Cancers

20 pages, 8346 KiB

Open AccessArticle

Stress Keratin 17 Is a Predictive Biomarker Inversely Associated with Response to Immune Check-Point Blockade in Head and Neck Squamous Cell Carcinomas and Beyond

by Taja Lozar, Israa Laklouk, Athena E. Golfinos, Niki Gavrielatou, Jin Xu, Christopher Flynn, Aysenur Keske, Menggang Yu, Justine Y. Bruce, Wei Wang, Cvetka Grasic Kuhar, Howard H. Bailey, Paul M. Harari, Huy Q. Dinh, David L. Rimm, Rong Hu, Paul F. Lambert and Megan B. Fitzpatrick

Cancers 2023, 15(19), 4905; https://doi.org/10.3390/cancers15194905 - 9 Oct 2023

Cited by 3 | Viewed by 2686

Abstract

Low response rates in immune check-point blockade (ICB)-treated head and neck squamous cell carcinoma (HNSCC) drive a critical need for robust, clinically validated predictive biomarkers. Our group previously showed that stress keratin 17 (CK17) suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated [...] Read more.

Low response rates in immune check-point blockade (ICB)-treated head and neck squamous cell carcinoma (HNSCC) drive a critical need for robust, clinically validated predictive biomarkers. Our group previously showed that stress keratin 17 (CK17) suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors, correlating with decreased response rate to pembrolizumab-based therapy in a pilot cohort of ICB-treated HNSCC (n = 26). Here, we performed an expanded analysis of the predictive value of CK17 in ICB-treated HNSCC according to the REMARK criteria and investigated the gene expression profiles associated with high CK17 expression. Pretreatment samples from pembrolizumab-treated HNSCC patients were stained via immunohistochemistry using a CK17 monoclonal antibody (n = 48) and subjected to spatial transcriptomic profiling (n = 8). Our findings were validated in an independent retrospective cohort (n = 22). CK17 RNA expression in pembrolizumab-treated patients with various cancer types was investigated for predictive significance. Of the 48 patients (60% male, median age of 61.5 years), 21 (44%) were CK17 high, and 27 (56%) were CK17 low. A total of 17 patients (35%, 77% CK17 low) had disease control, while 31 patients (65%, 45% CK17 low) had progressive disease. High CK17 expression was associated with a lack of disease control (p = 0.037), shorter time to treatment failure (p = 0.025), and progression-free survival (PFS, p = 0.004), but not overall survival (OS, p = 0.06). A high CK17 expression was associated with lack of disease control in an independent validation cohort (p = 0.011). PD-L1 expression did not correlate with CK17 expression or clinical outcome. CK17 RNA expression was predictive of PFS and OS in 552 pembrolizumab-treated cancer patients. Our findings indicate that high CK17 expression may predict resistance to ICB in HNSCC patients and beyond. Full article

(This article belongs to the Special Issue The Portrait of Cancer Immunotherapy: Tumor Microenvironment, Biomarkers and Immune Resistance—Volume II)

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20 pages, 2291 KiB

Open AccessSystematic Review

Hematological Toxicities with PARP Inhibitors in Prostate Cancer: A Systematic Review and Meta-Analysis of Phase II/III Randomized Controlled Trials

by Gartrell C. Bowling, Piragash Swargaloganathan, Carly Heintz, Ravi A. Madan, Binil Eldhose, Albert Dobi and Gregory T. Chesnut

Cancers 2023, 15(19), 4904; https://doi.org/10.3390/cancers15194904 - 9 Oct 2023

Cited by 2 | Viewed by 1959

Abstract

Background: Poly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based treatments for mCRPC, PARPis are not without drug-related hematological adverse events. Objective: To review the evidence on hematological toxicities, including anemia, thrombocytopenia, and [...] Read more.

Background: Poly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based treatments for mCRPC, PARPis are not without drug-related hematological adverse events. Objective: To review the evidence on hematological toxicities, including anemia, thrombocytopenia, and neutropenia from PARPis in prostate cancer. Study Methodology: A systematic review and meta-analysis using the PRISMA guidelines was performed for phase II and III randomized controlled trials (RCTs) of PARPis in prostate cancer. PubMed, Embase, and Ovid All EBM reviews—Cochrane were queried from inception to 9 June 2023. The Mantel–Haenszel method was used to report risk ratios (RR) and 95% confidence intervals (CI) for all-grade and high-grade anemia, thrombocytopenia, and neutropenia toxicities. Results: The systematic review retrieved eight phase II and III RCTs; specifically, eight were included in the anemia, five in the all-grade thrombocytopenia and neutropenia, and four in the high-grade thrombocytopenia and neutropenia outcomes. Compared to a placebo and/or other non-PARPi treatments, PARPi use was associated with an increased risk of all-grade anemia (RR, 3.37; 95% CI, 2.37–4.79; p < 0.00001), thrombocytopenia (RR, 4.54; 95% CI, 1.97–10.44; p = 0.0004), and neutropenia (RR, 3.11; 95% CI, 1.60–6.03; p = 0.0008). High-grade anemia (RR, 6.94; 95% CI, 4.06–11.86; p < 0.00001) and thrombocytopenia (RR, 5.52; 95% CI, 2.80–10.88; p < 0.00001) were also associated with an increased risk, while high-grade neutropenia (RR, 3.63; 95% CI, 0.77–17.23; p = 0.10) showed no significant association. Subgroup stratification analyses showed differences in various all-grade and high-grade toxicities. Conclusion: PARPis were associated with an increased risk of hematological AEs. Future studies with more pooled RCTs will enhance this understanding and continue to inform patient–physician shared decision-making. Future studies may also have a role in improving the current management strategies for these AEs. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

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19 pages, 5070 KiB

Open AccessArticle

Planning Strategy to Optimize the Dose-Averaged LET Distribution in Large Pelvic Sarcomas/Chordomas Treated with Carbon-Ion Radiotherapy

by Ankita Nachankar, Mansure Schafasand, Antonio Carlino, Eugen Hug, Markus Stock, Joanna Góra and Piero Fossati

Cancers 2023, 15(19), 4903; https://doi.org/10.3390/cancers15194903 - 9 Oct 2023

Cited by 5 | Viewed by 1312

Abstract

To improve outcomes in large sarcomas/chordomas treated with CIRT, there has been recent interest in LET optimization. We evaluated 22 pelvic sarcoma/chordoma patients treated with CIRT [large: HD-CTV ≥ 250 cm³ (n = 9), small: HD-CTV < 250 cm³ (n = [...] Read more.

To improve outcomes in large sarcomas/chordomas treated with CIRT, there has been recent interest in LET optimization. We evaluated 22 pelvic sarcoma/chordoma patients treated with CIRT [large: HD-CTV ≥ 250 cm³ (n = 9), small: HD-CTV < 250 cm³ (n = 13)], D_RBE|LEM-I = 73.6 (70.4–73.6) Gy (RBE)/16 fractions, using the local effect model-I (LEM-I) optimization and modified-microdosimetric kinetic model (mMKM) recomputation. We observed that to improve high-LETd distribution in large tumors, at least 27 cm³ (low-LETd region) of HD-CTV should receive LETd of ≥33 keV/µm (p < 0.05). Hence, LETd optimization using ‘distal patching’ was explored in a treatment planning setting (not implemented clinically yet). Distal-patching structures were created to stop beams 1–2 cm beyond the HD-PTV-midplane. These plans were reoptimized and D_RBE|LEM-I, D_RBE|mMKM, and LETd were recomputed. Distal patching increased (a) LETd50% in HD-CTV (from 38 ± 3.4 keV/µm to 47 ± 8.1 keV/µm), (b) LETdmin in low-LETd regions of the HD-CTV (from 32 ± 2.3 keV/µm to 36.2 ± 3.6 keV/µm), (c) the GTV fraction receiving LETd of ≥50 keV/µm, (from <10% to >50%) and (d) the high-LETd component in the central region of the GTV, without significant compromise in D_RBE distribution. However, distal patching is sensitive to setup/range uncertainties, and efforts to ascertain robustness are underway, before routine clinical implementation. Full article

(This article belongs to the Special Issue Carbon Ion Radiotherapy)

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10 pages, 542 KiB

Open AccessArticle

Hashimoto’s Thyroiditis and the Risk of Papillary Thyroid Cancer in Children

by Jean-Nicolas Gallant, Vivian L. Weiss, Sheau-Chiann Chen, Jiancong Liang, Ryan H. Belcher, Fei Ye, Hernan Correa and Huiying Wang

Cancers 2023, 15(19), 4902; https://doi.org/10.3390/cancers15194902 - 9 Oct 2023

Cited by 1 | Viewed by 1454

Abstract

The association between Hashimoto’s thyroiditis (HT) and pediatric thyroid cancer is controversial. Most studies examining this connection have been based on adults, and larger studies in children are lacking. We performed a retrospective study of all sequential pediatric patients who underwent a thyroidectomy [...] Read more.

The association between Hashimoto’s thyroiditis (HT) and pediatric thyroid cancer is controversial. Most studies examining this connection have been based on adults, and larger studies in children are lacking. We performed a retrospective study of all sequential pediatric patients who underwent a thyroidectomy for a neoplasm at our institution over a twenty-year period in order to explore the link between HT and pediatric thyroid cancer. A total of 153 patients, median age 16.5 (interquartile range [IQR] 14.2–18.3) years, underwent thyroid surgery for a neoplasm. Patients were mainly female (80%) and White (84%). Median follow-up was 58.6 (IQR 20.7–105.4) months. Thirty-five (23%) patients had HT. Patients who underwent thyroid surgery and had HT were more likely to harbor a malignant neoplasm (p = 0.05); specifically, papillary thyroid carcinoma (PTC, p = 0.02). There was a difference in the distribution of HT among the subtypes of PTC (p = 0.03). Despite this, there was no difference in terms of survival between patients with/without HT. In conclusion, children with a thyroid malignancy, specifically, PTC, are more likely to have HT. The association between HT and pediatric PTC appears to be subtype-specific but does not seem to affect patient survival. Full article

(This article belongs to the Section Pediatric Oncology)

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14 pages, 1726 KiB

Open AccessArticle

Influence of Neoadjuvant Chemotherapy on Survival Outcomes of Radical Cystectomy in Pathologically Proven Positive and Negative Lymph Nodes

by Krystian Kaczmarek, Bartosz Małkiewicz, Karolina Skonieczna-Żydecka and Artur Lemiński

Cancers 2023, 15(19), 4901; https://doi.org/10.3390/cancers15194901 - 9 Oct 2023

Viewed by 1384

Abstract

Patients receiving neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) typically show better survival outcomes than those undergoing immediate surgery for muscle-invasive bladder cancer. However, most studies have not considered the lymph node (LN) status when evaluating NAC’s survival benefits. This study sought [...] Read more.

Patients receiving neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) typically show better survival outcomes than those undergoing immediate surgery for muscle-invasive bladder cancer. However, most studies have not considered the lymph node (LN) status when evaluating NAC’s survival benefits. This study sought to delineate the impact of NAC on patients based on their pathologically determined LN status at the time of RC. We examined data from 1395 patients treated at two departments between 1991 and 2022. Of them, 481 had positive LNs. A comparison of overall survival (OS) outcomes revealed that patients without LN involvement ((y)pN0) benefited from NAC with a hazard ratio (HR) of 0.692 (95% confidence interval [CI] 0.524–0.915). In contrast, patients with (y)pN+ showed no improvement with NAC (HR 0.927, 95%CI 0.713–1.205). Notably, patients treated with NAC for stage <ypT2ypN+ tumours experienced reduced OS compared to their counterparts who did not receive NAC. The HR was 3.111 (95%CI 1.249–7.746). Given that persistent nodal disease after NAC correlates with a worse prognosis, additional post-operative treatments should be considered. Full article

(This article belongs to the Special Issue Cystectomy for Bladder Cancer)

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20 pages, 8909 KiB

Open AccessArticle

Mannose-Binding Lectin 2 as a Potential Therapeutic Target for Hepatocellular Carcinoma: Multi-Omics Analysis and Experimental Validation

by Hangyu Liao, Jun Yang, Yuyan Xu, Juncheng Xie, Ke Li, Kunling Chen, Jingyuan Pei, Qiong Luo and Mingxin Pan

Cancers 2023, 15(19), 4900; https://doi.org/10.3390/cancers15194900 - 9 Oct 2023

Viewed by 1624

Abstract

Mannose-binding lectin 2 (MBL2), a member of the multimeric lectin family, is crucial in immune regulation and tumor development. MBL2 gene polymorphisms are associated with the risk and prognosis of various tumors, including hepatocellular carcinoma (HCC). Its functional role in HCC remains largely [...] Read more.

Mannose-binding lectin 2 (MBL2), a member of the multimeric lectin family, is crucial in immune regulation and tumor development. MBL2 gene polymorphisms are associated with the risk and prognosis of various tumors, including hepatocellular carcinoma (HCC). Its functional role in HCC remains largely unclear. In this study, we aimed to identify whether MBL2 is a key regulator and a potential therapeutic target for HCC. A bioinformatics analysis revealed close relationships among MBL2 downregulation, the tumor-associated proliferation and metastasis pathway, and tumor immunosuppressive microenvironments. Lower expression of MBL2 in HCC patients was linked to an unfavorable prognosis. A cell counting kit-8 assay, colony formation assay, transwell migration assay, and wound healing assay further confirmed that the overexpression of MBL2 could directly inhibit the proliferation and metastasis of HCC. Moreover, MBL2 expression was regulated by miR-34c-3p, as confirmed by the dual-luciferase reporter assay, thereby demonstrating tumor progression in HCC cells. Thus, our study offers the first comprehensive confirmation of the role of MBL2 in the development of HCC through multi-omics analysis and experimental validation. Furthermore, miR-34c-3p was found to be an upstream mechanism of the downregulation of MBL2 expression and could be a promising therapeutic target, expanding treatment options for patients with HCC. Full article

(This article belongs to the Special Issue New Insights on Therapy in Hepatocellular Carcinoma)

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14 pages, 1437 KiB

Open AccessArticle

Enhanced Risk Stratification in Early-Stage Endometrial Cancer: Integrating POLE through Droplet Digital PCR and L1CAM

by Seungyeon Joe, Miseon Lee, Jun Kang, Joori Kim, Sook-Hee Hong, Sung Jong Lee, Keun Ho Lee and Ahwon Lee

Cancers 2023, 15(19), 4899; https://doi.org/10.3390/cancers15194899 - 9 Oct 2023

Cited by 3 | Viewed by 1920

Abstract

Aim: In order to enhance risk stratification in early-stage endometrial cancer (EC), we conducted molecular classification using surrogate markers, including the POLE droplet digital polymerase chain reaction (ddPCR) and L1CAM immunohistochemistry (IHC). Method: We analyzed archival tumor tissue from 183 early-stage EC patients. [...] Read more.

Aim: In order to enhance risk stratification in early-stage endometrial cancer (EC), we conducted molecular classification using surrogate markers, including the POLE droplet digital polymerase chain reaction (ddPCR) and L1CAM immunohistochemistry (IHC). Method: We analyzed archival tumor tissue from 183 early-stage EC patients. POLE pathogenic mutations of P286R, V411L, S297F, A456P, and S459F within exons 9, 13, and 14 were detected using a ddPCR, while the mismatch repair (MMR) status was determined by MMR protein IHC and MSI tests. Additionally, we conducted IHC for p53 and L1CAM. Results: The 183 ECs were categorized into four subgroups: POLE-mutated (15.9%), MMR-deficient (29.0%), p53-abnormal (8.7%), and non-specific molecular profile (NSMP, 46.4%). We further subcategorized the NSMP subgroup into NSMP-L1CAMneg (41.5%) and NSMP-L1CAMpos (4.9%), which we refer to as the molecular L1CAM classification. The molecular L1CAM classification was an independent prognostic factor for recurrence-free survival (RFS) and overall survival (OS) (p < 0.001, each). Conclusion: Integrating molecular L1CAM classification can enhance risk stratification in early-stage EC, providing valuable prognostic information to guide treatment decisions and improve patient outcomes. POLE ddPCR might be a cost-effective and easy-to-perform test as an alternative to POLE NGS. Full article

(This article belongs to the Special Issue Pathology of Gynecologic Cancer)

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25 pages, 1678 KiB

Open AccessReview

A Narrative Review on CD44’s Role in Glioblastoma Invasion, Proliferation, and Tumor Recurrence

by Akihiro Inoue, Takanori Ohnishi, Masahiro Nishikawa, Yoshihiro Ohtsuka, Kosuke Kusakabe, Hajime Yano, Junya Tanaka and Takeharu Kunieda

Cancers 2023, 15(19), 4898; https://doi.org/10.3390/cancers15194898 - 9 Oct 2023

Cited by 9 | Viewed by 2136

Abstract

High invasiveness is a characteristic of glioblastoma (GBM), making radical resection almost impossible, and thus, resulting in a tumor with inevitable recurrence. GBM recurrence may be caused by glioma stem-like cells (GSCs) that survive many kinds of therapy. GSCs with high expression levels [...] Read more.

High invasiveness is a characteristic of glioblastoma (GBM), making radical resection almost impossible, and thus, resulting in a tumor with inevitable recurrence. GBM recurrence may be caused by glioma stem-like cells (GSCs) that survive many kinds of therapy. GSCs with high expression levels of CD44 are highly invasive and resistant to radio-chemotherapy. CD44 is a multifunctional molecule that promotes the invasion and proliferation of tumor cells via various signaling pathways. Among these, paired pathways reciprocally activate invasion and proliferation under different hypoxic conditions. Severe hypoxia (0.5–2.5% O₂) upregulates hypoxia-inducible factor (HIF)-1α, which then activates target genes, including CD44, TGF-β, and cMET, all of which are related to tumor migration and invasion. In contrast, moderate hypoxia (2.5–5% O₂) upregulates HIF-2α, which activates target genes, such as vascular endothelial growth factor (VEGF)/VEGFR2, cMYC, and cyclin D1. All these genes are related to tumor proliferation. Oxygen environments around GBM can change before and after tumor resection. Before resection, the oxygen concentration at the tumor periphery is severely hypoxic. In the reparative stage after resection, the resection cavity shows moderate hypoxia. These observations suggest that upregulated CD44 under severe hypoxia may promote the migration and invasion of tumor cells. Conversely, when tumor resection leads to moderate hypoxia, upregulated HIF-2α activates HIF-2α target genes. The phenotypic transition regulated by CD44, leading to a dichotomy between invasion and proliferation according to hypoxic conditions, may play a crucial role in GBM recurrence. Full article

(This article belongs to the Special Issue Advanced Research in Oncology in 2023)

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21 pages, 873 KiB

Open AccessArticle

Multitask Learning with Convolutional Neural Networks and Vision Transformers Can Improve Outcome Prediction for Head and Neck Cancer Patients

by Sebastian Starke, Alex Zwanenburg, Karoline Leger, Fabian Lohaus, Annett Linge, Goda Kalinauskaite, Inge Tinhofer, Nika Guberina, Maja Guberina, Panagiotis Balermpas, Jens von der Grün, Ute Ganswindt, Claus Belka, Jan C. Peeken, Stephanie E. Combs, Simon Boeke, Daniel Zips, Christian Richter, Esther G. C. Troost, Mechthild Krause, Michael Baumann and Steffen Löck Show full author list Hide full author list

Cancers 2023, 15(19), 4897; https://doi.org/10.3390/cancers15194897 - 9 Oct 2023

Cited by 2 | Viewed by 1801

Abstract

Neural-network-based outcome predictions may enable further treatment personalization of patients with head and neck cancer. The development of neural networks can prove challenging when a limited number of cases is available. Therefore, we investigated whether multitask learning strategies, implemented through the simultaneous optimization [...] Read more.

Neural-network-based outcome predictions may enable further treatment personalization of patients with head and neck cancer. The development of neural networks can prove challenging when a limited number of cases is available. Therefore, we investigated whether multitask learning strategies, implemented through the simultaneous optimization of two distinct outcome objectives (multi-outcome) and combined with a tumor segmentation task, can lead to improved performance of convolutional neural networks (CNNs) and vision transformers (ViTs). Model training was conducted on two distinct multicenter datasets for the endpoints loco-regional control (LRC) and progression-free survival (PFS), respectively. The first dataset consisted of pre-treatment computed tomography (CT) imaging for 290 patients and the second dataset contained combined positron emission tomography (PET)/CT data of 224 patients. Discriminative performance was assessed by the concordance index (C-index). Risk stratification was evaluated using log-rank tests. Across both datasets, CNN and ViT model ensembles achieved similar results. Multitask approaches showed favorable performance in most investigations. Multi-outcome CNN models trained with segmentation loss were identified as the optimal strategy across cohorts. On the PET/CT dataset, an ensemble of multi-outcome CNNs trained with segmentation loss achieved the best discrimination (C-index: 0.29, 95% confidence interval (CI): 0.22–0.36) and successfully stratified patients into groups with low and high risk of disease progression (

p = 0.003

). On the CT dataset, ensembles of multi-outcome CNNs and of single-outcome ViTs trained with segmentation loss performed best (C-index: 0.26 and 0.26, CI: 0.18–0.34 and 0.18–0.35, respectively), both with significant risk stratification for LRC in independent validation (

p = 0.002

and

p = 0.011

). Further validation of the developed multitask-learning models is planned based on a prospective validation study, which has recently completed recruitment. Full article

(This article belongs to the Special Issue Radiomics in Head and Neck Cancer Care)

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11 pages, 955 KiB

Open AccessArticle

Clinical Characteristics and Treatment Outcomes of Oral Cancers Using Transoral Robotic Surgery in an Endemic Region

by Chia-Chun Chang, Chung-Hsiung Chen, Tsai-Ling Hsieh, Kuang-Hsi Chang, Jing-Yang Huang, Frank Cheau-Feng Lin and Stella Chin-Shaw Tsai

Cancers 2023, 15(19), 4896; https://doi.org/10.3390/cancers15194896 - 9 Oct 2023

Cited by 1 | Viewed by 1433

Abstract

Oral cancer poses a major health challenge in Taiwan, consistently ranking among the highest globally in both incidence and cancer-related mortality. Transoral robotic surgery (TORS) has potential advantages over open surgery, but its long-term oncologic outcomes are not well established. In this study, [...] Read more.

Oral cancer poses a major health challenge in Taiwan, consistently ranking among the highest globally in both incidence and cancer-related mortality. Transoral robotic surgery (TORS) has potential advantages over open surgery, but its long-term oncologic outcomes are not well established. In this study, we sought to elucidate the role of TORS in improving treatment outcomes among oral cancer patients. A case–control study with propensity score matching was conducted in a single teaching hospital in Taiwan. It included 72 oral cancer patients in each group to analyze and compare survival outcomes between the surgical approaches. The TORS group demonstrated a higher negative resection margin rate, a lower mortality risk and better overall survival than the open-surgery group. Multivariate Cox regression analysis confirmed TORS’s association with a reduced risk of death. Kaplan–Meier survival analysis and log-rank tests indicated significantly better survival outcomes for the TORS group across all cancer stages. Moreover, the TORS group exhibited improved overall survival rates for stage III and IV patients compared to the conventional open-surgery group. In conclusion, this study suggests that TORS may offer better overall survival rates and potential advantages over conventional surgery for oral cancer treatment. Full article

(This article belongs to the Collection Advances in Diagnostics and Treatment of Head and Neck Cancer)

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Graphical abstract

12 pages, 1172 KiB

Open AccessArticle

Risk Factors and Prognosis of Stroke in Gynecologic Cancer Patients

by Ji Young Kwon, Kena Park, Jeong Min Song, Seung Yeon Pyeon, Seon Hwa Lee, Young Shin Chung and Jong-Min Lee

Cancers 2023, 15(19), 4895; https://doi.org/10.3390/cancers15194895 - 9 Oct 2023

Cited by 1 | Viewed by 1549

Abstract

Increased life expectancy and cancer prevalence rates expose patients to a higher risk of developing other comorbidities such as stroke. This study aimed to evaluate the risk factors for and prognosis of stroke in patients with gynecological cancers. A single-center retrospective cohort study [...] Read more.

Increased life expectancy and cancer prevalence rates expose patients to a higher risk of developing other comorbidities such as stroke. This study aimed to evaluate the risk factors for and prognosis of stroke in patients with gynecological cancers. A single-center retrospective cohort study was conducted on patients with cervical, endometrial, and epithelial ovarian cancers. Patients were classified into three groups based on the period of stroke onset: at least one year before cancer diagnosis, within one year before cancer diagnosis to six months after the last treatment date, and six months after the last treatment date. Among the 644 patients, stroke occurred in 54 (8.4%). In univariate analysis, stroke was significantly associated with overall survival. In contrast, in multivariate analysis, stroke was significantly associated with age and hypertension, but not with overall survival. Age, pulmonary thromboembolism/deep vein thrombosis, histological grade, and tumor stage were significantly associated with overall survival. Therefore, it is important to establish an appropriate examination and treatment plan for patients with gynecologic cancers using a multidisciplinary approach that incorporates the patient’s age, medical condition, and tumor characteristics rather than excessively considering the adverse effects of stroke on cancer prognosis. Full article

(This article belongs to the Special Issue Clinical Management and Prognosis of Gynecological Cancer)

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13 pages, 1313 KiB

Open AccessArticle

Efficacy and Safety of Daratumumab, Pomalidomide, and Dexamethasone (DPd) Compared to Daratumumab, Bortezomib, and Dexamethasone (DVd) in Daratumumab–Naïve Relapsed Multiple Myeloma

by Aimaz Afrough, Shebli Atrash, Barry Paul, Evguenia Ouchveridze, Nausheen Ahmed, Zahra Mahmoudjafari, Anam Bashir, Omar Alkharabsheh, Hamza Hashmi and Al-Ola Abdallah

Cancers 2023, 15(19), 4894; https://doi.org/10.3390/cancers15194894 - 9 Oct 2023

Viewed by 2791

Abstract

Daratumumab-based combinations with pomalidomide/dexamethasone (DPd), or bortezomib/dexamethasone (DVd), have shown activity in relapsed/refractory multiple myeloma (RRMM) patients. However, no direct comparisons of safety or efficacy of the two regimens have been published to date. We conducted a retrospective study to compare the safety [...] Read more.

Daratumumab-based combinations with pomalidomide/dexamethasone (DPd), or bortezomib/dexamethasone (DVd), have shown activity in relapsed/refractory multiple myeloma (RRMM) patients. However, no direct comparisons of safety or efficacy of the two regimens have been published to date. We conducted a retrospective study to compare the safety and efficacy of DPd and DVd in daratumumab-naïve RRMM patients. We included 140 daratumumab-naïve patients who had received DPd or DVd for RRMM. Overall, the DPd group had a greater number of patients who had high-risk disease characteristics. Although response was deeper in the DPd group, the median progression-free survival (PFS) and overall survival (OS) were similar between the two groups. The DPd group exhibited a higher incidence of hematologic toxicities, whereas the DVd group had a higher incidence of peripheral neuropathy. The study results showed that while DPd may provide a deeper response, there was no significant difference in PFS or OS compared to DVd. For the high proportion of difficult-to-treat patients, duration of treatment may have contributed to these results, indicating that patient and disease characteristics should be considered when selecting salvage treatments. Full article

(This article belongs to the Section Cancer Drug Development)

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18 pages, 2628 KiB

Open AccessArticle

Human Breast Tissue Microbiota Reveals Unique Microbial Signatures that Correlate with Prognostic Features in Adult Ethiopian Women with Breast Cancer

by Zelalem Desalegn, Alana Smith, Meron Yohannes, Xueyuan Cao, Endale Anberber, Yonas Bekuretsion, Mathewos Assefa, Marcus Bauer, Martina Vetter, Eva Johanna Kantelhardt, Tamrat Abebe and Athena Starlard-Davenport

Cancers 2023, 15(19), 4893; https://doi.org/10.3390/cancers15194893 - 9 Oct 2023

Cited by 4 | Viewed by 1721

Abstract

Breast cancer (BC) is the leading cause of cancer mortality among women in Ethiopia. Overall, women of African ancestry have the highest death toll due to BC compared to other racial/ethnic groups. The cause of the disparity in mortality is unclear. Recently, studies [...] Read more.

Breast cancer (BC) is the leading cause of cancer mortality among women in Ethiopia. Overall, women of African ancestry have the highest death toll due to BC compared to other racial/ethnic groups. The cause of the disparity in mortality is unclear. Recently, studies conducted in the United States and other high-income countries highlighted the role of microbial dysbiosis in BC initiation, tumor growth, and treatment outcome. However, the extent to which inter-individual differences in the makeup of microbiota are associated with clinical and histopathological outcomes in Ethiopian women has not been studied. The goal of our study was to profile the microbiome in breast tumor and normal adjacent to tumor (NAT) tissues of the same donor and to identify associations between microbial composition and abundance and clinicopathological factors in Ethiopian women with BC. We identified 14 microbiota genera in breast tumor tissues that were distinct from NAT tissues, of which Sphingobium, Anaerococcus, Corynebacterium, Delftia, and Enhydrobacter were most significantly decreased in breast tumors compared to NAT tissues. Several microbial genera significantly differed by clinicopathological factors in Ethiopian women with BC. Specifically, the genus Burkholderia more strongly correlated with aggressive triple negative (TNBC) and basal-like breast tumors. The genera Alkanindiges, Anoxybacillus, Leifsonia, and Exiguobacterium most strongly correlated with HER2-E tumors. Luminal A and luminal B tumors also correlated with Anoxybacillus but not as strongly as HER2−E tumors. A relatively higher abundance of the genus Citrobacter most significantly correlated with advanced-stage breast tumors compared to early-stage tumors. This is the first study to report an association between breast microbial dysbiosis and clinicopathological factors in Ethiopian women. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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21 pages, 2132 KiB

Open AccessEditor’s ChoiceArticle

Enhancing Healthcare for Sarcoma Patients: Lessons from a Diagnostic Pathway Efficiency Analysis

by Maria Elyes, Philip Heesen, Georg Schelling, Beata Bode-Lesniewska, Gabriela Studer and Bruno Fuchs

Cancers 2023, 15(19), 4892; https://doi.org/10.3390/cancers15194892 - 9 Oct 2023

Cited by 4 | Viewed by 1322

Abstract

Sarcomas, rare and with lower survival rates than common tumors, offer insights into healthcare efficiency via the analysis of the total interval of the diagnostic pathway, combining the patient interval (time between the first symptom and visit with a physician) and diagnostic interval [...] Read more.

Sarcomas, rare and with lower survival rates than common tumors, offer insights into healthcare efficiency via the analysis of the total interval of the diagnostic pathway, combining the patient interval (time between the first symptom and visit with a physician) and diagnostic interval (time between first physician visit and histological diagnosis). Switzerland’s healthcare system, Europe’s costliest, lacks research on treating rare conditions, like mesenchymal tumors. This study examines the total interval of the diagnostic pathway for optimization strategies. Analyzing a dataset of 1028 patients presented from 2018 to 2021 to the Swiss Sarcoma Board (MDT/SB-SSN), this retrospective analysis delves into bone sarcoma (BS), soft-tissue sarcoma (STS), and their benign counterparts. Demographic and treatment data were extracted from medical records. The patient interval accounted for the largest proportion of the total interval and secondary care interval for the largest proportion of the diagnostic interval. Age, grade, and localization could be elicited as influencing factors of the length of different components of the total interval. An increasing age and tumor size, as well as the axial localization, could be elicited as factors increasing the probability of sarcoma. The patient and secondary care interval (SCI) offer the greatest potential for optimization, with SCI being the bottleneck of the diagnostic interval. New organizational structures for care work-ups are needed, such as integrated practice units (IPU) as integral part of value-based healthcare (VBHC). Full article

(This article belongs to the Special Issue Global Management of Sarcoma Data: Is Real-Time Predictive Analytics on the Horizon?)

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15 pages, 5946 KiB

Open AccessArticle

Modulation of the Tumor Microenvironment by Ellagic Acid in Rat Model for Hepatocellular Carcinoma: A Potential Target against Hepatic Cancer Stem Cells

by Wafaa S. Ramadan, Saleh Alkarim, Mohammed Moulay, Ghadeer Alrefeai, Fatma Alkudsy, Khalid Rehman Hakeem and Ashwaq Iskander

Cancers 2023, 15(19), 4891; https://doi.org/10.3390/cancers15194891 - 9 Oct 2023

Cited by 3 | Viewed by 1572

Abstract

The resistance to therapy and relapse in hepatocellular carcinoma (HCC) is highly attributed to hepatic cancer stem cells (HCSCs). HCSCs are under microenvironment control. This work aimed to assess the systemic effect of ellagic acid (EA) on the HCC microenvironment to decline HCSCs. [...] Read more.

The resistance to therapy and relapse in hepatocellular carcinoma (HCC) is highly attributed to hepatic cancer stem cells (HCSCs). HCSCs are under microenvironment control. This work aimed to assess the systemic effect of ellagic acid (EA) on the HCC microenvironment to decline HCSCs. Fifty Wistar rats were divided into six groups: negative control (CON), groups 2 and 3 for solvents (DMSO), and (OVO). Group 4 was administered EA only. The (HCC-M) group, utilized as an HCC model, administered CCL4 (0.5 mL/kg in OVO) 1:1 v/v, i.p) for 16 weeks. HCC-M rats were treated orally with EA (EA + HCC) 50 mg/kg bw for five weeks. Biochemical, morphological, histopathological, and immunohistochemical studies, and gene analysis using qRT-PCR were applied. Results revealed elevated liver injury biomarkers ALT, AST, ALP, and tumor biomarkers AFP and GGT, and marked nodularity of livers of HCC-M. EA effectively reduced the biomarkers and restored the altered structure of the livers. At the mRNA level, EA downregulated the expression of TGF-α, TGF-β, and VEGF, and restored p53 expression. This induced an increase in apoptotic cells immunostained with caspase3 and decreased the CD44 immunostained HCSCs. EA could modulate the tumor microenvironment in the HCC rat model and ultimately target the HCSCs. Full article

(This article belongs to the Section Tumor Microenvironment)

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17 pages, 6743 KiB

Open AccessReview

Intraoperative Imaging and Optical Visualization Techniques for Brain Tumor Resection: A Narrative Review

by Othman Bin-Alamer, Hussam Abou-Al-Shaar, Zachary C. Gersey, Sakibul Huq, Justiss A. Kallos, David J. McCarthy, Jeffery R. Head, Edward Andrews, Xiaoran Zhang and Constantinos G. Hadjipanayis

Cancers 2023, 15(19), 4890; https://doi.org/10.3390/cancers15194890 - 9 Oct 2023

Cited by 6 | Viewed by 3168

Abstract

Advancements in intraoperative visualization and imaging techniques are increasingly central to the success and safety of brain tumor surgery, leading to transformative improvements in patient outcomes. This comprehensive review intricately describes the evolution of conventional and emerging technologies for intraoperative imaging, encompassing the [...] Read more.

Advancements in intraoperative visualization and imaging techniques are increasingly central to the success and safety of brain tumor surgery, leading to transformative improvements in patient outcomes. This comprehensive review intricately describes the evolution of conventional and emerging technologies for intraoperative imaging, encompassing the surgical microscope, exoscope, Raman spectroscopy, confocal microscopy, fluorescence-guided surgery, intraoperative ultrasound, magnetic resonance imaging, and computed tomography. We detail how each of these imaging modalities contributes uniquely to the precision, safety, and efficacy of neurosurgical procedures. Despite their substantial benefits, these technologies share common challenges, including difficulties in image interpretation and steep learning curves. Looking forward, innovations in this field are poised to incorporate artificial intelligence, integrated multimodal imaging approaches, and augmented and virtual reality technologies. This rapidly evolving landscape represents fertile ground for future research and technological development, aiming to further elevate surgical precision, safety, and, most critically, patient outcomes in the management of brain tumors. Full article

(This article belongs to the Special Issue Advanced Imaging in Brain Tumor Patient Management)

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16 pages, 1613 KiB

Open AccessReview

RAGE as a Novel Biomarker for Prostate Cancer: A Systematic Review and Meta-Analysis

by Catherine C. Applegate, Michael B. Nelappana, Elaine A. Nielsen, Leszek Kalinowski, Iwona T. Dobrucki and Lawrence W. Dobrucki

Cancers 2023, 15(19), 4889; https://doi.org/10.3390/cancers15194889 - 9 Oct 2023

Cited by 2 | Viewed by 1759

Abstract

The receptor for advanced glycation end-products (RAGE) has been implicated in driving prostate cancer (PCa) growth, aggression, and metastasis through the fueling of chronic inflammation in the tumor microenvironment. This systematic review and meta-analysis summarizes and analyzes the current clinical and preclinical data [...] Read more.

The receptor for advanced glycation end-products (RAGE) has been implicated in driving prostate cancer (PCa) growth, aggression, and metastasis through the fueling of chronic inflammation in the tumor microenvironment. This systematic review and meta-analysis summarizes and analyzes the current clinical and preclinical data to provide insight into the relationships among RAGE levels and PCa, cancer grade, and molecular effects. A multi-database search was used to identify original clinical and preclinical research articles examining RAGE expression in PCa. After screening and review, nine clinical and six preclinical articles were included. The associations of RAGE differentiating benign prostate hyperplasia (BPH) or normal prostate from PCa and between tumor grades were estimated using odds ratios (ORs) and associated 95% confidence intervals (CI). Pooled estimates were calculated using random-effect models due to study heterogeneity. The clinical meta-analysis found that RAGE expression was highly likely to be increased in PCa when compared to BPH or normal prostate (OR: 11.3; 95% CI: 4.4–29.1) and that RAGE was overexpressed in high-grade PCa when compared to low-grade PCa (OR: 2.5; 95% CI: 1.8–3.4). In addition, meta-analysis estimates of preclinical studies performed by albatross plot generation found robustly positive associations among RAGE expression/activation and PCa growth and metastatic potential. This review demonstrates that RAGE expression is strongly tied to PCa progression and can serve as an effective diagnostic target to differentiate between healthy prostate, low-grade PCa, and high-grade PCa, with potential theragnostic applications. Full article

(This article belongs to the Section Cancer Biomarkers)

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28 pages, 1355 KiB

Open AccessReview

Focal Boost in Prostate Cancer Radiotherapy: A Review of Planning Studies and Clinical Trials

by Yutong Zhao, Annette Haworth, Pejman Rowshanfarzad and Martin A. Ebert

Cancers 2023, 15(19), 4888; https://doi.org/10.3390/cancers15194888 - 8 Oct 2023

Cited by 2 | Viewed by 2136

Abstract

Background: Focal boost radiotherapy was developed to deliver elevated doses to functional sub-volumes within a target. Such a technique was hypothesized to improve treatment outcomes without increasing toxicity in prostate cancer treatment. Purpose: To summarize and evaluate the efficacy and variability of focal [...] Read more.

Background: Focal boost radiotherapy was developed to deliver elevated doses to functional sub-volumes within a target. Such a technique was hypothesized to improve treatment outcomes without increasing toxicity in prostate cancer treatment. Purpose: To summarize and evaluate the efficacy and variability of focal boost radiotherapy by reviewing focal boost planning studies and clinical trials that have been published in the last ten years. Methods: Published reports of focal boost radiotherapy, that specifically incorporate dose escalation to intra-prostatic lesions (IPLs), were reviewed and summarized. Correlations between acute/late ≥G2 genitourinary (GU) or gastrointestinal (GI) toxicity and clinical factors were determined by a meta-analysis. Results: By reviewing and summarizing 34 planning studies and 35 trials, a significant dose escalation to the GTV and thus higher tumor control of focal boost radiotherapy were reported consistently by all reviewed studies. Reviewed trials reported a not significant difference in toxicity between focal boost and conventional radiotherapy. Acute ≥G2 GU and late ≥G2 GI toxicities were reported the most and least prevalent, respectively, and a negative correlation was found between the rate of toxicity and proportion of low-risk or intermediate-risk patients in the cohort. Conclusion: Focal boost prostate cancer radiotherapy has the potential to be a new standard of care. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

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16 pages, 59692 KiB

Open AccessArticle

Combined PI3K Inhibitor and Eribulin Enhances Anti-Tumor Activity in Preclinical Models of Paclitaxel-Resistant, PIK3CA-Mutated Endometrial Cancer

by Yeong Gyu Jeong, Nar Bahadur Katuwal, Min Sil Kang, Mithun Ghosh, Sa Deok Hong, Seong Min Park, Seul-Gi Kim, Tae Hoen Kim and Yong Wha Moon

Cancers 2023, 15(19), 4887; https://doi.org/10.3390/cancers15194887 - 8 Oct 2023

Cited by 4 | Viewed by 2310

Abstract

Endometrial cancer stands as the predominant gynecological malignancy in developed nations. For advanced or recurrent disease, paclitaxel-based chemotherapy is the standard front-line therapy. However, paclitaxel resistance eternally develops. Based on the high prevalence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, reaching 50%, [...] Read more.

Endometrial cancer stands as the predominant gynecological malignancy in developed nations. For advanced or recurrent disease, paclitaxel-based chemotherapy is the standard front-line therapy. However, paclitaxel resistance eternally develops. Based on the high prevalence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, reaching 50%, in endometrial cancer, we preclinically investigated the effectiveness of a combination of a phosphatidylinositol 3-kinase (PI3K) inhibitor with eribulin, a post-paclitaxel therapy for breast cancer, in treating paclitaxel-resistant, PIK3CA-mutated endometrial cancer. We generated paclitaxel-resistant cell lines from PIK3CA-mutated endometrial cancer cell lines by gradually increasing the concentration of paclitaxel in cell cultures. We observed that the PI3K/AKT and epithelial–mesenchymal transition (EMT) pathways in paclitaxel-resistant cells were significantly upregulated compared with those in parental cells. Then, we demonstrated that the combination of alpelisib (a PI3K inhibitor) and eribulin more effectively suppressed the cellular growth of paclitaxel-resistant cells in in vitro and in vivo xenograft models. Mechanistically, we demonstrated that the effect of the combination could be enhanced by inhibiting both the PI3K/AKT and EMT pathways. Therefore, we suggest that paclitaxel resistance is associated with the activation of the PIK3/AKT pathway in PIK3CA-mutated endometrial cancer, and the combination of a PI3K inhibitor and eribulin merits further clinical investigation. Full article

(This article belongs to the Section Clinical Research of Cancer)

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27 pages, 695 KiB

Open AccessReview

Current and Emerging Strategies to Treat Urothelial Carcinoma

by Berkha Rani, James J. Ignatz-Hoover, Priyanka S. Rana and James J. Driscoll

Cancers 2023, 15(19), 4886; https://doi.org/10.3390/cancers15194886 - 8 Oct 2023

Cited by 6 | Viewed by 3147

Abstract

Urothelial cell carcinoma (UCC, bladder cancer, BC) remains a difficult-to-treat malignancy with a rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those >55 years of age; it is ~four times more [...] Read more.

Urothelial cell carcinoma (UCC, bladder cancer, BC) remains a difficult-to-treat malignancy with a rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those >55 years of age; it is ~four times more commonly observed in men than women. The most important risk factor for developing BC is tobacco smoking, which accounts for ~50% of cases, followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC remains generally incurable and is associated with intrinsic and acquired drug and immune resistance. UCC is lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and a high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss therapies to improve UCC management and how comprehensive tumor profiling can identify actionable biomarkers and eventually fulfill the promise of precision medicine for UCC patients. Full article

(This article belongs to the Special Issue Targeted Therapy for Bladder Cancer)

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21 pages, 2884 KiB

Open AccessArticle

Pan-Cancer Analysis of Patient Tumor Single-Cell Transcriptomes Identifies Promising Selective and Safe Chimeric Antigen Receptor Targets in Head and Neck Cancer

by Sanna Madan, Sanju Sinha, Tiangen Chang, J. Silvio Gutkind, Ezra E. W. Cohen, Alejandro A. Schäffer and Eytan Ruppin

Cancers 2023, 15(19), 4885; https://doi.org/10.3390/cancers15194885 - 8 Oct 2023

Viewed by 2105

Abstract

Chimeric antigen receptor (CAR) T cell therapies have yielded transformative clinical successes for patients with blood tumors, but their full potential remains to be unleashed against solid tumors. One challenge is finding selective targets, which we define intuitively to be cell surface proteins [...] Read more.

Chimeric antigen receptor (CAR) T cell therapies have yielded transformative clinical successes for patients with blood tumors, but their full potential remains to be unleashed against solid tumors. One challenge is finding selective targets, which we define intuitively to be cell surface proteins that are expressed widely by cancer cells but minimally by healthy cells in the tumor microenvironment and other normal tissues. Analyzing patient tumor single-cell transcriptomics data, we first defined and quantified selectivity and safety scores of existing CAR targets for indications in which they are in clinical trials or approved. We then sought new candidate cell surface CAR targets that have better selectivity and safety scores than those currently being tested. Remarkably, in almost all cancer types, we could not find such better targets, testifying to the near optimality of the current target space. However, in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSC), for which there is currently a dearth of existing CAR targets, we identified a total of twenty candidate novel CAR targets, five of which have both superior selectivity and safety scores. These newly identified cell surface targets lay a basis for future investigations that may lead to better CAR treatments in HNSC. Full article

(This article belongs to the Special Issue Head and Neck Cancers—Novel Approaches and Future Outlook)

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12 pages, 1836 KiB

Open AccessArticle

by Chi Yuan, Zhongyu Jian, Shijian Feng, Menghua Wang, Liyuan Xiang, Hong Li, Xi Jin and Kunjie Wang

Cancers 2023, 15(19), 4884; https://doi.org/10.3390/cancers15194884 - 8 Oct 2023

Cited by 3 | Viewed by 1941

Abstract

Objective: This study aimed to investigate whether testosterone mediates or confounds the effect of obesity-related traits on prostate cancer (PCa) using Mendelian randomization (MR) analysis. Materials and Methods: Data of obesity-related traits (body mass index [BMI], waist-to-hip ratio [WHR], and waist-to-hip ratio adjusted [...] Read more.

Objective: This study aimed to investigate whether testosterone mediates or confounds the effect of obesity-related traits on prostate cancer (PCa) using Mendelian randomization (MR) analysis. Materials and Methods: Data of obesity-related traits (body mass index [BMI], waist-to-hip ratio [WHR], and waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) were obtained from up to 806,834 people of European ancestry; data of testosterone (bioavailable testosterone [BT], total testosterone [TT], and sex hormone-binding globulin [SHBG]) were extracted from up to 194,453 participants in the UK Biobank; and the summary-level data of PCa (79,194 cases and 61,112 controls) were obtained from the PRACTICAL consortium. Result: The results supported the causal relationship between higher BMI and a reduced risk of PCa (OR = 0.91, 95% confidence interval [CI]: 0.86–0.96). Furthermore, increased BT levels were associated with an elevated risk of PCa (OR = 1.15, 95% CI: 1.06–1.24). Importantly, our analysis revealed a unidirectional causal effect—higher BMI was linked to lower BT levels (beta = −0.27, 95% CI: −0.3–−0.24), but not the other way around. This suggests that BT may mediate the effect of BMI on PCa rather than confound it. Our multivariable MR results further demonstrated that considering BT as a mediator led to the weakening of BMI’s effect on PCa risk (OR = 0.97, 95% CI: 0.90–1.05), while the impact of BT on PCa remained unchanged when accounting for BMI. Moreover, we identified a significant indirect effect of BMI on PCa risk (OR = 0.96, 95% CI: 0.94–0.98). Conclusion: Our study provided genetic evidence that serum BT can mediate the effect of BMI on the risk of PCa, indicating the possible mechanism by which obesity reduces PCa risk. Full article

(This article belongs to the Special Issue Prostate Cancer Epidemiology and Genetics)

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15 pages, 4196 KiB

Open AccessArticle

Influence of Macrophages on Vascular Invasion of Inflammatory Breast Cancer Emboli Measured Using an In Vitro Microfluidic Multi-Cellular Platform

by Manasa Gadde, Melika Mehrabi-Dehdezi, Bisrat G. Debeb, Wendy A. Woodward and Marissa Nichole Rylander

Cancers 2023, 15(19), 4883; https://doi.org/10.3390/cancers15194883 - 8 Oct 2023

Cited by 3 | Viewed by 1738

Abstract

Inflammatory breast cancer (IBC) is an aggressive disease with a poor prognosis and a lack of effective treatments. It is widely established that understanding the interactions between tumor-associated macrophages (TAMs) and the tumor microenvironment is essential for identifying distinct targeting markers that help [...] Read more.

Inflammatory breast cancer (IBC) is an aggressive disease with a poor prognosis and a lack of effective treatments. It is widely established that understanding the interactions between tumor-associated macrophages (TAMs) and the tumor microenvironment is essential for identifying distinct targeting markers that help with prognosis and subsequent development of effective treatments. In this study, we present a 3D in vitro microfluidic IBC platform consisting of THP1 M0, M1, or M2 macrophages, IBC cells, and endothelial cells. The platform comprises a collagen matrix that includes an endothelialized vessel, creating a physiologically relevant environment for cellular interactions. Through the utilization of this platform, it was discovered that the inclusion of tumor-associated macrophages (TAMs) led to an increase in the formation of new blood vessel sprouts and enhanced permeability of the endothelium, regardless of the macrophage phenotype. Interestingly, the platforms containing THP-1 M1 or M2 macrophages exhibited significantly greater porosity in the collagen extracellular matrix (ECM) compared to the platforms containing THP-1 M0 and the MDA-IBC3 cells alone. Cytokine analysis revealed that IL-8 and MMP9 showed selective increases when macrophages were cultured in the platforms. Notably, intravasation of tumor cells into the vessels was observed exclusively in the platform containing MDA-IBC3 and M0 macrophages. Full article

(This article belongs to the Section Cancer Pathophysiology)

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23 pages, 2806 KiB

Open AccessArticle

Depth of Invasion: Influence of the Latest TNM Classification on the Prognosis of Clinical Early Stages of Oral Tongue Squamous Cell Carcinoma and Its Association with Other Histological Risk Factors

by Ignacio Navarro Cuéllar, Samuel Espías Alonso, Francisco Alijo Serrano, Isabel Herrera Herrera, José Javier Zamorano León, José Luis Del Castillo Pardo de Vera, Ana María López López, Cristina Maza Muela, Gema Arenas de Frutos, Santiago Ochandiano Caicoya, Manuel Tousidonis Rial, Alba García Sevilla, Raúl Antúnez-Conde, José Luis Cebrián Carretero, María Isabel García-Hidalgo Alonso, José Ignacio Salmerón Escobar, Miguel Burgueño García, Carlos Navarro Vila and Carlos Navarro Cuéllar

Cancers 2023, 15(19), 4882; https://doi.org/10.3390/cancers15194882 - 8 Oct 2023

Cited by 1 | Viewed by 2616

Abstract

Background: The American Joint Committee on Cancer (AJCC), in its 8th edition, introduces modifications to the previous TNM classification, incorporating tumour depth of invasion (DOI). The aim of this research is to analyse the prognosis (in terms of disease-free survival and overall survival) [...] Read more.

Background: The American Joint Committee on Cancer (AJCC), in its 8th edition, introduces modifications to the previous TNM classification, incorporating tumour depth of invasion (DOI). The aim of this research is to analyse the prognosis (in terms of disease-free survival and overall survival) of clinical early stage (I and II) squamous cell carcinomas of the oral tongue according to the DOI levels established by the AJCC in its latest TNM classification to assess changes to the T category and global staging system and to evaluate the association between DOI and other histological risk factors. Methods: A retrospective longitudinal observational study of a series of cases was designed. All patients were treated with upfront surgery at our institution between 2010 and 2019. The variables of interest were defined and classified into four groups: demographic, clinical, histological and evolutive control. Univariate and multivariate analyses were carried out and survival functions were calculated using the Kaplan–Meier method. Statistical significance was established for p values below 0.05. Results: Sixty-one patients were included. The average follow-up time was 47.42 months. Fifteen patients presented a loco-regional relapse (24.59%) and five developed distant disease (8.19%). Twelve patients died (19.67%). Statistically significant differences were observed, with respect to disease-free survival (p = 0.043), but not with respect to overall survival (p = 0.139). A total of 49.1% of the sample upstaged their T category and 29.5% underwent modifications of their global stage. The analysis of the relationship between DOI with other histological variables showed a significant association with the presence of pathological cervical nodes (p = 0.012), perineural invasion (p = 0.004) and tumour differentiation grade (p = 0.034). Multivariate analysis showed association between depth of invasion and perineural invasion. Conclusions: Depth of invasion is a histological risk factor in early clinical stages of oral tongue squamous cell carcinoma. Depth of invasion impacts negatively on patient prognosis, is capable per se of modifying the T category and the global tumour staging, and is associated with the presence of cervical metastatic disease, perineural invasion and tumoural differentiation grade. Full article

(This article belongs to the Special Issue Salivary Glands Tumors, Head and Neck Tumors and Thymoma: Current Understanding and Future Personalized Therapeutic Approach)

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3 pages, 174 KiB

Open AccessEditorial

Unveiling Insights into Ovarian Cancer Metabolism through Space- and Time-Resolved Analysis

by Wei Jia and Mengci Li

Cancers 2023, 15(19), 4881; https://doi.org/10.3390/cancers15194881 - 8 Oct 2023

Viewed by 1111

Abstract

High-grade serous carcinoma (HGSC) represents a formidable challenge in the realm of ovarian cancer, notorious for its elusive early detection, poor prognosis and limited understanding of the intricacies of its pathogenesis [...] Full article

(This article belongs to the Section Methods and Technologies Development)

11 pages, 4631 KiB

Open AccessArticle

Genome-Wide DNA Methylation Profiling as Frontline Diagnostics for Central Nervous System Embryonal Tumors in Hong Kong

by Otto C. H. Tam, Ronnie S. L. Ho, Shing Chan, Kay K. W. Li, Tit-Leung Lam, Elaine T. Y. Cheung, Oi-Yee Cheung, Wilson W. S. Ho, Kevin K. F. Cheng, Matthew M. K. Shing, Dennis T. L. Ku, Brian H. Y. Chung, Wanling Yang, Godfrey C. F. Chan, Ho-Keung Ng and Anthony P. Y. Liu

Cancers 2023, 15(19), 4880; https://doi.org/10.3390/cancers15194880 - 7 Oct 2023

Viewed by 1357

Abstract

This paper examines the link between CNS tumor biology and heterogeneity and the use of genome-wide DNA methylation profiling as a clinical diagnostic platform. CNS tumors are the most common solid tumors in children, and their prognosis remains poor. This study retrospectively analyzed [...] Read more.

This paper examines the link between CNS tumor biology and heterogeneity and the use of genome-wide DNA methylation profiling as a clinical diagnostic platform. CNS tumors are the most common solid tumors in children, and their prognosis remains poor. This study retrospectively analyzed pediatric patients with CNS embryonal tumors in Hong Kong between 1999 and 2017, using data from the territory-wide registry and available formalin-fixed paraffin-embedded tumor tissue. After processing archival tumor tissue via DNA extraction, quantification, and methylation profiling, the data were analyzed by using the web-based DKFZ classifier (Molecular Neuropathology (MNP) 2.0 v11b4) and t-SNE analysis. Methylation profiles were deemed informative in 85 samples. Epigenetic data allowed molecular subgrouping and confirmed diagnosis in 65 samples, verified histologic diagnosis in 8, and suggested an alternative diagnosis in 12. This study demonstrates the potential of DNA methylation profiling in characterizing pediatric CNS embryonal tumors in a large cohort from Hong Kong, which should enable regional and international collaboration in future pediatric neuro-oncology research. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Treatment of Pediatric Solid Tumors)

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31 pages, 4316 KiB

Open AccessReview

Extracellular Vesicles in Triple–Negative Breast Cancer: Immune Regulation, Biomarkers, and Immunotherapeutic Potential

by Kaushik Das, Subhojit Paul, Arnab Ghosh, Saurabh Gupta, Tanmoy Mukherjee, Prem Shankar, Anshul Sharma, Shiva Keshava, Subhash C. Chauhan, Vivek Kumar Kashyap and Deepak Parashar

Cancers 2023, 15(19), 4879; https://doi.org/10.3390/cancers15194879 - 7 Oct 2023

Cited by 12 | Viewed by 3345

Abstract

Triple–negative breast cancer (TNBC) is an aggressive subtype accounting for ~10–20% of all human BC and is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) amplification. Owing to its unique molecular profile [...] Read more.

Triple–negative breast cancer (TNBC) is an aggressive subtype accounting for ~10–20% of all human BC and is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) amplification. Owing to its unique molecular profile and limited targeted therapies, TNBC treatment poses significant challenges. Unlike other BC subtypes, TNBC lacks specific molecular targets, rendering endocrine therapies and HER2–targeted treatments ineffective. The chemotherapeutic regimen is the predominant systemic treatment modality for TNBC in current clinical practice. However, the efficacy of chemotherapy in TNBC is variable, with response rates varying between a wide range of patients, and the emerging resistance further adds to the difficulties. Furthermore, TNBC exhibits a higher mutational burden and is acknowledged as the most immunogenic of all BC subtypes. Consequently, the application of immune checkpoint inhibition has been investigated in TNBC, yielding promising outcomes. Recent evidence identified extracellular vesicles (EVs) as an important contributor in the context of TNBC immunotherapy. In view of the extraordinary ability of EVs to transfer bioactive molecules, such as proteins, lipids, DNA, mRNAs, and small miRNAs, between the cells, EVs are considered a promising diagnostic biomarker and novel drug delivery system among the prospects for immunotherapy. The present review provides an in–depth understanding of how EVs influence TNBC progression, its immune regulation, and their contribution as a predictive biomarker for TNBC. The final part of the review focuses on the recent key advances in immunotherapeutic strategies for better understanding the complex interplay between EVs and the immune system in TNBC and further developing EV–based targeted immunotherapies. Full article

(This article belongs to the Special Issue Emerging Trends in Immunotherapy for Triple Negative Breast Cancer)

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10 pages, 1041 KiB

Open AccessArticle

The Relationship between Furin and Chronic Inflammation in the Progression of Cervical Intraepithelial Neoplasia to Cancer: A Cross-Sectional Study

by Selim Afsar, Gulay Turan, Gurhan Guney, Gozde Sahin, Merve Aldıkactıoglu Talmac and Cigdem Usul Afsar

Cancers 2023, 15(19), 4878; https://doi.org/10.3390/cancers15194878 - 7 Oct 2023

Cited by 2 | Viewed by 1277

Abstract

Objective: The current study aimed to delineate the relationship between furin and chronic inflammation while cervical intraepithelial neoplasia progresses to cancer. Study Design: This cross-sectional study included 81 women who required colposcopic examinations. The study groups were formed based on pathological results: Group [...] Read more.

Objective: The current study aimed to delineate the relationship between furin and chronic inflammation while cervical intraepithelial neoplasia progresses to cancer. Study Design: This cross-sectional study included 81 women who required colposcopic examinations. The study groups were formed based on pathological results: Group I included women with cervical intraepithelial neoplasia (CIN) I (n = 30); Group II included women with CIN II-III (n = 28); and Group III included women with cervical cancer (CC) (n = 23). Furin, ki-67, and p16 levels were evaluated based on immunostaining intensity. The inflammatory indices were calculated in parallel with the literature from routine blood samples retrieved within one week before the procedure. Results: Furin expression gradually increased from CIN I to CIN II-III and from CIN II-III to CC, respectively (p < 0.001, p = 0.005). NLR, MLR, PLR, and SII were significantly higher in the CC group (p < 0.001). ROC curve analysis unveiled that NLR, MLR, PLR, and SII predicted the presence of CC with a cutoff value of 2.39 for NLR (sensitivity: 91.3%, specificity: 63.8%, AUROC: 0.79, p < 0.001); a cutoff value of 0.27 for MLR (sensitivity: 78.3%, specificity: 72.4%, AUROC: 0.77, p = 0.009); a cutoff value of 123 for PLR (sensitivity: 100%, specificity: 41.4%, AUROC: 0.70, p = 0.04); and a cutoff value of 747 for SII (sensitivity: 69.6%, specificity: 90.7%, AUROC: 0.71, p = 0.014). Conclusion: Furin expression increased gradually in parallel with the severity of cervical intraepithelial neoplasia. The inflammatory indices were higher in the presence of CC and denoted a good discrimination ability for predicting cervical cancer. Full article

(This article belongs to the Section Molecular Cancer Biology)

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11 pages, 904 KiB

Open AccessArticle

The Site of Origin of Medulloblastoma: Surgical Observations Correlated to Molecular Groups

by Olga Ciobanu-Caraus, Thomas Czech, Andreas Peyrl, Christine Haberler, Gregor Kasprian, Julia Furtner, Marcel Kool, Martin Sill, Josa M. Frischer, Anna Cho, Irene Slavc, Karl Rössler, Johannes Gojo and Christian Dorfer

Cancers 2023, 15(19), 4877; https://doi.org/10.3390/cancers15194877 - 7 Oct 2023

Cited by 2 | Viewed by 1578

Abstract

Developmental gene expression data from medulloblastoma (MB) suggest that WNT-MB originates from the region of the embryonic lower rhombic lip (LRL), whereas SHH-MB and non-WNT/non-SHH MB arise from cerebellar precursor matrix regions. This study aimed to analyze detailed intraoperative data with regard to [...] Read more.

Developmental gene expression data from medulloblastoma (MB) suggest that WNT-MB originates from the region of the embryonic lower rhombic lip (LRL), whereas SHH-MB and non-WNT/non-SHH MB arise from cerebellar precursor matrix regions. This study aimed to analyze detailed intraoperative data with regard to the site of origin (STO) and compare these findings with the hypothesized regions of origin associated with the molecular group. A review of the institutional database identified 58 out of 72 pediatric patients who were operated for an MB at our department between 1996 and 2020 that had a detailed operative report and a surgical video as well as clinical and genetic classification data available for analysis. The STO was assessed based on intraoperative findings. Using the intraoperatively defined STO, “correct” prediction of molecular groups was feasible in 20% of WNT-MB, 60% of SHH-MB and 71% of non-WNT/non-SHH MB. The positive predictive values of the neurosurgical inspection to detect the molecular group were 0.21 (95% CI 0.08–0.48) for WNT-MB, 0.86 (95% CI 0.49–0.97) for SHH-MB and 0.73 (95% CI 0.57–0.85) for non-WNT/non-SHH MB. The present study demonstrated a limited predictive value of the intraoperatively observed STO for the prediction of the molecular group of MB. Full article

(This article belongs to the Section Pediatric Oncology)

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Open AccessSystematic Review

Fatty Pancreas Is a Risk Factor for Pancreatic Cancer: A Systematic Review and Meta-Analysis of 2956 Patients

by Mónika Lipp, Dorottya Tarján, Jimin Lee, Ádám Zolcsák, Eszter Szalai, Brigitta Teutsch, Nándor Faluhelyi, Bálint Erőss, Péter Hegyi and Alexandra Mikó

Cancers 2023, 15(19), 4876; https://doi.org/10.3390/cancers15194876 - 7 Oct 2023

Cited by 3 | Viewed by 2694

Abstract

Pancreatic cancer (PC) is one of the most lethal cancers worldwide. Recently, fatty pancreas (FP) has been studied thoroughly, and although its relationship to PC is not fully understood, FP is suspected to contribute to the development of PC. We aimed to assess [...] Read more.

Pancreatic cancer (PC) is one of the most lethal cancers worldwide. Recently, fatty pancreas (FP) has been studied thoroughly, and although its relationship to PC is not fully understood, FP is suspected to contribute to the development of PC. We aimed to assess the association between PC and FP by conducting a systematic review and meta-analysis. We systematically searched three databases, MEDLINE, Embase, and CENTRAL, on 21 October 2022. Case–control and cross-sectional studies reporting on patients where the intra-pancreatic fat deposition was determined by modern radiology or histology were included. As main outcome parameters, FP in patients with and without PC and PC in patients with and without FP were measured. Proportion and odds ratio (OR) with a 95% confidence interval (CI) were used for effect size measure. PC among patients with FP was 32% (OR 1.32; 95% CI 0.42–4.16). However, the probability of having FP among patients with PC was more than six times higher (OR 6.13; 95% CI 2.61–14.42) than in patients without PC, whereas the proportion of FP among patients with PC was 0.62 (95% CI 0.42–0.79). Patients identified with FP are at risk of developing PC. Proper screening and follow-up of patients with FP may be recommended. Full article

(This article belongs to the Special Issue Oncogenesis of Pancreatic Cancer: Where Are We)

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Cancers, Volume 15, Issue 19 (October-1 2023) – 233 articles

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