Cancers doi: 10.3390/cancers16132397

Authors: Magrassi Pinton Luzzi Comincini Scravaglieri Gigliotti Bernardoni D’Agostino Juretich La Motta Garavaglia

Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes necessary for the oxidation of all-trans or 9-cis retinal to retinoic acid (RA). Retinoic acid and its derivatives are important for normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. Moreover, in recent years, it has been demonstrated that ALDH1A members are also expressed and functional in several human cancers where their role is not limited to the synthesis of RA. Here, we review the current knowledge about ALDH1A3, one of the 1A isoforms, in cancers with an emphasis on two of the deadliest tumors that affect humans: glioblastoma multiforme and mesothelioma. In both tumors, ALDH1A3 is considered a negative prognostic factor, and its level correlates with excessive proliferation, chemoresistance, and invasiveness. We also review the recent attempts to develop both ALDH1A3-selective inhibitors for cancer therapy and ALDH1A3-specific fluorescent substrates for fluorescence-guided tumor resection.

Cancers doi: 10.3390/cancers16132396

Authors: Tina Decorte Charlotte Van Calster Caren Randon Vickie Van Besien Mathilde Ketels Luc Vanden Bossche Mieke De Schryver Chris Monten

: Background: Validated questionnaires of self-reported LEL are important in the assessment and diagnosis of LEL. The aim of this study was to validate and translate a Dutch version of the screening questionnaire, the LELSQ developed and validated by Yost et al. Methods: We tested the questionnaire on a group of healthy women and a group of patients diagnosed with LEL. The translation was carried out using the forward and backward method from English to Dutch. Statistical analyses: SPSS (IBM corp, Armonk, New York) version 28.0.1.0 (001) was used for statistical analysis in the process of validation. The internal consistency was assessed by determining Cronbach’s alpha. The reliability was tested by test–retest reliability. The validity was determined by ROC analysis, and content and face validity were evaluated. Results: The internal consistency score in both groups had a strong value (0.83 to 0.90). The test–retest reliability was also strong in both groups. Face and content validity showed the LELSQ is an easy, understandable questionnaire that is not too time-consuming in the early detection of LEL. The ROC analysis showed an AUC value of 0.93, indicating strong validity. Conclusions: The validated Dutch translation showed high values for internal consistency, test–retest reliability, and validity, which allows us to implement the questionnaire in the early detection of LEL after gynecological cancer treatment.

Cancers doi: 10.3390/cancers16132395

Authors: Adrienne B. Shannon Jonathan S. Zager Matthew C. Perez

Rare histologic subtypes of melanoma, including acral, mucosal, uveal, and desmoplastic melanomas, only make up 5% of all diagnosed melanomas and are often underrepresented in large, randomized trials. Recent advancements in systemic therapy have shown marked improvement in pathologic response rates, improving progression-free and overall survival among cutaneous melanoma patients, but there are limited data to demonstrate improved survival among rarer subtypes of melanoma. Acral melanoma has a poor response to immunotherapy and is associated with worse survival. Mucosal melanoma has a large variability in its presentation, a poor prognosis, and a low mutational burden. Uveal melanoma is associated with a high rate of liver metastasis; recent adoption of infusion and perfusion therapies has demonstrated improved survival among these patients. Desmoplastic melanoma, a high-risk cutaneous melanoma, is associated with high locoregional recurrence rates and mutational burden, suggesting this melanoma may have enhanced response to immunotherapy. While these variants of melanoma represent distinct disease entities, this review highlights the clinicopathologic characteristics and treatment recommendations for each of these rare melanomas and highlights the utility of modern therapies for each of them.

Cancers doi: 10.3390/cancers16132388

Authors: Neslihan Cabioglu Semen Onder Hüseyin Karatay Aysel Bayram Gizem Oner Mustafa Tukenmez Mahmut Muslumanoglu Abdullah Igci Ahmet Dinccag Vahit Ozmen Adnan Aydiner Pınar Saip Ekrem Yavuz

Background: We aim to investigate any possible associations between chemokine receptor expression and responses to neoadjuvant chemotherapy (NAC) along with outcomes in patients with triple-negative breast cancer (TNBC) with locally advanced disease. Method: Expressions of chemokine receptors were examined immunohistochemically after staining archival tissue of surgical specimens (n = 63) using specific antibodies for CCR5, CCR7, CXCR4, and CXCR5. Results: Patients with high CCR5, CCR7, CXCR4, and CXCR5 expression on tumors and high CXCR4 expression on tumor-infiltrating lymphocytes (TILs) were less likely to have a pathological complete response (pCR) or Class 0-I RCB-Index compared to others. Patients with residual lymph node metastases (ypN-positive), CCR5TM(tumor), and CXCR4TM expressions had an increased hazard ratio (HR) compared to others (DFS: HR = 2.655 [1.029–6.852]; DSS: HR = 2.763 [1.008–7.574]), (DFS: HR = 2.036 [0.805–5.148]; DSS: HR = 2.689 [1.020–7.090]), and (DFS: HR = 2.908 [1.080–7.829]; DSS: HR = 2.132 (0.778–5.846)), respectively. However, patients without CXCR5TIL expression had an increased HR compared to those with CXCR5TIL (DFS: 2.838 [1.266–6.362]; DSS: 4.211 [1.770–10.016]. Conclusion: High expression of CXCR4TM and CCR5TM was found to be associated with poor prognosis, and CXCR5TM was associated with poor chemotherapy response in the present cohort with locally advanced TNBC. Our results suggest that patients with TNBC could benefit from a chemokine receptor inhibitor therapy containing neoadjuvant chemotherapy protocols.

Cancers doi: 10.3390/cancers16132393

Authors: Anastasia Xagara Maria Goulielmaki Sotirios P. Fortis Alexandros Kokkalis Evangelia Chantzara George Christodoulopoulos Ioannis Samaras Emmanouil Saloustros Konstantinos Tsapakidis Vasileios Papadopoulos Ioannis S. Pateras Vasilis Georgoulias Constantin N. Baxevanis Athanasios Kotsakis

T-cell-mediated anti-tumoral responses may have significant clinical relevance as a biomarker for response to immunotherapy. The value of peripheral blood pre-existing tumor antigen-specific T cells (PreI+) as a predictive immunotherapy biomarker in NSCLC patients was investigated, along with the frequency of various circulating immune cells. Fifty-two treatment-naïve, stage III/IV NSCLC patients, treated with front-line immune checkpoint inhibitors (ICI)-containing regimens were enrolled. PreI was calculated as the percentages of CD3+IFNγ+ cells after in vitro co-cultures of PBMCs with peptides against four different Tumor-Associated Antigens (TAA). Immunophenotyping of peripheral blood immune cells was performed using multicolor flow cytometry. PreI+ T cells were detected in 44% of patients. Median overall survival (OS) was significantly higher in PreI+ patients compared to PreI– patients (not reached vs. 321 days, respectively; p = 0.014). PreI+ patients had significantly higher numbers of possible exhausted CD3+CD8+PD-1+ cells and lower percentages of immunosuppressive Tregs compared to PreI− patients. Additionally, patients with PreI+ and low numbers of peripheral blood M-MDSCs had a significant survival advantage compared to the rest of the patients. Thus, combining pre-existing tumor antigen-specific immunity before initiation of ICI in NSCLC patients with selected immune-suppressive cells could identify patients who have a favorable clinical outcome when treated with ICI-containing regimens.

Cancers doi: 10.3390/cancers16132394

Authors: Sven Zürcher Zora Martignoni Robert E. Hunger Michael Benzaquen S. Morteza Seyed Jafari

Background: The first-line treatment of the localized form of cutaneous squamous cell carcinoma (cSCC) remains surgical excision. Either conventional excision (CE) with margins or Mohs micrographic surgery (MMS) may be preferred, depending on the risk factors of cSCC, the characteristics of the tumor, and the available technical facilities. Methods: This article presents a systematic review of the current literature spanning from 1974 to 2023, comparing outcomes of cSCC treated with MMS versus cSCC treated with conventional excision. Results: Out of the 6821 records identified through the database search, a total of 156 studies were screened, of which 10 were included in the review. The majority of the included studies showed that treatment of cSCC with MMS consistently exhibits a significantly lower risk of recurrence compared to treatment with CE. In addition, MMS is emerging as the preferred technique for the resection of cSCC located in aesthetically or functionally challenging anatomical areas. Conclusion: The studies generally demonstrate that MMS is a safer and more effective treatment of cSCC than CE. Nevertheless, outcomes such as recurrence rates and cost-effectiveness should be assessed more precisely, in order to allow for a more tailored approach in determining the appropriate indication for the use of MMS.

Cancers doi: 10.3390/cancers16132392

Authors: Giacomo D’Andrea Giorgia Deroma Annarita Miluzio Stefano Biffo

Ribosomopathies are defined as inherited diseases in which ribosomal factors are mutated. In general, they present multiorgan symptoms. In spite of the fact that in cellular models, ribosomal insufficiency leads to a reduced rate of oncogenic transformation, patients affected by ribosomopathies present a paradoxical increase in cancer incidence. Several hypotheses that explain this paradox have been formulated, mostly on the assumption that altered ribosomes in a stem cell induce compensatory changes that lead to a cancer cell. For instance, the lack of a specific ribosomal protein can lead to the generation of an abnormal ribosome, an oncoribosome, that itself leads to altered translation and increased tumorigenesis. Alternatively, the presence of ribosomal stress may induce compensatory proliferation that in turns selects the loss of tumor suppressors such as p53. However, modern views on cancer have shifted the focus from the cancer cell to the tumor microenvironment. In particular, it is evident that human lymphocytes are able to eliminate mutant cells and contribute to the maintenance of cancer-free tissues. Indeed, many tumors develop in conditions of reduced immune surveillance. In this review, we summarize the current evidence and attempt to explain cancer and ribosomopathies from the perspective of the microenvironment.

Cancers doi: 10.3390/cancers16132391

Authors: Ismael Villanueva-Miranda Ruichen Rong Peiran Quan Zhuoyu Wen Xiaowei Zhan Donghan M. Yang Zhikai Chi Yang Xie Guanghua Xiao

Recent advances in foundation models have revolutionized model development in digital pathology, reducing dependence on extensive manual annotations required by traditional methods. The ability of foundation models to generalize well with few-shot learning addresses critical barriers in adapting models to diverse medical imaging tasks. This work presents the Granular Box Prompt Segment Anything Model (GB-SAM), an improved version of the Segment Anything Model (SAM) fine-tuned using granular box prompts with limited training data. The GB-SAM aims to reduce the dependency on expert pathologist annotators by enhancing the efficiency of the automated annotation process. Granular box prompts are small box regions derived from ground truth masks, conceived to replace the conventional approach of using a single large box covering the entire H&E-stained image patch. This method allows a localized and detailed analysis of gland morphology, enhancing the segmentation accuracy of individual glands and reducing the ambiguity that larger boxes might introduce in morphologically complex regions. We compared the performance of our GB-SAM model against U-Net trained on different sizes of the CRAG dataset. We evaluated the models across histopathological datasets, including CRAG, GlaS, and Camelyon16. GB-SAM consistently outperformed U-Net, with reduced training data, showing less segmentation performance degradation. Specifically, on the CRAG dataset, GB-SAM achieved a Dice coefficient of 0.885 compared to U-Net’s 0.857 when trained on 25% of the data. Additionally, GB-SAM demonstrated segmentation stability on the CRAG testing dataset and superior generalization across unseen datasets, including challenging lymph node segmentation in Camelyon16, which achieved a Dice coefficient of 0.740 versus U-Net’s 0.491. Furthermore, compared to SAM-Path and Med-SAM, GB-SAM showed competitive performance. GB-SAM achieved a Dice score of 0.900 on the CRAG dataset, while SAM-Path achieved 0.884. On the GlaS dataset, Med-SAM reported a Dice score of 0.956, whereas GB-SAM achieved 0.885 with significantly less training data. These results highlight GB-SAM’s advanced segmentation capabilities and reduced dependency on large datasets, indicating its potential for practical deployment in digital pathology, particularly in settings with limited annotated datasets.

Cancers doi: 10.3390/cancers16132389

Authors: Massimiliano Chetta Anna Basile Marina Tarsitano Maria Rivieccio Maria Oro Nazzareno Capitanio Nenad Bukvic Manuela Priolo Alessandra Rosati

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene variations are linked to the development of numerous cancers, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). The lack of typical drug-binding sites has long hampered the discovery of therapeutic drugs targeting KRAS. Since “CodeBreaK 100” demonstrated Sotorasib’s early safety and efficacy and led to its approval, especially in the treatment of non-small cell lung cancer (NSCLC), the subsequent identification of specific inhibitors for the p.G12C mutation has offered hope. However, the CodeBreaK 200 study found no significant difference in overall survival (OS) between patients treated with Docetaxel and Sotorasib (AMG 510), adding another degree of complexity to this ongoing challenge. The current study compares the three-dimensional structures of the two major KRAS isoforms, KRAS4A and KRAS4B. It also investigates the probable structural changes caused by the three major mutations (p.G12C, p.G12D, and p.G12V) within Sotorasib’s pocket domain. The computational analysis demonstrates that the wild-type and mutant isoforms have distinct aggregation propensities, resulting in the creation of alternate oligomeric configurations. This study highlights the increased complexity of the biological issue of using KRAS as a therapeutic target. The present study stresses the need for a better understanding of the structural dynamics of KRAS and its mutations to design more effective therapeutic approaches. It also emphasizes the potential of computational approaches to shed light on the complicated molecular pathways that drive KRAS-mediated oncogenesis. This study adds to the ongoing efforts to address the therapeutic hurdles presented by KRAS in cancer treatment.

Cancers doi: 10.3390/cancers16132390

Authors: Mangone Marinelli Bisceglia Braghiroli Banzi Damato Iori Pinto Cerullo Pellegri Zizzo Morabito Neri Giorgi Rossi

Colorectal cancer emerged as the third most prevalent malignancy worldwide, affecting nearly 2 million individuals in the year 2020. This study elucidates the pivotal role of a multidisciplinary team (MDT) in influencing the prognosis, as measured by relative survival rates, depending upon the stage and age. Cases recorded in an Italian Cancer Registry between 2017 and 2018 were included. Relative survival was reported at 1 and 3 years after diagnosis comparing MDT vs. no-MDT approaches. During the study period, 605 CRCs were recorded while 361 (59.7%) were taken care of by an MDT. Compared to no-MDT, MDT patients were younger with earlier stages and received more surgery. One year after diagnosis, survival was 78.7% (90% in MDT vs. 62% in no-MDT); stratifying by stage, in the MDT group there was no survival advantage for stage I (97.2% vs. 89.9%) and II (96.8% vs. 89.4%), but an advantage was observed for stage III (86.4% vs. 56.9%) and stage IV (63.7% vs. 27.4%). Similar values were observed at 3 years where a marked advantage was observed for stages III (69.9% vs. 35.1%) and IV (29.2% vs. 5.1%). The univariable analysis confirmed an excess risk in the no-MDT group (HR 2.6; 95%CI 2.0–3.3), also confirmed in the multivariable regression analysis (HR 2.0; 95% CI 1.5–2.5). Despite the increase in the number of MDT patients in 2018 (from 50% to 69%), this does not correspond to an improvement in outcome.

Cancers doi: 10.3390/cancers16132386

Authors: Young Choi Andrew Bedford Simcha Pollack

Abstract: Background: Barrett’s esophagus (BE) is a pre-neoplastic condition associated with an increased risk of esophageal adenocarcinoma (EAC). The accurate diagnosis of BE and grading of dysplasia can help to optimize the management of patients with BE. However, BE may be missed and the accurate grading of dysplasia based on a routine histology has a considerable intra- and interobserver variability. Thus, well-defined biomarker testing remains indispensable. The aim of our study was to identify routinely applicable and relatively specific biomarkers for an accurate diagnosis of BE, as well as determining biomarkers to predict the risk of progression in BE–dysplasia. Methods: Retrospectively, we performed immunohistochemistry to test mucin 2(MUC2), trefoil factor 3 (TFF3), p53, p16, cyclin D1, Ki-67, beta-catenin, and minichromosome maintenance (MCM2) in biopsies. Prospectively, to identify chromosomal alterations, we conducted fluorescent in situ hybridization testing on fresh brush samples collected at the time of endoscopy surveillance. Results: We discovered that MUC2 and TFF3 are specific markers for the diagnosis of BE. Aberrant expression, including the loss and strong overexpression of p53, Ki-67, p16, beta-catenin, cyclin D1, and MCM2, was significantly associated with low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC histology, with a relatively high risk of neoplastic changes. Furthermore, the aberrant expressions of p53 and p16 in BE-indefinite dysplasia (IND) progressor cohorts predicted the risk of progression. Conclusions: Assessing the biomarkers would be a suitable adjunct to accurate BE histology diagnoses and improve the accuracy of BE–dysplasia grading, thus reducing interobserver variability, particularly of LGD and risk prediction.

Cancers doi: 10.3390/cancers16132387

Authors: Michihisa Moriguchi Seita Kataoka Yoshito Itoh

Systemic therapy for hepatocellular carcinoma (HCC) has undergone substantial advancements. With the advent of atezolizumab plus bevacizumab (ATZ/BEV) combination therapy, followed by durvalumab plus tremelimumab, the era of immunotherapy for HCC has commenced. The emergence of systemic treatment with high response rates has led to improvements in overall survival while enabling conversion to radical surgical resection in some patients with HCC. In patients with intermediate-stage HCC, new treatment strategies combining systemic treatment and transcatheter arterial chemoembolization (TACE) are under development in clinical trials. Moreover, the addition of local therapies, such as TACE, to systemic treatment according to the treatment effect could achieve a certain percentage of complete response. In the IMbrave050 trial, the efficacy of ATZ/BEV combination therapy was validated in patients predicted to have a high risk of recurrence, especially in those who had undergone radical surgery or radiofrequency ablation for HCC. Therefore, systemic treatment for HCC is entering a new phase for all disease stages. The objective of this review is to organize the current position of systemic therapy for each HCC stage and discuss the development of new treatment methods and strategies, with a focus on regimens incorporating immune checkpoint inhibitors, along with future prospects.

Cancers doi: 10.3390/cancers16132385

Authors: Senija Eminović Emina Babarović Marko Klarić Dora Fučkar Čupić

We studied 115 cases of EEC diagnosed on hysterectomy specimens. Double immunohistochemical staining (D2-40/CD31) was performed in all 115 cases to show LVI and BVI on the same slide. MELF pattern invasion was present in 24/115 (21%) cases. MELF-positive tumors had a higher frequency of LVI than MELF-negative tumors (58% and 23%, respectively); the frequency of BVI was twice as high in MELF-positive tumors in comparison to MELF-negative tumors (25% and 12%, respectively). These differences were significant (p ˂ 0.0001). All tumors with positive BVI also had a concomitant LVI. The presence of MELF invasion had no impact on overall survival, confirming previous studies. 5-year survival rates were almost equal in cases with negative LVSI and cases with positive isolated LVI (98% vs. 97%). However, in cases where BVI was also present, the 5-year survival rate was significantly lower, 63% (p ˂ 0.0001). Furthermore, BVI proved to be an independent prognostic factor for overall survival, disease-free survival, and recurrence in the multivariate analysis. In conclusion, MELF pattern invasion is a good predictor of lymphatic and blood vessel invasion but has no prognostic value. Our results suggest that BVI in EEC has greater clinical value than isolated LVI or myometrial invasion patterns, and the therapeutic approach should be guided by BVI presence. Therefore, we hope this study will promote the routine evaluation of BVI in the context of EEC diagnostic procedures.

Cancers doi: 10.3390/cancers16132384

Authors: Yoichi Muramoto Naoya Murakami Noriyuki Okonogi Jun Takatsu Kotaro Iijima Tatsuya Inoue Kanade Kato Tatsuki Karino Kanako Kojima Masaki Oshima Yasuo Kosugi Terufumi Kawamoto Takashi Hirayama Kazunari Fujino Yasuhisa Terao Naoto Shikama

Purpose: Analyzing dose distributions to regional lymph-node metastases (RLNMs) in locally advanced cervical cancer (LACC) patients undergoing intracavitary and interstitial hybrid brachytherapy (IC/IS). Methods: Dose distributions of eleven LACC patients with 38 RLNMs, and who received 38 IC/IS sessions were analyzed in EQD2, considering RLNM positions and ipsilateral interstitial needles; these RLNMs, excepting the para-aortic region, were classified into four groups. Results: RLNMs had a median of two ipsilateral interstitial needles per session. Significant differences were observed in total RLNM D90, depending on whether the position was cranial or caudal of the uterine base (85.5 vs. 378.9 cGy, p < 0.0001), and whether the RLNM D90 was associated with a number of ipsilateral interstitial needles between 0–1 or 2 or more (68.4 vs. 112.2 cGy, p = 0.006) per session. At each session, Group 1 RLNMs (cranial of the uterine base, 0–1 ipsilateral interstitial needle) had a mean D90 of 21.1 cGy; Group 2 (cranial, 2 or more), 73.8; Group 3 (caudal, 0–1), 94.7; and Group 4 (caudal, 2 or more), 136.1. Conclusion: RLNMs located caudal of the uterine base associated with two or more ipsilateral interstitial needles in IC/IS had a higher dose contribution, which should be considered when calculating the RLNMs’ dose of external beam boost irradiation.

Cancers doi: 10.3390/cancers16132383

Authors: Fatemeh Doraneh-Gard Daniel Christoph Amberger Carina Amend Melanie Weinmann Christoph Schwepcke Lara Klauer Olga Schutti Hedayatollah Hosseini Doris Krämer Andreas Rank Christoph Schmid Helga Maria Schmetzer

Hypoxia can modulate the immune system by affecting the function and activity of immune cells, potentially leading to altered immune responses. This study investigated the generation of leukemia-derived dendritic cells (DCleu) from leukemic blasts and their impact on immune cell activation under hypoxic (5–10% O2) compared to normoxic (21% O2) conditions using various immunomodulatory Kits. The results revealed that DC/DCleu-generation was similar under hypoxic and normoxic conditions, with no significant differences observed in frequencies of generated DC/DCleu. Furthermore, the study showed that the activation of immune cells and their anti-leukemic activity improved when T cell-enriched immunoreactive cells were co-cultured with DC/DCleu which were generated with Kit I and M compared to the control after mixed lymphocyte cultures. The anti-leukemic activity was improved under hypoxic compared to normoxic conditions after MLCWB-DC Kit M. These findings suggest that DC/DCleu-cultures of leukemic whole blood with Kits under hypoxic conditions yield comparable frequencies of DC/DCleu and can even increase the anti-leukemic activity compared to normoxic conditions. Overall, this research highlights the potential of utilizing DC/DCleu (potentially induced in vivo with Kits) as a promising approach to enhance immune response in patients with acute myeloid leukemia.

Cancers doi: 10.3390/cancers16132382

Authors: Ali Razaghi Mikael Björnstedt

Selenoprotein P (SELENOP) acts as a crucial mediator, distributing selenium from the liver to other tissues within the body. Despite its established role in selenium metabolism, the specific functions of SELENOP in the development of liver cancer remain enigmatic. This study aims to unravel SELENOP’s associations in hepatocellular carcinoma (HCC) by scrutinizing its expression in correlation with disease characteristics and investigating links to hormonal and lipid/triglyceride metabolism biomarkers as well as its potential as a prognosticator for overall survival and predictor of hypoxia. SELENOP mRNA expression was analyzed in 372 HCC patients sourced from The Cancer Genome Atlas (TCGA), utilizing statistical methodologies in R programming and machine learning techniques in Python. SELENOP expression significantly varied across HCC grades (p < 0.000001) and among racial groups (p = 0.0246), with lower levels in higher grades and Asian individuals, respectively. Gender significantly influenced SELENOP expression (p < 0.000001), with females showing lower altered expression compared to males. Notably, the Spearman correlation revealed strong positive connections of SELENOP with hormonal markers (AR, ESR1, THRB) and key lipid/triglyceride metabolism markers (PPARA, APOC3, APOA5). Regarding prognosis, SELENOP showed a significant association with overall survival (p = 0.0142) but explained only a limited proportion of variability (~10%). Machine learning suggested its potential as a predictive biomarker for hypoxia, explaining approximately 18.89% of the variance in hypoxia scores. Future directions include validating SELENOP’s prognostic and diagnostic value in serum for personalized HCC treatment. Large-scale prospective studies correlating serum SELENOP levels with patient outcomes are essential, along with integrating them with clinical parameters for enhanced prognostic accuracy and tailored therapeutic strategies.

Cancers doi: 10.3390/cancers16132381

Authors: Omar S. Al-Odat Emily Nelson Tulin Budak-Alpdogan Subash C. Jonnalagadda Dhimant Desai Manoj K. Pandey

MM is a common type of cancer that unfortunately leads to a significant number of deaths each year. The majority of the reported MM cases are detected in the advanced stages, posing significant challenges for treatment. Additionally, all MM patients eventually develop resistance or experience relapse; therefore, advances in treatment are needed. However, developing new anti-cancer drugs, especially for MM, requires significant financial investment and a lengthy development process. The study of drug repurposing involves exploring the potential of existing drugs for new therapeutic uses. This can significantly reduce both time and costs, which are typically a major concern for MM patients. The utilization of pre-existing non-cancer drugs for various myeloma treatments presents a highly efficient and cost-effective strategy, considering their prior preclinical and clinical development. The drugs have shown promising potential in targeting key pathways associated with MM progression and resistance. Thalidomide exemplifies the success that can be achieved through this strategy. This review delves into the current trends, the challenges faced by conventional therapies for MM, and the importance of repurposing drugs for MM. This review highlights a noncomprehensive list of conventional therapies that have potentially significant anti-myeloma properties and anti-neoplastic effects. Additionally, we offer valuable insights into the resources that can help streamline and accelerate drug repurposing efforts in the field of MM.

Cancers doi: 10.3390/cancers16132380

Authors: Vijaya T. Daniel Vincent Azzolino Maria Abraham Nicholas Leonard Kaitlin Blankenship Karan Lal Julie Flahive Regina Brown Elizabeth Tkachenko Shereen Teymour Abdel Kader El Tal Bassel H. Mahmoud

How patient and tumor factors influence clearance margins and the number of Mohs Micrographic Surgery (MMS) stages when treating basal cell carcinoma (BCC) remains widely uncharacterized. It is important to elucidate these relationships, as surgical outcomes may be compared nationally between colleagues. Our objective is to evaluate the relationships between defect size and patient demographics, as well as between BCC subtypes and the number of MMS stages. Our second objective is to compare practice patterns and characteristics of patients requiring MMS at academic centers and private practices. A retrospective chart review was performed using data collected at academic centers (2015–2018) and private practices (2011–2018) of BCC patients older than 18 years old who underwent MMS. In total, 7651 patients with BCC requiring MMS were identified. Academic center adjusted analyses demonstrated clearance margins 0.1 mm higher for every year’s increase in age (p < 0.0001) and 0.25 increase in MMS stages for high-risk BCC (p < 0.0001). Private practice adjusted analyses demonstrated clearance margins 0.04 mm higher for every year’s increase in age (p < 0.0001). Clearance margins correlate with older age, and additional MMS stages correlate with high-risk BCC, suggesting the role patient and tumor factors may play in predicting tumor clearance and MMS stages.

Cancers doi: 10.3390/cancers16132379

Authors: Robert Michael O’Connell Emir Hoti

The incidence of colorectal cancer and colorectal liver metastases (CRLM) is increasing globally due to an interaction of environmental and genetic factors. A minority of patients with CRLM have surgically resectable disease, but for those who have resection as part of multimodal therapy for their disease, long-term survival has been shown. Precision surgery—the idea of careful patient selection and targeting of surgical intervention, such that treatments shown to be proven to benefit on a population level are the optimal treatment for each individual patient—is the new paradigm of care. Key to this is the understanding of tumour molecular biology and clinically relevant mutations, such as KRAS, BRAF, and microsatellite instability (MSI), which can predict poorer overall outcomes and a poorer response to systemic therapy. The emergence of immunotherapy and hepatic artery infusion (HAI) pumps show potential to convert previously unresectable disease to resectable disease, in addition to established systemic and locoregional therapies, but the surgeon must be wary of poor-quality livers and the spectre of post-hepatectomy liver failure (PHLF). Volume modulation, a cornerstone of hepatic surgery for a generation, has been given a shot in the arm with the advent of liver venous depletion (LVD) ensuring significantly more hypertrophy of the future liver remnant (FLR). The optimal timing of liver resection for those patients with synchronous disease is yet to be truly established, but evidence would suggest that those patients requiring complex colorectal surgery and major liver resection are best served with a staged approach. In the operating room, parenchyma-preserving minimally invasive surgery (MIS) can dramatically reduce the surgical insult to the patient and lead to better perioperative outcomes, with quicker return to function.

Cancers doi: 10.3390/cancers16132377

Authors: Tomasz Tabernacki Lindsey Wang David C. Kaelber Rong Xu Nathan A. Berger

Lung cancer (LC) is the second most common cancer and the leading cause of cancer deaths in the U.S. Insulin therapy, a key treatment for managing Type 2 Diabetes Mellitus (T2DM), is associated with increased LC risk. The impact of non-insulin antidiabetic drugs, particularly GLP-1 receptor agonists (GLP-1RAs), on LC risk is not well understood. This study evaluated LC risk in T2DM patients, comparing seven non-insulin antidiabetic agents to insulin. Using the TriNetX Analytics platform, we analyzed the de-identified electronic health records of 1,040,341 T2DM patients treated between 2005 and 2019, excluding those with prior antidiabetic use or LC diagnoses. We calculated hazard ratios and confidence intervals for LC risk and used propensity score matching to control for confounding factors. All non-insulin antidiabetic drugs, except alpha-glucosidase inhibitors, were associated with significantly reduced LC risk compared to insulin, with GLP-1RAs showing the greatest reduction (HR: 0.49, 95% CI: 0.41, 0.59). GLP-1RAs were consistently associated with lowered LC risk across all histological types, races, genders, and smoking statuses. These findings suggest that non-insulin antidiabetic drugs, particularly GLP-1RAs, may be preferable for managing T2DM while reducing LC risk.

Cancers doi: 10.3390/cancers16132378

Authors: Natalia Papaleo Andrea Molina-Alvarez Ricard Onieva Diana Fuertes Blanca Sanchez-Gonzalez Xenia Riera David Lopez-Segura Carmen Lome-Maldonado Xavier Ara-Mancebo Jose Yelamos Marta Salido Ivonne Vazquez Xavier Calvo Luis Colomo

Background: LMO2 is a relevant gene involved in B-cell ontogeny and a survival predictor of aggressive large B-cell lymphomas (aLBCL). Most studies assessing LMO2 mRNA expression have relied on microarray platforms or qRT-PCR methods, overlooking tissue morphology. In this study, we evaluate LMO2 RNA expression by chromogenic in situ hybridization (CISH) in normal tissue and in a series of 82 aLBCL. Methods: LMO2 CISH was performed in formalin-fixed paraffin-embedded tissues, scored by three different methods, and correlated with a transcriptome panel. Results: We obtained statistically significant results correlating the methods of evaluation with LMO2 protein expression and gene expression results. Normal tonsil tissue showed high levels of LMO2, particularly within the light zone of the germinal center. Conversely, in aLBCL, a notable reduction in LMO2 expression was noted, remarkably in cases carrying MYC rearrangements. Furthermore, significant results were obtained through overall survival and Cox regression survival analysis, incorporating International Prognostic Index data alongside LMO2 expression levels. Conclusions: We show a reliable method to identify LMO2 mRNA expression by CISH, effectively capturing many of the reported biologic features of LMO2.

Cancers doi: 10.3390/cancers16132376

Authors: Mohamed Mortagy Marie Line El Asmar Kandiah Chandrakumaran John Ramage

Background: Neuroendocrine neoplasms (NENs) are increasing in incidence globally. Previous analysis of the UK cancer database (National Cancer Registration and Analysis Service (NCRAS)) showed a notable female survival advantage in most tumour sites. This study aims to compare NCRAS to the Surveillance, Epidemiology, and End Results Program (SEER) to validate these results using the same statistical methods. Methods: A total of 14,834 and 108,399 patients with NENs were extracted from NCRAS and SEER, respectively. Sixty-months survival for both males and females for each anatomical site of NENs were calculated using restricted mean survival time (RMST) and Kaplan–Meier Survival estimates. The sixty-month RMST female survival advantage (FSA) was calculated. Results: FSA was similar in NCRAS and SEER. The highest FSA occurred in lung and stomach NENs. Conclusions: The data from SEER confirm the findings published by NCRAS. Female survival advantage remains unexplained.

Cancers doi: 10.3390/cancers16132375

Authors: Jingbo Wang Ji Eun Moon Xin Guo Jiaqi Yu Junlin Yi Sun Hyun Bae

Background: Because of the rarity, heterogeneous histology, and diverse anatomical sites of salivary gland cancer (SGC), there are a limited number of clinical studies on its management. This study reports the cumulative evidence of postoperative radiotherapy (PORT) for SGC of the head and neck. Methods: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases between 7th and 10th November 2023. Results: A total of 2962 patients from 26 studies between 2007 and 2023 were included in this meta-analysis. The median RT dose was 64 Gy (range: 56–66 Gy). The median proportions of high-grade, pathological tumor stage 3 or 4 and pathological lymph node involvement were 42% (0–100%), 40% (0–77%), and 31% (0–75%). The pooled locoregional control rates at 3, 5, and 10 years were 92% (95% confidence interval [CI], 89–94%), 89% (95% CI, 86–93%), and 84% (95% CI, 73–92%), respectively. The pooled disease-free survival (DFS) rates at 3, 5, and 10 years were 77% (95% CI, 70–83%), 67% (95% CI, 60–74%), and 61% (95% CI, 55–67%), respectively. The pooled overall survival rates at 3, 5, and 10 years were 84% (95% CI, 79–88%), 75% (95% CI, 72–79%), and 68% (95% CI, 62–74%), respectively. Severe late toxicity ≥ grade 3 occurred in 7% (95% CI, 3–14%). Conclusion: PORT showed favorable long-term efficacy and safety in SGC, especially for patients with high-grade histology. Considering that DFS continued to decrease, further clinical trials exploring treatment intensification are warranted.

Cancers doi: 10.3390/cancers16132374

Authors: Nicola De Stefano Damiano Patrono Fabio Colli Giorgia Rizza Gianluca Paraluppi Renato Romagnoli

Hepatocellular carcinoma (HCC) remains the leading oncological indication for liver transplantation (LT), with evolving and broadened inclusion criteria. Immune checkpoint inhibitors (ICIs) gained a central role in systemic HCC treatment and showed potential in the peri-transplant setting as downstaging/bridging therapy before LT or as a treatment for HCC recurrence following LT. However, the antagonistic mechanisms of action between ICIs and immunosuppressive drugs pose significant challenges, particularly regarding the risk of acute rejection (AR). This review analyzes the main signaling pathways targeted by ICI therapies and summarizes current studies on ICI therapy before and after LT. The literature on this topic is limited and highly heterogeneous, precluding definitive evidence-based conclusions. The use of ICIs before LT appears promising, provided that a sufficient wash-out period is implemented. In contrast, the results of post-LT ICI therapy do not support its wide clinical application due to high AR rates and overall poor response to treatment. In the future, modern graft preservation techniques might support the selection of good ICI responders, but data from high-level studies are urgently needed.

Cancers doi: 10.3390/cancers16132373

Authors: Thomas J. Vogl John Bielfeldt Ulrich Kübler Hamzah Adwan

This study shall retrospectively evaluate the efficacy and safety of liquid-nitrogen based CT-guided cryoablation (CA) as a minimal-invasive technique for the curative treatment of primary breast cancer. A total of 45 female patients with 56 tumors were treated by CT-guided CA in analgosedation as an outpatient procedure. We used a liquid-nitrogen based system with a single cryoprobe and performed two freeze cycles with an intermediate thawing. The mean tumor diameter was 1.6 ± 0.7 cm. Follow-up was conducted via contrast-enhanced MR images of the breast. No complications were observed in all 56 ablations. Initial complete ablation was achieved in 100% of cases. Four cases of local tumor progression were reported, resulting in a rate of 8.9%, and 6 cases of intramammary distant recurrence at a rate of 13.3%. The extramammary tumor progression was observed in 7 patients at a rate of 15.6%. The mean overall survival was 4.13 years (95% CI: 3.7–4.5). The mean overall progression-free survival was 2.5 years (95% CI: 1.8–3.2) and the mean local progression-free survival was 2.9 years (95% CI: 2.3–3.6). Cryoablation is a safe and effective treatment for primary breast cancer tumors, which can be performed in analgosedation and as an outpatient procedure. However, potential for improvement exists and further evidence is necessary.

Cancers doi: 10.3390/cancers16132372

Authors: Camelia Abid Jenny Tannoury Mthieu Uzzan Edouard Reizine Sébastien Mulé Julia Chalaye Alain Luciani Emmanuel Itti Iradj Sobhani

Introduction and aim: Simultaneous positron emission tomography/magnetic resonance imaging (PET-MRI) combines the high sensitivity of PET with the high specificity of MRI and is a tool for the assessment of gastroenteropancreatic neuroendocrine neoplasms (G-NENs). However, it remains poorly evaluated with no clear recommendations in current guidelines. Thus, we evaluated the prognostic impact of PET-MRI in G-NEN patients. Methods: From June 2017 to December 2021, 71 G-NEN patients underwent whole-body PET-MRI for staging and/or follow-up purposes. A whole-body emission scan with 18F-6-fluoro-L-dihydroxyphenylalanine (18FDOPA, n = 30), 18F-fluoro-2-deoxy-D-glucose (18FDG, n = 21), or 68Ga-(DOTA(0)-Phe(1)-Tyr(3))-octreotide (68Ga-DOTATOC, n = 20) with the simultaneous acquisition of a T1-Dixon sequence and diffusion-weighed imaging (DWI), followed by a dedicated step of MRI sequences with a Gadolinium contrast was performed. The patients underwent PET-MRI every 6–12 months during the follow-up period until death. Over this period, 50 patients with two or more PET-MRI were evaluated. Results: The mean age was 61 [extremes, 31–92] years. At the baseline, PET-MRI provided new information in 12 cases (17%) as compared to conventional imaging: there were more metastases in eight, an undescribed location (myocardia) in two, and an unknown primary location in two cases. G grading at the baseline influenced overall survival. During the follow-up (7–381 months, mean 194), clinical and therapy managements were influenced by PET-MRI in three (6%) patients due to new metastases findings when neither overall, nor disease-free survivals in these two subgroups (n = 12 vs. n = 59), were different. Conclusion: Our study suggests that using PET/MRI with the appropriate radiotracer improves the diagnostic performance with no benefit on survival. Further studies are warranted to evaluate the cost-effectiveness of this procedure.

Cancers doi: 10.3390/cancers16132371

Authors: Majid Esmaeilzadeh Oday Atallah Jörg Andreas Müller Frank Bengel Manolis Polemikos Hans E. Heissler Joachim K. Krauss

Intracranial metastases from thyroid cancer are rare. Although the prognosis of thyroid cancer patients is generally favorable, the prognosis of patients with intracranial metastases from thyroid cancer has been considered unfavorable owing to lower survival rates among such patients compared to those without intracranial involvement. Many questions about their management remain unclear. The aim of the present study was to analyze the characteristics, treatment modalities, and outcomes of patients with brain metastases from thyroid cancer. Among 4320 patients with thyroid cancer recorded in our institutional database over a 30-year period, the data of 20 patients with brain metastasis were retrospectively collected and analyzed. The clinical characteristics, histological type of primary cancer and metastatic brain tumor, additional previous distant metastasis, treatment modalities, locations and characteristics on radiologic findings, time interval between the first diagnosis of primary thyroid cancer and brain metastasis, and survival were analyzed. Among our patient cohort, the mean age at initial diagnosis was 59.3 ± 14.1 years, and at the manifestation of diagnosis of cerebral metastasis, the mean age was found to be 64.8 ± 14.9 years. The histological types of primary thyroid cancer were identified as papillary in ten patients, follicular in seven, and poorly differentiated carcinoma in three. The average interval between the diagnosis of thyroid cancer and brain metastasis was 63.4 ± 58.4 months (range: 0–180 months). Ten patients were identified as having a single intracranial lesion, and ten patients were found to have multiple lesions. Surgical resection was primarily performed in fifteen patients, and whole-brain radiotherapy, radiotherapy, or tyrosine kinase inhibitors were applied in the remaining five patients. The overall median survival time was 15 months after the diagnosis of BMs from TC (range: 1–252 months). Patients with thyroid cancer can develop brain metastasis even many years after the diagnosis of the primary tumor. The results of our study demonstrate increased overall survival in patients younger than 60 years of age at the time of diagnosis of brain metastasis. There was no difference in survival between patients with brain metastasis from papillary carcinoma and those with follicular thyroid carcinoma.

Cancers doi: 10.3390/cancers16132370

Authors: Marco Colella Andrea Iannucci Claudia Maresca Francesco Albano Carmela Mazzoccoli Federica Laudisi Ivan Monteleone Giovanni Monteleone

The reorganization of the cell cytoskeleton and changes in the content of cell adhesion molecules are crucial during the metastatic spread of tumor cells. Colorectal cancer (CRC) cells express high SMAD7, a protein involved in the control of CRC cell growth. In the present study, we evaluated whether SMAD7 regulates the cytoskeleton reorganization and dynamics in CRC. Knockdown of SMAD7 with a specific antisense oligonucleotide (AS) in HCT116 and DLD1, two human CRC cell lines, reduced the migration rate and the content of F-ACTIN filaments. A gene array, real-time PCR, and Western blotting of SMAD7 AS-treated cells showed a marked down-regulation of the X-linked inhibitor of apoptosis protein (XIAP), a member of the inhibitor of apoptosis family, which has been implicated in cancer cell migration. IL-6 and IL-22, two cytokines that activate STAT3, enhanced XIAP in cancer cells, and such induction was attenuated in SMAD7-deficient cells. Finally, in human CRC, SMAD7 mRNA correlated with XIAP expression. Our data show that SMAD7 positively regulates XIAP expression and migration of CRC cells, and suggest a mechanism by which SMAD7 controls the architecture components of the CRC cell cytoskeleton.

Cancers doi: 10.3390/cancers16132369

Authors: Maen Abdelrahim Abdullah Esmail Aiwu Ruth He Moh’d Khushman Yaser Rayyan

The increasing incidence of global cancer rates has created an entirely new demand for curative treatment modalities to improve patient outcomes [...]

Cancers doi: 10.3390/cancers16132368

Authors: Paraskevi Apostolou Vasiliki Dellatola Athanasios Papathanasiou Despoina Kalfakakou Elena Fountzilas Dimitrios Tryfonopoulos Sofia Karageorgopoulou Drakoulis Yannoukakos Irene Konstantopoulou Florentia Fostira

Early-onset breast cancer constitutes a major criterion for genetic testing referral. Nevertheless, studies focusing on breast cancer patients (≤30 years) are limited. We investigated the contribution and spectrum of known breast-cancer-associated genes in 267 Greek women with breast cancer ≤30 years while monitoring their clinicopathological characteristics and outcomes. In this cohort, a significant proportion (39.7%) carried germline pathogenic variants (PVs) distributed in 8 genes. The majority, namely 36.7%, involved BRCA1, TP53, and BRCA2. PVs in BRCA1 were the most prevalent (28.1%), followed by TP53 (4.5%) and BRCA2 (4.1%) PVs. The contribution of PVs in CHEK2, ATM, PALB2, PTEN, and RAD51C was limited to 3%. In the patient group ≤26 years, TP53 PVs were significantly higher compared to the group 26–30 years (p = 0.0023). A total of 74.8% of TP53 carriers did not report a family history of cancer. Carriers of PVs receiving neoadjuvant chemotherapy showed an improved event-free survival (p<0.0001) compared to non-carriers. Overall, many women with early-onset breast cancer carry clinically actionable variants, mainly in the BRCA1/2 and TP53 genes. The inclusion of timely testing of TP53 in these patients provides essential information for appropriate clinical management. This is important for countries where reimbursement involves the cost of genetic analysis of BRCA1/2 only.

Cancers doi: 10.3390/cancers16132367

Authors: Hanjing Peng Yukinori Endo Wen Jin Wu

The mechanisms of mAb-induced ADCC have been well established. However, the ADCC bioassays used to quantify mAb-induced ADCC require continued development/refinement to properly assess and compare the potency of newly developed therapeutic mAbs and biosimilars to meet regulatory requirements. We used trastuzumab and a lactate dehydrogenase (LDH)-based ADCC bioassay as a model to define critical parameters of the ADCC bioassay, describing how several bioassay parameters, including preparation of effector cells, E/T ratio, target cell selection, bioassay media components, and treatment time can influence the data quality of the ADCC activity. We confirm that a 4 to 24 h recovery cultivation is required to restore peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cell activity toward ADCC when using cryopreserved PBMCs. Furthermore, we delineated the cellular mechanisms underlying the restored ADCC activity following the recovery cultivation. We observed that CD69, an early marker of NK cell activation, was upregulated and a new subset CD56dim/CD16dim population was dramatically increased in the recovered NK cells, which led to an increase in expression and secretion of perforin, granzyme B, and cytokine production. This study provides comprehensive technical insights into ADCC bioassay optimization to inform trastuzumab biosimilar development. The knowledge gained from this study can also be leveraged to guide bioassay development for therapeutic mAbs with ADCC as the primary mechanism of action.

Cancers doi: 10.3390/cancers16132366

Authors: Kimbrough Marin-Acevedo Drusbosky Mooradian Zhao Manochakian Lou

Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR, KRAS, ALK, ROS1, BRAF, NTRK, ERBB2, RET, MET, PIK3CA, STK11, and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher’s exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18–102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53. Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK, ROS1, BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53. Individuals ≥ 70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA. We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC.

Cancers doi: 10.3390/cancers16132364

Authors: Margaret A. Park Christopher J. Whelan Sabeen Ahmed Tabitha Boeringer Joel Brown Sylvia L. Crowder Kenneth Gage Christopher Gregg Daniel K. Jeong Heather S. L. Jim Andrew R. Judge Tina M. Mason Nathan Parker Smitha Pillai Aliya Qayyum Sahana Rajasekhara Ghulam Rasool Sara M. Tinsley Matthew B. Schabath Paul Stewart Jeffrey West Patricia McDonald Jennifer B. Permuth

For many patients, the cancer continuum includes a syndrome known as cancer-associated cachexia (CAC), which encompasses the unintended loss of body weight and muscle mass, and is often associated with fat loss, decreased appetite, lower tolerance and poorer response to treatment, poor quality of life, and reduced survival. Unfortunately, there are no effective therapeutic interventions to completely reverse cancer cachexia and no FDA-approved pharmacologic agents; hence, new approaches are urgently needed. In May of 2022, researchers and clinicians from Moffitt Cancer Center held an inaugural retreat on CAC that aimed to review the state of the science, identify knowledge gaps and research priorities, and foster transdisciplinary collaborative research projects. This review summarizes research priorities that emerged from the retreat, examples of ongoing collaborations, and opportunities to move science forward. The highest priorities identified include the need to (1) evaluate patient-reported outcome (PRO) measures obtained in clinical practice and assess their use in improving CAC-related outcomes; (2) identify biomarkers (imaging, molecular, and/or behavioral) and novel analytic approaches to accurately predict the early onset of CAC and its progression; and (3) develop and test interventions (pharmacologic, nutritional, exercise-based, and through mathematical modeling) to prevent CAC progression and improve associated symptoms and outcomes.

Cancers doi: 10.3390/cancers16132365

Authors: Adhari AlZaabi Stephen Piccolo Steven Graves Marc Hansen

Here, we assess how the differential expression of low molecular weight serum peptides might predict breast cancer progression with high confidence. We apply an LC/MS-MS-based, unbiased ‘omics’ analysis of serum samples from breast cancer patients to identify molecules that are differentially expressed in stage I and III breast cancer. Results were generated using standard and machine learning-based analytical workflows. With standard workflow, a discovery study yielded 65 circulating biomarker candidates with statistically significant differential expression. A second study confirmed the differential expression of a subset of these markers. Models based on combinations of multiple biomarkers were generated using an exploratory algorithm designed to generate greater diagnostic power and accuracy than any individual markers. Individual biomarkers and the more complex multi-marker models were then tested in a blinded validation study. The multi-marker models retained their predictive power in the validation study, the best of which attained an AUC of 0.84, with a sensitivity of 43% and a specificity of 88%. One of the markers with m/z 761.38, which was downregulated, was identified as a fibrinogen alpha chain. Machine learning-based analysis yielded a classifier that correctly categorizes every subject in the study and demonstrates parameter constraints required for high confidence in classifier output. These results suggest that serum peptide biomarker models could be optimized to assess breast cancer stage in a clinical setting. 

Cancers doi: 10.3390/cancers16132363

Authors: Yasuhiro Tsutani Yoshihiro Miyata Kenji Suzuki Fumihiro Tanaka Hiroyuki Ito Yoshinori Yamashita Morihito Okada

The objective of this study was to evaluate the relationship between pathologic response and survival in patients with clinical stage II/IIIA nonsquamous non-small-cell lung cancer (NSCLC) who intended to undergo neoadjuvant chemotherapy with bevacizumab, followed by surgery. In this phase II NAVAL study evaluating the feasibility of neoadjuvant chemotherapy with cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg), followed by surgery, progression-free survival (PFS) and overall survival (OS) were assessed as the secondary endpoints. Patients were categorized based on the proportion of residual viable primary tumor in the resected specimen after neoadjuvant chemotherapy: those with residual tumor in less than one-third were classified as pathologic responders, the rest as nonresponders. Of the 30 patients, 25 underwent surgical resection after three cycles of neoadjuvant chemotherapy with bevacizumab; 5 did not undergo surgery. Among all 30 patients, the rates of 2- and 5-year PFS were 41.5% and 34.6%, respectively, and the rates of 2- and 5-year OS were 70.0% and 60.0%, respectively. A total of 6 patients (20%) were classified as pathologic responders; the other 24 (80%), as nonresponders. The five-year PFS differed significantly between pathologic responders (100%) and nonresponders (17.5%; p = 0.002). The five-year OS also differed significantly between pathologic responders (100%) and nonresponders (43.5%; p = 0.006). Pathologic response seems to be a predictor of survival. Long-term survival after surgery is expected for pathologic responders, whereas additional therapy is needed for nonresponders.

Cancers doi: 10.3390/cancers16132362

Authors: Antonella Farina Valentina Viggiani Francesca Cortese Marta Moretti Sara Tartaglione Antonio Angeloni Emanuela Anastasi

“Background/Aim”: the current inability to diagnose Pancreatic Cancer Adenocarcinoma (PDAC) at an early stage strongly influences therapeutic strategies. Protein Induced by Vitamin K Absence (PIVKA II) showed an accurate diagnostic performance for PDAC. Since circulating PIVKA II has been recently associated with pancreatic origin cells with Vimentin, an epithelial-to-mesenchymal transition (EMT) early activation marker, the aim of this study was to investigate in vivo the combination between the two proteins. “Materials and Methods”: we assayed the presence of PIVKA II and Vimentin proteins by using different diagnostic methods. A total of 20 PDAC patients and 10 healthy donors were tested by Western Blot analysis; 74 PDAC patient and 46 healthy donors were assayed by ECLIA and Elisa. “Results”: Western Blot analysis showed the concomitant expression of PIVKA II and Vimentin in PDAC patient sera. Immunometric assay performed on a larger cohort of patients demonstrated that 72% of PIVKA II-positive PDAC patients were Vimentin-positive. Additionally, in a group of PDAC patients with PIVKA II levels ≥2070 ng/mL, the percentage of Vimentin-positive subjects reached 84%. “Conclusion“: the association between PIVKA II protein and the EMT suggests that this molecule could be considered a marker of the acquisition of an aggressive phenotype.

Cancers doi: 10.3390/cancers16132361

Authors: Annarita Libia Tiziana Marchese Stefano D’Ugo Prisco Piscitelli Fabio Castellana Maria Lisa Clodoveo Roberta Zupo Marcello Giuseppe Spampinato

Background: The rising diffusion of vascular resections during complex pancreatectomy for malignancy, for both oncological and technical matters, brought with it the use of vascular shunts, either temporary or definitive, to prevent bowel congestion and liver ischemia. This study aimed to systematically review the literature on the technical feasibility of vascular shunts during advanced pancreatic surgery, analyzing intraoperative and postoperative outcomes. Methods: A systematic literature search was performed on PubMed, Scopus, Web of Science, and the Cochrane Library Central, according to PRISMA guidelines. Studies published before 2006 were excluded, considering the lack of a standardized definition of locally advanced pancreatic cancer. The main outcomes evaluated were the overall complication rate and shunt patency. Results: Among 789 papers retrieved from the database search, only five fulfilled the inclusion criteria and were included in the review, amounting to a total of 145 patients undergoing a shunt creation at the time of pancreatectomy. Pancreatic adenocarcinoma (PDAC) was found to be the most common diagnosis and pancreaticoduodenectomy was the main surgical procedure, accounting for 88% and 83% of the overall cohort, respectively. The distal splenorenal shunt was the most performed. Overall, 44 out of 145 patients (30%) experienced postoperative complications; the long-term patency of definitive shunts was 83% (110 out of 120 patients). Conclusions: An increasing number of patients with borderline resectable or locally advanced PDAC are becoming amenable to resection and shunt creation may facilitate vascular resection with clear margins, becoming a valid tool of modern pancreatic surgery.

Cancers doi: 10.3390/cancers16132360

Authors: Chetan Kumawat Toshiyuki Takahashi Isao Date Yousuke Tomita Masato Tanaka Shinya Arataki Tadashi Komatsubara Angel O. P. Flores Dongwoo Yu Mukul Jain

Spinal cord tumors, though rare, present formidable challenges in clinical management due to their intricate nature. Traditional treatment modalities like surgery, radiation therapy, and chemotherapy have been the mainstay for managing these tumors. However, despite significant advancements, challenges persist, including the limitations of surgical resection and the potential side effects associated with radiation therapy. In response to these limitations, a wave of innovative approaches is reshaping the treatment landscape for spinal cord tumors. Advancements in gene therapy, immunotherapy, and targeted therapy are offering groundbreaking possibilities. Gene therapy holds the potential to modify the genes responsible for tumor growth, while immunotherapy harnesses the body’s own immune system to fight cancer cells. Targeted therapy aims to strike a specific vulnerability within the tumor cells, offering a more precise and potentially less toxic approach. Additionally, novel surgical adjuncts are being explored to improve visualization and minimize damage to surrounding healthy tissue during tumor removal. These developments pave the way for a future of personalized medicine for spinal cord tumors. By delving deeper into the molecular makeup of individual tumors, doctors can tailor treatment strategies to target specific mutations and vulnerabilities. This personalized approach offers the potential for more effective interventions with fewer side effects, ultimately leading to improved patient outcomes and a better quality of life. This evolving landscape of spinal cord tumor management signifies the crucial integration of established and innovative strategies to create a brighter future for patients battling this complex condition.

Cancers doi: 10.3390/cancers16132359

Authors: Federico Mosna

The potential of the immune system to eradicate leukemic cells has been consistently demonstrated by the Graft vs. Leukemia effect occurring after allo-HSCT and in the context of donor leukocyte infusions. Various immunotherapeutic approaches, ranging from the use of antibodies, antibody–drug conjugates, bispecific T-cell engagers, chimeric antigen receptor (CAR) T-cells, and therapeutic infusions of NK cells, are thus currently being tested with promising, yet conflicting, results. This review will concentrate on various types of immunotherapies in preclinical and clinical development, from the point of view of a clinical hematologist. The most promising therapies for clinical translation are the use of bispecific T-cell engagers and CAR-T cells aimed at lineage-restricted antigens, where overall responses (ORR) ranging from 20 to 40% can be achieved in a small series of heavily pretreated patients affected by refractory or relapsing leukemia. Toxicity consists mainly in the occurrence of cytokine-release syndrome, which is mostly manageable with step-up dosing, the early use of cytokine-blocking agents and corticosteroids, and myelosuppression. Various cytokine-enhanced natural killer products are also being tested, mainly as allogeneic off-the-shelf therapies, with a good tolerability profile and promising results (ORR: 20–37.5% in small trials). The in vivo activation of T lymphocytes and NK cells via the inhibition of their immune checkpoints also yielded interesting, yet limited, results (ORR: 33–59%) but with an increased risk of severe Graft vs. Host disease in transplanted patients. Therefore, there are still several hurdles to overcome before the widespread clinical use of these novel compounds.

Cancers doi: 10.3390/cancers16132358

Authors: Vanda Leipold Ivana Alerić Mihaela Mlinarić Domagoj Kosmina Fran Stanić Mladen Kasabašić Damir Štimac Hrvoje Kaučić Giovanni Ursi Karla Schwarz Igor Nikolić Denis Klapan Dragan Schwarz

Image-guided radiotherapy supported by surface guidance can help to track lower lung lesions’ respiratory motion while reducing a patient’s exposure to ionizing radiation. However, it is not always clear how the skin’s respiratory motion magnitude and its correlation with the lung lesion’s respiratory motion vary between different skin regions of interest (ROI). Four-dimensional computed tomography (4DCT) images provide information on both the skin and lung respiratory motion and are routinely acquired for the purpose of treatment planning in our institution. An analysis of 4DCT images for 57 patients treated in our institution has been conducted to provide information on the respiratory motion magnitudes of nine skin ROIs of the torso, a tracking structure (TS) representing a lower lung lobe lesion, as well as the respiratory motion correlations between the nine ROIs and the TS. The effects of gender and the adipose tissue volume and distribution on these correlations and magnitudes have been analyzed. Significant differences between the ROIs in both the respiratory motion magnitudes and their correlations with the TS have been detected. An overall negative correlation between the ROI respiratory magnitudes and the adipose tissue has been detected for ROIs with rib cage support. A weak to moderate negative correlation between the adipose tissue volume and ROI-to-TS respiratory correlations has been detected for upper thorax ROIs. The respiratory magnitudes in regions without rib support tend to be larger for men than for women, but no differences in the ROI-to-TS correlation between sexes have been detected. The described findings should be considered when choosing skin surrogates for lower lung lesion motion management.

Cancers doi: 10.3390/cancers16132357

Authors: Yang Deng Chia-Wen Tsai Wen-Shin Chang Yifan Xu Maosheng Huang Da-Tian Bau Jian Gu

Bladder cancer is an age-related disease, with over three-quarters of cases occurring in individuals aged 65 years and older. Accelerated biological aging has been linked to elevated cancer risks. Epigenetic clocks serve as excellent predictors of biological age, yet it remains unclear whether they are associated with bladder cancer risk. In this large case–control study, we assessed the associations between four well-established epigenetic clocks—HannumAge, HorvathAge, GrimAge, and PhenoAge—and bladder cancer risk. Utilizing single nucleotide polymorphisms (SNPs), which were identified in a genome-wide association study (GWAS), linked to these clocks as instruments, we constructed a weighted genetic risk score (GRS) for each clock. We discovered that higher HannumAge and HorvathAge GRS were significantly associated with increased bladder cancer risk (OR = 1.69 per SD increase, 95% CI, 1.44–1.98, p = 1.56 × 10−10 and OR = 1.09 per SD increase, 95% CI, 1.00–1.19, p = 0.04, respectively). Employing a summary statistics-based Mendelian randomization (MR) method, inverse-variance weighting (IVW), we found consistent risk estimates for bladder cancer with both HannumAge and HorvathAge. Sensitivity analyses using weighted median analysis and MR-Egger regression further supported the validity of the IVW method. However, GrimAge and PhenoAge were not associated with bladder cancer risk. In conclusion, our data provide the first evidence that accelerated biological aging is associated with elevated bladder cancer risk.

Cancers doi: 10.3390/cancers16132356

Authors: Valéria Tavares Joana Savva-Bordalo Mariana Rei Joana Liz-Pimenta Joana Assis Deolinda Pereira Rui Medeiros

Ovarian cancer (OC) is the deadliest gynaecological malignancy. Identifying new prognostic biomarkers is an important research field. Haemostatic components together with leukocytes can drive cancer progression while increasing the susceptibility to venous thromboembolism (VTE) through immunothrombosis. Unravelling the underlying complex interactions offers the prospect of uncovering relevant OC prognostic biomarkers, predictors of cancer-associated thrombosis (CAT), and even potential targets for cancer therapy. Thus, this study evaluated the expression of F3, F5, F8, F13A1, TFPI1, and THBD in peripheral blood cells (PBCs) of 52 OC patients. Those with VTE after tumour diagnosis had a worse overall survival (OS) compared to their counterparts (mean OS of 13.8 ± 4.1 months and 47.9 ± 5.7 months, respectively; log-rank test, p = 0.001). Low pre-chemotherapy F3 and F8 expression levels were associated with a higher susceptibility for OC-related VTE after tumour diagnosis (χ2, p < 0.05). Regardless of thrombogenesis, patients with low baseline F8 expression had a shorter progression-free survival (PFS) than their counterparts (adjusted hazard ratio (aHR) = 2.54; p = 0.021). Among those who were not under platelet anti-aggregation therapy, low F8 levels were also associated with a shorter OS (aHR = 6.16; p = 0.006). Moving forward, efforts should focus on external validation in larger cohorts.

Cancers doi: 10.3390/cancers16132355

Authors: Rachel S. Goodman Seungyeon Jung Kylie Fletcher Hannah Burnette Ismail Mohyuddin Rebecca Irlmeier Fei Ye Douglas B. Johnson

Identifying patients likely to benefit from immune checkpoint inhibitor (ICI) treatment remains a crucial goal for melanoma. The objective of this study is to assess the association between primary tumor features and immunotherapy response and survival in advanced melanoma patients. In this single-center retrospective cohort study, disease characteristics, response to immunotherapy, PFS, and OS were assessed among melanoma patients (excluding mucosal and uveal primaries) treated with ICI. Among 447 patients, 300 (67.1%) received anti-PD-1 monotherapy and 147 (32.9%) received ipilimumab/nivolumab. A total of 338 (75.6%) had cutaneous melanoma, 29 (6.5%) had acral melanoma, and 80 (17.9%) had melanoma of unknown primary. Ulceration and stage at initial presentation were associated with inferior outcomes on univariate analysis. However, on multivariate analysis, this result was not observed, but cutaneous melanoma and each of its subtypes (superficial spreading, nodular, other, unknown) were positively associated with response, longer PFS, and longer OS. Metastatic stage (M1c, M1d) at presentation (OR = 1.8, p < 0.05) and BRAFV600E mutation status (OR = 1.6, p < 0.001) were associated with shorter PFS. This study is limited by its retrospective and single-center design. Cutaneous melanoma and its subtypes were significantly associated with response, PFS, and OS compared with acral or unknown primary melanoma.

Cancers doi: 10.3390/cancers16132354

Authors: Oleksii S. Rukhlenko Hiroaki Imoto Ayush Tambde Amy McGillycuddy Philipp Junk Anna Tuliakova Walter Kolch Boris N. Kholodenko

Understanding signaling patterns of transformation and controlling cell phenotypes is a challenge of current biology. Here we applied a cell State Transition Assessment and Regulation (cSTAR) approach to a perturbation dataset of single cell phosphoproteomic patterns of multiple breast cancer (BC) and normal breast tissue-derived cell lines. Following a separation of luminal, basal, and normal cell states, we identified signaling nodes within core control networks, delineated causal connections, and determined the primary drivers underlying oncogenic transformation and transitions across distinct BC subtypes. Whereas cell lines within the same BC subtype have different mutational and expression profiles, the architecture of the core network was similar for all luminal BC cells, and mTOR was a main oncogenic driver. In contrast, core networks of basal BC were heterogeneous and segregated into roughly four major subclasses with distinct oncogenic and BC subtype drivers. Likewise, normal breast tissue cells were separated into two different subclasses. Based on the data and quantified network topologies, we derived mechanistic cSTAR models that serve as digital cell twins and allow the deliberate control of cell movements within a Waddington landscape across different cell states. These cSTAR models suggested strategies of normalizing phosphorylation networks of BC cell lines using small molecule inhibitors.

Cancers doi: 10.3390/cancers16132353

Authors: Diedron Lewis Laura Jimenez Manel Haj Mansour Susan Horton William W. L. Wong

Gastric cancer (GC) poses notable economic and health burdens in settings where the incidence of disease is prevalent. Some countries have established early screening and treatment programs to address these challenges. The objectives of this systematic review were to summarize the cost-effectiveness of gastric cancer screening presented in the literature and to identify the critical factors that influence the cost-effectiveness of screening. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Economic evaluation studies of gastric cancer screening were reviewed from SCOPUS and PubMed. The Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) was used to assess the quality of reporting presented in the selected articles. Only primary economic evaluation studies addressing the cost-effectiveness, cost–utility, and cost–benefit of gastric cancer screening were selected. Two reviewers scrutinized the selected articles (title, abstract, and full text) to determine suitability for the systematic review based on inclusion and exclusion criteria. Authors’ consensus was relied on where disagreements arose. The main outcome measures of concern in the systematic review were cost, effectiveness (as measured by either quality-adjusted life years (QALY) or life-years saved (LYS)), and incremental cost-effectiveness ratio (ICER) of screening versus either no screening or an alternative screening method. Thirty-one studies were selected for the final review. These studies investigated the cost-effectiveness of GC screening based on either primary, secondary, or a combination of primary and secondary interventions. The main primary intervention was Helicobacter pylori (Hp) screening with eradication, while the main secondary intervention was endoscopic screening. Cost-effectiveness was evaluated against no screening or screening using an alternative method in both observational and model-based studies. Screening was mainly cost-effective in Asian countries or their diasporas where the prevalence of GC was high. GC screening was generally not cost-effective among Western countries. GC screening can be cost-effective, but cost-effectiveness is dependent on context-specific factors, including geographical location, the prevalence of GC in the local population, and the screening tool adopted. However, there is benefit in targeting high-risk population groups in Asian countries and their diaspora for GC screening.

Cancers doi: 10.3390/cancers16132352

Authors: Cody MacDonald Gabriela Ilie George Kephart Ricardo Rendon Ross Mason Greg Bailly David Bell Nikhilesh Patil David Bowes Derek Wilke Andrea Kokorovic Robert D. H. Rutledge

Understanding how interventions reduce psychological distress in patients with prostate cancer is crucial for improving patient care. This study examined the roles of self-efficacy, illness perceptions, and heart rhythm coherence in mediating the effects of the Prostate Cancer Patient Empowerment Program (PC-PEP) on psychological distress compared to standard care. In a randomized controlled trial, 128 patients were assigned to either the PC-PEP intervention or standard care. The PC-PEP, a six-month program emphasizing daily healthy living habits, included relaxation and stress management, diet, exercise, pelvic floor muscle exercises, and strategies to improve relationships and intimacy, with daily activities supported by online resources and live sessions. Participants in the intervention group showed significant improvements in self-efficacy and specific illness perceptions, such as personal control and emotional response, compared to the control group. These factors mediated the relationship between the intervention and its psychological benefits, with self-efficacy accounting for 52% of the reduction in psychological distress. No significant differences in heart rhythm coherence were observed. This study highlights the critical role of self-efficacy and illness perceptions in enhancing psychological health in prostate cancer patients through the PC-PEP. The results underscore this program’s effectiveness and the key mechanisms through which it operates. Given the high rates of distress among men undergoing prostate cancer treatments, these findings emphasize the importance of integrating the PC-PEP into clinical practice. The implementation of the PC-PEP in clinical settings can provide a structured approach to reducing psychological distress and improving overall patient well-being.

Cancers doi: 10.3390/cancers16132351

Authors: Alexa Childs Craig Gerrand Bernadette Brennan Robin Young Kenneth S. Rankin Michael Parry Jonathan Stevenson Adrienne M. Flanagan Rachel M. Taylor Lorna Fern Dominique Heymann Filipa Vance Jenny Sherriff Saurabh Singh Rubina Begum Sharon L. Forsyth Krystyna Reczko Kate Sparksman William Wilson Sandra J. Strauss

There has been little change to the standard treatment for osteosarcoma (OS) over the last 25 years and there is an unmet need to identify new biomarkers and novel therapeutic approaches if outcomes are to improve. Furthermore, there is limited evidence on the impact of OS treatment on patient-reported outcomes (PROs). ICONIC (Improving Outcomes through Collaboration in Osteosarcoma; NCT04132895) is a prospective observational cohort study recruiting newly diagnosed OS patients across the United Kingdom (UK) with matched longitudinal collection of clinical, biological, and PRO data. During Stage 1, which assessed the feasibility of recruitment and data collection, 102 patients were recruited at 22 sites with representation from patient groups frequently excluded in OS studies, including patients over 50 years and those with less common primary sites. The feasibility of collecting clinical and biological samples, in addition to PRO data, has been established and there is ongoing analysis of these data as part of Stage 2. ICONIC will provide a unique, prospective cohort of newly diagnosed OS patients representative of the UK patient population, with fully annotated clinical outcomes linked to molecularly characterised biospecimens, allowing for comprehensive analyses to better understand biology and develop new biomarkers and novel therapeutic approaches.

Cancers doi: 10.3390/cancers16132350

Authors: Tianhong Li Weijie Ma Ebaa Al-Obeidi

First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades. First, molecularly targeted therapy for a growing number of gain-of-function molecular targets has been shown to improve progression-free survival (PFS) and overall survival (OS) with favorable toxicity profiles compared to platinum-containing chemotherapy and can be given as first-line systemic therapy in ~25% of patients with NSCLC. Actionable genetic alterations include EGFR, BRAF V600E, and MET exon 14 splicing site-sensitizing mutations, as well as ALK-, ROS1-, RET-, and NTRK-gene fusions. Secondly, inhibitors of programmed cell death protein 1 or its ligand 1 (PD-1/L1) such as pembrolizumab, atezolizumab, or cemiplimab monotherapy have become a standard of care for ~25% of patients with NSCLC whose tumors have high PD-L1 expression (total proportion score (TPS) ≥50%) and no sensitizing EGFR/ALK alterations. Lastly, for the remaining ~50% of patients who are fit and whose tumors have no or low PD-L1 expression (TPS of 0–49%) and no sensitizing EGFR/ALK aberrations, platinum-containing chemotherapy with the addition of a PD-1/L1 inhibitor alone or in combination of a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor improves PFS and OS compared to chemotherapy alone. The objectives of this review are to summarize the current data and perspectives on first-line systemic treatment in patients with unresectable NSCLC and propose a practical algorithm for implementing precision biomarker testing at diagnosis.

Cancers doi: 10.3390/cancers16132349

Authors: Kwon Hoffman Ellison Bednarz

Radiopharmaceutical therapy (RPT) is evolving as a promising strategy for treating cancer. As interest grows in short-range particles, like Auger electrons, understanding the dose–response relationship at the deoxyribonucleic acid (DNA) level has become essential. In this study, we used the Geant4-DNA toolkit to evaluate DNA damage caused by the Auger-electron-emitting isotope I-125. We compared the energy deposition and single-strand break (SSB) yield at each base pair location in a short B-form DNA (B-DNA) geometry with existing simulation and experimental data, considering both physical direct and chemical indirect hits. Additionally, we evaluated dosimetric differences between our high-resolution B-DNA target and a previously published simple B-DNA geometry. Overall, our benchmarking results for SSB yield from I-125 decay exhibited good agreement with both simulation and experimental data. Using this simulation, we then evaluated the SSB and double strand break (DSB) yields caused by a theranostic Br-77-labeled poly ADP ribose polymerase (PARP) inhibitor radiopharmaceutical. The results indicated a predominant contribution of chemical indirect hits over physical direct hits in generating SSB and DSB. This study lays the foundation for future investigations into the nano-dosimetric properties of RPT.

Cancers doi: 10.3390/cancers16132348

Authors: Kazim Z. Gumus Julien Nicolas Dheeraj R. Gopireddy Jose Dolz Seyed Behzad Jazayeri Mark Bandyk

Background: Bladder cancer (BC) segmentation on MRI images is the first step to determining the presence of muscular invasion. This study aimed to assess the tumor segmentation performance of three deep learning (DL) models on multi-parametric MRI (mp-MRI) images. Methods: We studied 53 patients with bladder cancer. Bladder tumors were segmented on each slice of T2-weighted (T2WI), diffusion-weighted imaging/apparent diffusion coefficient (DWI/ADC), and T1-weighted contrast-enhanced (T1WI) images acquired at a 3Tesla MRI scanner. We trained Unet, MAnet, and PSPnet using three loss functions: cross-entropy (CE), dice similarity coefficient loss (DSC), and focal loss (FL). We evaluated the model performances using DSC, Hausdorff distance (HD), and expected calibration error (ECE). Results: The MAnet algorithm with the CE+DSC loss function gave the highest DSC values on the ADC, T2WI, and T1WI images. PSPnet with CE+DSC obtained the smallest HDs on the ADC, T2WI, and T1WI images. The segmentation accuracy overall was better on the ADC and T1WI than on the T2WI. The ECEs were the smallest for PSPnet with FL on the ADC images, while they were the smallest for MAnet with CE+DSC on the T2WI and T1WI. Conclusions: Compared to Unet, MAnet and PSPnet with a hybrid CE+DSC loss function displayed better performances in BC segmentation depending on the choice of the evaluation metric.

Cancers doi: 10.3390/cancers16132347

Authors: Giuseppe Quero Davide De Sio Claudio Fiorillo Chiara Lucinato Edoardo Panza Beatrice Biffoni Lodovica Langellotti Vito Laterza Giulia Scaglione Flavia Taglioni Giuseppe Massimiani Roberta Menghi Fausto Rosa Teresa Mezza Sergio Alfieri Vincenzo Tondolo

The influencing role of resection margin (R) status on long-term outcomes, namely overall (OS) and disease-free survival (DFS), after pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) is not still clear. The aim of this study is to evaluate the prognostic impact of R status after PD and to define tumor characteristics associated with a positive resection margin (R1). All PDs for PDAC performed between 2012 and 2023 were retrospectively enrolled. The effect of R status, patient clinico-demographic features, and tumor features on OS and DFS were assessed. One-hundred and sixty-seven patients who underwent PD for PDAC were included in the study. R0 was achieved in 105 cases (62.8%), while R1 was evidenced in 62 patients (37.1%). R1 was associated with a decreased OS (23 (13–38) months) as compared to R0 (36 (21–53) months) (p = 0.003). Similarly, DFS was shorter in R1 patients (10 (6–25) months) as compared to the R0 cohort (18 (9–70) months) (p = 0.004), with a consequent higher recurrence rate in cases of R1 (74.2% vs. 64.8% in the R0 group; p = 0.04). In the multivariate analysis, R1 and positive lymph nodes (N+) were the only independent influencing factors for OS (OR: 1.6; 95% CI: 1–2.5; p = 0.03 and OR: 1.7; 95% CI: 1–2.8; p = 0.04) and DFS (OR: 1.5; 95% CI: 1–2.1; p = 0.04 and OR: 1.8; 95% CI: 1.1–2.7; p = 0.009). Among 111 patients with N+ disease, R1 was associated with a significantly decreased DFS (10 (8–11) months) as compared to R0N+ patients (16 (11–21) months) (p = 0.05). In conclusion, the achievement of a negative resection margin is associated with survival benefits, particularly in cases of N1 disease. In addition, R0 was recognized as an independent prognostic feature for both OS and DFS. This further outlines the relevant role of radical surgery on long-term outcomes.

Cancers doi: 10.3390/cancers16132346

Authors: Jin-Hee Kwon Heyjin Kim Jin Kyung Lee Young Jun Hong Hye Jin Kang Yoon Jung Jang

Rising cancer survival rates have led to an increased risk of multiple primary cancers (MPCs). Data on MPCs in South Korea are limited. This study aimed to address incidence and clinical characteristics of MPCs in a single cancer center in Korea during a 20-year period. We retrospectively analyzed 96,174 cancer patients at the Korea Cancer Center Hospital between 2003 and 2022, identifying 2167 patients with metachronous MPCs based on Surveillance, Epidemiology, and End Results SEER criteria. We categorized patients by cancer type (15 major solid cancer groups and 3 major hematologic cancer groups), including pathological diagnosis, assessed latency periods, and relative risks (RRs) for developing MPCs. The overall MPC incidence was 2.3%. Breast cancer (15.7%) was the most common primary cancer, and lung cancer (15.2%) was the most frequent second primary cancer. The median latency period for second primary cancers was 4.1 years. Decreasing latency periods for third and fourth primary cancers were observed (2.1 years and 1.6 years, respectively). Most cancers maintained their dominant pathological type despite notable changes in the prevalence of specific pathologies for certain types of second primaries. Lymphoma showed the highest RR (2.1) for developing MPCs. Significant associations were found between specific primary and subsequent cancers, including breast–ovary, thyroid–breast, stomach–pancreas, colorectal–head and neck, lung–prostate, and lymphoma–myeloid neoplasms. These findings contribute to a better understanding of MPC occurrence. They can inform future research on their etiology and development of improved management strategies.

Cancers doi: 10.3390/cancers16132345

Authors: Razan Muhtadi Denise Bernhardt Gabriele Multhoff Lisa Hönikl Stephanie E. Combs Sandro M. Krieg Jens Gempt Bernhard Meyer Vahé Barsegian Monika Lindemann Mandy Kasper Samantha Stewart Matthias Port Michael Abend Christian D. Diehl Patrick Ostheim

GBM WHO CNS Grade 4 represents a major challenge for oncology due to its aggressive behavior. Conventional imaging has restrictions in detecting tumor recurrence. This prospective study aims to identify gene-based biomarkers in whole blood instead of isolating exosomes for the early detection of tumor recurrence. Blood samples (n = 33) were collected from seven GBM patients at time points before and after surgery as well as upon tumor recurrence. Four tumor tissue samples were assessed in parallel. Next-generation sequencing (NGS), including mRNA-seq and small RNA-seq, was used to analyze gene expression profiles in blood samples and tumor tissues. A novel filtering pipeline was invented to narrow down potential candidate genes. In total, between 6–93 mRNA and 1–19 small RNA candidates could be identified among the seven patients. The overlap of genes between the patients was minimal, indicating significant inter-individual variance among GBM patients. In summary, this prospective study supports the applicability of gene expression measurements in whole blood for the detection of tumor recurrence. It might provide an alternative to the challenging workflow of liquid biopsy after laborious exosome isolation from whole blood.

Cancers doi: 10.3390/cancers16132344

Authors: Meerim Park Dong-Eun Lee Yuna Hong Jin Kyung Suh Jun Ah Lee Myungshin Kim Hyeon Jin Park

We examined the leukocyte relative telomere length (RTL) in Korean adolescent and young adult (AYA) survivors of childhood cancer and evaluated the association of leukocyte RTL with multiple factors, including malignancy type, cancer treatment, age, and chronic health conditions (CHCs). Eighty-eight AYA survivors of childhood cancer with a median follow-up period of 73 months were recruited. RTL in pediatric cancer survivors was not significantly shorter than the predicted value for age-matched references. Neither age at diagnosis nor duration of therapy influenced the RTL. Among the 43 patients with hematologic malignancies, those who underwent allogeneic hematopoietic stem cell transplantation (HSCT) showed a significant shortening of the RTL compared with those who did not (p = 0.039). Among the 15 patients who underwent allogeneic HSCT, those who developed acute graft-versus-host disease (GVHD) of grade II or higher had significantly shorter RTL than those who did not (p = 0.012). Patients with grade II CHCs had significantly shorter RTL than those without CHCs or with grade I CHCs (p = 0.001). Survivors with ≥2 CHCs also exhibited shorter RTL (p = 0.027). Overall, pediatric cancer survivors had similar telomere lengths compared to age-matched references. HSCT recipients and patients with severe or multiple CHCs had shorter telomeres. GVHD augmented telomere attrition in HSCT recipients.

Cancers doi: 10.3390/cancers16132343

Authors: Watanabe Tanahashi Suzuki Yoshii Kohama Iguchi Endo

Twenty years have passed since uniportal video-assisted thoracoscopic surgery (VATS) was first reported. Several reports have already proven the minimal invasiveness of uniportal VATS. In addition, two large clinical trials recently demonstrated the benefits of segmentectomy for small peripheral early-stage non-small cell lung cancer. Uniportal VATS segmentectomy is considered the most beneficial minimally invasive surgery for patients with early-stage lung cancer. However, a high level of skill and experience are required to achieve this goal. Only a few reports have discussed specific techniques, particularly for complex segmentectomies. In this Special Issue, we reviewed previous reports on uniportal VATS segmentectomy regarding the indications, instrument selection, marking of the tumor location, methods of intersegmental plane identification, and lymph node dissection, including our own techniques with video content.

Cancers doi: 10.3390/cancers16132342

Authors: Jiunn-Tyng Yeh Hung-Pin Peng Fei-Hung Hung Chen-Fang Hung Ling-Ling Hsieh An-Suei Yang Yong Alison Wang

Germline (Lynch syndrome, LS) and somatic deficiencies of mismatch repair proteins (MMRd) are linked to colorectal and endometrial cancer; however, their prognostic impact in Asian populations remains unclear. This prospective cohort study aimed to determine the prevalence and outcome of germline and somatic MMRd in cancer patients suspected of LS. Patients with colorectal or endometrial cancer suspected of LS were enrolled and underwent gene sequencing for germline MMRd (gMMRd) and immunohistochemistry staining of MMR proteins in a subset of the pathological samples (pMMRd). Among the 451 enrolled patients, 36 patients were gMMRd (+). Compared with gMMRd (−) patients, the 10-year relapse-free survival in gMMRd (+) patients was significantly higher (100% vs. 77.9%; p = 0.006), whereas the 10-year overall survival was similar (100% vs. 90.9%; p = 0.12). Among the 102 gMMRd (−) patients with available pMMR status, 13.7% were pMMRd (+). The 5-year relapse-free survival was 62.9% in gMMRd (−) pMMRd (+) patients and 35.0% in gMMRd (−) pMMRd (−) patients, both lower than gMMRd (+) patients (100%; p < 0.001). This study showed that having LS confers a favorable outcome in colorectal and endometrial cancer patients and highlights the importance of germline genetic testing following the detection of somatic MMRd.

Cancers doi: 10.3390/cancers16132341

Authors: Puja Bhattacharyya Richard I. Christopherson Kristen K. Skarratt Stephen J. Fuller

B cells are central to the adaptive immune response and provide long-lasting immunity after infection. B cell activation is mediated by the surface membrane-bound B cell receptor (BCR) following recognition of a specific antigen. The BCR has been challenging to analyse using mass spectrometry (MS) due to the difficulty of isolating and enriching this membrane-bound protein complex. There are approximately 120,000 BCRs on the B cell surface; however, depending on the B cell activation state, there may be hundreds-of-millions to billions of proteins in a B cell. Consequently, advanced proteomic techniques such as MS workflows that use purified proteins to yield structural and protein-interaction information have not been published for the BCR complex. This paper describes a method for enriching the BCR complex that is MS-compatible. The method involves a Protein G pull down on agarose beads using an intermediary antibody to each of the BCR complex subcomponents (CD79a, CD79b, and membrane immunoglobulin). The enrichment process is shown to pull down the entire BCR complex and has the advantage of being readily compatible with further proteomic study including MS analysis. Using intermediary antibodies has the potential to enrich all isotypes of the BCR, unlike previous methods described in the literature that use protein G-coated beads to directly pull down the membrane IgG (mIgG) but cannot be used for other mIg isotypes.

Cancers doi: 10.3390/cancers16132340

Authors: Víctor Escrich Cristina Romero-Aranda Rosario López María de Toro Ángela Metola Begoña Ezcurra Eva Gómez-Orte Juan Cabello

The human Integrator complex is a set of 15 subunits that mediates processing of small nuclear RNAs (snRNAs), and which later participates in splicing messenger RNAs (mRNAs). In addition, it controls the pause and release of RNA polymerase II (RNA pol II) at specific gene promoters in response to growth factors. Mutations in Integrator-complex subunit 6 (INTS6) are associated with different types of tumors. However, the INTS6 gene product does not have a significant prognostic value as a biomarker for tumor progression. Here we show that Integrator-complex deregulation is involved in 8.3% of the colorectal cancer cases diagnosed from the population screen carried out in La Rioja (Spain) from the years 2017 to 2019. Lack of Integrator-complex function, measured by an increased level of unprocessed snRNA, is a prognostic biomarker and correlates with a poorer prognosis in colorectal-cancer patients. The transcriptomic profile of all analyzed colorectal tumors shows a strong alteration of the metabolic state of tumor cells, which compromises standard energy production through mitochondrial respiration, known as the Warburg effect. Furthermore, there is a significant upregulation of genes involved in extracellular matrix organization and collagen rearrangement. This is consistent with tissue reorganization in a growing tumor forming a polyp. Crossing the molecular data generated in this study with the follow-up of patients from population screening indicates that population screening combined with early typing of tumors appears to be the most efficient way to increase patient survival.

Cancers doi: 10.3390/cancers16132338

Authors: Juan Carlos Restrepo Darly Martínez Guevara Andrés Pareja López John Fernando Montenegro Palacios Yamil Liscano

Non-small-cell lung cancer (NSCLC) comprises approximately 85% of all lung cancer cases, often diagnosed at advanced stages, which diminishes the effective treatment options and survival rates. This systematic review assesses the utility of emerging biomarkers—circulating tumor DNA (ctDNA), microRNAs (miRNAs), and the blood tumor mutational burden (bTMB)—enhanced by next-generation sequencing (NGS) to improve the diagnostic accuracy, prognostic evaluation, and treatment strategies in NSCLC. Analyzing data from 37 studies involving 10,332 patients from 2020 to 2024, the review highlights how biomarkers like ctDNA and PD-L1 expression critically inform the selection of personalized therapies, particularly beneficial in the advanced stages of NSCLC. These biomarkers are critical for prognostic assessments and in dynamically adapting treatment plans, where high PD-L1 expression and specific genetic mutations (e.g., ALK fusions, EGFR mutations) significantly guide the use of targeted therapies and immunotherapies. The findings recommend integrating these biomarkers into standardized clinical pathways to maximize their potential in enhancing the treatment precision, ultimately fostering significant advancements in oncology and improving patient outcomes and quality of life. This review substantiates the prognostic and predictive value of these biomarkers and emphasizes the need for ongoing innovation in biomarker research.

Cancers doi: 10.3390/cancers16132339

Authors: Ji Hyun Kim Eun Taeg Kim Se Ik Kim Eun Young Park Min Young Park Sang-Yoon Park Myong Cheol Lim

Background: This multicenter retrospective study aimed to investigate the prognostic value of the CA-125 elimination rate constant K (KELIM) in EOC patients who received platinum-based chemotherapy followed by PARP inhibitors, in either upfront or interval treatment settings. Methods: Between July 2019 and November 2022, we identified stage III–IV EOC patients who underwent primary or interval cytoreductive surgery and received olaparib or niraparib. Individual KELIM values were assessed based on validated kinetics and classified into favorable and unfavorable cohorts. Results: In a study of 252 patients undergoing frontline maintenance therapy with olaparib or niraparib, favorable KELIM (≥1) scores were associated with a higher PFS benefit in the primary cytoreductive surgery (PCS) cohort (hazard ratio (HR) for disease progression or death 3.51, 95% confidence interval (CI); 1.37–8.97, p = 0.009). Additionally, within the interval cytoreductive surgery (ICS) cohort, a favorable KELIM score (≥1) significantly increased the likelihood of achieving complete resection following cytoreductive surgery, with 59.4% in the favorable KELIM group compared to 37.8% in those with unfavorable KELIM. Conclusions: A favorable KELIM score was associated with improved PFS in patients with advanced EOC undergoing PCS. Furthermore, in the ICS cohort, a favorable KELIM score increased the probability of complete cytoreduction.

Cancers doi: 10.3390/cancers16132337

Authors: Paola Tacchetti Simona Barbato Katia Mancuso Elena Zamagni Michele Cavo

Bispecific antibodies (BsAbs) are artificially engineered antibodies that can bind simultaneously to the CD3 subunit within the T-cell receptor complex and an antigen on tumor cells, leading to T-cell activation and tumor cell killing. BsAbs against BCMA or GPRC5D have shown impressive clinical activity in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), with some agents having already received regulatory approval after the third (by the European Medicines Agency, EMA) or fourth (by the Food and Drug Administration, FDA) line of therapy; the results of early-phase clinical trials targeting FcRH5 are also promising. Overall, BsAbs as monotherapy correlated with an ORR that exceeded 60%, with a high CR rate ranging between 25% and 50% and a median PFS of around 1 year among patients with a median of 4–6 prior lines of therapy. The main toxicities include cytokine release syndrome, cytopenias, hypogammaglobulinemia, and infections; on-target off-tumor adverse events involving the skin, mucosa, hair, and nails may also occur with anti-GPRC5D BsAbs. Active research to increase their efficacy and improve their tolerance is still in progress, including combination therapies and application in earlier treatment lines and the development of novel agents. A better understanding of the mechanisms of resistance is a challenge and could lead to more personalized approaches.

Cancers doi: 10.3390/cancers16132335

Authors: Rafał Staszkiewicz Dawid Sobański Wojciech Pulka Dorian Gładysz Marcin Gadzieliński Damian Strojny Beniamin Oskar Grabarek

This study explores the role of circadian clock genes in the progression of astrocytic tumors, a prevalent type of brain tumor. The aim was to assess the expression patterns of these genes in relation to the tumor grade. Using microarray analysis, qRT-PCR, and methylation-specific PCR, we examined gene expression, DNA methylation patterns, and microRNA interactions in tumor samples from 60 patients. Our results indicate that the expression of key circadian clock genes, such as clock circadian regulator (CLOCK), protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1), protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2), protein kinase AMP-activated non-catalytic subunit beta 1 (PRKAB1), protein kinase AMP-activated non-catalytic subunit beta 2 (PRKAB2), period circadian regulator 1 (PER1), period circadian regulator 2 (PER2) and period circadian regulator 3 (PER3)., varies significantly with the tumor grade. Notably, increased CLOCK gene expression and protein levels were observed in higher-grade tumors. DNA methylation analysis revealed that the promoter regions of PER1-3 genes were consistently methylated, suggesting a mechanism for their reduced expression. Our findings also underscore the complex regulatory mechanisms involving miRNAs, such as hsa-miR-106-5p, hsa-miR-20b-5p, and hsa-miR-30d-3p, which impact the expression of circadian clock-related genes. This underscores the importance of circadian clock genes in astrocytic tumor progression and highlights their potential as biomarkers and therapeutic targets. Further research is needed to validate these results and explore their clinical implications.

Cancers doi: 10.3390/cancers16132336

Authors: Michael Schwake Wesam Said Marco Gallus Emanuele Maragno Stephanie Schipmann Dorothee Spille Walter Stummer Benjamin Brokinkel

Background: The main treatment modality for spinal meningiomas (SM) is gross total resection (GTR). However, the optimal timing of surgery, especially in cases with absent or mild neurological symptoms, remains unclear. The aim of this study is to assess the impact of early-stage resection on neurological outcome, quality of life (QoL), and quality of care. The primary objective is a favorable neurological outcome (McCormick scale 1). Methods: We retrospectively analyzed data from patients who underwent operations for SM between 2011 and 2021. Patients with mild neurological symptoms preoperatively (McCormick scale 1 and 2) were compared to those with more severe neurological symptoms (McCormick scale 3–5). Disabilities and QoL were assessed according to validated questionnaires (SF-36, ODI, NDI). Results: Age, spinal cord edema, thoracic localization, and spinal canal occupancy ratio were associated with more severe neurological symptoms (all p < 0.05). Patients presenting with mild symptoms were associated with favorable neurological outcomes (OR: 14.778 (95%CI 3.918–55.746, p < 0.001)), which is associated with shorter hospitalization, better QoL, and fewer disabilities (p < 0.05). Quality of care was comparable in both cohorts. Conclusions: Early surgical intervention for SM, before the development of severe neurological deficits, should be considered as it is associated with a favorable neurological outcome and quality of life.

Cancers doi: 10.3390/cancers16132334

Authors: Anne Weidlich Klaus-Dieter Schaser Jürgen Weitz Johanna Kirchberg Johannes Fritzmann Christian Reeps Philipp Schwabe Ingo Melcher Alexander Disch Adrian Dragu Doreen Winkler Elisabeth Mehnert Hagen Fritzsche

Introduction: Bone sarcoma or direct pelvic carcinoma invasion of the sacrum represent indications for partial or total sacrectomy. The aim was to describe the oncosurgical management and complication profile and to analyze our own outcome results following sacrectomy. Methods: In a retrospective analysis, 27 patients (n = 8/10/9 sarcoma/chordoma/locally recurrent rectal cancer (LRRC)) were included. There was total sacrectomy in 9 (incl. combined L5 en bloc spondylectomy in 2), partial in 10 and hemisacrectomy in 8 patients. In 12 patients, resection was navigation-assisted. For reconstruction, an omentoplasty, VRAM-flap or spinopelvic fixation was performed in 20, 10 and 13 patients, respectively. Results: With a median follow-up (FU) of 15 months, the FU rate was 93%. R0-resection was seen in 81.5% (no significant difference using navigation), and 81.5% of patients suffered from one or more minor-to-moderate complications (especially wound-healing disorders/infection). The median overall survival was 70 months. Local recurrence occurred in 20%, while 44% developed metastases and five patients died of disease. Conclusion: Resection of sacral tumors is challenging and associated with a high complication profile. Interdisciplinary cooperation with visceral/vascular and plastic surgery is essential. In chordoma patients, systemic tumor control is favorable compared to LRRC and sarcomas. Navigation offers gain in intraoperative orientation, even if there currently seems to be no oncological benefit. Complete surgical resection offers long-term survival to patients undergoing sacrectomy for a variety of complex diseases.

Cancers doi: 10.3390/cancers16132333

Authors: Haytham Derbel Athena Galletto Pregliasco Sébastien Mulé Julien Calderaro Youssef Zaarour Laetitia Saccenti Mario Ghosn Edouard Reizine Maxime Blain Alexis Laurent Raffaele Brustia Vincent Leroy Giuliana Amaddeo Alain Luciani Vania Tacher Hicham Kobeiter

Background: Current guidelines do not indicate any comprehensive management of hepatic hypervascular incidentalomas (HVIs) discovered in hepatocellular carcinoma (HCC) patients during intra-arterial therapies (IATs). This study aims to evaluate the prognostic value of HVIs detected on per-interventional cone beam computed tomography (CBCT) during IAT for HCC in patients waiting for liver transplantation (LT). Material and methods: In this retrospective single-institutional study, all liver-transplanted HCC patients between January 2014 and December 2018 who received transarterial chemoembolization (TACE) or radioembolization (TARE) before LT were included. The number of ≥10 mm HCCs diagnosed on contrast-enhanced pre-interventional imaging (PII) was compared with that detected on per-interventional CBCT with a nonparametric Wilcoxon test. The correlation between the presence of an HVI and histopathological criteria associated with poor prognosis (HPP) on liver explants was investigated using the chi-square test. Tumor recurrence (TR) and TR-related mortality were investigated using the chi-square test. Recurrence-free survival (RFS), TR-related survival (TRRS), and overall survival (OS) were assessed according to the presence of HVI using Kaplan–Meier analysis. Results: Among 63 included patients (average age: 59 ± 7 years, H/F = 50/13), 36 presented HVIs on per-interventional CBCT. The overall nodule detection rate of per-interventional CBCT was superior to that of PII (median at 3 [Q1:2, Q3:5] vs. 2 [Q1:1, Q3:3], respectively, p < 0.001). No significant correlation was shown between the presence of HVI and HPP (p = 0.34), TR (p = 0.095), and TR-related mortality (0.22). Kaplan–Meier analysis did not show a significant impact of the presence of HVI on RFS (p = 0.07), TRRS (0.48), or OS (p = 0.14). Conclusions: These results may indicate that the treatment plan during IAT should not be impacted or modified in response to HVI detection.

Cancers doi: 10.3390/cancers16132332

Authors: Corrado Chiappa Maltecca Greta Leoni Miriam Giuseppe Ietto Davide Inversini Andrea Ballabio Alice Bonetti Alberto Mangano Rossana Gueli Giulio Carcano Francesca Angela Rovera

The correlation between TNM staging and histology variations in a sample of patients who underwent neoadjuvant chemotherapy demonstrates a positive impact on both increasing conservative surgery and achieving pCR, resulting in better outcomes in terms of disease-free survival (DFS) and the risk of relapse. Benefits have also been highlighted in terms of cosmetic outcomes, postoperative complications, and psychological benefits. However, the overall outcomes must be evaluated according to the subtype and individual characteristics of the patients.

Cancers doi: 10.3390/cancers16132331

Authors: María Antonia Gómez-Aparicio Fernando López-Campos David Buchser Antonio Lazo Patricia Willisch Abrahams Ocanto Paul Sargos Mohamed Shelan Felipe Couñago

The treatment landscape for metastatic hormone-sensitive prostate cancer continues to evolve, with systemic treatment being the mainstay of current treatment. Prognostic and predictive factors such as tumour volume and disease presentation have been studied to assess responses to different treatments. Intensification and de-escalation strategies arouse great interest, so several trials are being developed to further personalize the therapy in these populations. Is there an optimal sequence and a possible option to de-intensify treatment in selected patients with a favourable profile? This and other goals will be the subject of this review.

Cancers doi: 10.3390/cancers16132330

Authors: Yoannis Imbert-Fernandez Simone M. Chang Lilibeth Lanceta Nicole M. Sanders Jason Chesney Brian F. Clem Sucheta Telang

Rapidly proliferative processes in mammalian tissues including tumorigenesis and embryogenesis rely on the glycolytic pathway for energy and biosynthetic precursors. The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) plays an important regulatory role in glycolysis by activating the key rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase (PFK-1). We have previously determined that decreased PFKFB3 expression reduced glycolysis and growth in transformed cells in vitro and suppressed xenograft growth in vivo. In earlier studies, we created a constitutive knockout mouse to interrogate the function of PFKFB3 in vivo but failed to generate homozygous offspring due to the requirement for PFKFB3 for embryogenesis. We have now developed a novel transgenic mouse model that exhibits inducible homozygous pan-tissue Pfkfb3 gene deletion (Pfkfb3fl/fl). We have induced Pfkfb3 genomic deletion in these mice and found that it effectively decreased PFKFB3 expression and activity. To evaluate the functional consequences of Pfkfb3 deletion in vivo, we crossed Cre-bearing Pfkfb3fl/fl mice with oncogene-driven tumor models and found that Pfkfb3 deletion markedly decreased their glucose uptake and growth. In summary, our studies reveal a critical regulatory function for PFKFB3 in glycolysis and tumorigenesis in vivo and characterize an effective and powerful model for further investigation of its role in multiple biological processes.

Cancers doi: 10.3390/cancers16132329

Authors: Viviana Cortiana Rabab Hunaid Abbas Harshal Chorya Jade Gambill Diksha Mahendru Chandler H. Park Yan Leyfman

Pancreatic cancer, with its alarming rising incidence, is predicted to become the second deadliest type of solid tumor by 2040, highlighting the urgent need for improved diagnostic and treatment strategies. Despite medical advancements, the five-year survival rate for pancreatic cancer remains about 14%, dropping further when metastasized. This review explores the promise of biomarkers for early detection, personalized treatment, and disease monitoring. Molecular classification of pancreatic cancer into subtypes based on genetic mutations, gene expression, and protein markers guides treatment decisions, potentially improving outcomes. A plethora of clinical trials investigating different strategies are currently ongoing. Targeted therapies, among which those against CLAUDIN 18.2 and inhibitors of Claudin 18.1, have shown promise. Next-generation sequencing (NGS) has emerged as a powerful tool for the comprehensive genomic analysis of pancreatic tumors, revealing unique genetic alterations that drive cancer progression. This allows oncologists to tailor therapies to target specific molecular abnormalities. However, challenges remain, including limited awareness and uptake of biomarker-guided therapies. Continued research into the molecular mechanisms of pancreatic cancer is essential for developing more effective treatments and improving patient survival rates.

Cancers doi: 10.3390/cancers16132328

Authors: Anna Polz Kamal Morshed Bartłomiej Drop Małgorzata Polz-Dacewicz

Early diagnosis and effective therapy are the fundamental challenge for modern oncology. Hence, many researchers focus on the search for new or improved biomarkers. Due to the great importance of nuclear factor kappa B (NF-κB) in physiological and pathological processes, we focused on assessing its usefulness as a biomarker in OPSCC. The purpose of the research presented here was to evaluate the prevalence and the level of NF-κB in the serum of OPSCC patients (ELISA). Serum NF-κB levels were also assessed depending on the degree of histological differentiation of the tumor and TN classification. Additionally, we considered the existence of a correlation between the concentration of NF-κB and EBV antibody titers, viral load and selected MMPs—MMP3 and MMP9. Taken together, the obtained results demonstrated that NF-κB level was significantly higher among patients with EBV-related OPSCC than among those without EBV. In addition, the level of NF-κB was significantly higher in more advanced clinical stages. Moreover, a positive correlation was found between the concentration of NF-κB and the level of selected EBV antibodies, viral load and both tested MMPs. The diagnostic accuracy of NF-κB was confirmed by ROC analysis.

Cancers doi: 10.3390/cancers16132327

Authors: Pilenzi Anaclerio Dell’Elice Minelli Giansante Cicirelli Tinari Grassadonia Pantalone Grossi Canale Bruno Calabrese Ballerini Stuppia Antonucci

Hereditary cancer syndromes caused by germline mutations account for 5–10% of all cancers. The finding of a genetic mutation could have far-reaching consequences for pharmaceutical therapy, personalized prevention strategies, and cascade testing. According to the National Comprehensive Cancer Network’s (NCCN) and the Italian Association of Medical Oncology (AIOM) guidelines, unaffected family members should be tested only if the affected one is unavailable. This article explores whether germline genetic testing may be offered to high-risk families for hereditary cancer even if a living affected relative is missing. A retrospective study was carried out on 103 healthy subjects tested from 2017 to 2023. We enrolled all subjects with at least two first- or second-degree relatives affected by breast, ovarian, pancreatic, gastric, prostate, or colorectal cancer. All subjects were tested by Next Generation Sequencing (NGS) multi-gene panel of 27 cancer-associated genes. In the study population, 5 (about 5%) pathogenic/likely pathogenic variants (PVs/LPVs) were found, while 40 (42%) had a Variant of Uncertain Significance (VUS). This study highlights the importance of genetic testing for individuals with a strong family history of hereditary malignancies. This approach would allow women who tested positive to receive tailored treatment and prevention strategies based on their personal mutation status.

Cancers doi: 10.3390/cancers16132326

Authors: Saori Yoshida Hotaka Kawai Yamin Soe Htoo Shwe Eain Sho Sanou Kiyofumi Takabatake Yohei Takeshita Miki Hisatomi Hitoshi Nagatsuka Junichi Asaumi Yoshinobu Yanagi

Cisplatin is a platinum-based compound that is widely used for treating inoperable oral squamous cell carcinoma (OSCC) in Japan; however, resistance to cisplatin presents a challenge and innovative approaches are required. We aimed to investigate the therapeutic potential of targeting the chemokine receptor CXCR4, which is involved in angiogenesis and tumor progression, using the CXCR4 inhibitor AMD3100, in combination with cisplatin. AMD3100 induced necrosis and bleeding in OSCC xenografts by inhibiting angiogenesis. We investigated the combined ability of AMD3100 plus cisplatin to enhance the antitumor effect in cisplatin-resistant OSCC. An MTS assay identified HSC-2 cells as cisplatin-resistant cells in vitro. Mice treated with the cisplatin-AMD combination exhibited the most significant reduction in tumor volume, accompanied by extensive hemorrhage and necrosis. Histological examination indicated thin and short tumor vessels in the AMD and cisplatin–AMD groups. These results indicated that cisplatin and AMD3100 had synergistic antitumor effects, highlighting their potential for vascular therapy of refractory OSCC. Antitumor vascular therapy using cisplatin combined with a CXCR4 inhibitor provides a novel strategy for addressing cisplatin-resistant OSCC.

Cancers doi: 10.3390/cancers16132325

Authors: Rajadurai Ravindran Lee Md Pauzi Chiew Teoh S. Raja Gopal Md Yusof Yip

Breast cancer is one of the most common cancers in Malaysia. Recently, a new nomenclature was introduced for breast cancers with human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 1+, or 2+ with negative in situ hybridization (ISH), i.e., HER2-low breast cancer. In current clinical practice, these breast cancers are reported as HER2-negative. Clinical trials have shown that HER2-low breast cancer benefits from targeted therapy with anti-HER2 antibody-drug conjugates. Unfortunately, various challenges and obstacles are faced by local pathologists in HER2 testing, which may jeopardize the standard of care for patients with HER2-low breast cancer. This consensus guideline aims to elucidate standard practices pertaining to HER2 testing and HER2-low interpretation in Malaysia. Topics discussed among a panel of local experts include tissue sampling and handling, assay and antibody selection, result interpretation and reporting, and quality assurance. Practice recommendations made in this consensus guideline reflect current international guidelines and, where appropriate, adapted to the Malaysian landscape.

Cancers doi: 10.3390/cancers16132324

Authors: Tamar A. Gootzen Ashwin Kalra Katrina Sarig Monika Sobočan Samuel George Oxley Nina Dworschak Ariadni Georgiannakis Sevasti Glynou Angeliki Taniskidi Subhasheenee Ganesan Michelle Ferris Rosa Legood Ros Eeles D Gareth R Evans Caitlin T. Fierheller Ranjit Manchanda

BRCA genetic testing is available for UK Jewish individuals but the provision of information online for BRCA is unknown. We aimed to evaluate online provision of BRCA information by UK organisations (UKO), UK Jewish community organisations (JCO), and genetic testing providers (GTP). Google searches for organisations offering BRCA information were performed using relevant sets of keywords. The first 100 website links were categorised into UKOs/JCOs/GTPs; additional JCOs were supplemented through community experts. Websites were reviewed using customised questionnaires for BRCA information. Information provision was assessed for five domains: accessibility, scope, depth, accuracy, and quality. These domains were combined to provide a composite score (maximum score = 5). Results were screened (n = 6856) and 45 UKOs, 16 JCOs, and 18 GTPs provided BRCA information. Accessibility was high (84%,66/79). Scope was lacking with 35% (28/79) addressing >50% items. Most (82%, 65/79) described BRCA-associated cancers: breast and/or ovarian cancer was mentioned by 78%(62/79), but only 34% (27/79) mentioned ≥1 pancreatic, prostate, melanoma. Few websites provided carrier frequencies in the general (24%,19/79) and Jewish populations (20%,16/79). Only 15% (12/79) had quality information with some/minimal shortcomings. Overall information provision was low-to-moderate: median scores UKO = 2.1 (IQR = 1), JCO = 1.6 (IQR = 0.9), and GTP = 2.3 (IQR = 1) (maximum-score = 5). There is a scarcity of high-quality BRCA information online. These findings have implications for UK Jewish BRCA programmes and those considering BRCA testing.

Cancers doi: 10.3390/cancers16132323

Authors: José Luis Venegas-Rodríguez Jesús Arturo Hernández-Sandoval Melva Gutiérrez-Angulo José Miguel Moreno-Ortiz Anahí González-Mercado Jorge Peregrina-Sandoval Helen Haydee Fernanda Ramírez-Plascencia Beatriz Armida Flores-López Carlos Rogelio Alvizo-Rodríguez Jesús Alonso Valenzuela-Pérez Sergio Cervantes-Ortiz María de la Luz Ayala-Madrigal

We searched for the prevalence of actionable somatic mutations in exon 2 of the KRAS gene in western Mexican patients with CRC. Tumor tissue DNA samples from 150 patients with sporadic CRC recruited at the Civil Hospital of Guadalajara were analyzed. Mutations in exon 2 of the KRAS gene were identified using Sanger sequencing, and the data were analyzed considering clinical–pathological characteristics. Variants in codon 12 (rs121913529 G>A, G>C, and G>T) and codon 13 (rs112445441 G>A) were detected in 26 patients (with a prevalence of 17%). No significant associations were found between these variants and clinical–pathological characteristics (p > 0.05). Furthermore, a comprehensive search was carried out in PubMed/NCBI and Google for the prevalence of KRAS exon 2 mutations in Latin American populations. The 17 studies included 12,604 CRC patients, with an overall prevalence of 30% (95% CI = 0.26–0.35), although the prevalence ranged from 13 to 43% across the different data sources. Determining the variation and frequency of KRAS alleles in CRC patients will enhance their potential to receive targeted treatments and contribute to the understanding of the genomic profile of CRC.

Cancers doi: 10.3390/cancers16132322

Authors: Alina Badlaeva Anna Tregubova Andrea Palicelli Aleksandra Asaturova

According to recent reports, ovarian serous borderline tumor (SBT) harboring the BRAF V600E mutation is associated with a lower risk of progression to low-grade serous carcinoma. Preliminary observations suggest that there may be an association between eosinophilic cells (ECs) and the above-mentioned mutation, so this study aimed to evaluate interobserver reproducibility for assessing ECs. Forty-two samples of SBTs were analyzed for ECs with abundant eosinophilic cytoplasm. Immunohistochemical staining and genetic pro-filing were performed in all cases to verify the BRAF V600E mutation. A BRAF V600E mutation was found in 19 of 42 (45%) cases. Inter-observer reproducibility in the assessment of ECs was substantial (κ = 0.7). The sensitivity and specificity for predicting the mutation were 79% and 91%, respectively. Patients with BRAF-mutated SBTs were significantly younger than those without mutation (p = 0.005). SBTs with BRAF mutation were less likely to be accompanied by non-invasive implants than wild-type SBT: 12% (2/17) versus 33% (6/18). Seven cases were excluded due to incomplete cytoreductive surgery. Nevertheless, Fisher’s exact test showed no significant differences between the two groups (p = 0.228). Overall, this study strengthens the idea that ECs in ovarian SBTs may represent a mutation with prognostic significance, which can serve as a primary screening test for BRAF V600E mutation in this pathologic entity.

Cancers doi: 10.3390/cancers16132320

Authors: Stacey Stauffer Jacob S. Roth Edjay R. Hernandez Joshua T. Kowalczyk Nancy E. Sealover Katie E. Hebron Amy James Kristine A. Isanogle Lisa A. Riffle Lilia Ileva Xiaoling Luo Jin-Qiu Chen Noemi Kedei Robert L. Kortum Haiyan Lei Jack F. Shern Joseph D. Kalen Elijah F. Edmondson Matthew D. Hall Simone Difilippantonio Carol J. Thiele Marielle E. Yohe

Activating mutations in the RAS/MAPK pathway are observed in relapsed neuroblastoma. Preclinical studies indicate that these tumors have an increased sensitivity to inhibitors of the RAS/MAPK pathway, such as MEK inhibitors. MEK inhibitors do not induce durable responses as single agents, indicating a need to identify synergistic combinations of targeted agents to provide therapeutic benefit. We previously showed preclinical therapeutic synergy between a MEK inhibitor, trametinib, and a monoclonal antibody specific for IGF1R, ganitumab in RAS-mutated rhabdomyosarcoma. Neuroblastoma cells, like rhabdomyosarcoma cells, are sensitive to the inhibition of the RAS/MAPK and IGF1R/AKT/mTOR pathways. We hypothesized that the combination of trametinib and ganitumab would be effective in RAS-mutated neuroblastoma. In this study, trametinib and ganitumab synergistically suppressed neuroblastoma cell proliferation and induced apoptosis in cell culture. We also observed a delay in tumor initiation and prolongation of survival in heterotopic and orthotopic xenograft models treated with trametinib and ganitumab. However, the growth of both primary and metastatic tumors was observed in animals receiving the combination of trametinib and ganitumab. Therefore, more preclinical work is necessary before testing this combination in patients with relapsed or refractory RAS-mutated neuroblastoma.

Cancers doi: 10.3390/cancers16132321

Authors: Fernando Martínez de Juan Samuel Navarro Isidro Machado

Background: The low positive predictive value for lymph node metastases (LNM) of common practice risk criteria (CPRC) in T1 colorectal carcinoma (CRC) leads to manyunnecessary additional surgeries following local resection. This study aimed to identify criteria that may improve on the CPRC. Methods: Logistic regression analysis was performed to determine the association of diverse variables with LNM or ‘poor outcome’ (LNM and/or distant metastases and/or recurrence) in a single center T1 CRC cohort. The diagnostic capacity of the set of variables obtained was compared with that of the CPRC. Results: The study comprised 161 cases. Poorly differentiated clusters (PDC) and tumor budding grade > 1 (TB > 1) were the only independent variables associated with LNM. The area under the curve (AUC) for these criteria was 0.808 (CI 95% 0.717–0.880) compared to 0.582 (CI 95% 0.479–0.680) for CPRC. TB > 1 and lymphovascular invasion (LVI) were independently associated with ‘poor outcome’, with an AUC of 0.801 (CI 95% 0.731–0.859), while the AUC for CPRC was 0.691 (CI 95% 0.603–0.752). TB > 1, combined either with PDC or LVI, would reduce false positives between 41.5% and 45% without significantly increasing false negatives. Conclusions: Indicating additional surgery in T1 CRC only when either TB > 1, PDC, or LVI are present could reduce unnecessary surgeries significantly

Cancers doi: 10.3390/cancers16132319

Authors: Elvis Martinez-Jaramillo Fatemeh Jamali Farah H. Abdalbari Bassam Abdulkarim Bertrand J. Jean-Claude Carlos M. Telleria Siham Sabri

Glioblastoma (GBM) is the most prevalent and advanced malignant primary brain tumor in adults. GBM frequently harbors epidermal growth factor receptor (EGFR) wild-type (EGFRwt) gene amplification and/or EGFRvIII activating mutation. EGFR-driven GBM relies on the thioredoxin (Trx) and/or glutathione (GSH) antioxidant systems to withstand the excessive production of reactive oxygen species (ROS). The impact of EGFRwt or EGFRvIII overexpression on the response to a Trx/GSH co-targeting strategy is unknown. In this study, we investigated Trx/GSH co-targeting in the context of EGFR overexpression in GBM. Auranofin is a thioredoxin reductase (TrxR) inhibitor, FDA-approved for rheumatoid arthritis. L-buthionine-sulfoximine (L-BSO) inhibits GSH synthesis by targeting the glutamate–cysteine ligase catalytic (GCLC) enzyme subunit. We analyzed the mechanisms of cytotoxicity of auranofin and the interaction between auranofin and L-BSO in U87MG, U87/EGFRwt, and U87/EGFRvIII GBM isogenic GBM cell lines. ROS-dependent effects were assessed using the antioxidant N-acetylsteine. We show that auranofin decreased TrxR1 activity and increased ROS. Auranofin decreased cell vitality and colony formation and increased protein polyubiquitination through ROS-dependent mechanisms, suggesting the role of ROS in auranofin-induced cytotoxicity in the three cell lines. ROS-dependent PARP-1 cleavage was associated with EGFRvIII downregulation in U87/EGFRvIII cells. Remarkably, the auranofin and L-BSO combination induced the significant depletion of intracellular GSH and synergistic cytotoxicity regardless of EGFR overexpression. Nevertheless, molecular mechanisms associated with cytotoxicity were modulated to a different extent among the three cell lines. U87/EGFRvIII exhibited the most prominent ROS increase, P-AKT(Ser-473), and AKT decrease along with drastic EGFRvIII downregulation. U87/EGFRwt and U87/EGFRvIII displayed lower basal intracellular GSH levels and synergistic ROS-dependent DNA damage compared to U87MG cells. Our study provides evidence for ROS-dependent synergistic cytotoxicity of auranofin and L-BSO combination in GBM in vitro. Unraveling the sensitivity of EGFR-overexpressing cells to auranofin alone, and synergistic auranofin and L-BSO combination, supports the rationale to repurpose this promising pro-oxidant treatment strategy in GBM.

Cancers doi: 10.3390/cancers16132318

Authors: Cristina Picardi Francesca Caparrotti Michael Montemurro Daniel Christen Nora-Brunner Schaub Marie Fargier-Voiron Laetitia Lestrade Jeremy Meyer Guillaume Meurette Emilie Liot Daniel Helbling Jan Schmidt Jean-Pierre Gutzwiller Marco Bernardi Oscar Matzinger Frederic Ris

Rectal cancer typically necessitates a combination of radiotherapy (RT), chemotherapy, and surgery. The associated functional disorders and reduction in quality of life have led to an increasing interest in organ preservation strategies. Response strongly correlates with RT dose, but dose escalation with external beam remains limited even with modern external beam RT techniques because of toxicity of the surrounding tissues. This study reports on the use of Papillon, an endocavitary Radiotherapy device, in the treatment of rectal cancer. The device delivers low energy X-rays, allowing for safe dose escalation and better complete response rate. Between January 2015 and February 2024, 24 rectal cancer patients were treated with the addition of a boost delivered by Papillon to standard RT, with or without chemotherapy, in an upfront organ preservation strategy. After a median follow-up (FU) of 43 months, the organ preservation rate was 96% (23/24), and the local relapse rate was 8% (2/24). None of our patients developed grade 3 or more toxicities. Our results demonstrate that the addition of Papillon contact RT provides a high rate of local remission with sustained long-term organ preservation, offering a promising alternative to traditional surgical approaches in patients with rectal cancer.

Cancers doi: 10.3390/cancers16132317

Authors: Vaibhav Jain Swaroop Bose Awadhesh K. Arya Tasleem Arif

The Cancers Editorial Office retracts the article entitled ‘Lysosomes in Stem Cell Quiescence: A Potential Therapeutic Target in Acute Myeloid Leukemia’ [...]

Cancers doi: 10.3390/cancers16132316

Authors: Kun-Yu Tsai Po-Shuan Huang Po-Yu Chu Thi Ngoc Anh Nguyen Hsin-Yuan Hung Chia-Hsun Hsieh Min-Hsien Wu

The ability to predict or detect colorectal cancer (CRC) recurrence early after surgery enables physicians to apply appropriate treatment plans and different follow-up strategies to improve patient survival. Overall, 30–50% of CRC patients experience cancer recurrence after radical surgery, but current surveillance tools have limitations in the precise and early detection of cancer recurrence. Circulating tumor cells (CTCs) are cancer cells that detach from the primary tumor and enter the bloodstream. These can provide real-time information on disease status. CTCs might become novel markers for predicting CRC recurrence and, more importantly, for making decisions about additional adjuvant chemotherapy. In this review, the clinical application of CTCs as a therapeutic marker for stage II CRC is described. It then discusses the utility of CTCs for monitoring cancer recurrence in advanced rectal cancer patients who undergo neoadjuvant chemoradiotherapy. Finally, it discusses the roles of CTC subtypes and CTCs combined with clinicopathological factors in establishing a multimarker model for predicting CRC recurrence.

Cancers doi: 10.3390/cancers16132315

Authors: Annalisa Cespiati Daniel Smith Rosa Lombardi Anna Ludovica Fracanzani

Introduction: Hepatocellular carcinoma (HCC) represents a major global health concern, characterized by evolving etiological patterns and a range of treatment options. Among various prognostic factors, sarcopenia, characterized by loss of skeletal muscle mass, strength, and function, has emerged as a pivotal contributor to HCC outcomes. Focusing on liver transplantation, surgical resection, locoregional treatments, and systemic therapies, this review aims to analyze the impact of sarcopenia on HCC treatment outcomes, shedding light on an underexplored subject in the pursuit of more personalized management. Methods: A comprehensive literature review was conducted by searching peer-reviewed articles on sarcopenia and treatment outcomes in patients with HCC from inception up to October 2023. Results: Sarcopenia was found to be prevalent among HCC patients, exhibiting different occurrence, possibly attributable to diverse diagnostic criteria. Notably, despite variations in studies utilizing skeletal muscle indices, sarcopenia independently correlated with lower overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS) across surgical (both transplantation and resection), locoregional, and systemic therapies, including tyrosine-kinase inhibitors (TKIs) and immune-checkpoint inhibitors (ICIs). Moreover, a link between sarcopenia and increased rate and severity of adverse events, particularly in surgery and TKIs recipients, and larger tumor size at diagnosis was observed. While baseline sarcopenia negatively influenced treatment outcomes, alterations in muscle mass post-treatment emerged as primary determinants of reduced OS. Conclusions: Sarcopenia, either present before or after HCC treatment, negatively correlates with response to it, across all etiologies and therapeutic strategies. Although only a few studies have evaluated the impact of supervised physical activity training on muscle mass and OS after HCC treatment, it is crucial to evaluate the presence of sarcopenia before treatment initiation, to better stratify patients’ prognosis, thus performing a more tailored approach, and identify therapies able to restore muscle mass in HCC patients. Conversely, the impact of sarcopenia on HCC recurrence and extrahepatic spread remains inadequately explored.

Cancers doi: 10.3390/cancers16132314

Authors: Stefania Kokkali Ioannis Boukovinas Eelco de de Bree Anna Koumarianou Vassilis Georgoulias Anastasios Kyriazoglou Nikolaos Tsoukalas Nikolaos Memos John Papanastassiou Anastasia Stergioula Konstantinos Tsapakidis Konstantia Loga Jose Duran-Moreno Panagiotis Papanastasopoulos Nikolaos Vassos Vasileios Kontogeorgakos Ilias Athanasiadis Luiza Mahaira Efthymios Dimitriadis Dionysios J. Papachristou George Agrogiannis

Precise classification of sarcomas is crucial to optimal clinical management. In this prospective, multicenter, observational study within the Hellenic Group of Sarcoma and Rare Cancers (HGSRC), we assessed the effect of expert pathology review, coupled with the application of molecular diagnostics, on the diagnosis and management of sarcoma patients. Newly diagnosed sarcoma patients were addressed by their physicians to one of the two sarcoma pathologists of HGSRC for histopathological diagnostic assessment. RNA next-generation sequencing was performed on all samples using a platform targeting 86 sarcoma gene fusions. Additional molecular methods were performed in the opinion of the expert pathologist. Therefore, the expert pathologist provided a final diagnosis based on the histopathological findings and, when necessary, molecular tests. In total, 128 specimens from 122 patients were assessed. Among the 119 cases in which there was a preliminary diagnosis by a non-sarcoma pathologist, there were 37 modifications in diagnosis (31.1%) by the sarcoma pathologist, resulting in 17 (14.2%) modifications in management. Among the 110 cases in which molecular tests were performed, there were 29 modifications in diagnosis (26.4%) through the genomic results, resulting in 12 (10.9%) modifications in management. Our study confirms that expert pathology review is of utmost importance for optimal sarcoma diagnosis and management and should be assisted by molecular methods in selected cases.

Cancers doi: 10.3390/cancers16132313

Authors: Feng Liu-Smith Jianjian Lin

Melanoma tumors exhibit a wide range of heterogeneity in genomics even with shared mutations in the MAPK pathway, including BRAF mutations. Consistently, adaptive drug resistance to BRAF inhibitors and/or BRAF plus MEK inhibitors also exhibits a wide range of heterogeneous responses, which poses an obstacle for discovering common genes and pathways that can be used in clinic for overcoming drug resistance. This study objectively analyzed two sets of previously published tumor genomics data comparing pre-treated melanoma tumors and BRAFi- and/or MEKi-resistant tumors. Heterogeneity in response to BRAFi and BRAFi/MEKi was evident because the pre-treated tumors and resistant tumors did not exhibit a tendency of clustering together. Differentially expressed gene (DEG) analysis revealed eight genes and two related enriched signature gene sets (matrisome and matrisome-associated signature gene sets) shared by both sets of data. The matrisome was closely related to the tumor microenvironment and immune response, and five out of the eight shared genes were also related to immune response. The PLXNC1 gene links the shared gene set and the enriched signature gene sets as it presented in all analysis results. As the PLXNC1 gene was up-regulated in the resistant tumors, we validated the up-regulation of this gene in a laboratory using vemurafenib-resistant cell lines. Given its role in promoting inflammation, this study suggests that resistant tumors exhibit an inflammatory tumor microenvironment. The involvement of the matrisome and the specific set of immune genes identified in this study may provide new opportunities for developing future therapeutic methods.

Cancers doi: 10.3390/cancers16132311

Authors: Libing Zhu Yi Rong Lisa A. McGee Jean-Claude M. Rwigema Samir H. Patel

Purpose: This study aimed to develop a retrained large language model (LLM) tailored to the needs of HN cancer patients treated with radiotherapy, with emphasis on symptom management and survivorship care. Methods: A comprehensive external database was curated for training ChatGPT-4, integrating expert-identified consensus guidelines on supportive care for HN patients and correspondences from physicians and nurses within our institution’s electronic medical records for 90 HN patients. The performance of our model was evaluated using 20 patient post-treatment inquiries that were then assessed by three Board certified radiation oncologists (RadOncs). The rating of the model was assessed on a scale of 1 (strongly disagree) to 5 (strongly agree) based on accuracy, clarity of response, completeness s, and relevance. Results: The average scores for the 20 tested questions were 4.25 for accuracy, 4.35 for clarity, 4.22 for completeness, and 4.32 for relevance, on a 5-point scale. Overall, 91.67% (220 out of 240) of assessments received scores of 3 or higher, and 83.33% (200 out of 240) received scores of 4 or higher. Conclusion: The custom-trained model demonstrates high accuracy in providing support to HN patients offering evidence-based information and guidance on their symptom management and survivorship care.

Cancers doi: 10.3390/cancers16132312

Authors: Aron Popovtzer Aviram Mizrachi Mark A. D’Andrea Noam A. VanderWalde Noga Kurman Eli Rosenfeld Ran Ben-Hur Salvatore Roberto Bellia Giacomo Feliciani David Silvern Anna Sarnelli Matthew T. Ballo Pradeep Patra Gil’ad N. Cohen Antonio L. Damato Yotam Shkedy Robert B. Den Christopher A. Barker Tomer Charas Nir Hirshoren

The initial favorable efficacy and safety profile for Alpha DaRT have been demonstrated (NCT04377360); however, the longer-term safety and durability of the treatment are unknown. This pooled analysis of four prospective trials evaluated the long-term safety and efficacy of Alpha DaRT for the treatment of head and neck or skin tumors. A total of 81 lesions in 71 patients were treated across six international institutions, with a median follow-up of 14.1 months (range: 2–51 months). Alpha DaRT sources were delivered via a percutaneous interstitial technique and placed to irradiate the tumor volume with the margin. The sources were removed two to three weeks following implantation. A complete response was observed in 89% of treated lesions (n = 72) and a partial response in 10% (n = 8). The two-year actuarial local recurrence-free survival was 77% [95% CI 63–87]. Variables, including recurrent versus non-recurrent lesions, baseline tumor size, or histology, did not impact long-term outcomes. Twenty-seven percent of patients developed related acute grade 2 or higher toxicities, which resolved with conservative measures. No grade 2 or higher late toxicities were observed. These data support the favorable safety profile of Alpha DaRT, which is currently being explored in a pivotal US trial.

Cancers doi: 10.3390/cancers16132310

Authors: Sarah Tsz-Yui Yau Eman Yee-Man Leung Chi-Tim Hung Martin Chi-Sang Wong Ka-Chun Chong Albert Lee Eng-Kiong Yeoh

Background: Most liver cancer scoring systems focus on patients with preexisting liver diseases such as chronic viral hepatitis or liver cirrhosis. Patients with diabetes are at higher risk of developing liver cancer than the general population. However, liver cancer scoring systems for patients in the absence of liver diseases or those with diabetes remain rare. This study aims to develop a risk scoring system for liver cancer prediction among diabetes patients and a sub-model among diabetes patients without cirrhosis/chronic viral hepatitis. Methods: A retrospective cohort study was performed using electronic health records of Hong Kong. Patients who received diabetes care in general outpatient clinics between 2010 and 2019 without cancer history were included and followed up until December 2019. The outcome was diagnosis of liver cancer during follow-up. A risk scoring system was developed by applying random survival forest in variable selection, and Cox regression in weight assignment. Results: The liver cancer incidence was 0.92 per 1000 person-years. Patients who developed liver cancer (n = 1995) and those who remained free of cancer (n = 1969) during follow-up (median: 6.2 years) were selected for model building. In the final time-to-event scoring system, presence of chronic hepatitis B/C, alanine aminotransferase, age, presence of cirrhosis, and sex were included as predictors. The concordance index was 0.706 (95%CI: 0.676–0.741). In the sub-model for patients without cirrhosis/chronic viral hepatitis, alanine aminotransferase, age, triglycerides, and sex were selected as predictors. Conclusions: The proposed scoring system may provide a parsimonious score for liver cancer risk prediction among diabetes patients.

Cancers doi: 10.3390/cancers16132309

Authors: Dean Y. Huang Majed Alsadiq Gibran T. Yusuf Annamaria Deganello Maria E. Sellars Paul S. Sidhu

Conventional ultrasonography (US), including greyscale imaging and colour Doppler US (CDUS), is pivotal for diagnosing scrotal pathologies, but it has limited specificity. Historically, solid focal testicular abnormalities often led to radical orchidectomy. This retrospective study evaluated the utilisation of contrast-enhanced ultrasound (CEUS) and strain elastography (SE) in investigating intratesticular focal abnormalities. A total of 124 cases were analysed. This study underscored the superior diagnostic capabilities of CEUS in detecting vascular enhancement in all malignant cases, even those with undetectable vascularity by CDUS. It also highlighted the potential of CEUS in identifying distinctive vascular patterns in benign vascular tumours. Definitive confirmation of benignity could be obtained when the absence of enhancement was demonstrated on CEUS. While SE alone offered no distinctive advantage in differentiating between benign and malignant pathologies, we demonstrated that incorporating a combination of CEUS and SE into the evaluation of focal testicular abnormalities could improve diagnostic performance metrics over conventional CDUS. Our findings underscore the role of advanced ultrasound techniques in enhancing the evaluation of focal testicular abnormalities in clinical practice and could aid a shift towards testis-sparing management strategies.

Cancers doi: 10.3390/cancers16132308

Authors: Tuan D. Pham Taichiro Tsunoyama

Extravasation, the unintended leakage of intravenously administered substances, poses significant challenges in cancer treatment, particularly during chemotherapy and radiotherapy. This comprehensive review explores the pathophysiology, incidence, risk factors, clinical presentation, diagnosis, prevention strategies, management approaches, complications, and long-term effects of extravasation in cancer patients. It also outlines future directions and research opportunities, including identifying gaps in the current knowledge and proposing areas for further investigation in extravasation prevention and management. Emerging technologies and therapies with the potential to improve extravasation prevention and management in both chemotherapy and radiotherapy are highlighted. Such innovations include advanced vein visualization technologies, smart catheters, targeted drug delivery systems, novel topical treatments, and artificial intelligence-based image analysis. By addressing these aspects, this review not only provides healthcare professionals with insights to enhance patient safety and optimize clinical practice but also underscores the importance of ongoing research and innovation in improving outcomes for cancer patients experiencing extravasation events.

Cancers doi: 10.3390/cancers16132307

Authors: Richard C. Garfinkle Nicholas P. McKenna

Postoperative bowel dysfunction following restorative proctectomy, commonly referred to as Low Anterior Resection Syndrome (LARS), is a common long term sequela of rectal cancer treatment. While many of the established risk factors for LARS are non-modifiable, others may be well within the surgeon’s control. Several pre-, intra-, and postoperative decisions may have a significant impact on postoperative bowel function. Some of these factors include the extent of surgical resection, surgical approach, choice of anastomotic reconstruction, and use of fecal diversion. This review article summarizes the available evidence regarding how surgical decision-making can affect postoperative bowel function.

Cancers doi: 10.3390/cancers16132306

Authors: Juan Morote Nahuel Paesano Natàlia Picola Berta Miró José M. Abascal Pol Servian Enrique Trilla Olga Méndez

Since the optimal scheme for targeted biopsies of magnetic resonance imaging (MRI) suspicious lesions remains unclear, we compare the efficacy of two schemes for these index lesions. A prospective trial was conducted in 1,161 men with Prostate Imaging Reporting and Data System v 2.1 3-5 undergoing targeted and 12-core systematic biopsy in four centers between 2021 and 2023. Two- to four-core MRI-transrectal ultrasound fusion-targeted biopsies via the transperineal route were conducted in 900 men in three centers, while a mapping per 0.5 mm core method (saturated scheme) was employed in 261 men biopsied in another center. A propensity-matched 261 paired cases were selected for avoiding confounders other than the targeted biopsy scheme. CsPCa (grade group >2) was identified in 125 index lesions (41.1%) when the two- to four-core scheme was employed, while in 187 (71.9%) when the saturated biopsy (p < 0.001) was used. Insignificant PCa (iPCa) was detected in 18 and 11.1%, respectively (p = 0.019). Rates of csPCa and iPCa remained similar in systematic biopsies. CsPCa detected only in systematic biopsies were 5 and 1.5%, respectively (p = 0.035) in each group. The saturated scheme for targeted biopsies detected more csPCa and less iPCa than did the two- to four-core scheme in the index lesions. The rate of csPCa detected only in the systematic biopsies decreased when the saturated scheme was employed.

Cancers doi: 10.3390/cancers16132305

Authors: Gabriele Tonni Andrea Palicelli Maria Bassi Federica Torricelli Ilaria Vacca Lorenzo Aguzzoli Vincenzo Mandato

Background: Gastrointestinal stromal tumors (GISTs) are a rare neoplasm, sometimes mimicking primary ovarian tumors (OTs) and/or metastasizing to the ovaries (M-OT). We performed a systematic literature review (SLR) of OTs and M-OTs, investigating differences in recurrence-free and overall survival. Methods: Our SLR was performed according to PRISMA guidelines, searching in Pubmed, Scopus, and Web of Science databases from inception until 21 April 2024. Results: Overall, 59 OTs (Group 1) and 21 M-OTs (Group 2) were retrieved. The absence of residual disease after surgery was achieved significantly in a higher percentage of patients with Group 1 GISTs (91.5%) compared with Group 2 GISTs (57.1%). Chemotherapy was more frequently administered to Group 2 patients (33% vs. 0%). Recurrence and deaths for disease were significantly more frequent in Group 2 than Group 1 cases (54.5% vs. 6.8%, and 37.5% vs. 9.8%, respectively). Conclusions: GISTs can rarely mimic primary ovarian cancers or even more rarely metastasize to the ovaries. Group 1 GISTs occurred in younger women, were not associated with elevated tumor markers, and had a better prognosis. In contrast, Group 2 GISTs occurred in older women, may exhibit elevated tumor markers, and presented a worse prognosis. However, no significant statistical difference for survival between the two studied groups was detected. Computed tomography scans can define the size of GISTs, which correlate to stage and prognostic risk classes. The gold standard treatment is complete surgical resection, which was achieved in almost all cases of Group 1 GISTs and in half of Group 2. Histopathology and immunohistochemistry are essential for the final diagnosis and guide chemotherapy treatment.

Cancers doi: 10.3390/cancers16132303

Authors: Konstantinos Kavallieros Lampros Karakozis Romilly Hayward Emmanuel Giannas Lucio Selvaggi Christos Kontovounisios

Wearable devices are increasingly utilised to monitor patients perioperatively, allowing for continuous data collection and early complication detection. There is considerable variability in the types and usage settings of wearables, particularly within colorectal surgery. To address this, a scoping review was conducted to investigate current utilisation of wearable devices in colorectal surgery. A systematic search across MEDLINE and Embase was conducted following PRISMA Scoping Review guidelines. Results were synthesised narratively, categorised by perioperative phase (preoperative; postoperative; combination), and supplemented with descriptive statistics and tables. Out of 1525 studies initially identified, 20 were included, reporting data on 10 different wearable devices. Use of wearable devices varied across settings with those used preoperatively tending to focus on baseline physical status or prehabilitation, while postoperative use centred around monitoring and identification of complications. Wearable devices can enhance perioperative monitoring, enable proactive interventions, and promote personalised care for improved patient outcomes in colorectal surgery.

Cancers doi: 10.3390/cancers16132304

Authors: Lucillia Bezu Dilara Akçal Öksüz Max Bell Donal Buggy Oscar Diaz-Cambronero Mats Enlund Patrice Forget Anil Gupta Markus W. Hollmann Daniela Ionescu Iva Kirac Daqing Ma Zhirajr Mokini Tobias Piegeler Giuseppe Pranzitelli Laura Smith The EuroPeriscope Group The EuroPeriscope Group

Surgical excision of the primary tumor represents the most frequent and curative procedure for solid malignancies. Compelling evidence suggests that, despite its beneficial effects, surgery may impair immunosurveillance by triggering an immunosuppressive inflammatory stress response and favor recurrence by stimulating minimal residual disease. In addition, many factors interfere with the immune effectors before and after cancer procedures, such as malnutrition, anemia, or subsequent transfusion. Thus, the perioperative period plays a key role in determining oncological outcomes and represents a short phase to circumvent anesthetic and surgical deleterious factors by supporting the immune system through the use of synergistic pharmacological and non-pharmacological approaches. In line with this, accumulating studies indicate that anesthetic agents could drive both protumor or antitumor signaling pathways during or after cancer surgery. While preclinical investigations focusing on anesthetics’ impact on the behavior of cancer cells are quite convincing, limited clinical trials studying the consequences on survival and recurrences remain inconclusive. Herein, we highlight the main factors occurring during the perioperative period of cancer surgery and their potential impact on immunomodulation and cancer progression. We also discuss patient management prior to and during surgery, taking into consideration the latest advances in the literature.

Cancers doi: 10.3390/cancers16132302

Authors: Jesse Bucksot Katherine Ritchie Matthew Biancalana John A. Cole Daniel Cook

Despite the high variability in cancer biology, cancers nevertheless exhibit cohesive hallmarks across multiple cancer types, notably dysregulated metabolism. Metabolism plays a central role in cancer biology, and shifts in metabolic pathways have been linked to tumor aggressiveness and likelihood of response to therapy. We therefore sought to interrogate metabolism across cancer types and understand how intrinsic modes of metabolism vary within and across indications and how they relate to patient prognosis. We used context specific genome-scale metabolic modeling to simulate metabolism across 10,915 patients from 34 cancer types from The Cancer Genome Atlas and the MMRF-COMMPASS study. We found that cancer metabolism clustered into modes characterized by differential glycolysis, oxidative phosphorylation, and growth rate. We also found that the simulated activities of metabolic pathways are intrinsically prognostic across cancer types, especially tumor growth rate, fatty acid biosynthesis, folate metabolism, oxidative phosphorylation, steroid metabolism, and glutathione metabolism. This work shows the prognostic power of individual patient metabolic modeling across multiple cancer types. Additionally, it shows that analyzing large-scale models of cancer metabolism with survival information provides unique insights into underlying relationships across cancer types and suggests how therapies designed for one cancer type may be repurposed for use in others.

Cancers doi: 10.3390/cancers16132301

Authors: Alejandro Martín García-Sancho María Presa Carlos Pardo Victoria Martín-Escudero Itziar Oyagüez Valentín Ortiz-Maldonado

Purpose: To estimate the cost-effectiveness of axi-cel vs. salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem-cell transplantation (HDT+ASCT) for responders to second-line treatment for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Methods: A partitioned survival mixture-cure model comprising three health states was used to estimate the costs, life years gained (LYG), and quality-adjusted life years (QALYs) accumulated over a lifetime horizon. Overall survival, event-free survival, and time to the next treatment with axi-cel and HDT+ASCT were derived from the ZUMA-7 study. The total costs (EUR, 2022) included drug acquisition and administration, ASCT, subsequent treatment, disease and adverse event management, and palliative care. The unitary costs were derived from local databases and the literature. A 3% discount rate was applied to the costs and outcomes. Results: Compared with HDT+ASCT, axi-cel provided higher LYG per patient (10.00 vs. 8.28 LYG/patient) and greater QALYs gained per patient (7.85 vs. 6.04 QALY/patient). The lifetime total costs were 343,581 EUR/patient with axi-cel vs. 257,994 EUR/patient with IQT+ASCT. The incremental cost-effectiveness ratio of axi-cel vs. HDT+ASCT was 49,627 EUR/LYG, and the incremental cost-utility ratio was 47,309 EUR/QALY. Sensitivity analyses confirmed the robustness of the model. Conclusion: Axi-cel is a potentially cost-effective alternative to HDT+ASCT for the treatment of R/R DLBCL in Spain.

Cancers doi: 10.3390/cancers16132300

Authors: Ruhi Gulati Yasmeen Fleifil Katherine Jennings Alex Bondoc Greg Tiao James Geller Lubov Timchenko Nikolai Timchenko

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers.

Cancers doi: 10.3390/cancers16132299

Authors: Atsushi Kurabayashi Hideo Fukuhara Kaoru Furihata Waka Iwashita Mutsuo Furihata Keiji Inoue

Bladder cancer (BC) possesses distinct molecular profiles that influence progression depending on its biological nature and delivered treatment intensity. Muscle-invasive BC (MIBC) and non-MIBC (NMIBC) demonstrate great intrinsic heterogeneity regarding different prognoses, survival, progression, and treatment outcomes. Transurethral resection of bladder tumor (TURBT) is the standard of care in treating NMIBC and serves both diagnostic and therapeutic purposes despite the prevalent recurrence and progression among many patients. In particular, flat urothelial carcinoma in situ and urothelial carcinoma with lamina propria invasion are the major precursors of MIBC. A new-generation photosensitizer, 5-Aminolevulinic acid (5-ALA), demonstrates high tumor specificity by illuminating the tumor lesion with a specific wavelength of light to produce fluorescence and has been studied for photodynamic diagnosis to detect precise tumor areas by TURBT. Additionally, it has been applied for treatment by producing its cytotoxic reactive oxygen species, as well as screening for urological carcinomas by excreting porphyrin in the blood and urine. Moreover, 5-ALA may contribute to screening before and after TURBT in NMIBC. Here, we summarize the updated evidence and ongoing research on photodynamic technology for NMIBC, providing insight into the potential for improving patient outcomes.

Cancers doi: 10.3390/cancers16132298

Authors: Carolina Noronha Ana Sofia Ribeiro Rita Carvalho Nuno Mendes Joaquim Reis Claudia C. Faria Ricardo Taipa Joana Paredes

Cadherins are cell–cell adhesion proteins which have been strongly implicated in cancer invasion, dissemination and metastasis capacity; thus, they are key players in the epithelial-to-mesenchymal transition (EMT) program. However, their role in glioblastoma (GBM), a primary central nervous system aggressive tumor, remains to be clarified. N-, E- and P-cadherin expression was analyzed on a large series of GBMs, characterized with clinical, imaging and neuropathological parameters, as well as with patients’ survival data. In addition, cadherins’ expression was studied in match-recurrent cases. Using TCGA data, cadherin expression profiles were also evaluated according to GBM transcription subtypes. N-cadherin expression was observed in 81.5% of GBM, followed by E-cadherin in 31% and P-cadherin in 20.8%. Upon tumor recurrence, P-cadherin was the only significantly upregulated cadherin compared with the primary tumor, being positive in 65.8% of the cases. Actually, P-cadherin gain was observed in 51.4% of matched primary-recurrent cases. Cadherins’ co-expression was also explored. Interestingly, E- and N-cadherin co-expression identified a GBM subgroup with frequent epithelial differentiation and a significant survival benefit. On the other hand, subgroups with P-cadherin expression carried the worse prognosis. P- and N-cadherin co-expression correlated with the presence of a mesenchymal phenotype. Expressions of isolated P-cadherin or E- and P-cadherin co-expression were associated with imaging characteristics of aggressiveness, to highly heterogeneous tumors, an d to worse patient survival. Classical cadherins co-expression subgroups present consistent clinical, imaging, neuropathological and survival differences, which probably reflect different states of an EMT-like program in GBM.