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Cancers, Volume 13, Issue 8 (April-2 2021) – 241 articles

Cover Story (view full-size image): Sivakumar, Abu-Shah et al. used high dimensional analysis to characterise T cell subsets, functional states and checkpoint expression within the tumour microenvironment of treatment-naïve pancreatic cancer patients. They found an activated regulatory T-cell population, characterised by a highly immunosuppressive state with high TIGIT, ICOS and CD39 gene expression. The exhausted CD8 T-cells had lower PD1 levels but high levels of TIGIT and Tim3, as well as the presence of a significant senescent T-cell population—this is when cells have gone down an irreversible cell cycle arrest and are no longer responsive to antigen stimuli. As a result, this means that new potential checkpoint immunotherapy avenues that target these populations should be trialled in pancreatic cancer. View this paper
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Article
Predictors of Survival in Atypical Meningiomas
Cancers 2021, 13(8), 1970; https://doi.org/10.3390/cancers13081970 - 21 Apr 2021
Cited by 3 | Viewed by 744
Abstract
Introduction: Predictors of survival and progression of disease in atypical meningiomas are less well documented in the literature compared to benign meningiomas. Higher grade meningiomas tend to recur often and one of the most critical aspects is how to best deal with relapses. [...] Read more.
Introduction: Predictors of survival and progression of disease in atypical meningiomas are less well documented in the literature compared to benign meningiomas. Higher grade meningiomas tend to recur often and one of the most critical aspects is how to best deal with relapses. Methods: A total of 77 consecutive patients who underwent craniotomy for atypical meningioma between 1990–2010 at Oslo University Hospital (OUH) were reviewed. Results: Median age at surgery was 62.21 [interquartile range (IQR): 22.87] years. Fifty-one patients (66.2%) had neurological deficits at presentation. Fifty-four patients (70.1%) underwent gross total resection (GTR). Thirty-nine patients (50.7%) had improved/stable neurological outcomes at 6–12 months. Twenty-two patients (28.6%) underwent retreatment, of whom 20 (26.0%) were subjected to resection followed by adjuvant radiotherapy. Overall survival (OS) was significantly longer in patients <65 years (p < 0.001), with preoperative Karnofsky performance scale (KPS) score of ≥ 70 (p = 0.006), and who required no retreatment (p = 0.033). GTR significantly prolonged the retreatment-free survival rate (p < 0.001). STR carried almost a six-fold greater risk of neurological outcome deterioration (p = 0.044). Conclusions: GTR significantly prolonged retreatment-free survival but had no significant impact on OS. STR was a significant risk factor for deteriorated neurological outcome. Age, preoperative KPS, and retreatment were all strong predictors of OS. Median time-to-retreatment (TTR) did not shorten significantly throughout repeated surgeries. Full article
(This article belongs to the Special Issue Advances in Research on Human Meningiomas)
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Review
Harnessing Natural Killer Cells in Cancer Immunotherapy: A Review of Mechanisms and Novel Therapies
Cancers 2021, 13(8), 1988; https://doi.org/10.3390/cancers13081988 - 20 Apr 2021
Cited by 4 | Viewed by 1751
Abstract
Natural killer (NK) cells are lymphocytes that are integral to the body’s innate immunity, resulting in a rapid immune response to stressed or infected cells in an antigen-independent manner. The innate immune system plays an important role in the recognition of tumor-derived stress-related [...] Read more.
Natural killer (NK) cells are lymphocytes that are integral to the body’s innate immunity, resulting in a rapid immune response to stressed or infected cells in an antigen-independent manner. The innate immune system plays an important role in the recognition of tumor-derived stress-related factors and is critical to subsequent adaptive immune responses against tumor antigens. The aim of this review is to discuss mechanisms by which tumor cells evade NK cells and to outline strategies that harness NK cells for cancer immunotherapy. We discuss strategies to relieve the exhausted state of NK cells, recent therapies focused on targeting NK-cell-specific activating and inhibitory receptors, the use of cytokines IL-2 and IL-15 to stimulate autologous or allogeneic NK cells, and ongoing trials exploring the use of genetically modified NK cells and chimeric antigen-receptor-modified NK (CAR-NK) cells. Full article
(This article belongs to the Special Issue Targeting Innate Immunity to Treat Cancer)
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Article
Down-Regulation of the Proteoglycan Decorin Fills in the Tumor-Promoting Phenotype of Ionizing Radiation-Induced Senescent Human Breast Stromal Fibroblasts
Cancers 2021, 13(8), 1987; https://doi.org/10.3390/cancers13081987 - 20 Apr 2021
Cited by 4 | Viewed by 985
Abstract
Down-regulation of the small leucine-rich proteoglycan decorin in the stroma is considered a poor prognostic factor for breast cancer progression. Ionizing radiation, an established treatment for breast cancer, provokes the premature senescence of the adjacent to the tumor stromal fibroblasts. Here, we showed [...] Read more.
Down-regulation of the small leucine-rich proteoglycan decorin in the stroma is considered a poor prognostic factor for breast cancer progression. Ionizing radiation, an established treatment for breast cancer, provokes the premature senescence of the adjacent to the tumor stromal fibroblasts. Here, we showed that senescent human breast stromal fibroblasts are characterized by the down-regulation of decorin at the mRNA and protein level, as well as by its decreased deposition in the pericellular extracellular matrix in vitro. Senescence-associated decorin down-regulation is a long-lasting process rather than an immediate response to γ-irradiation. Growth factors were demonstrated to participate in an autocrine manner in decorin down-regulation, with bFGF and VEGF being the critical mediators of the phenomenon. Autophagy inhibition by chloroquine reduced decorin mRNA levels, while autophagy activation using the mTOR inhibitor rapamycin enhanced decorin transcription. Interestingly, the secretome from a series of both untreated and irradiated human breast cancer cell lines with different molecular profiles inhibited decorin expression in young and senescent stromal fibroblasts, which was annulled by SU5402, a bFGF and VEGF inhibitor. The novel phenotypic trait of senescent human breast stromal fibroblasts revealed here is added to their already described cancer-promoting role via the formation of a tumor-permissive environment. Full article
(This article belongs to the Collection Matrix Effectors and Cancer)
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Review
Liquid Biopsy in Pancreatic Cancer: Are We Ready to Apply It in the Clinical Practice?
Cancers 2021, 13(8), 1986; https://doi.org/10.3390/cancers13081986 - 20 Apr 2021
Cited by 16 | Viewed by 1418
Abstract
Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, disease monitoring, evaluation of the response and prognosis. Liquid biopsy (LB), in its different modalities, represents a particularly interesting tool for these purposes, since it is a minimally invasive and risk-free procedure that can detect both the presence of genetic material from the tumor and circulating tumor cells (CTCs) in the blood and therefore distantly reflect the global status of the disease. In this work we review the current status of the main LB modalities (ctDNA, exosomes, CTCs and cfRNAs) for detecting and monitoring PDAC. Full article
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Article
Evaluation of PSA and PSA Density in a Multiparametric Magnetic Resonance Imaging-Directed Diagnostic Pathway for Suspected Prostate Cancer: The INNOVATE Trial
Cancers 2021, 13(8), 1985; https://doi.org/10.3390/cancers13081985 - 20 Apr 2021
Cited by 1 | Viewed by 1353
Abstract
Objectives: To assess the clinical outcomes of mpMRI before biopsy and evaluate the space remaining for novel biomarkers. Methods: The INNOVATE study was set up to evaluate the validity of novel fluidic biomarkers in men with suspected prostate cancer who undergo pre-biopsy [...] Read more.
Objectives: To assess the clinical outcomes of mpMRI before biopsy and evaluate the space remaining for novel biomarkers. Methods: The INNOVATE study was set up to evaluate the validity of novel fluidic biomarkers in men with suspected prostate cancer who undergo pre-biopsy mpMRI. We report the characteristics of this clinical cohort, the distribution of clinical serum biomarkers, PSA and PSA density (PSAD), and compare the mpMRI Likert scoring system to the Prostate Imaging–Reporting and Data System v2.1 (PI-RADS) in men undergoing biopsy. Results: 340 men underwent mpMRI to evaluate suspected prostate cancer. 193/340 (57%) men had subsequent MRI-targeted prostate biopsy. Clinically significant prostate cancer (csigPCa), i.e., overall Gleason ≥ 3 + 4 of any length OR maximum cancer core length (MCCL) ≥4 mm of any grade including any 3 + 3, was found in 96/195 (49%) of biopsied patients. Median PSA (and PSAD) was 4.7 (0.20), 8.0 (0.17), and 9.7 (0.31) ng/mL (ng/mL/mL) in mpMRI scored Likert 3,4,5 respectively for men with csigPCa on biopsy. The space for novel biomarkers was shown to be within the group of men with mpMRI scored Likert3 (178/340) and 4 (70/350), in whom an additional of 40% (70/178) men with mpMRI-scored Likert3, and 37% (26/70) Likert4 could have been spared biopsy. PSAD is already considered clinically in this cohort to risk stratify patients for biopsy, despite this 67% (55/82) of men with mpMRI-scored Likert3, and 55% (36/65) Likert4, who underwent prostate biopsy had a PSAD below a clinical threshold of 0.15 (or 0.12 for men aged <50 years). Different thresholds of PSA and PSAD were assessed in mpMRI-scored Likert4 to predict csigPCa on biopsy, to achieve false negative levels of ≤5% the proportion of patients whom who test as above the threshold were unsuitably high at 86 and 92% of patients for PSAD and PSA respectively. When PSA was re tested in a sub cohort of men repeated PSAD showed its poor reproducibility with 43% (41/95) of patients being reclassified. After PI-RADS rescoring of the biopsied lesions, 66% (54/82) of the Likert3 lesions received a different PI-RADS score. Conclusions: The addition of simple biochemical and radiological markers (Likert and PSAD) facilitate the streamlining of the mpMRI-diagnostic pathway for suspected prostate cancer but there remains scope for improvement, in the introduction of novel biomarkers for risk assessment in Likert3 and 4 patients, future application of novel biomarkers tested in a Likert cohort would also require re-optimization around Likert3/PI-RADS2, as well as reproducibility testing. Full article
(This article belongs to the Section Cancer Biomarkers)
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Article
Fibroblast MMP14-Dependent Collagen Processing Is Necessary for Melanoma Growth
Cancers 2021, 13(8), 1984; https://doi.org/10.3390/cancers13081984 - 20 Apr 2021
Cited by 4 | Viewed by 1190
Abstract
Skin homeostasis results from balanced synthesis and degradation of the extracellular matrix in the dermis. Deletion of the proteolytic enzyme MMP14 in dermal fibroblasts (MMP14Sf−/−) leads to a fibrotic skin phenotype with the accumulation of collagen type I, resulting from impaired [...] Read more.
Skin homeostasis results from balanced synthesis and degradation of the extracellular matrix in the dermis. Deletion of the proteolytic enzyme MMP14 in dermal fibroblasts (MMP14Sf−/−) leads to a fibrotic skin phenotype with the accumulation of collagen type I, resulting from impaired proteolysis. Here, we show that melanoma growth in these mouse fibrotic dermal samples was decreased, paralleled by reduced tumor cell proliferation and vessel density. Using atomic force microscopy, we found increased peritumoral matrix stiffness of early but not late melanomas in the absence of fibroblast-derived MMP14. However, total collagen levels were increased at late melanoma stages in MMP14Sf−/− mice compared to controls. In ex vivo invasion assays, melanoma cells formed smaller tumor islands in MMP14Sf−/− skin, indicating that MMP14-dependent matrix accumulation regulates tumor growth. In line with these data, in vitro melanoma cell growth was inhibited in high collagen 3D spheroids or stiff substrates. Most importantly, in vivo induction of fibrosis using bleomycin reduced melanoma tumor growth. In summary, we show that MMP14 expression in stromal fibroblasts regulates melanoma tumor progression by modifying the peritumoral matrix and point to collagen accumulation as a negative regulator of melanoma. Full article
(This article belongs to the Section Tumor Microenvironment)
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Article
Fourteen-Day Gemcitabine-Docetaxel Chemotherapy Is Effective and Safer Compared to 21-Day Regimen in Patients with Advanced Soft Tissue and Bone Sarcoma
Cancers 2021, 13(8), 1983; https://doi.org/10.3390/cancers13081983 - 20 Apr 2021
Cited by 2 | Viewed by 1173
Abstract
Gemcitabine-docetaxel (G-D) combination is an effective chemotherapy for patients with advanced soft tissue and bone sarcoma, first developed with G administered on days 1 and 8, and D on day 8 every 21 days and later modified to be administered every 14 days [...] Read more.
Gemcitabine-docetaxel (G-D) combination is an effective chemotherapy for patients with advanced soft tissue and bone sarcoma, first developed with G administered on days 1 and 8, and D on day 8 every 21 days and later modified to be administered every 14 days in 2012. The 14-day regimen has become increasingly adopted. However, its efficacy and toxicities have not been compared. We identified 161 patients with metastatic or locally advanced soft tissue and bone sarcoma treated with either a 14-day or 21-day regimen within Northern California Kaiser Permanente from 1 January 2017 to 30 July 2020 and compared the outcomes and toxicity profiles of patients treated with the either regimen. Seventy-nine (49%) and 82 (51%) patients received the 14-day and the 21-day regimen, respectively, with similar response rate (22.8% and 15.8%, p = 0.26), median progression-free survival (PFS, 4.0 and 3.2 months, p = 0.15), and median overall survival (OS, 12.6 and 14.7 months, p = 0.55). Subset analysis of the untreated patients (approximately 60% of the entire cohort) as well as the patients with leiomyosarcoma only (approximately 50% of the entire cohort) showed that OS was not significantly different between the two regimens. Febrile neutropenia requiring hospitalization occurred in 10 and one patients (p = 0.006) and intolerance leading to discontinuation of chemotherapy occurred in 12 and two patients (p = 0.006) treated with the 21-day and the 14-day regimens, respectively. CDKN2A deletion/mutation or CDK4 amplification was associated with worse median OS (p = 0.06), while a RB1 deletion/mutation was associated with better median PFS (p = 0.05), and these two genomic alterations were mutually exclusive. Our data demonstrate that, compared to the traditional 21-day G-D regimen, the 14-day G-D regimen is equally effective but safer. In addition, CDKN2A and RB1 pathways play significant role on the outcomes of the patients. Full article
(This article belongs to the Section Cancer Therapy)
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Article
Associations of Variability in Metabolic Parameters with Lung Cancer: A Nationwide Population-Based Study
Cancers 2021, 13(8), 1982; https://doi.org/10.3390/cancers13081982 - 20 Apr 2021
Cited by 1 | Viewed by 836
Abstract
We investigated whether visit-to-visit variability in metabolic parameters is associated with lung cancer risk. We used nationally representative data from the Korean National Health Insurance System, and 8,011,209 lung-cancer-free subjects who underwent over three health examinations from 2005 to 2010 were followed until [...] Read more.
We investigated whether visit-to-visit variability in metabolic parameters is associated with lung cancer risk. We used nationally representative data from the Korean National Health Insurance System, and 8,011,209 lung-cancer-free subjects who underwent over three health examinations from 2005 to 2010 were followed until 2017. Variability of fasting blood glucose, total cholesterol, systolic blood pressure, and body weight were measured by the variability independent of the mean, assessed by quartiles. There were 44,982 lung cancer events. The hazard ratio (HR) and 95% confidence interval (CI) for lung cancer risk was 1.07 (1.04, 1.10) for fasting blood glucose in the highest quartile, 1.08 (1.05, 1.10) for systolic blood pressure, 1.04 (1.01, 1.07) for weight, and 1.11 (1.08, 1.14) for total cholesterol. When comparing ≥3 vs. 0 high-variability metabolic parameters, the HR for lung cancer was 1.18 (95% CI, 1.14, 1.22). However, while ≥3 high-variability parameters showed an increased lung cancer risk in men (HR 1.26, 95% CI 1.21, 1.31), women did not show increased risk (HR 0.99, 95% CI 0.92, 1.06). High variability in each metabolic parameter, and a higher number of high-variability parameters, were associated with increased lung cancer risk. Full article
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Review
New Insights into YES-Associated Protein Signaling Pathways in Hematological Malignancies: Diagnostic and Therapeutic Challenges
Cancers 2021, 13(8), 1981; https://doi.org/10.3390/cancers13081981 - 20 Apr 2021
Cited by 5 | Viewed by 1038
Abstract
The Hippo/YES-associated protein (YAP) signaling pathway is a cell survival and proliferation-control system with its main activity that of regulating cell growth and organ volume. YAP operates as a transcriptional coactivator in regulating the onset, progression, and treatment response in numerous human tumors. [...] Read more.
The Hippo/YES-associated protein (YAP) signaling pathway is a cell survival and proliferation-control system with its main activity that of regulating cell growth and organ volume. YAP operates as a transcriptional coactivator in regulating the onset, progression, and treatment response in numerous human tumors. Moreover, there is evidence suggesting the involvement of YAP in the control of the hematopoietic system, in physiological conditions rather than in hematological diseases. Nevertheless, several reports have proposed that the effects of YAP in tumor cells are cell-dependent and cell-type-determined, even if YAP usually interrelates with extracellular signaling to stimulate the onset and progression of tumors. In the present review, we report the most recent findings in the literature on the relationship between the YAP system and hematological neoplasms. Moreover, we evaluate the possible therapeutic use of the modulation of the YAP system in the treatment of malignancies. Given the effects of the YAP system in immunosurveillance, tumorigenesis, and chemoresistance, further studies on interactions between the YAP system and hematological malignancies will offer very relevant information for the targeting of these diseases employing YAP modifiers alone or in combination with chemotherapy drugs. Full article
(This article belongs to the Special Issue YAP (Yes-Associated Protein) in Cancer)
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Article
Growing Human Hepatocellular Tumors Undergo a Global Metabolic Reprogramming
Cancers 2021, 13(8), 1980; https://doi.org/10.3390/cancers13081980 - 20 Apr 2021
Cited by 5 | Viewed by 1220
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis, high morbidity and mortality concerning with lack of effective diagnosis and high postoperative recurrence. Similar with other cancers, HCC cancer cells have to alter their metabolism to adapt to the changing requirements imposed [...] Read more.
Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis, high morbidity and mortality concerning with lack of effective diagnosis and high postoperative recurrence. Similar with other cancers, HCC cancer cells have to alter their metabolism to adapt to the changing requirements imposed by the environment of the growing tumor. In less vascularized regions of tumor, cancer cells experience hypoxia and nutrient starvation. Here, we show that HCC undergoes a global metabolic reprogramming during tumor growth. A combined proteomics and metabolomics analysis of paired peritumoral and tumor tissues from 200 HCC patients revealed liver-specific metabolic reprogramming and metabolic alterations with increasing tumor sizes. Several proteins and metabolites associated with glycolysis, the tricarboxylic acid cycle and pyrimidine synthesis were found to be differentially regulated in serum, tumor and peritumoral tissue with increased tumor sizes. Several prognostic metabolite biomarkers involved in HCC metabolic reprogramming were identified and integrated with clinical and pathological data. We built and validated this combined model to discriminate against patients with different recurrence risks. An integrated and comprehensive metabolomic analysis of HCC is provided by our present work. Metabolomic alterations associated with the advanced stage of the disease and poor clinical outcomes, were revealed. Targeting cancer metabolism may deliver effective therapies for HCC. Full article
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Article
Risk of Pharmacological or Hospital Treatment for Depression in Patients with Colorectal Cancer–Associations with Pre-Cancer Lifestyle, Comorbidity and Clinical Factors
Cancers 2021, 13(8), 1979; https://doi.org/10.3390/cancers13081979 - 20 Apr 2021
Cited by 1 | Viewed by 751
Abstract
We investigated the risk of depression in colorectal cancer (CRC) patients and associated risk factors. The 1324 patients with CRC and 6620 matched cancer-free participants from the Diet, Cancer and Health study were followed for up to 16 years for either a first [...] Read more.
We investigated the risk of depression in colorectal cancer (CRC) patients and associated risk factors. The 1324 patients with CRC and 6620 matched cancer-free participants from the Diet, Cancer and Health study were followed for up to 16 years for either a first hospitalization for depression or antidepressant prescription after diagnosis of CRC cancer or study entry date. Information on the outcome and covariates was retrieved from the Danish Colorectal Cancer Group database, the national health registries and questionnaires. Cumulative incidence of depression was estimated, and Cox regression models were used to evaluate the association between risk factors and depression incidence. During follow-up, 191 (14.4%) patients with CRC and 175 (2.6%) cancer-free comparison persons experienced depression. After adjustments, in the first year after cancer diagnosis, patients with CRC had a 12-fold higher hazard compared with the cancer-free population (HR, 12.01; 95% CI, 7.89–18.28). The risk decreased during follow-up but remained significantly elevated with an HR of 2.65 (95% CI, 1.61–4.36) after five years. Identified risk factors were presence of comorbidities, advanced disease stage and use of radiotherapy, while life style factors (pre-cancer or at diagnosis) and chemotherapy did not seem to contribute to the increased risk. Full article
(This article belongs to the Special Issue Cancer Survivorship)
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Article
Inter-Reader Agreement of Diffusion-Weighted Magnetic Resonance Imaging for Breast Cancer Detection: A Multi-Reader Retrospective Study
Cancers 2021, 13(8), 1978; https://doi.org/10.3390/cancers13081978 - 20 Apr 2021
Cited by 3 | Viewed by 704
Abstract
Purpose: In order to evaluate the use of un-enhanced magnetic resonance imaging (MRI) for detecting breast cancer, we evaluated the accuracy and the agreement of diffusion-weighted imaging (DWI) through the inter-reader reproducibility between expert and non-expert readers. Material and Methods: Consecutive breast MRI [...] Read more.
Purpose: In order to evaluate the use of un-enhanced magnetic resonance imaging (MRI) for detecting breast cancer, we evaluated the accuracy and the agreement of diffusion-weighted imaging (DWI) through the inter-reader reproducibility between expert and non-expert readers. Material and Methods: Consecutive breast MRI performed in a single centre were retrospectively evaluated by four radiologists with different levels of experience. The per-breast standard of reference was the histological diagnosis from needle biopsy or surgical excision, or at least one-year negative follow-up on imaging. The agreement across readers (by inter-reader reproducibility) was examined for each breast examined using Cohen’s and Fleiss’ kappa (κ) statistics. The Wald test was used to test the difference in inter-reader agreement between expert and non-expert readers. Results: Of 1131 examinations, according to our inclusion and exclusion criteria, 382 women were included (49.5 ± 12 years old), 40 of them with unilateral mastectomy, totaling 724 breasts. Overall inter-reader reproducibility was substantial (κ = 0.74) for expert readers and poor (κ = 0.37) for non- expert readers. Pairwise agreement between expert readers and non-expert readers was moderate (κ = 0.60) and showed a statistically superior agreement of the expert readers over the non-expert readers (p = 0.003). Conclusions: DWI showed substantial inter-reader reproducibility among expert-level readers. Pairwise comparison showed superior agreement of the expert readers over the non-expert readers, with the expert readers having higher inter-reader reproducibility than the non-expert readers. These findings open new perspectives for prospective studies investigating the actual role of DWI as a stand-alone method for un-enhanced breast MRI. Full article
(This article belongs to the Special Issue New Challenges in Cancer Imaging)
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Article
The Role of Advance Care Planning in Cancer Patient and Caregiver Grief Resolution: Helpful or Harmful?
Cancers 2021, 13(8), 1977; https://doi.org/10.3390/cancers13081977 - 20 Apr 2021
Cited by 1 | Viewed by 1329
Abstract
Cancer patients and their family caregivers experience various losses when patients become terminally ill, yet little is known about the grief experienced by patients and caregivers and factors that influence grief as patients approach death. Additionally, few, if any, studies have explored associations [...] Read more.
Cancer patients and their family caregivers experience various losses when patients become terminally ill, yet little is known about the grief experienced by patients and caregivers and factors that influence grief as patients approach death. Additionally, few, if any, studies have explored associations between advance care planning (ACP) and grief resolution among cancer patients and caregivers. To fill this knowledge gap, the current study examined changes in grief over time in patients and their family caregivers and whether changes in patient grief are associated with changes in caregiver grief. We also sought to determine how grief changed following the completion of advance directives. The sample included advanced cancer patients and caregivers (n = 98 dyads) from Coping with Cancer III, a federally funded, multi-site prospective longitudinal study of end-stage cancer care. Participants were interviewed at baseline and at follow-up roughly 2 months later. Results suggest synchrony, whereby changes in patient grief were associated with changes in caregiver grief. We also found that patients who completed a living will (LW) experienced increases in grief, while caregivers of patients who completed a do-not-resuscitate (DNR) order experienced reductions in grief, suggesting that ACP may prompt “grief work” in patients while promoting grief resolution in caregivers. Full article
(This article belongs to the Special Issue Supportive and Palliative Care in Oncology)
Review
The Role of lncRNAs in the Pathobiology and Clinical Behavior of Multiple Myeloma
Cancers 2021, 13(8), 1976; https://doi.org/10.3390/cancers13081976 - 20 Apr 2021
Cited by 2 | Viewed by 962
Abstract
MM is a hematological neoplasm that is still considered an incurable disease. Besides established genetic alterations, recent studies have shown that MM pathogenesis is also characterized by epigenetic aberrations, such as the gain of de novo active chromatin marks in promoter and enhancer [...] Read more.
MM is a hematological neoplasm that is still considered an incurable disease. Besides established genetic alterations, recent studies have shown that MM pathogenesis is also characterized by epigenetic aberrations, such as the gain of de novo active chromatin marks in promoter and enhancer regions and extensive DNA hypomethylation of intergenic regions, highlighting the relevance of these non-coding genomic regions. A recent study described how long non-coding RNAs (lncRNAs) correspond to 82% of the MM transcriptome and an increasing number of studies have demonstrated the importance of deregulation of lncRNAs in MM. In this review we focus on the deregulated lncRNAs in MM, including their biological or functional mechanisms, their role as biomarkers to improve the prognosis and monitoring of MM patients, and their participation in drug resistance. Furthermore, we also discuss the evidence supporting the role of lncRNAs as therapeutic targets through different novel RNA-based strategies. Full article
(This article belongs to the Special Issue Molecular Features in Multiple Myeloma)
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Article
Profiling of Adipose and Skeletal Muscle in Human Pancreatic Cancer Cachexia Reveals Distinct Gene Profiles with Convergent Pathways
Cancers 2021, 13(8), 1975; https://doi.org/10.3390/cancers13081975 - 20 Apr 2021
Cited by 1 | Viewed by 1205
Abstract
The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought [...] Read more.
The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n = 11) and patients with PDAC (n = 24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia. Full article
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Article
Towards Targeted Alpha Therapy with Actinium-225: Chelators for Mild Condition Radiolabeling and Targeting PSMA—A Proof of Concept Study
Cancers 2021, 13(8), 1974; https://doi.org/10.3390/cancers13081974 - 20 Apr 2021
Cited by 7 | Viewed by 2073
Abstract
Currently, targeted alpha therapy is one of the most investigated topics in radiopharmaceutical cancer management. Especially, the alpha emitter 225Ac has excellent nuclear properties and is gaining increasing popularity for the treatment of various tumor entities. We herein report on the synthesis [...] Read more.
Currently, targeted alpha therapy is one of the most investigated topics in radiopharmaceutical cancer management. Especially, the alpha emitter 225Ac has excellent nuclear properties and is gaining increasing popularity for the treatment of various tumor entities. We herein report on the synthesis of two universal 225Ac-chelators for mild condition radiolabeling and binding to conjugate molecules of pharmacological interest via the copper-mediated click chemistry. A convenient radiolabeling procedure was investigated as well as the complex stability proved for both chelators and two PSMA (prostate-specific membrane antigen)-targeting model radioconjugates. Studies regarding affinity and cell survival were performed on LNCaP cells followed by biodistribution studies, which were performed using LNCaP tumor-bearing mice. High efficiency radiolabeling for all conjugates was demonstrated. Cell binding studies revealed a fourfold lower cell affinity for the PSMA radioconjugate with one targeting motif compared to the radioconjugate owing two targeting motifs. Additionally, these differences were verified by in vitro cell survival evaluation and biodistribution studies, both showing a higher cell killing efficiency for the same dose, a higher tumor uptake (15%ID/g) and a rapid whole body clearance after 24 h. The synthesized chelators will overcome obstacles of lacking stability and worse labeling needs regarding 225Ac complexation using the DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid) chelator. Moreover, the universal functionalization expands the coverage of these chelators in combination with any sensitive bio(macro)molecule, thus improving treatment of any addressable tumor target. Full article
(This article belongs to the Special Issue Prostate-Specific Membrane Antigen (PSMA))
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Review
Interplay between Metabolism Reprogramming and Epithelial-to-Mesenchymal Transition in Cancer Stem Cells
Cancers 2021, 13(8), 1973; https://doi.org/10.3390/cancers13081973 - 20 Apr 2021
Cited by 10 | Viewed by 1661
Abstract
Tumor cells display important plasticity potential, which contributes to intratumoral heterogeneity. Notably, tumor cells have the ability to retrodifferentiate toward immature states under the influence of their microenvironment. Importantly, this phenotypical conversion is paralleled by a metabolic rewiring, and according to the metabostemness [...] Read more.
Tumor cells display important plasticity potential, which contributes to intratumoral heterogeneity. Notably, tumor cells have the ability to retrodifferentiate toward immature states under the influence of their microenvironment. Importantly, this phenotypical conversion is paralleled by a metabolic rewiring, and according to the metabostemness theory, metabolic reprogramming represents the first step of epithelial-to-mesenchymal transition (EMT) and acquisition of stemness features. Most cancer stem cells (CSC) adopt a glycolytic phenotype even though cells retain functional mitochondria. Such adaptation is suggested to reduce the production of reactive oxygen species (ROS), protecting CSC from detrimental effects of ROS. CSC may also rely on glutaminolysis or fatty acid metabolism to sustain their energy needs. Besides pro-inflammatory cytokines that are well-known to initiate the retrodifferentiation process, the release of catecholamines in the microenvironment of the tumor can modulate both EMT and metabolic changes in cancer cells through the activation of EMT transcription factors (ZEB1, Snail, or Slug (SNAI2)). Importantly, the acquisition of stem cell properties favors the resistance to standard care chemotherapies. Hence, a better understanding of this process could pave the way for the development of therapies targeting CSC metabolism, providing new strategies to eradicate the whole tumor mass in cancers with unmet needs. Full article
(This article belongs to the Special Issue Cell Plasticity in Cancer Progression)
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Article
Intersection of DNA Repair Pathways and the Immune Landscape Identifies PD-L2 as a Prognostic Marker in Epithelial Ovarian Cancer
Cancers 2021, 13(8), 1972; https://doi.org/10.3390/cancers13081972 - 20 Apr 2021
Viewed by 930
Abstract
Background: Targeting DNA repair and immune checkpoint pathways has been the focus of multiple clinical trials. In this study, we explore the association between DNA repair proteins, immune response markers, and clinical outcome in women with EOC. Methods: Immunohistochemical analysis of TMA with [...] Read more.
Background: Targeting DNA repair and immune checkpoint pathways has been the focus of multiple clinical trials. In this study, we explore the association between DNA repair proteins, immune response markers, and clinical outcome in women with EOC. Methods: Immunohistochemical analysis of TMA with 181 EOC samples was used to determine expression levels for DNA repair proteins (PARP, PTEN, p53, H2Ax, FANCD2, and ATM) and immune-markers (CD4, CD8, CD68, PD-L2, PD-L1, and FOXP3). Biomarker expression was correlated to clinical data. Prognostic discriminatory ability was assessed per the combination of biomarkers. Results: Tumor immunity biomarkers correlated with HRD biomarkers. High PD-L2 was significantly associated with high expression of CD8 (r = 0.18), CD68 (r = 0.17), and FOXp3 (r = 0.16) (all, p < 0.05). In a multivariate analysis, PD-L2 (hazard ratio (HR) 1.89), PARP (HR 1.75), and PTEN (HR 1.96) expressions were independently associated with decreased progression-free survival (PFS), whereas PD-L1 (HR 0.49) and CD4 (HR 0.67) were associated with improved PFS (all, p < 0.05). In 15 biomarker combinations, six combinations exhibited a discriminatory ability of >20% for the 4.5-year PFS rate, with four based on PD-L2 (PARP, PTEN, CD4, and PD-L1, 20.5–30.0%). Conclusions: Increased PD-L2 expression is a prognostic marker of decreased survival in EOC. Interaction between tumor DNA repair and microenvironment determines tumor progression and survival. Full article
(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)
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Review
Surgical Treatment of Pancreatic Ductal Adenocarcinoma
Cancers 2021, 13(8), 1971; https://doi.org/10.3390/cancers13081971 - 20 Apr 2021
Cited by 7 | Viewed by 1100
Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents an aggressive tumor of the digestive system with still low five-year survival of less than 10%. Although there are improvements for multimodal therapy of PDAC, surgery still remains the effective way to treat the disease. Combined with adjuvant [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) represents an aggressive tumor of the digestive system with still low five-year survival of less than 10%. Although there are improvements for multimodal therapy of PDAC, surgery still remains the effective way to treat the disease. Combined with adjuvant and/or neoadjuvant treatment, pancreatic surgery is able to enhance the five-year survival up to around 20%. However, pancreatic resection is always associated with a high risk of complications and regarded as one of the most complex fields in abdominal surgery. This review gives a summary on the surgical treatment for PDAC based on the current literature with a special focus on resection techniques. Full article
(This article belongs to the Special Issue Surgical Treatment of Pancreatic Ductal Adenocarcinoma)
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Article
Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma
Cancers 2021, 13(8), 1969; https://doi.org/10.3390/cancers13081969 - 19 Apr 2021
Cited by 5 | Viewed by 1196
Abstract
The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis [...] Read more.
The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis is not always available. In addition, myeloma patients with favorable cytogenetics can display an aggressive clinical course. Therefore, it is necessary to develop additional prognostic and predictive markers for this disease to allow for patient risk stratification and personalized clinical decision-making. Genomic instability is a prominent characteristic in MM, and we have previously shown that the three-dimensional (3D) nuclear organization of telomeres is a marker of both genomic instability and genetic heterogeneity in myeloma. In this study, we compared in a longitudinal prospective study blindly the 3D telomeric profiles from bone marrow samples of 214 initially treatment-naïve patients with either monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with a minimum follow-up of 5 years. Here, we report distinctive 3D telomeric profiles correlating with disease aggressiveness and patient response to treatment in MM patients, and also distinctive 3D telomeric profiles for disease progression in smoldering multiple myeloma patients. In particular, lower average intensity (telomere length, below 13,500 arbitrary units) and increased number of telomere aggregates are associated with shorter survival and could be used as a prognostic factor to identify high-risk SMM and MM patients. Full article
(This article belongs to the Special Issue Multiple Myeloma: Targeted Therapy and Immunotherapy)
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Review
Myelodysplasia Syndrome, Clonal Hematopoiesis and Cardiovascular Disease
Cancers 2021, 13(8), 1968; https://doi.org/10.3390/cancers13081968 - 19 Apr 2021
Cited by 2 | Viewed by 1511
Abstract
The development of myelodysplasia syndromes (MDS) is multiphasic and can be driven by a plethora of genetic mutations and/or abnormalities. MDS is characterized by a hematopoietic differentiation block, evidenced by increased immature hematopoietic cells, termed blast cells and decreased mature circulating leukocytes in [...] Read more.
The development of myelodysplasia syndromes (MDS) is multiphasic and can be driven by a plethora of genetic mutations and/or abnormalities. MDS is characterized by a hematopoietic differentiation block, evidenced by increased immature hematopoietic cells, termed blast cells and decreased mature circulating leukocytes in at least one lineage (i.e., cytopenia). Clonal hematopoiesis of indeterminate potential (CHIP) is a recently described phenomenon preceding MDS development that is driven by somatic mutations in hemopoietic stem cells (HSCs). These mutant HSCs have a competitive advantage over healthy cells, resulting in an expansion of these clonal mutated leukocytes. In this review, we discuss the multiphasic development of MDS, the common mutations found in both MDS and CHIP, how a loss-of-function in these CHIP-related genes can alter HSC function and leukocyte development and the potential disease outcomes that can occur with dysfunctional HSCs. In particular, we discuss the novel connections between MDS development and cardiovascular disease. Full article
(This article belongs to the Special Issue Recent Advances in Myelodysplastic Syndrome)
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Graphical abstract

Systematic Review
Distal Pancreatectomy with Celiac Axis Resection: Systematic Review and Meta-Analysis
Cancers 2021, 13(8), 1967; https://doi.org/10.3390/cancers13081967 - 19 Apr 2021
Cited by 4 | Viewed by 951
Abstract
Background: Major vascular invasion represents one of the most frequent reasons to consider pancreatic adenocarcinomas unresectable, although in the last decades, demolitive surgeries such as distal pancreatectomy with celiac axis resection (DP-CAR) have become a therapeutical option. Methods: A meta-analysis of studies comparing [...] Read more.
Background: Major vascular invasion represents one of the most frequent reasons to consider pancreatic adenocarcinomas unresectable, although in the last decades, demolitive surgeries such as distal pancreatectomy with celiac axis resection (DP-CAR) have become a therapeutical option. Methods: A meta-analysis of studies comparing DP-CAR and standard DP in patients with pancreatic adenocarcinoma was conducted. Moreover, a systematic review of studies analyzing oncological, postoperative and survival outcomes of DP-CAR was conducted. Results: Twenty-four articles were selected for the systematic review, whereas eleven were selected for the meta-analysis, for a total of 1077 patients. Survival outcomes between the two groups were similar in terms of 1 year overall survival (OS) (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.34 to 1.31, p = 0.24). Patients who received DP-CAR were more likely to have T4 tumors (OR 28.45, 95% CI 10.46 to 77.37, p < 0.00001) and positive margins (R+) (OR 2.28, 95% CI 1.24 to 4.17, p = 0.008). Overall complications (OR, 1.72, 95% CI, 1.15 to 2.58, p = 0.008) were more frequent in the DP-CAR group, whereas rates of pancreatic fistula (OR 1.16, 95% CI 0.81 to 1.65, p = 0.41) were similar. Conclusions: DP-CAR was not associated with higher mortality compared to standard DP; however, overall morbidity was higher. Celiac axis involvement should no longer be considered a strict contraindication to surgery in patients with locally advanced pancreatic adenocarcinoma. Considering the different baseline tumor characteristics, DP-CAR may need to be compared with palliative therapies instead of standard DP. Full article
(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)
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Systematic Review
Systematic Review and Network Meta-Analysis of Anaplastic Lymphoma Kinase (ALK) Inhibitors for Treatment-Naïve ALK-Positive Lung Cancer
Cancers 2021, 13(8), 1966; https://doi.org/10.3390/cancers13081966 - 19 Apr 2021
Cited by 14 | Viewed by 1964
Abstract
Several anaplastic lymphoma kinase inhibitors (ALKIs) have demonstrated excellent efficacy on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and also better adverse effect (AE) profiles compared to cytotoxic chemotherapy in advanced stage anaplastic lymphoma kinase (ALK) rearrangement-positive non-small cell lung [...] Read more.
Several anaplastic lymphoma kinase inhibitors (ALKIs) have demonstrated excellent efficacy on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and also better adverse effect (AE) profiles compared to cytotoxic chemotherapy in advanced stage anaplastic lymphoma kinase (ALK) rearrangement-positive non-small cell lung cancer (NSCLC) in phase III randomized clinical trials (RCTs). We conducted this systematic review and network meta-analysis to provide a ranking of ALKIs for treatment-naïve ALK-positive patients in terms of PFS, ORR, and AEs. In addition, a sub-group analysis of treatment benefits in patients with baseline brain metastasis was also conducted. Contrast-based analysis was performed for multiple treatment comparisons with the restricted maximum likelihood approach. Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being the best (Prbest) reference. All next-generation ALKIs were superior to crizotinib in PFS but lorlatinib and brigatinib had increased AEs. The probability of lorlatinib being ranked first among all treatment arms was highest (SUCRA = 93.3%, Prbest = 71.8%), although there were no significant differences in pairwise comparisons with high- (600 mg twice daily) and low- (300 mg twice daily) dose alectinib. In subgroup analysis of patients with baseline brain metastasis, low-dose alectinib had the best PFS (SUCRA = 87.3%, Prbest = 74.9%). Lorlatinib was associated with the best ranking for ORR (SUCRA = 90.3%, Prbest = 71.3%), although there were no significant differences in pairwise comparisons with the other ALKIs. In addition, low-dose alectinib had the best safety performance (SUCRA = 99.4%, Prbest = 97.9%). Lorlatinib and low-dose alectinib had the best PFS and ORR in the overall population and baseline brain metastasis subgroup, respectively. Low-dose alectinib had the lowest AE risk among the available ALKIs. Further head-to-head large-scale phase III RCTs are needed to verify our conclusions. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer with Targetable Driver Mutations)
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Obituary
Health Science Community Will Miss This Bright and Uniting Star: In Memory of Professor Gjumrakch Aliev, M.D, Ph.D.
Cancers 2021, 13(8), 1965; https://doi.org/10.3390/cancers13081965 - 19 Apr 2021
Cited by 1 | Viewed by 1100
Abstract
It is with deep sadness that we offer our memorial on the unexpected demise of our dear colleague, Professor Gjumrakch Aliev [...] Full article
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Article
The Pan-Immune-Inflammation-Value Predicts the Survival of Patients with Human Epidermal Growth Factor Receptor 2 (HER2)—Positive Advanced Breast Cancer Treated with First-Line Taxane-Trastuzumab-Pertuzumab
Cancers 2021, 13(8), 1964; https://doi.org/10.3390/cancers13081964 - 19 Apr 2021
Cited by 10 | Viewed by 1055
Abstract
Different peripheral blood parameters have emerged as prognostic biomarkers in breast cancer (BC), but their predictive role in Human Epidermal growth factor Receptor 2 positive (HER2+) advanced BC (aBC) patients receiving dual anti-HER2 blockade remains unclear. We evaluated the impact of the Pan-Immune-Inflammatory [...] Read more.
Different peripheral blood parameters have emerged as prognostic biomarkers in breast cancer (BC), but their predictive role in Human Epidermal growth factor Receptor 2 positive (HER2+) advanced BC (aBC) patients receiving dual anti-HER2 blockade remains unclear. We evaluated the impact of the Pan-Immune-Inflammatory Value (PIV), defined as the product of peripheral blood neutrophil, platelet, and monocyte counts divided by lymphocyte counts, on the prognosis of HER2+ aBC patients treated with first line trastuzumab-pertuzumab-based biochemotherapy. We also evaluated the association between the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and the monocyte to lymphocyte ratio (MLR) and clinical outcomes. Cox regression models were used to estimate the impact of these variables, as well as of other clinically relevant covariates, on patient survival. We included 57 HER2+ aBC patients treated with taxane-trastuzumab-pertuzumab in our Institution. High baseline MLR, PLR, and PIV were similarly predictive of worse PFS at univariate analysis, but only high PIV was associated with a trend toward worse PFS at multivariable analysis. Regarding OS, both high PIV and MLR were associated with significantly worse patient survival at univariate analysis, but only the PIV was statistically significantly associated with worse overall survival at multivariable analysis (HR 7.96; 95% CI: 2.18–29.09). Our study reveals the PIV as a new and potent predictor of OS in HER2+ aBC patients treated with first line trastuzumab-pertuzumab-containing biochemotherapy. Prospective studies are needed to validate this new prognostic parameter in HER2+ aBC. Full article
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Article
Impact of Grade Groups on Prostate Cancer-Specific and Other-Cause Mortality: Competing Risk Analysis from a Large Single Institution Series
Cancers 2021, 13(8), 1963; https://doi.org/10.3390/cancers13081963 - 19 Apr 2021
Cited by 3 | Viewed by 627
Abstract
Objective: To assess the risk of cancer-specific mortality (CSM) and other-cause mortality (OCM) using post-operative International Society of Urological Pathology Grade Group (GG) model in patients after radical prostatectomy (RP). Patients and Methods: Overall 1921 consecutive men who underwent RP during 2001 to [...] Read more.
Objective: To assess the risk of cancer-specific mortality (CSM) and other-cause mortality (OCM) using post-operative International Society of Urological Pathology Grade Group (GG) model in patients after radical prostatectomy (RP). Patients and Methods: Overall 1921 consecutive men who underwent RP during 2001 to 2017 in a single tertiary center were included in the study. Multivariate competing risk regression analysis was used to identify significant predictors and quantify cumulative incidence of CSM and OCM. Time-depending area under the curve (AUC) depicted the performance of GG model on prediction of CSM. Results: Over a median follow-up of 7.9-year (IQR 4.4-11.7) after RP, 235 (12.2%) deaths were registered, and 52 (2.7%) of them were related to PCa. GG model showed high and stable performance (time-dependent AUC 0.88) on prediction of CSM. Cumulative 10-year CSM in GGs 1 to 5 was 0.9%, 2.3%, 7.6%, 14.7%, and 48.6%, respectively; 10-year OCM in GGs was 15.5%, 16.1%, 12.6%, 17.7% and 6.5%, respectively. The ratio between 10-year CSM/OCM in GGs 1 to 5 was 1:17, 1:7, 1:2, 1:1, and 7:1, respectively. Conclusions: Cancer-specific and other-cause mortality differed widely between GGs. Presented findings could aid in personalized clinical decision making for active treatment. Full article
(This article belongs to the Special Issue Diagnosis and Treatment of Prostate Adenocarcinoma)
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Review
The Current Landscape of Clinical Trials for Systemic Treatment of HCC
Cancers 2021, 13(8), 1962; https://doi.org/10.3390/cancers13081962 - 19 Apr 2021
Cited by 10 | Viewed by 1797
Abstract
The clinical development of systemic treatments for hepatocellular carcinoma (HCC) has gained significant momentum in recent years. After the unexpected failure of the phase 3 trials testing the PD1-inhibitors nivolumab and pembrolizumab as monotherapy in advanced HCC, a multitude of trials employing different [...] Read more.
The clinical development of systemic treatments for hepatocellular carcinoma (HCC) has gained significant momentum in recent years. After the unexpected failure of the phase 3 trials testing the PD1-inhibitors nivolumab and pembrolizumab as monotherapy in advanced HCC, a multitude of trials employing different agents in various combinations and at different disease stages have been initiated. The first positive results reported for the combination of atezolizumab and bevacizumab, as the first line treatment of advanced HCC, will bring lasting change to the management of HCC and has increased the odds of success for alternative combination therapies. This review article seeks to provide clarity on the complex and evolving landscape of clinical trials on systemic treatments of HCC. It covers current trials which test various systemic treatments (i) in the first and second line in advanced HCC, (ii) in intermediate HCC, (iii) as adjuvant as well as (iv) neoadjuvant strategies, and (v) including immune interventions other than immune checkpoint inhibition. Full article
(This article belongs to the Collection Novel Therapies for Hepatocellular Carcinoma)
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Review
NKL-Code in Normal and Aberrant Hematopoiesis
Cancers 2021, 13(8), 1961; https://doi.org/10.3390/cancers13081961 - 19 Apr 2021
Cited by 7 | Viewed by 1105
Abstract
We have recently described physiological expression patterns of NKL homeobox genes in early hematopoiesis and in subsequent lymphopoiesis and myelopoiesis, including terminally differentiated blood cells. We thereby systematized differential expression patterns of eleven such genes which form the so-called NKL-code. Due to the [...] Read more.
We have recently described physiological expression patterns of NKL homeobox genes in early hematopoiesis and in subsequent lymphopoiesis and myelopoiesis, including terminally differentiated blood cells. We thereby systematized differential expression patterns of eleven such genes which form the so-called NKL-code. Due to the developmental impact of NKL homeobox genes, these data suggest a key role for their activity in normal hematopoietic differentiation processes. On the other hand, the aberrant overexpression of NKL-code-members or the ectopical activation of non-code members have been frequently reported in lymphoid and myeloid leukemia/lymphoma, revealing the oncogenic potential of these genes in the hematopoietic compartment. Here, I provide an overview of the NKL-code in normal hematopoiesis and instance mechanisms of deregulation and oncogenic functions of selected NKL genes in hematologic cancers. As well as published clinical studies, our conclusions are based on experimental work using hematopoietic cell lines which represent useful models to characterize the role of NKL homeobox genes in specific tumor types. Full article
(This article belongs to the Special Issue NKL Homeobox Genes in Normal and Aberrant Hematopoiesis)
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Article
Radiation-Induced Pneumonitis in the Era of the COVID-19 Pandemic: Artificial Intelligence for Differential Diagnosis
Cancers 2021, 13(8), 1960; https://doi.org/10.3390/cancers13081960 - 19 Apr 2021
Cited by 4 | Viewed by 788
Abstract
(1) Aim: To test the performance of a deep learning algorithm in discriminating radiation therapy-related pneumonitis (RP) from COVID-19 pneumonia. (2) Methods: In this retrospective study, we enrolled three groups of subjects: pneumonia-free (control group), COVID-19 pneumonia and RP patients. CT images were [...] Read more.
(1) Aim: To test the performance of a deep learning algorithm in discriminating radiation therapy-related pneumonitis (RP) from COVID-19 pneumonia. (2) Methods: In this retrospective study, we enrolled three groups of subjects: pneumonia-free (control group), COVID-19 pneumonia and RP patients. CT images were analyzed by mean of an artificial intelligence (AI) algorithm based on a novel deep convolutional neural network structure. The cut-off value of risk probability of COVID-19 was 30%; values higher than 30% were classified as COVID-19 High Risk, and values below 30% as COVID-19 Low Risk. The statistical analysis included the Mann–Whitney U test (significance threshold at p < 0.05) and receiver operating characteristic (ROC) curve, with fitting performed using the maximum likelihood fit of a binormal model. (3) Results: Most patients presenting RP (66.7%) were classified by the algorithm as COVID-19 Low Risk. The algorithm showed high sensitivity but low specificity in the detection of RP against COVID-19 pneumonia (sensitivity = 97.0%, specificity = 2%, area under the curve (AUC = 0.72). The specificity increased when an estimated COVID-19 risk probability cut-off of 30% was applied (sensitivity 76%, specificity 63%, AUC = 0.84). (4) Conclusions: The deep learning algorithm was able to discriminate RP from COVID-19 pneumonia, classifying most RP cases as COVID-19 Low Risk. Full article
(This article belongs to the Special Issue Radiology and Imaging of Cancer)
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Article
Implementation of Double Immune Checkpoint Blockade Increases Response Rate to Induction Chemotherapy in Head and Neck Cancer
Cancers 2021, 13(8), 1959; https://doi.org/10.3390/cancers13081959 - 19 Apr 2021
Cited by 6 | Viewed by 1016
Abstract
To determine whether a single dose of double immune checkpoint blockade (induction chemoimmunotherapy (ICIT)) adds benefit to induction single-cycle platinum doublet (induction chemotherapy (IC)) in locally advanced head and neck squamous cell carcinoma (HNSCC), patients treated with cisplatin 30 mg/m2 d1-3 and [...] Read more.
To determine whether a single dose of double immune checkpoint blockade (induction chemoimmunotherapy (ICIT)) adds benefit to induction single-cycle platinum doublet (induction chemotherapy (IC)) in locally advanced head and neck squamous cell carcinoma (HNSCC), patients treated with cisplatin 30 mg/m2 d1-3 and docetaxel 75 mg/m2 d1 combined with durvalumab 1500 mg fixed dose d5 and tremelimumab 75 mg fixed dose d5 (ICIT) within the CheckRad-CD8 trial were compared with a retrospective cohort receiving the same chemotherapy (IC) without immunotherapy. The endpoint of this analysis was the complete response rate (CR). A total of 53 patients were treated with ICIT and 104 patients with IC only. CR rates were 60.3% for ICIT and 40.3% for IC (p = 0.018). In the total population (n = 157), the most important predictor to achieve a CR was treatment type (OR: 2.21 for ICIT vs. IC; p = 0.038, multivariate analysis). The most diverse effects in CR rates between ICIT and IC were observed in younger (age ≤ 60) patients with HPV-positive OPSCCs (82% vs. 33%, p = 0.176), while there was no difference in older patients without HPV-positive OPSCCs (53% vs. 48%). The analysis provides initial evidence that ICIT could result in higher CR rates than IC. Young patients with HPV-positive OPSCCs may have the greatest benefit from additional immune checkpoint inhibitors. Full article
(This article belongs to the Special Issue New Approaches in the Management of Head and Neck Cancer)
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