exceptionally poor survival. Hyperthermic intrathoracic chemoperfusion (HITHOC) is commonly used with surgery in limited disease. However, data on its effect on survival are limited. In this systematic review and meta-analysis, we analyzed a total of 11 observational articles. HITHOC was compared to control arm that did not receive HITHOC in three studies including 762 patients. The pooled analysis of these studies revealed an SMD of 0.24, with 95% CI of 0.06–0.41 favoring the HITHOC group, reaching statistical significance. The survival effect of HITHOC in epithelioid MPM vs. non-epithelioid MPM was analyzed in four studies. Pooled analysis showed an SMD of 0.79 (95% CI = 0.48–1.10) favoring epithelioid MPM. Based on available data, there seems to be a benefit with HITHOC in regards to overall survival in the treatment of all mesothelioma patients. Multicenter randomized controlled trials are needed to validate and standardize this treatment approach. Full article

(This article belongs to the Special Issue Recent Research on Mesothelioma)

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17 pages, 3732 KiB

Open AccessFeature PaperArticle

Comparing Tumor Cell Invasion and Myeloid Cell Composition in Compatible Primary and Relapsing Glioblastoma

by Dongxu Zhao, Huabin Zhang, Ramazan Uyar, Jubayer A. Hossain, Hrvoje Miletic, Jörg-Christian Tonn, Rainer Glass and Roland E. Kälin

Cancers 2021, 13(14), 3636; https://doi.org/10.3390/cancers13143636 - 20 Jul 2021

Cited by 7 | Viewed by 3380

Abstract

Glioblastoma (GBM) recurrence after treatment is almost inevitable but addressing this issue with adequate preclinical models has remained challenging. Here, we introduce a GBM mouse model allowing non-invasive and scalable de-bulking of a tumor mass located deeply in the brain, which can be [...] Read more.

Glioblastoma (GBM) recurrence after treatment is almost inevitable but addressing this issue with adequate preclinical models has remained challenging. Here, we introduce a GBM mouse model allowing non-invasive and scalable de-bulking of a tumor mass located deeply in the brain, which can be combined with conventional therapeutic approaches. Strong reduction of the GBM volume is achieved after pharmacologically inducing a tumor-specific cell death mechanism. This is followed by GBM re-growth over a predictable timeframe. Pharmacological de-bulking followed by tumor relapse was accomplished with an orthotopic mouse glioma model. Relapsing experimental tumors recapitulated pathological features often observed in recurrent human GBM, like increased invasiveness or altered immune cell composition. Orthotopic implantation of GBM cells originating from biopsies of one patient at initial or follow-up treatment reproduced these findings. Interestingly, relapsing GBM of both models contained a much higher ratio of monocyte-derived macrophages (MDM) versus microglia than primary GBM. This was not altered when combining pharmacological de-bulking with invasive surgery. We interpret that factors released from viable primary GBM cells preferentially attract microglia whereas relapsing tumors preponderantly release chemoattractants for MDM. All in all, this relapse model has the capacity to provide novel insights into clinically highly relevant aspects of GBM treatment. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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21 pages, 12925 KiB

Open AccessArticle

PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1

by Alice Matheux, Matthieu Gassiot, Gaëlle Fromont, Fanny Leenhardt, Abdelhay Boulahtouf, Eric Fabbrizio, Candice Marchive, Aurélie Garcin, Hanane Agherbi, Eve Combès, Alexandre Evrard, Nadine Houédé, Patrick Balaguer, Céline Gongora, Litaty C. Mbatchi and Philippe Pourquier

Cancers 2021, 13(14), 3635; https://doi.org/10.3390/cancers13143635 - 20 Jul 2021

Cited by 9 | Viewed by 2737

Abstract

Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor [...] Read more.

Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor level. Here, we studied the role of PXR (Pregnane X Receptor), a master regulator of metabolism, in the resistance to KIs in a prostate cancer setting. We confirmed that PXR is expressed in prostate tumors and is more frequently detected in advanced forms of the disease. We showed that stable expression of PXR in 22Rv1 prostate cancer cells conferred a resistance to dasatinib and a higher sensitivity to erlotinib, dabrafenib, and afatinib. Higher sensitivity to afatinib was due to a ~ 2-fold increase in its intracellular accumulation and involved the SLC16A1 transporter as its pharmacological inhibition by BAY-8002 suppressed sensitization of 22Rv1 cells to afatinib and was accompanied with reduced intracellular concentration of the drug. We found that PXR could bind to the SLC16A1 promoter and induced its transcription in the presence of PXR agonists. Together, our results suggest that PXR could be a biomarker of response to kinase inhibitors in castration-resistant prostate cancers. Full article

(This article belongs to the Special Issue Advances in Companion Biomarker Development for Prostate Cancer)

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18 pages, 833 KiB

Open AccessReview

Immune Microenvironment Features and Dynamics in Hodgkin Lymphoma

by Clara Bertuzzi, Elena Sabattini and Claudio Agostinelli

Cancers 2021, 13(14), 3634; https://doi.org/10.3390/cancers13143634 - 20 Jul 2021

Cited by 11 | Viewed by 2409

Abstract

Classical Hodgkin’s lymphoma (cHL) accounts for 10% of all lymphoma diagnosis. The peculiar feature of the disease is the presence of large multinucleated Reed–Sternberg and mononuclear Hodgkin cells interspersed with a reactive microenvironment (ME). Due to the production of a large number of [...] Read more.

Classical Hodgkin’s lymphoma (cHL) accounts for 10% of all lymphoma diagnosis. The peculiar feature of the disease is the presence of large multinucleated Reed–Sternberg and mononuclear Hodgkin cells interspersed with a reactive microenvironment (ME). Due to the production of a large number of cytokines, Hodgkin cells (HCs) and Hodgkin Reed–Sternberg cells (HRSCs) attract and favour the expansion of different immune cell populations, modifying their functional status in order to receive prosurvival stimuli and to turn off the antitumour immune response. To this purpose HRSCs shape a biological niche by organizing the spatial distribution of cells in the ME. This review will highlight the contribution of the ME in the pathogenesis and prognosis of cHL and its role as a possible therapeutic target. Full article

(This article belongs to the Special Issue Recent Advances in Hodgkin’s Lymphoma)

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12 pages, 1086 KiB

Open AccessArticle

Characteristics and Lenvatinib Treatment Response of Unresectable Hepatocellular Carcinoma with Iso-High Intensity in the Hepatobiliary Phase of EOB-MRI

by Akinori Kubo, Goki Suda, Megumi Kimura, Osamu Maehara, Yoshimasa Tokuchi, Takashi Kitagataya, Masatsugu Ohara, Ren Yamada, Taku Shigesawa, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi and Naoya Sakamoto

Cancers 2021, 13(14), 3633; https://doi.org/10.3390/cancers13143633 - 20 Jul 2021

Cited by 12 | Viewed by 2452

Abstract

In hepatocellular carcinoma (HCC), CTNNB-1 mutations, which cause resistance to immune checkpoint inhibitors, are associated with HCC with iso-high intensity in the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) in resectable HCC; however, analyses on unresectable HCC are lacking. This study [...] Read more.

In hepatocellular carcinoma (HCC), CTNNB-1 mutations, which cause resistance to immune checkpoint inhibitors, are associated with HCC with iso-high intensity in the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) in resectable HCC; however, analyses on unresectable HCC are lacking. This study analyzed the prevalence, characteristics, response to lenvatinib, and CTNNB-1 mutation frequency in unresectable HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI. In 52 patients with unresectable HCC treated with lenvatinib, the prevalence of iso-high intensity in the hepatobiliary phase of EOB-MRI was 13%. All patients had multiple HCCs, and 3 patients had multiple HCCs with iso-high intensity in the hepatobiliary phase of EOB-MRI. Lenvatinib response to progression-free survival and overall survival were similar between patients with or without iso-high intensity in the hepatobiliary phase of EOB-MRI. Seven patients (three and four patients who had unresectable HCC with or without iso-high intensity in the hepatobiliary phase of EOB-MRI, respectively) underwent genetic analyses. Among these, two (67%, 2/3) who had HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI carried a CTNNB-1 mutation, while all four patients who had HCC without iso-high intensity in the hepatobiliary phase of EOB-MRI did not carry the CTNNB-1 mutation. This study’s findings have clinical implications for the detection and treatment of HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI. Full article

(This article belongs to the Section Cancer Biomarkers)

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14 pages, 2286 KiB

Open AccessArticle

Targeted Next-Generation Sequencing Analysis Predicts the Recurrence in Resected Lung Adenocarcinoma Harboring EGFR Mutations

by In Ae Kim, Jae Young Hur, Hee Joung Kim, Song Am Lee, Jae Joon Hwang, Wan Seop Kim and Kye Young Lee

Cancers 2021, 13(14), 3632; https://doi.org/10.3390/cancers13143632 - 20 Jul 2021

Cited by 4 | Viewed by 2331

Abstract

Targeted NGS, widely applied to identify driver oncogenes in advanced lung adenocarcinoma, may also be applied to resected early stage cancers. We investigated resected EGFR-mutated lung adenocarcinoma mutation profiles to evaluate prognostic impacts. Tissues from 131 patients who had complete resection of [...] Read more.

Targeted NGS, widely applied to identify driver oncogenes in advanced lung adenocarcinoma, may also be applied to resected early stage cancers. We investigated resected EGFR-mutated lung adenocarcinoma mutation profiles to evaluate prognostic impacts. Tissues from 131 patients who had complete resection of stage I–IIIA EGFR-mutated lung adenocarcinoma were analyzed by targeted NGS for 207 cancer-related genes. Recurrence free survival (RFS) was estimated according to genetic alterations using the Kaplan–Meier method and Cox proportional regression analysis. The relapse rate was 25.2% (33/131). Five-year RFS of stages IA, IB, II, and IIIA were 82%, 75%, 35%, and 0%, respectively (p < 0.001). RFS decreased with the number of co-mutations (p = 0.025). Among co-mutations, the CTNNB1 mutation was associated with short RFS in a multivariate analysis (hazard ratio: 5.4, 95% confidence interval: 2.1–14.4; p = 0.001). TP53 mutations were associated with short RFS in stage IB–IIIA (p = 0.01). RFS was shorter with EGFR exon 19 deletion (19-del) than with mutation 21-L858R in stage IB–IIIA tumors (p = 0.008). Among 19-del subtypes, pL747_P753delinS (6/56, 8.9%) had shorter RFS than pE746_A750del (39/56, 69.6%), the most frequent subtype (p = 0.004). Full article

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

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14 pages, 882 KiB

Open AccessReview

Circadian Clock and Liver Cancer

by María Crespo, Magdalena Leiva and Guadalupe Sabio

Cancers 2021, 13(14), 3631; https://doi.org/10.3390/cancers13143631 - 20 Jul 2021

Cited by 21 | Viewed by 4446

Abstract

Circadian clocks control several homeostatic processes in mammals through internal molecular mechanisms. Chronic perturbation of circadian rhythms is associated with metabolic diseases and increased cancer risk, including liver cancer. The hepatic physiology follows a daily rhythm, driven by clock genes that control the [...] Read more.

Circadian clocks control several homeostatic processes in mammals through internal molecular mechanisms. Chronic perturbation of circadian rhythms is associated with metabolic diseases and increased cancer risk, including liver cancer. The hepatic physiology follows a daily rhythm, driven by clock genes that control the expression of several proteins involved in distinct metabolic pathways. Alteration of the liver clock results in metabolic disorders, such as non-alcoholic fatty liver diseases (NAFLD) and impaired glucose metabolism, that can trigger the activation of oncogenic pathways, inducing spontaneous hepatocarcinoma (HCC). In this review, we provide an overview of the role of the liver clock in the metabolic and oncogenic changes that lead to HCC and discuss new potentially useful targets for prevention and management of HCC. Full article

(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)

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17 pages, 3832 KiB

Open AccessArticle

Rapid Response to the Combination of Lenvatinib and Pembrolizumab in Patients with Advanced Carcinomas (Lung Adenocarcinoma and Malignant Pleural Mesothelioma)

by Walid Shalata, Muhammed Iraqi, Baisali Bhattacharya, Vered Fuchs, Laila C. Roisman, Ahron Yehonatan Cohen, Ismaell Massalha, Alexander Yakobson, Manu Prasad, Moshe Elkabets, Angel Porgador and Nir Peled

Cancers 2021, 13(14), 3630; https://doi.org/10.3390/cancers13143630 - 20 Jul 2021

Cited by 8 | Viewed by 3821

Abstract

The new era of cancer treatments has made immune checkpoint inhibitors (ICIs) and emerging multikinase inhibitors (TKIs) the standards of care, thus drastically improving patient prognoses. Pembrolizumab is an anti-programmed cell death-1 antibody drug, and lenvatinib is a TKI with preferential antiangiogenic activity. [...] Read more.

The new era of cancer treatments has made immune checkpoint inhibitors (ICIs) and emerging multikinase inhibitors (TKIs) the standards of care, thus drastically improving patient prognoses. Pembrolizumab is an anti-programmed cell death-1 antibody drug, and lenvatinib is a TKI with preferential antiangiogenic activity. We present, to our knowledge, the first reported series of cases consisting of patients with metastatic non–small cell lung cancer and malignant pleural mesothelioma who were treated with several types of chemotherapy combinations and ICIs followed by disease progression. They were subsequently treated with combined immunotherapy and TKI treatment, resulting in a near complete response within a very short time. Clinical responses were supported by in vitro testing of each patient’s lymphocytic response to pembrolizumab after pre-exposure of target cancer cells to lenvatinib. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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23 pages, 3168 KiB

Open AccessArticle

Development of Multidrug Resistance in Acute Myeloid Leukemia Is Associated with Alterations of the LPHN1/GAL-9/TIM-3 Signaling Pathway

by Zuzana Kocibalova, Martina Guzyova, Ivana Borovska, Lucia Messingerova, Lucia Copakova, Zdena Sulova and Albert Breier

Cancers 2021, 13(14), 3629; https://doi.org/10.3390/cancers13143629 - 20 Jul 2021

Cited by 8 | Viewed by 3412

Abstract

P-glycoprotein (known as ABCB1 transporter) expression in myeloid blasts of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) leads to the commonly observed multidrug resistance. Overexpression of latrophilin-1 was detected in leukemic cells from AML patients. In a previous study, we showed that [...] Read more.

P-glycoprotein (known as ABCB1 transporter) expression in myeloid blasts of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) leads to the commonly observed multidrug resistance. Overexpression of latrophilin-1 was detected in leukemic cells from AML patients. In a previous study, we showed that ABCB1 overexpression is associated with decreased latrophilin-1 expression in MOLM-13/VCR and SKM-1/VCR AML cell variants derived from MOLM-13 and SKM-1 cells by vincristine selection/adaptation. In the present study, we found that if ABCB1 overexpression occurs in myeloid blasts of newly diagnosed MDS patients, latrophilin-1 expression is attenuated. Latrophilin-1 may initiate TIM-3- and galectin-9-mediated immune escape. We demonstrated changes in the expression of both proteins by comparing ABCB1-positive cell variants (MOLM-13/VCR, SKM-1/VCR) with their ABCB1-negative counterparts. Galectin-9 was present in our cell lines in eight protein isoforms for which we identified the respective transcription variants resulting from alternative splicing, and we verified their structure by sequencing. The isoform profile of galectin-9 was different between ABCB1-positive and ABCB1-negative cell variants. The interaction partner of galectin-9 is CD44, and its expression was altered in the ABCB1-positive variants MOLM-13/VCR and SKM-1/VCR compared to their ABCB1-negative counterparts. Full article

(This article belongs to the Section Cancer Biomarkers)

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22 pages, 1673 KiB

Open AccessSystematic Review

Stakeholder Perceptions of Key Aspects of High-Quality Cancer Care to Assess with Patient Reported Outcome Measures: A Systematic Review

by Angela M. Stover, Rachel Kurtzman, Jennifer Walker Bissram, Jennifer Jansen, Philip Carr, Thomas Atkinson, C. Tyler Ellis, Ashley T. Freeman, Kea Turner and Ethan M. Basch

Cancers 2021, 13(14), 3628; https://doi.org/10.3390/cancers13143628 - 20 Jul 2021

Cited by 6 | Viewed by 2505

Abstract

Performance measurement is the process of collecting, analyzing, and reporting standardized measures of clinical performance that can be compared across practices to evaluate how well care was provided. We conducted a systematic review to identify stakeholder perceptions of key symptoms and health domains [...] Read more.

Performance measurement is the process of collecting, analyzing, and reporting standardized measures of clinical performance that can be compared across practices to evaluate how well care was provided. We conducted a systematic review to identify stakeholder perceptions of key symptoms and health domains to test as patient-reported performance measures in oncology. Stakeholders included cancer patients, caregivers, clinicians, and healthcare administrators. Standard review methodology was used, consistent with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). MEDLINE/PubMed, EMBASE, and the Cochrane Library were searched to identify relevant studies through August 2020. Four coders independently reviewed entries and conflicts were resolved by a fifth coder. Efficacy and effectiveness studies, and studies focused exclusively on patient experiences of care (e.g., communication skills of providers) were excluded. Searches generated 1813 articles and 1779 were coded as not relevant, leaving 34 international articles for extraction. Patients, caregivers, clinicians, and healthcare administrators prioritize psychosocial care (e.g., distress) and symptom management for patient-reported performance measures. Patients and caregivers also perceive that maintaining physical function and daily activities are critical. Clinicians and administrators perceive control of specific symptoms to be critical (gastrointestinal symptoms, pain, poor sleep). Results were used to inform testing at six US cancer centers. Full article

(This article belongs to the Special Issue Systematic Reviews of Patient-Reported Outcomes in Patients with Cancer)

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14 pages, 1470 KiB

Open AccessArticle

Pre-Therapeutic Measurements of Iodine Avidity in Papillary and Poorly Differentiated Thyroid Cancer Reveal Associations with Thyroglobulin Expression, Histological Variants and Ki-67 Index

by Joachim N. Nilsson, Jonathan Siikanen, Christel Hedman, C. Christofer Juhlin and Catharina Ihre Lundgren

Cancers 2021, 13(14), 3627; https://doi.org/10.3390/cancers13143627 - 20 Jul 2021

Cited by 12 | Viewed by 2666

Abstract

Papillary thyroid cancer (PTC) and poorly differentiated thyroid cancer (PDTC) are treated with radioiodine to reduce recurrence and to treat the spread of disease. Adequate iodine accumulation in cancer tissue, iodine avidity, is important for treatment effect. This study investigated which clinical and [...] Read more.

Papillary thyroid cancer (PTC) and poorly differentiated thyroid cancer (PDTC) are treated with radioiodine to reduce recurrence and to treat the spread of disease. Adequate iodine accumulation in cancer tissue, iodine avidity, is important for treatment effect. This study investigated which clinical and histological tumour characteristics correlate with avidity. To quantify avidity in cancer tissue, tracer amounts of iodine-131 were given to 45 patients with cytologically confirmed thyroid cancer. At pathology grossing, representative samples of tumour and lymph nodes were taken and subjected to radioactivity quantification ex vivo to determine avidity. Afterwards, samples underwent extended pathology work-up and analysis. We found that tumoural Tg expression and Ki-67 index were correlated with avidity, whereas tumour size and pT stage were not. The histological variant of thyroid cancer was also correlated with iodine avidity. Variants associated with worse clinical prognoses displayed lower avidity than variants with better prognoses. This work provides new information on which tumours have low iodine avidity. Lower avidity in aggressive histological PTC variants may explain their overall poorer prognoses. Our findings also suggest that radioiodine dosage could be adapted to Tg expression, Ki-67 index or histological variant instead of pT stage, potentially improving the efficacy of radioiodine therapy. Full article

(This article belongs to the Special Issue Molecular Alterations in Thyroid Cancer – with Special Focus on Diagnosis, Prognosis and Treatment)

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13 pages, 1173 KiB

Open AccessArticle

Prognostic Impact of Immunoglobulin Kappa C (IGKC) in Early Breast Cancer

by Marcus Schmidt, Karolina Edlund, Jan G. Hengstler, Anne-Sophie Heimes, Katrin Almstedt, Antje Lebrecht, Slavomir Krajnak, Marco J. Battista, Walburgis Brenner, Annette Hasenburg, Jörg Rahnenführer, Mathias Gehrmann, Pirkko-Liisa Kellokumpu-Lehtinen, Ralph M. Wirtz and Heikki Joensuu

Cancers 2021, 13(14), 3626; https://doi.org/10.3390/cancers13143626 - 20 Jul 2021

Cited by 9 | Viewed by 2968

Abstract

We studied the prognostic impact of tumor immunoglobulin kappa C (IGKC) mRNA expression as a marker of the humoral immune system in the FinHer trial patient population, where 1010 patients with early breast cancer were randomly allocated to either docetaxel-containing or [...] Read more.

We studied the prognostic impact of tumor immunoglobulin kappa C (IGKC) mRNA expression as a marker of the humoral immune system in the FinHer trial patient population, where 1010 patients with early breast cancer were randomly allocated to either docetaxel-containing or vinorelbine-containing adjuvant chemotherapy. HER2-positive patients were additionally allocated to either trastuzumab or no trastuzumab. Hormone receptor-positive patients received tamoxifen. IGKC was evaluated in 909 tumors using quantitative real-time polymerase chain reaction, and the influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan–Meier estimates. Interactions were analyzed using Cox regression. IGKC expression, included as continuous variable, was independently associated with DDFS in a multivariable analysis also including age, molecular subtype, grade, and pT and pN stage (HR 0.930, 95% CI 0.870–0.995, p = 0.034). An independent association with DDFS was also found in a subset analysis of triple-negative breast cancers (TNBC) (HR 0.843, 95% CI 0.724–0.983, p = 0.029), but not in luminal (HR 0.957, 95% CI 0.867–1.056, p = 0.383) or HER2-positive (HR 0.933, 95% CI 0.826–1.055, p = 0.271) cancers. No significant interaction between IGKC and chemotherapy or trastuzumab administration was detected (P_interaction = 0.855 and 0.684, respectively). These results show that humoral immunity beneficially influences the DDFS of patients with early TNBC. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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7 pages, 251 KiB

Open AccessEditorial

Immunotherapies in Non-Hodgkin’s Lymphoma

by Christine Bezombes and Patricia Pérez-Galán

Cancers 2021, 13(14), 3625; https://doi.org/10.3390/cancers13143625 - 20 Jul 2021

Cited by 4 | Viewed by 1972

Abstract

Immune-based therapies mobilize the immune system to promote or restore an effective antitumor immune response [...] Full article

(This article belongs to the Special Issue Immunotherapy in B-cell Non-Hodgkin Lymphomas)

4 pages, 197 KiB

Open AccessComment

Comment on Hopkins et al. Value of the Lung Immune Prognostic Index in Patients with Non-Small Cell Lung Cancer Initiating First-Line Atezolizumab Combination Therapy: Subgroup Analysis of the IMPOWER150 Trial. Cancers 2021, 13, 1176

by Edouard Auclin, Laura Mezquita and Benjamin Besse

Cancers 2021, 13(14), 3624; https://doi.org/10.3390/cancers13143624 - 20 Jul 2021

Cited by 2 | Viewed by 1624

Abstract

We read, with great interest, the recently published article by Hopkins et al. [...] Full article

(This article belongs to the Special Issue Cancer-Mediated Immunomodulation—Pathogenetic, Diagnostic and Therapeutic Aspects)

13 pages, 839 KiB

Open AccessSystematic Review

Stereotactic Body Radiotherapy for Patients with Lung Oligometastatic Disease: A Five-Year Systematic Review

by Guillaume Virbel, Clara Le Fèvre, Georges Noël and Delphine Antoni

Cancers 2021, 13(14), 3623; https://doi.org/10.3390/cancers13143623 - 20 Jul 2021

Cited by 8 | Viewed by 2224

Abstract

For several years, oligometastatic disease has represented an intermediate state between localized disease accessible to local treatment and multimetastatic disease requiring systemic therapy. The lung represents one of the most common metastatic locations. Stereotactic body radiation therapy (SBRT) appears to be the treatment [...] Read more.

For several years, oligometastatic disease has represented an intermediate state between localized disease accessible to local treatment and multimetastatic disease requiring systemic therapy. The lung represents one of the most common metastatic locations. Stereotactic body radiation therapy (SBRT) appears to be the treatment of choice for these patients. There are few data defining the place of radiotherapy and reporting outcome after SBRT in lung metastases. This 5-year review aimed to determine areas of SBRT usefulness and methods for the management of pulmonary metastasis in oligometastatic patients. A search for articles on PubMed allowed selection of the most relevant studies. Eighteen articles were selected according to pre-established criteria for this purpose. The analysis concludes that SBRT is an effective and safe treatment in selected patients when the disease remains localized from one to three organs. Full article

(This article belongs to the Special Issue Oligometastatic Disease)

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19 pages, 6473 KiB

Open AccessArticle

D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy

by Jonathan Barra, Javier Cerda-Infante, Lisette Sandoval, Patricia Gajardo-Meneses, Jenny F. Henriquez, Mariana Labarca, Claudia Metz, Jaime Venegas, Claudio Retamal, Claudia Oyanadel, Jorge Cancino, Andrea Soza, Mauricio A. Cuello, Juan Carlos Roa, Viviana P. Montecinos and Alfonso Gonzalez

Cancers 2021, 13(14), 3622; https://doi.org/10.3390/cancers13143622 - 20 Jul 2021

Cited by 4 | Viewed by 3171

Abstract

Cancer therapy may be improved by the simultaneous interference of two or more oncogenic pathways contributing to tumor progression and aggressiveness, such as EGFR and p53. Tumor cells expressing gain-of-function (GOF) mutants of p53 (mutp53) are usually resistant to EGFR inhibitors and display [...] Read more.

Cancer therapy may be improved by the simultaneous interference of two or more oncogenic pathways contributing to tumor progression and aggressiveness, such as EGFR and p53. Tumor cells expressing gain-of-function (GOF) mutants of p53 (mutp53) are usually resistant to EGFR inhibitors and display invasive migration and AKT-mediated survival associated with enhanced EGFR recycling. D-Propranolol (D-Prop), the non-beta blocker enantiomer of propranolol, was previously shown to induce EGFR internalization through a PKA inhibitory pathway that blocks the recycling of the receptor. Here, we first show that D-Prop decreases the levels of EGFR at the surface of GOF mutp53 cells, relocating the receptor towards recycling endosomes, both in the absence of ligand and during stimulation with high concentrations of EGF or TGF-α. D-Prop also inactivates AKT signaling and reduces the invasive migration and viability of these mutp53 cells. Unexpectedly, mutp53 protein, which is stabilized by interaction with the chaperone HSP90 and mediates cell oncogenic addiction, becomes destabilized after D-Prop treatment. HSP90 phosphorylation by PKA and its interaction with mutp53 are decreased by D-Prop, releasing mutp53 towards proteasomal degradation. Furthermore, a single daily dose of D-Prop reproduces most of these effects in xenografts of aggressive gallbladder cancerous G-415 cells expressing GOF R282W mutp53, resulting in reduced tumor growth and extended mice survival. D-Prop then emerges as an old drug endowed with a novel therapeutic potential against EGFR- and mutp53-driven tumor traits that are common to a large variety of cancers. Full article

(This article belongs to the Section Molecular Cancer Biology)

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15 pages, 1786 KiB

Open AccessArticle

HPV Infection Leaves a DNA Methylation Signature in Oropharyngeal Cancer Affecting Both Coding Genes and Transposable Elements

by Diego Camuzi, Luisa Aguirre Buexm, Simone de Queiroz Chaves Lourenço, Davide Degli Esposti, Cyrille Cuenin, Monique de Souza Almeida Lopes, Francesca Manara, Fazlur Rahman Talukdar, Zdenko Herceg, Luis Felipe Ribeiro Pinto and Sheila Coelho Soares-Lima

Cancers 2021, 13(14), 3621; https://doi.org/10.3390/cancers13143621 - 20 Jul 2021

Cited by 14 | Viewed by 3520

Abstract

HPV oncoproteins can modulate DNMT1 expression and activity, and previous studies have reported both gene-specific and global DNA methylation alterations according to HPV status in head and neck cancer. However, validation of these findings and a more detailed analysis of the transposable elements [...] Read more.

HPV oncoproteins can modulate DNMT1 expression and activity, and previous studies have reported both gene-specific and global DNA methylation alterations according to HPV status in head and neck cancer. However, validation of these findings and a more detailed analysis of the transposable elements (TEs) are still missing. Here we performed pyrosequencing to evaluate a 5-CpG methylation signature and Line1 methylation in an oropharyngeal squamous cell carcinoma (OPSCC) cohort. We further evaluated the methylation levels of the TEs, their correlation with gene expression and their impact on overall survival (OS) using the TCGA cohort. In our dataset, the 5-CpG signature distinguished HPV-positive and HPV-negative OPSCC with 66.67% sensitivity and 84.33% specificity. Line1 methylation levels were higher in HPV-positive cases. In the TCGA cohort, Line1, Alu and long terminal repeats (LTRs) showed hypermethylation in a frequency of 60.5%, 58.9% and 92.3%, respectively. ZNF541 and CCNL1 higher expression was observed in HPV-positive OPSCC, correlated with lower methylation levels of promoter-associated Alu and LTR, respectively, and independently associated with better OS. Based on our findings, we may conclude that a 5-CpG methylation signature can discriminate OPSCC according to HPV status with high accuracy and TEs are differentially methylated and may regulate gene expression in HPV-positive OPSCC. Full article

(This article belongs to the Special Issue Human Papillomavirus and Head and Neck Cancer)

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14 pages, 7498 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Pyroptosis in Cancer: Friend or Foe?

by Xiuxia Lu, Tianhui Guo and Xing Zhang

Cancers 2021, 13(14), 3620; https://doi.org/10.3390/cancers13143620 - 20 Jul 2021

Cited by 46 | Viewed by 4528

Abstract

Pyroptosis is an inflammatory form of programmed cell death that is mediated by pore-forming proteins such as the gasdermin family (GSDMs), including GSDMA-E. Upon cleavage by activated caspases or granzyme proteases, the N-terminal of GSDMs oligomerizes in membranes to form pores, resulting in [...] Read more.

Pyroptosis is an inflammatory form of programmed cell death that is mediated by pore-forming proteins such as the gasdermin family (GSDMs), including GSDMA-E. Upon cleavage by activated caspases or granzyme proteases, the N-terminal of GSDMs oligomerizes in membranes to form pores, resulting in pyroptosis. Though all the gasdermin proteins have been studied in cancer, the role of pyroptosis in cancer remains mysterious, with conflicting findings. Numerous studies have shown that various stimuli, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and chemotherapeutic drugs, could trigger pyroptosis when the cells express GSDMs. However, it is not clear whether pyroptosis in cancer induced by chemotherapeutic drugs or CAR T cell therapy is beneficial or harmful for anti-tumor immunity. This review discusses the discovery of pyroptosis as well as its role in inflammatory diseases and cancer, with an emphasis on tumor immunity. Full article

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13 pages, 1881 KiB

Open AccessReview

An Update on Hepatocellular Carcinoma in Chronic Kidney Disease

by Fabrizio Fabrizi, Roberta Cerutti, Carlo M. Alfieri and Ezequiel Ridruejo

Cancers 2021, 13(14), 3617; https://doi.org/10.3390/cancers13143617 - 20 Jul 2021

Cited by 8 | Viewed by 2891

Abstract

Chronic kidney disease is a major public health issue globally and the risk of cancer (including HCC) is greater in patients on long-term dialysis and kidney transplant compared with the general population. According to an international study on 831,804 patients on long-term dialysis, [...] Read more.

Chronic kidney disease is a major public health issue globally and the risk of cancer (including HCC) is greater in patients on long-term dialysis and kidney transplant compared with the general population. According to an international study on 831,804 patients on long-term dialysis, the standardized incidence ratio for liver cancer was 1.2 (95% CI, 1.0–1.4) and 1.5 (95% CI, 1.3–1.7) in European and USA cohorts, respectively. It appears that important predictors of HCC in dialysis population are hepatotropic viruses (HBV and HCV) and cirrhosis. 1-, 3-, and 5-year survival rates are lower in HCC patients on long-term dialysis than those with HCC and intact kidneys. NAFLD is a metabolic disease with increasing prevalence worldwide and recent evidence shows that it is an important cause of liver-related and extra liver-related diseases (including HCC and CKD, respectively). Some longitudinal studies have shown that patients with chronic hepatitis B are aging and the frequency of comorbidities (such as HCC and CKD) is increasing over time in these patients; it has been suggested to connect these patients to an appropriate care earlier. Antiviral therapy of HBV and HCV plays a pivotal role in the management of HCC in CKD and some combinations of DAAs (elbasvir/grazoprevir, glecaprevir/pibrentasvir, sofosbuvir-based regimens) are now available for HCV positive patients and advanced chronic kidney disease. The interventional management of HCC includes liver resection. Some ablative techniques have been suggested for HCC in CKD patients who are not appropriate candidates to surgery. Transcatheter arterial chemoembolization has been proposed for HCC in patients who are not candidates to liver surgery due to comorbidities. The gold standard for early-stage HCC in patients with chronic liver disease and/or cirrhosis is still liver transplant. Full article

(This article belongs to the Special Issue Liver Transplantation and Hepatocellular Carcinoma)

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13 pages, 3105 KiB

Open AccessArticle

Elevated Levels of CTRP1 in Obesity Contribute to Tumor Progression in a p53-Dependent Manner

by Rackhyun Park, Minsu Jang, Yea-In Park, Yeonjeong Park, Sim Namkoong, Jin I. Lee and Junsoo Park

Cancers 2021, 13(14), 3619; https://doi.org/10.3390/cancers13143619 - 19 Jul 2021

Cited by 7 | Viewed by 2014

Abstract

Mounting evidence supports the relationship between obesity and cancer. However, the molecular mechanisms linking obesity with cancer remain largely uninvestigated. In this study, we demonstrate that the expression of C1q/TNF-related protein 1 (CTRP1), an adiponectin paralogue, contributes to tumor growth by regulating the [...] Read more.

Mounting evidence supports the relationship between obesity and cancer. However, the molecular mechanisms linking obesity with cancer remain largely uninvestigated. In this study, we demonstrate that the expression of C1q/TNF-related protein 1 (CTRP1), an adiponectin paralogue, contributes to tumor growth by regulating the tumor suppressor p53. In our study, obese mice on a high-fat diet showed higher serum CTRP1 levels. Through in vitro experiments, we showed that the secreted form of CTRP1 in the culture medium decreased p53 expression and p53-dependent transcription in the cells. Moreover, CTRP1 treatment enhanced colony formation and cell migration. These results collectively suggest that elevated levels of CTRP1 in obesity significantly contribute to tumor progression. Full article

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20 pages, 4981 KiB

Open AccessArticle

TRAF6 Phosphorylation Prevents Its Autophagic Degradation and Re-Shapes LPS-Triggered Signaling Networks

by Julia Busch, Rita Moreno, Laureano de la Vega, Vera Vivian Saul, Susanne Bacher, Felix von Zweydorf, Marius Ueffing, Axel Weber, Christian Johannes Gloeckner, Uwe Linne, Michael Kracht and Michael Lienhard Schmitz

Cancers 2021, 13(14), 3618; https://doi.org/10.3390/cancers13143618 - 19 Jul 2021

Cited by 4 | Viewed by 2693

Abstract

The ubiquitin E3 ligase TNF Receptor Associated Factor 6 (TRAF6) participates in a large number of different biological processes including innate immunity, differentiation and cell survival, raising the need to specify and shape the signaling output. Here, we identify a lipopolysaccharide (LPS)-dependent increase [...] Read more.

The ubiquitin E3 ligase TNF Receptor Associated Factor 6 (TRAF6) participates in a large number of different biological processes including innate immunity, differentiation and cell survival, raising the need to specify and shape the signaling output. Here, we identify a lipopolysaccharide (LPS)-dependent increase in TRAF6 association with the kinase IKKε (inhibitor of NF-κB kinase subunit ε) and IKKε-mediated TRAF6 phosphorylation at five residues. The reconstitution of TRAF6-deficient cells, with TRAF6 mutants representing phosphorylation-defective or phospho-mimetic TRAF6 variants, showed that the phospho-mimetic TRAF6 variant was largely protected from basal ubiquitin/proteasome-mediated degradation, and also from autophagy-mediated decay in autolysosomes induced by metabolic perturbation. In addition, phosphorylation of TRAF6 and its E3 ligase function differentially shape basal and LPS-triggered signaling networks, as revealed by phosphoproteome analysis. Changes in LPS-triggered phosphorylation networks of cells that had experienced autophagy are partially dependent on TRAF6 and its phosphorylation status, suggesting an involvement of this E3 ligase in the interplay between metabolic and inflammatory circuits. Full article

(This article belongs to the Special Issue NF-kB Signaling in Cellular Responses to Threats, Cancer Development and Therapy)

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16 pages, 5715 KiB

Open AccessArticle

Risk Score Generated from CT-Based Radiomics Signatures for Overall Survival Prediction in Non-Small Cell Lung Cancer

by Viet-Huan Le, Quang-Hien Kha, Truong Nguyen Khanh Hung and Nguyen Quoc Khanh Le

Cancers 2021, 13(14), 3616; https://doi.org/10.3390/cancers13143616 - 19 Jul 2021

Cited by 27 | Viewed by 3561

Abstract

This study aimed to create a risk score generated from CT-based radiomics signatures that could be used to predict overall survival in patients with non-small cell lung cancer (NSCLC). We retrospectively enrolled three sets of NSCLC patients (including 336, 84, and 157 patients [...] Read more.

This study aimed to create a risk score generated from CT-based radiomics signatures that could be used to predict overall survival in patients with non-small cell lung cancer (NSCLC). We retrospectively enrolled three sets of NSCLC patients (including 336, 84, and 157 patients for training, testing, and validation set, respectively). A total of 851 radiomics features for each patient from CT images were extracted for further analyses. The most important features (strongly linked with overall survival) were chosen by pairwise correlation analysis, Least Absolute Shrinkage and Selection Operator (LASSO) regression model, and univariate Cox proportional hazard regression. Multivariate Cox proportional hazard model survival analysis was used to create risk scores for each patient, and Kaplan–Meier was used to separate patients into two groups: high-risk and low-risk, respectively. ROC curve assessed the prediction ability of the risk score model for overall survival compared to clinical parameters. The risk score, which developed from ten radiomics signatures model, was found to be independent of age, gender, and stage for predicting overall survival in NSCLC patients (HR, 2.99; 95% CI, 2.27–3.93; p < 0.001) and overall survival prediction ability was 0.696 (95% CI, 0.635–0.758), 0.705 (95% CI, 0.649–0.762), 0.657 (95% CI, 0.589–0.726) (AUC) for 1, 3, and 5 years, respectively, in the training set. The risk score is more likely to have a better accuracy in predicting survival at 1, 3, and 5 years than clinical parameters, such as age 0.57 (95% CI, 0.499–0.64), 0.552 (95% CI, 0.489–0.616), 0.621 (95% CI, 0.544–0.689) (AUC); gender 0.554, 0.546, 0.566 (AUC); stage 0.527, 0.501, 0.459 (AUC), respectively, in 1, 3 and 5 years in the training set. In the training set, the Kaplan–Meier curve revealed that NSCLC patients in the high-risk group had a lower overall survival time than the low-risk group (p < 0.001). We also had similar results that were statistically significant in the testing and validation set. In conclusion, risk scores developed from ten radiomics signatures models have great potential to predict overall survival in NSCLC patients compared to the clinical parameters. This model was able to stratify NSCLC patients into high-risk and low-risk groups regarding the overall survival prediction. Full article

(This article belongs to the Special Issue Radiomics/Radiogenomics in Cancer)

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27 pages, 2043 KiB

Open AccessReview

Chemotherapy-Induced Myopathy: The Dark Side of the Cachexia Sphere

by Dean G. Campelj, Craig A. Goodman and Emma Rybalka

Cancers 2021, 13(14), 3615; https://doi.org/10.3390/cancers13143615 - 19 Jul 2021

Cited by 27 | Viewed by 5907

Abstract

Cancer cachexia is a debilitating multi-factorial wasting syndrome characterised by severe skeletal muscle wasting and dysfunction (i.e., myopathy). In the oncology setting, cachexia arises from synergistic insults from both cancer–host interactions and chemotherapy-related toxicity. The majority of studies have surrounded the cancer–host interaction [...] Read more.

Cancer cachexia is a debilitating multi-factorial wasting syndrome characterised by severe skeletal muscle wasting and dysfunction (i.e., myopathy). In the oncology setting, cachexia arises from synergistic insults from both cancer–host interactions and chemotherapy-related toxicity. The majority of studies have surrounded the cancer–host interaction side of cancer cachexia, often overlooking the capability of chemotherapy to induce cachectic myopathy. Accumulating evidence in experimental models of cachexia suggests that some chemotherapeutic agents rapidly induce cachectic myopathy, although the underlying mechanisms responsible vary between agents. Importantly, we highlight the capacity of specific chemotherapeutic agents to induce cachectic myopathy, as not all chemotherapies have been evaluated for cachexia-inducing properties—alone or in clinically compatible regimens. Furthermore, we discuss the experimental evidence surrounding therapeutic strategies that have been evaluated in chemotherapy-induced cachexia models, with particular focus on exercise interventions and adjuvant therapeutic candidates targeted at the mitochondria. Full article

(This article belongs to the Special Issue Impact of Cancer Cachexia on Cardiac and Skeletal Muscle: Role of Exercise Training)

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