Cancers doi: 10.3390/cancers17010105

Authors: Adebiyi Sobitan Nosimot Buhari Zainab Youssri Fayuan Wen Dawit Kidane Shaolei Teng

Background/Objectives: Somatic and genetic mutations in glutathione peroxidases (GPxs), including GPx7 and GPx8, have been linked to intellectual disability, microcephaly, and various tumors. GPx7 and GPx8 evolved the latest among the GPx enzymes and are present in the endoplasmic reticulum. Although lacking a glutathione binding domain, GPx7 and GPx8 possess peroxidase activity that helps the body respond to cellular stress. However, the protein mutations in these peroxidases remain relatively understudied. Methods: By elucidating the structural and stability consequences of missense mutations, this study aims to provide insights into the pathogenic mechanisms involved in different cancers, thereby aiding clinical diagnosis, treatment strategies, and the development of _targeted therapies. We performed saturated computational mutagenesis to analyze 2926 and 3971 missense mutations of GPx7 and GPx8, respectively. Results: The results indicate that G153H and G153F in GPx7 are highly destabilizing, while E93M and W142F are stabilizing. In GPx8, N74W and G173W caused the most instability while S70I and S119P increased stability. Our analysis shows that highly destabilizing somatic and genetic mutations are more likely pathogenic compared to stabilizing mutations. Conclusions: This comprehensive analysis of missense mutations in GPx7 and GPx8 provides critical insights into their impact on protein structure and stability, contributing to a deeper understanding of the roles of somatic mutations in cancer development and progression. These findings can inform more precise clinical diagnostics and _targeted treatment approaches for cancers.

Cancers doi: 10.3390/cancers17010104

Authors: Omer Jamy Talha Badar

The treatment of Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-cell ALL) has seen substantial progress over the past two decades. The introduction of BCR::ABL1 tyrosine kinase inhibitor (TKIs) has resulted in dramatic improvements in long-term survival. Allogeneic hematopoietic stem cell transplantation (allo-HSCT), with its curative potential, has always been an integral part of the treatment algorithm of Ph+ ALL. Recently, the approval of novel therapies such as blinatumomab, inotuzumab ozogamicin and chimeric antigen receptor T-cell (CAR-T) therapy in relapse and refractory (R/R) ALL have further improved outcomes of B-cell ALL. With potent TKIs and novel _targeted therapy, the treatment guidelines for Ph+ ALL are evolving rapidly. Additionally, with improved tools for detecting measurable residual disease (MRD), there has been recent interest in redefining the role of allo-HSCT for some patients. In this context, we discuss the current evidence for the utilization of allo-HSCT for Ph+ ALL, focusing on novel therapies and MRD-directed care.

Cancers doi: 10.3390/cancers17010103

Authors: Chunyan Zhang Huan Yang Liwei Pan Guangfu Zhao Ruofei Zhang Tianci Zhang Zhixiong Xiao Ying Tong Yi Zhang Richard Hu Stephen J. Pandol Yuan-Ping Han

In the original publication [...]

Cancers doi: 10.3390/cancers17010102

Authors: Paweł Lipowski Adam Ostrowski Jan Adamowicz Przemysław Jasiewicz Filip Kowalski Tomasz Drewa Kajetan Juszczak

Introduction: Intravenous fluid management is integral to perioperative care, particularly under enhanced recovery after surgery (ERAS) protocols. In radical cystectomy (RC), which carries high risks of complications and mortality, optimizing fluid management poses a significant challenge due to the absence of definitive guidelines. Aim: the purpose of this study was to investigate the effects of intravenous fluid administration on postoperative complications in patients undergoing RC. Material and methods: This study involved 288 patients who underwent laparoscopic RC and urinary diversion from 2018 to 2022. ERAS protocols were implemented for all patients. Participants were divided into four groups based on the type of urinary diversion (ureterocutaneostomy vs. ileal conduit) and the intraoperative fluid volume input (less than 1000 mL vs. more than 1000 mL). Postoperative complications were evaluated at 30 and 90 days post-surgery using the Clavien-Dindo scale. The fluid management effectiveness was measured using the absolute Vascular Bed Filling Index (aVBFI) and the adjusted Vascular Bed Filling Index (adjVFBI). Results: The UCS is associated with a lower risk of increased severity of postoperative complications. The administration of more than 1000 mL of fluids was associated with a higher risk of complications (p = 0.035). However, after adjusting for the duration of the surgery and BMI, this association did not hold statistical significance, indicating that fluid volume alone is not a direct predictor of postoperative complications. At aVBFI values between zero and eight, urinary diversion using the UCS method is associated with a lower risk of complications compared to the IC. When aVBFI equals eight, the differences in the severity of complications between the UCS and the IC are minimal. However, when aVBFI exceeds eight, the IC is associated with fewer complications during the 30 days post-operation compared to the UCS. The correlation between the adjVFBI (B = −0.27; 95% CI: −0.45 to −0.08; p = 0.005) and the severity of complications up to 30 days postoperatively is similar to that seen with the aVBFI. Similarly, the correlation of the adjVFBI with the method of urinary diversion (B = 0.24; 95% CI: 0.06 to 0.43; p = 0.011) resembles that of the aVBFI. The volume of fluids administered and the indices aVBFI and adjVFBI did not influence the occurrence of complications 90 days postoperatively. Conclusions: The volume of fluids administered is not a factor directly affecting the occurrence of complications following RC when the ERAS protocol is used. The amount of intraoperative fluid administration should be adjusted according to the intraoperative blood loss. Our findings endorse the utility of aVBFI and adjVFBI as valuable tools in guiding fluid therapy within the framework of ERAS protocols. However, further multicenter randomized trials are needed to definitively determine the best fluid therapy regimen for patients undergoing RC.

Cancers doi: 10.3390/cancers17010101

Authors: Masakatsu Tsurusaki Keitaro Sofue Takamichi Murakami Noboru Tanigawa

The liver is supplied by a dual blood flow system consisting of the portal vein and hepatic artery. Imaging techniques for diagnosing hepatocellular carcinoma (HCC) have been developed along with blood flow imaging, which visualizes the amount of arterial and portal blood flow. The diagnosis of HCC differentiation is important for early-stage liver cancer screening and determination of treatment strategies. Dynamic computed tomography/magnetic resonance imaging (MRI) includes blood flow imaging and MRI with contrast-enhanced ultrasound and liver-specific contrast agents are used in combination. In addition, unlike the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1), which is the standard for determining treatment efficacy for solid tumors in general, tumor necrosis is generally considered a treatment effect in HCC, and the modified RECIST and Liver Cancer Direct Effectiveness Criteria (RECICL) are widely used. Familiarity with the definitions, criteria, and potential challenges of the mRECIST and RECICL is essential for their effective application in clinical practice. This review integrates the latest advancements in systemic treatments and imaging techniques, including the role of LI-RADS and updates on molecular-_targeted therapies such as regorafenib, supported by some systematic review and meta-analysis.

Cancers doi: 10.3390/cancers17010099

Authors: Juan Gómez Rivas Luis Enrique Ortega Polledo Irene De La Parra Sánchez Beatriz Gutiérrez Hidalgo Javier Martín Monterrubio María Jesús Marugán Álvarez Bhaskar K. Somani Dmitry Enikeev Javier Puente Vázquez Noelia Sanmamed Salgado María Isabel Galante Romo Jesús Moreno Sierra

Localized high-risk (HR) prostate cancer (PCa) is a heterogeneous disease whose likelihood of a biochemical recurrence, metastatic progression and cancer-related mortality after initial treatment is higher when compared with patients with low (LR) or intermediate-risk (IR) disease. In the past, neoadjuvant therapy has shown an improvement in postoperative oncological variables but failed to demonstrate any survival advantages. With the promising results from novel treatments in metastatic and non-metastatic castration resistant PCa settings, new evidence has appeared in the literature in the neoadjuvant setting. Background/Objectives: To describe the current evidence for different neoadjuvant treatments before a radical prostatectomy in high-risk prostate cancer. Methods: We performed a comprehensive English literature search for original and review articles through January–August 2024, using Pubmed, Medline and ClinicalTrials.gov databases, as well as a comprehensive review of different international guidelines, searching the following terms: “neoadjuvant ADT prostate cancer”, “neoadjuvant ADT”, “prostate cancer surgery” and “neoadjuvant high-risk prostate cancer”. We included 61 papers for the final review. Results and Discussion: Neoadjuvant therapy is not recommended in daily practice by any international guideline. The National Comprehensive Cancer Network (NCCN) guidelines strongly discourage the use of ADT as a neoadjuvant therapy outside of clinical trials. ADT + ARTAs show promising data in phase-II trials, including favorable pCR, MRD, PSA relapse and salvage therapy rates. Clinical trials on chemotherapy, 177Lu-PSMA, genomic-_targeted therapies and markers of response leave room for further evidence acquisition due to their encouraging results. Conclusions: Currently, no phase III data supports systemic neoadjuvant therapy before RP. Phase II studies show promising data for ADT with second-generation agents, including favorable pCR, MRD, PSA relapse and salvage therapy rates.

Cancers doi: 10.3390/cancers17010100

Authors: Matthew Krell Suedeh Ranjbar Saige Gitlin Diego R. Alvarez Vega Rachel Wilson Kenya Thrasher Zachary J. Brown

Despite therapeutic treatments and the growing utilization of multimodal therapies, gastric cancer (GC) remains a highly aggressive malignancy with high mortality worldwide. Much of the complexity in treating GC is due to the high incidence of peritoneal metastasis (PM), with mean overall survival typically ranging from 4 to 10 months. With current systemic therapy, _targeted therapies, and immunotherapies continuing to remain ineffective for GC/PM, there has been a significant growing interest in intraperitoneal (IP) therapies for the treatment of GC/PM. In this review, we summarize the development of PM and evolving treatment strategies for GC/PM. Furthermore, we explore the various advancements and outcomes of IP therapies, including heated intraperitoneal chemotherapy (HIPEC), neoadjuvant HIPEC, and pressurized intraperitoneal aerosolized chemotherapy (PIPAC).

Cancers doi: 10.3390/cancers17010098

Authors: Simone E. Dekker Lei Deng

In the original publication [...]

Cancers doi: 10.3390/cancers17010097

Authors: Sukjoo Cho Jamie L. Fierstein Racha T. Khalaf John M. Morrison Jonathan Metts

Background/Objectives: Prior studies suggest that blood transfusion may adversely affect the survival of patients with cancer via transfusion-related immunomodulation. The objective of our study is to investigate the association between transfusion during neoadjuvant chemotherapy and survival in children, adolescent, and young adult (CAYA, 39 years old or younger) patients with osteosarcoma. Methods: This is a multicenter retrospective cohort study of patients between 2007 and 2022. Our primary exposure was receipt of any blood product in the neoadjuvant period (i.e., neoadjuvant transfusion). The primary outcome of interest was 3-year event-free survival (EFS) calculated using the Kaplan–Meier method, while secondary outcomes of interest included 5-year EFS and 3- and 5-year overall survival (OS). Firth multivariable logistic regression models were constructed to evaluate the adjusted association between transfusion status and 3- and 5-year EFS and OS. Results: In total, 73 patients were included in the analytic sample; among them, 34 received neoadjuvant transfusion. There was no significant difference between transfused and non-transfused groups in race, ethnicity, tumor location, stage at diagnosis, histologic response to neoadjuvant chemotherapy, and receipt of ifosfamide or radiation during initial treatment. The transfusion group included more females (p = 0.02) and lower median hemoglobin at diagnosis (p = 0.002) than the non-transfusion group. EFS and OS did not significantly vary by transfusion status or type. Conclusions: We did not observe an adjusted association between neoadjuvant transfusion and survival in CAYA patients with osteosarcoma.

Cancers doi: 10.3390/cancers17010096

Authors: Hsien-Chun Tseng Chao-Yu Shen Pan-Fu Kao Chun-Yi Chuang Da-Yi Yan Yi-Han Liao Xuan-Ping Lu Ting-Jung Sheu Wei-Chih Shen

Background/Objectives: The duration of the response to radiotherapy-related treatment is a critical prognostic indicator for patients with nasopharyngeal carcinoma (NPC). Persistent tumor status, including residual tumor presence and early recurrence, is associated with poorer survival outcomes. To address this, we developed a prediction model to identify patients at a high risk of persistent tumor status prior to initiating treatment. Methods: This retrospective study included 104 patients with NPC receiving radiotherapy-related treatment who had completed a 3-year follow-up period; 29 were classified into the persistent tumor status group and 75 into the disease-free group. Radiomic features were extracted from pretreatment positron emission tomography (PET) images and used to construct a prediction model by employing machine learning algorithms. The model’s diagnostic performance was assessed using the area under the receiver operating characteristic curve (AUC), whereas SHapley Additive exPlanations (SHAP) analysis was conducted to determine the contribution of individual features to the model. Results: The prediction model developed using the AdaBoost algorithm and validated through five-fold cross-validation achieved the highest AUC of 0.934. Its sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 89.66%, 86.67%, 72.22%, 95.59%, and 87.5%, respectively. SHAP analysis revealed that the feature of high dependence low metabolic uptake emphasis50 had the greatest impact on model predictions. Furthermore, patients classified as disease-free exhibited markedly higher overall survival rates compared with those with persistent tumor status. Conclusions: In conclusion, the proposed prediction model efficiently identified patients with NPC at a high risk of persistent tumor status by using radiomic features extracted from pretreatment PET images.

Cancers doi: 10.3390/cancers17010095

Authors: Noa Rippel Richard Sheppard Adam S. Kittai

Richter transformation (RT) is a rare albeit devastating complication of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). RT is defined as an aggressive lymphoma, typically diffuse large B-cell lymphoma, in the setting of CLL. A clonal relationship to the preceding CLL clone is detected in the majority of RT cases and confers more aggressive clinicopathologic kinetics, resistance to standard chemoimmunotherapy regimens, and inferior survival. Taken together, these considerations precipitate a significant unmet need for novel therapeutic strategies that improve the outcomes of patients with RT. Through this review, we will explore current data on emerging regimens _targeting BTK, BCL-2, CD79, CD20, PI3K, and PD-1—both as single agents and as combination therapies with or without concurrent chemoimmunotherapy. Furthermore, we will review the role of bispecific T-cell engagers, anti-CD19 chimeric antigen receptor T-cell therapies, and hematopoietic stem cell transplantation in RT. To guide therapeutic decision-making, we will outline an algorithmic approach to the management of RT, with particular emphasis on prioritization of clinical trial enrollment and utilization of an ever-evolving array of novel therapies.

Cancers doi: 10.3390/cancers17010094

Authors: Matteo Bisio Luca Legato Filippo Fasano Corrado Benevolo Savelli Carola Boccomini Maura Nicolosi Elisa Santambrogio Roberto Freilone Mattia Novo Barbara Botto

Backgroud: The introduction of highly active immunotherapies has changed the outcome of B-cell non-Hodgkin lymphomas (B-NHLs) in the last two decades. Since then, important progress has been shown using newer and more active immunotherapies, including chimeric antigen receptor T-cell therapy (CAR-T), conjugated monoclonal antibodies, and bispecific antobodies, which currently plays a significant role in the treatment of diffuse large B-cell (DLBCL), follicular (FL), and mantle cell (MCL) lymphoma. Purpose: In this review, we provide an updated overview of recently completed and ongoing BsAb trials in patients with relapsed/refractory(R/R) B-NHL and Hodgkin’s lymphoma, including single-agent results, emerging combinations, safety data, and novel constructs. Conclusions: Bispecific antibodies (BsAbs) are a novel class of “off-the-shelf” T-cell-redirecting drugs capable of _targeting various cell-surface antigens. New antigen _targets are currently under investigation, such as CD19 × CD3 and CD30 × CD3 or CD30 × CD16, in different settings. BsAbs are among the most promising therapeutic options for lymphoma today since they have demonstrated significant single-agent activity, along with a manageable toxicity profile, in patients with heavily pretreated B-NHL.

Cancers doi: 10.3390/cancers17010093

Authors: Giovanni Mazzucato Fabian Falkenbach Marie-Lena Schmalhofer Farzad Shenas Maria Angela Cerruto Alessandro Antonelli Pierre Tennstedt Markus Graefen Felix Preisser Philipp Mandel Sophie Knipper Lars Budäus Daniel Koehler Tobias Maurer

Background: To examine the feasibility and safety of the SENSEI® drop-in gamma probe for robot-assisted, prostate-specific membrane antigen (PSMA)-radioguided salvage surgery (RGS) in lymph node or local oligorecurrent prostate cancer (PCa), detected via PSMA positron emission tomography/computed tomography (PET/CT). Methods: The first thirteen patients with pelvic oligorecurrent PCa who underwent [99mTc]Tc-PSMA-I&S RGS using the SENSEI® drop-in gamma probe at the Martini-Klinik (February–June 2024) were retrospectively analyzed. Radioactivity measurements in counts per second (CPS) as absolute values or ratios (CPS of tumor specimens/mean CPS from the patients’ benign tissues) were correlated with preoperative imaging and pathological findings (benign/malignant, lesion size). Postoperative complete biochemical response (cBR) was defined as prostate-specific antigen (PSA) levels of <0.2 ng/mL. Results: Fifty-four specimens were removed from 13 patients, with nineteen (35%) containing PCa. All patients had one PSMA PET/CT-positive lesion, which were all detected intraoperatively. These lesions showed higher ex vivo CPS, CPS ratios, and larger cancer diameters than PSMA PET/CT-negative lesions (all p < 0.05). Cancer-containing specimens exhibited higher CPS and CPS ratios than benign tissues (median values of 45 vs. 3, and 9.9 vs. 1.0, both p < 0.001). In total, 12/13 (92%) patients achieved cBR. Conclusions: This device yielded excellent detection rates with good correlation to preoperative imaging and histological results without adverse events.

Cancers doi: 10.3390/cancers17010092

Authors: Maria Benkhadra Rola Ghasoub Reem Hajeomar Awni Alshurafa Nabeel Mohammad Qasem Giuseppe Saglio Jorge Cortes Islam Elkonaissi Rasha Kaddoura Mohamed A. Yassin

Background: Renal adverse drug reactions (ADRs) associated with tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) are relatively rare, and there is currently no standardized protocol for their management. Therefore, this study aimed to summarize renal ADRs related to TKIs use in CML and propose an evidence-based approach to monitor and manage these ADRs. Methods: A systematic literature review was performed to identify renal ADRs associated with TKIs in CML. Two authors screened the search results and extracted data from 37 eligible studies. These findings were then used to develop a scheme for clinicians to monitor and manage these ADRs. Results: Overall, imatinib seemed to be significantly linked to renal adverse events compared to other TKIs, and switching to dasatinib or nilotinib significantly improved renal function. Similar events were reported with bosutinib, although they were not statistically significant. However, most of the renal events reported on dasatinib were described as nephrotic syndrome that resolved with switching to imatinib. Few cases were reported with nilotinib that described tumor lysis syndrome (TLS)-related kidney injury. Conclusions: Recommendations include monitoring for progressive decline in the estimated glomerular filtration rate with imatinib, nephrotic syndrome with dasatinib, and TLS with nilotinib. Additionally, holding the offending TKI and managing renal ADRs according to local guidelines were adopted more frequently than reducing the TKI dose.

Cancers doi: 10.3390/cancers17010091

Authors: Naotoshi Sugimoto Shingo Noura Takeshi Kato Shinichi Yoshioka Taishi Hata Atsushi Naito Mitsuyoshi Tei Hiroshi Tamagawa Takamichi Komori Yoshihito Ide Takayuki Fukuzaki Katsuki Danno Genta Sawada Yoshinori Kagawa Toshio Shimokawa Norikatsu Miyoshi Takayuki Ogino Mamoru Uemura Hirofumi Yamamoto Kohei Murata Yuichiro Doki Hidetoshi Eguchi

Background: FOLFIRI (5-FU + leucovorin + irinotecan) plus ramucirumab is one of the standards in second-line metastatic colorectal cancer (CRC) patients progressing after treatment with oxaliplatin/fluoropyrimidine with bevacizumab, but there is no evidence on its efficacy without prior bevacizumab. Moreover, VEGF-D has not been confirmed as a predictive biomarker for ramucirumab’s efficacy, either. Methods: The RAINCLOUD study was a multicenter, single-arm, phase II trial conducted in Japan. Patients with recurrent CRC pretreated with fluoropyrimidine and oxaliplatin without bevacizumab were analyzed. The primary endpoint was progression-free survival (PFS). The secondary endpoints measured were overall survival (OS), overall response rate (ORR), and safety. Results: A total of 48 patients were enrolled from 15 sites between September 2017 and September 2020. Their median age was 63.5 years (25~77), 20.1% had a right-sided tumor, and 68.8% had RAS-mutant cancer. The median PFS was 8.9 months (90% CI: 6.3–11.8), so the primary endpoint was met. Their median OS and ORR were 22.3 months (95% CI: 17.4-NA) and 41.7% (95% CI: 4.9–7.6), respectively. An incidence of grade 3/4 adverse events that reached over 5% applied to neutropenia (44%), leucopenia (10%), and hypertension (8%). In the biomarker analysis, the serum VEGF-D levels post-treatment were higher than those pre-treatment, but the PFS in those with high VEGF-D levels trended towards being worse than that in those with low VEGF-D (7.6M/5.6M (p = 0.095; HR: 0.56)). Instead, those with low TSP-2 had a better PFS than those with high TSP-2 (7.5M/4.3M (p = 0.022; HR: 0.45)). Conclusions: Our data suggested that FOLFIRI plus ramucirumab was effective and tolerable for CRC refractory to fluoropyrimidine and oxaliplatin without anti-angiogenesis. Serum VEGF-D levels may not be predictive but TSP-2 may be a potential prognostic biomarker for ramucirumab’s efficacy.

Cancers doi: 10.3390/cancers17010089

Authors: Sahib Singh Antonio Facciorusso Rakesh Vinayek Sudhir Dutta Dushyant Singh Dahiya Ganesh Aswath Neil Sharma Sumant Inamdar

Pancreatic cancer is associated with high rates of morbidity and mortality. Endoscopic ultrasound (EUS)-guided biopsy has become the standard diagnostic modality per the guidelines. The use of EUS has been growing for providing various treatments in patients with pancreatic cancers: biliary and gallbladder drainage for those with malignant biliary obstruction, gastroenterostomy for malignant gastric outlet obstruction, celiac plexus/ganglia neurolysis for pain control, radiofrequency ablation, placement of fiducial markers, and injection of local chemotherapeutic agents. In this review, we explore the recent clinical studies evaluating the EUS-guided treatments in pancreatic cancer.

Cancers doi: 10.3390/cancers17010088

Authors: Théo Fourrier Caroline Truntzer Morgane Peroz Valentin Derangère Julie Vincent Leila Bengrine-Lefèvre Audrey Hennequin Rémi Palmier David Orry Thomas Rabel François Ghiringhelli

Background/Objectives: Metastatic colorectal cancer (mCRC) is mainly treated with 5-Fluoro-Uracil (5-FU), Oxaliplatin and Irinotecan chemotherapies and anti-Epidermal Growth Factor Receptor (EGFR) or anti-Vascular Endothelial Growth Factor (VEGF) _targeted therapies. Due to chemotherapy-related toxicity, patients receive induction treatment to achieve tumour response followed by maintenance therapy with less cytotoxic molecules or a chemotherapy-free interval to reduce chemotherapy-related toxicity. In this study, the aim was to determine the patient, cancer and treatment factors that influence the duration of maintenance therapy (DMT). Methods: We collected retrospective data on a cohort of 133 patients treated at the Centre Georges François Leclerc (CGFL) cancer centre in Dijon between March 2014 and June 2022. Patients had unresectable or potentially resectable diseases. They received first-line induction treatment with chemotherapy and/or _targeted therapy and maintenance treatment, defined as the interruption of at least one chemotherapy agent. Results: In the multivariate analysis, age (HR: 1.02, 95% CI 1.00–1.04, p = 0.031), N2 nodal status (HR: 1.78, 95% CI 1.09–2.89, p = 0.021) and the presence of peritoneal metastases (HR: 2.05, 95% CI 1.25–3.36, p = 0.004), as well as baseline carcino-embryonic antigen (CEA) level (HR: 1.10, 95% CI 1.00–1.20, p = 0.052), were significantly associated to poor DMT. Local treatment of liver metastases also significantly reduced the DMT (HR: 0.49, 95% CI 0.28–0.86, p = 0.013). In our cohort, induction triplet chemotherapy significantly increased the CEA delta (70% vs. 44%, p = 0.047) compared to doublet chemotherapy and led to a higher rate of liver surgery (40% vs. 21%, p = 0.014) and a trend for a higher rate of local treatment of metastases (62% vs. 45%, p = 0.059). Conclusions: Duration of maintenance therapy is determined by the initial patient and colorectal cancer characteristics. However, it is significantly increased by local treatment of liver metastases. By reducing the tumour burden, a triplet induction chemotherapy regimen increases the rate of liver metastase resection.

Cancers doi: 10.3390/cancers17010090

Authors: Seema Kumari Mundla Srilatha Ganji Purnachandra Nagaraju

Dysbiosis in the gut microbiota plays a significant role in GI cancer development by influencing immune function and disrupting metabolic functions. Dysbiosis can drive carcinogenesis through pathways like immune dysregulation and the release of carcinogenic metabolites, and altered metabolism, genetic instability, and pro-inflammatory signalling, contributing to GI cancer initiation and progression. Helicobacter pylori infection and genotoxins released from dysbiosis, lifestyle and dietary habits are other factors that contribute to GI cancer development. Emerging diagnostic and therapeutic approaches show promise in colorectal cancer treatment, including the multi_target faecal immunochemical test (mtFIT), standard FIT, and faecal microbiota transplantation (FMT) combined with PD-1 inhibitors. We used search engine databases like PubMed, Scopus, and Web of Science. This review discusses the role of dysbiosis in GI cancer onset and explores strategies such as FMT, probiotics, and prebiotics to enhance the immune response and improve cancer therapy outcomes.

Cancers doi: 10.3390/cancers17010087

Authors: Pedro Marílio Cardoso Eduardo Rodrigues-Pinto

Colorectal cancer (CRC) is a leading cause of cancer mortality, with many patients presenting with malignant colorectal obstruction (MCO). Self-expandable metal stents (SEMSs) have emerged as a minimally invasive key intervention, both as a bridge to surgery (BTS) in curative setting sand for palliation in advanced disease. This review aims to provide an evidence-based analysis of SEMS indications, contraindications, and efficacy across curative and palliative contexts, with focus on long-term outcomes. Based on data from recent trials and guidelines, we examine SEMS placement outcomes, focusing on specific scenarios, including BTS for left-sided MCO, chemotherapy (with angiogenic agents) safety during stent therapy, the optimal timing between SEMS placement and surgery, and oncological outcomes. We also discuss the use of SEMSs in challenging contexts such as proximal colon obstruction and extracolonic obstruction, and the relevant technical considerations. Findings indicate that using a SEMS in the BTS setting reduces emergency surgery needs, minimizes complications, and decreases stoma formation. Long-term oncologic outcomes, particularly recurrence, are still debated, but recent evidence shows that SEMS placement is safe, without worsening long term outcomes. Palliative SEMS placement shows high efficacy in symptom relief with manageable adverse events. Success depends on patient selection and technical expertise, with multidisciplinary approaches essential for optimal outcomes.

Cancers doi: 10.3390/cancers17010086

Authors: Andrea Emanuele Guerini Giulia Marvaso Sandro Tonoli Giulia Corrao Maria Ausilia Teriaca Matteo Sepulcri Melissa Scricciolo Alessandro Gava Sabrina Montrone Niccolò Giaj-Levra Barbara Noris Chiorda Giovanna Mantello Francesco Fiorica Simona Borghesi Liliana Belgioia Angela Caroli Alba Fiorentino Radioncovid Study Group Radioncovid Study Group Barbara Alicja Jereczek-Fossa Stefano Maria Magrini Michela Buglione

Methods and materials: Patients with ongoing or planned anticancer treatment at 19 Italian Radiation Oncology centers were included in the study retrospectively from 3 February 2020 to 31 December 2020 and prospectively from 1 January 2021 to 31 May 2021. Anonymized data were processed through a specific website and database. Antineoplastic treatment characteristics and timing and outcomes of COVID-19 and its impact on radiotherapy or systemic therapy were described. Results: The retrieved cohort included 41,039 patients that received treatment or were planned for therapy in the study period. Overall, 123 patients had a confirmed COVID-19 diagnosis during antineoplastic treatment (group A) and 99 patients before treatment start (group B). The incidence of COVID-19 across the whole cohort in the index period was 0.54% (groups A + B) and 0.30% considering only group A. A total of 60 patients developed severe COVID-19, and a total of 45 patients died as a consequence of the infection (incidence of 0.15% and 0.11%, respectively). Nonetheless, mortality among COVID-19 patients was high, with an attributable death rate after confirmed infection of 20.27%. Among the 123 patients in group A, 37.4% required temporary treatment suspension, 32.5% definitive suspension and 37 patients continued treatment while positive. As for the 99 patients in group B, 53.5% experienced temporary delay, 20.2% experienced definitive treatment suspension and 26.3% had no delay. Conclusions: Most of the patients with a COVID-19 diagnosis in our cohort recovered and completed their treatment; nonetheless, the attributable death rate after confirmed infection was 20.27%, and mortality was high among cancer patients with severe COVID-19 presentation. The global incidence of death due to COVID-19 or severe COVID-19 was low and decreased over time. Radiation oncology activity could be safely continued during the COVID-19 pandemic with the adoption of adequate preventive measures.

Cancers doi: 10.3390/cancers17010085

Authors: Yakun Zhang Jiajun Zhou Yitong Jin Chenyu Liu Hanxiao Zhou Yue Sun Han Jiang Jing Gan Caiyu Zhang Qianyi Lu Yetong Chang Yunpeng Zhang Xia Li Shangwei Ning

Background: Immunosenescence is the aging of the immune system, which is closely related to the development and prognosis of lung cancer. _targeting immunosenescence is considered a promising therapeutic approach. Methods: We defined an immunosenescence gene set (ISGS) and examined it across 33 TCGA tumor types and 29 GTEx normal tissues. We explored the 46,993 single cells of two lung cancer datasets. The immunosenescence risk model (ISRM) was constructed in TCGA LUAD by network analysis, immune infiltration analysis, and lasso regression and validated by survival analysis, cox regression, and nomogram in four lung cancer cohorts. The predictive ability of ISRM for drug response and immunotherapy was detected by the oncopredict algorithm and XGBoost model. Results: We found that senescent lung tissues were significantly enriched in ISGS and revealed the heterogeneity of immunosenescence in pan-cancer. Single-cell and bulk transcriptomics characterized the distinct immune microenvironment between old and young lung cancer. The ISGS network revealed the crucial function modules and transcription factors. Multiplatform analysis revealed specific associations between immunosenescence and the tumor progression of lung cancer. The ISRM consisted of five risk genes (CD40LG, IL7, CX3CR1, TLR3, and TLR2), which improved the prognostic stratification of lung cancer across multiple datasets. The ISRM showed robustness in immunotherapy and anti-tumor therapy. We found that lung cancer patients with a high-risk score showed worse survival and lower expression of immune checkpoints, which were resistant to immunotherapy. Conclusions: Our study performed a comprehensive framework for assessing immunosenescence levels and provided insights into the role of immunosenescence in cancer prognosis and biomarker discovery.

Cancers doi: 10.3390/cancers17010084

Authors: Athina C. Tsili

Urogenital neoplasms represent some of the most common malignancies [...]

Cancers doi: 10.3390/cancers17010081

Authors: Marieke Rosier Anja Krstulović Hyejeong Rosemary Kim Nihardeep Kaur Erhumuoghene Mary Enakireru Deebie Symmes Katalin Dobra Ruihuan Chen Caroline A. Evans Annica K. B. Gad

Background: The epithelial-to-mesenchymal transition (EMT) is a common feature in early cancer invasion. Increased vimentin is a canonical marker of the EMT; however, the role of vimentin in EMT remains unknown. Methods: To clarify this, we induced EMT in lung cancer cells with TGF-β1, followed by treatment with the vimentin-_targeting drug ALD-R491, live-cell imaging, and quantitative proteomics. Results: We identified 838 proteins in the intermediate filament fraction of cells. TGF-β1 treatment increased the proportion of vimentin in this fraction and the levels of 24 proteins. Variants of fibronectin showed the most pronounced increase (137-fold), followed by regulators of the cytoskeleton, cell motility, and division, such as the mRNA-splicing protein SON. TGF-β1 increased cell spreading and cell migration speed, and changed a positive correlation between cell migration speed and persistence to negative. ALD-R491 reversed these mesenchymal phenotypes to epithelial and the binding of RNA-binding proteins, including SON. Conclusions: These findings present many new interactors of intermediate filaments, describe how EMT and vimentin filament dynamics influence the intermediate filament interactome, and present ALD-R491 as a possible EMT-inhibitor. The observations support the hypothesis that the dynamic turnover of vimentin filaments and their interacting proteins govern mesenchymal cell migration, EMT, cell invasion, and cancer metastasis.

Cancers doi: 10.3390/cancers17010083

Authors: Yasmeen Fleifil Ruhi Gulati Katherine Jennings Alexander Miethke Alexander Bondoc Gregory Tiao James I. Geller Rebekah Karns Lubov Timchenko Nikolai Timchenko

Background and Aims: Hepatoblastoma (HBL) and fibrolamellar hepatocellular carcinoma (FLC) are the most common liver malignancies in children and young adults. FLC oncogenesis is associated with the generation of the fusion kinase, DNAJB1-PKAc (J-PKAc). J-PKAc has been found in 90% of FLC patients’ tumors but not in other liver cancers. Since previous studies of J-PKAc were performed with adolescent patients, we asked if young children may express J-PKAc and if there are consequences of such expression. Methods: The biobank of the pediatric HBL/HCN-NOS specimens was examined by QRT-PCR, Western blots, RNA-Seq, and immunostaining with fusion-specific antibodies. Results: J-PKAc is expressed in 70% of the HBL/HCN-NOS patients. RNA-Seq analysis revealed that HBL tumors that do not have cells expressing J-PKAc show elevated expression of the membrane attack complex (MAC), which eliminates cells expressing J-PKAc. The fusion-positive HBL/HCN-NOS samples have several signaling pathways that are different from fusion-negative HBLs. Upregulated pathways included genes involved in the G1 to S transition and in liver cancer. Downregulated pathways included over 60 tumor suppressors, the CYP family, and the SLC family. The repression of these genes involves J-PKAc-β-catenin-TCF4-mediated elevation of the HDAC1-Sp5 pathway. The identified upregulated and downregulated pathways are direct _targets of the fusion kinase. The J-PKAc kinase is also detected in livers of 1-year-old children with biliary atresia (BA). Conclusions: J-PKAc is expressed in both HBL tumor and BA liver samples, contributing to the development of HBL and creating a transcriptome profiling consistent with the potential development of liver cancer in young patients.

Cancers doi: 10.3390/cancers17010082

Authors: Anh L. Nguyen Caroline O. B. Facey Bruce M. Boman

Fibroblast growth factors (FGFs) have diverse functions in the regulation of cell proliferation and differentiation in development, tissue maintenance, wound repair, and angiogenesis. The goal of this review paper is to (i) deliberate on the role of FGFs and FGF receptors (FGFRs) in different cancers, (ii) present advances in FGF-_targeted cancer therapies, and (iii) explore cell signaling mechanisms that explain how FGF expression becomes dysregulated during cancer development. FGF is often mutated and overexpressed in cancer and the different FGF and FGFR isoforms have unique expression patterns and distinct roles in different cancers. Among the FGF members, the FGF 15/19 subfamily is particularly interesting because of its unique protein structure and role in endocrine function. The abnormal expression of FGFs in different cancer types (breast, colorectal, hepatobiliary, bronchogenic, and others) is examined and correlated with patient prognosis. The classification of FGF ligands based on their mode of action, whether autocrine, paracrine, endocrine, or intracrine, is illustrated, and an analysis of the binding specificity of FGFs to FGFRs is also provided. Moreover, the latest advances in cancer therapeutic strategies involving small molecules, ligand traps, and monoclonal antibody-based FGF inhibitors are presented. Lastly, we discuss how the dysregulation of FGF and FGFR expression affects FGF signaling and its role in cancer development.

Cancers doi: 10.3390/cancers17010080

Authors: Jack Korleski Sweta Sudhir Yuan Rui Christopher A. Caputo Sophie Sall Amanda L. Johnson Harmon S. Khela Tanmaya Madhvacharyula Anisha Rasamsetty Yunqing Li Bachchu Lal Weiqiang Zhou Karen Smith-Connor Stephany Y. Tzeng Jordan J. Green John Laterra Hernando Lopez-Bertoni

Background/Objectives: CSCs are critical drivers of the tumor and stem cell phenotypes of glioblastoma (GBM) cells. Chromatin modifications play a fundamental role in driving a GBM CSC phenotype. The goal of this study is to further our understanding of how stem cell-driving events control changes in chromatin architecture that contribute to the tumor-propagating phenotype of GBM. Methods: We utilized computational analyses to identify a subset of clinically relevant genes that were predicted to be repressed in a Polycomb repressive complex 2 (PRC2)-dependent manner in GBM upon induction of stem cell-driving events. These associations were validated in patient-derived GBM neurosphere models using state-of-the-art molecular techniques to express, silence, and measure microRNA (miRNA) and gene expression changes. Advanced Poly(β-amino ester) nanoparticle formulations (PBAEs) were used to deliver miRNAs in vivo to orthotopic human GBM tumor models. Results: We show that glioma stem cell (GSC) formation and tumor propagation involve the crosstalk between multiple epigenetic mechanisms, resulting in the repression of the miRNAs that regulate PRC2 function and histone H3 lysine 27 tri-methylation (H3K27me3). We also identified miR-217-5p as an EZH2 regulator repressed in GSCs and showed that miR-217-5p reconstitution using advanced nanoparticle formulations re-activates the PRC2-repressed genes, inhibits GSC formation, impairs tumor growth, and enhances the effects of ionizing radiation in an orthotopic model of GBM. Conclusions: These findings suggest that inhibiting PRC2 function by _targeting EZH2 with miR-217-5p advanced nanoparticle formulations could have a therapeutic benefit in GBM.

Cancers doi: 10.3390/cancers17010077

Authors: Zhi Sheng Patrick Beck Maegan Gabby Semhar Habte-Mariam Katherine Mitkos

The dysregulation of phosphatidylinositol 3-kinase (PI3K) signaling plays a pivotal role in driving neoplastic transformation by promoting uncontrolled cell survival and proliferation. This oncogenic activity is primarily caused by mutations that are frequently found in PI3K genes and constitutively activate the PI3K signaling pathway. However, tumorigenesis can also arise from nonmutated PI3K proteins adopting unique active conformations, further complicating the understanding of PI3K-driven cancers. Recent structural studies have illuminated the functional divergence among highly homologous PI3K proteins, revealing how subtle structural alterations significantly impact their activity and contribute to tumorigenesis. In this review, we summarize current knowledge of Class I PI3K proteins and aim to unravel the complex mechanism underlying their oncogenic traits. These insights will not only enhance our understanding of PI3K-mediated oncogenesis but also pave the way for the design of novel PI3K-based therapies to combat cancers driven by this signaling pathway.

Cancers doi: 10.3390/cancers17010079

Authors: Roberto Regazzoni Sergio Ferrante Emanuela Morenghi Diego Lopane Manuela Pastore Daniela Cattani Simone Cosmai Francesco Colotta Elena Azzolini Marco Sguanci Giovanni Cangelosi Luca Cozzaglio Beatrice Mazzoleni Stefano Mancin

Background/Objectives: Hematopoietic cell transplantation (HCT) is a curative treatment for various hematological diseases but can lead to complications which increase malnutrition risk, particularly in allogeneic transplantation patients. This study evaluates the nutritional status evolution of patients undergoing HCT during hospitalization and follow-up. Methods: This retrospective observational study included 365 patients, divided into two groups: 134 underwent allogeneic HCT, while 231 underwent autologous transplantation or CAR-T therapy. Nutritional status was evaluated using Body Mass Index (BMI), Malnutrition Universal Screening Tool (MUST), and Global Leadership Initiative on Malnutrition (GLIM) criteria at four-time points: hospital admission, discharge, two-week follow-up, and one-month follow-up. Non-relapse-related complications were assessed based on hospital readmissions and reports during follow-up visits. Results: Patients experienced significant nutritional deterioration, with decreases in Body Mass Index (BMI) (p < 0.001) and increases in Malnutrition Universal Screening Tool (MUST) (p < 0.001) and Global Leadership Initiative on Malnutrition (GLIM) scores (p < 0.001), particularly among allogeneic transplant recipients (p = 0.025). Severe malnutrition or high malnutrition risk at discharge correlated with increased hospital readmissions during the follow-up (p = 0.024). Conclusions: The observed decline in nutritional status and its associated complications highlight the necessity of multidisciplinary interventions, such as nutritional prehabilitation programs and nutritional support protocols, to enhance clinical outcomes and reduce complications in HCT patients.

Cancers doi: 10.3390/cancers17010078

Authors: Shauna Levy Abdallah Attia Rami M. Elshazli Ahmed Abdelmaksoud Danielle Tatum Hani Aiash Eman A. Toraih

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated significant efficacy in obesity treatment beyond their original development for type-2 diabetes management. This comprehensive study investigated the relationship between GLP-1RA use and cancer incidence in individuals with obesity across a 5-year follow-up period. Methods: We conducted a large-scale cohort study using the TriNetX US Collaborative Network database (2013–2023) examining adult patients with obesity. The study utilized propensity score matching to pair GLP-1RA-treated patients with controls (1:1) using the nearest neighbor method. Cancer incidence served as the primary outcome measure over the 5-year follow-up, with subgroup analyses considering individual GLP-1RA agents, patient sex, and BMI categories. Results: Analysis revealed significant cancer-risk reductions associated with GLP-1RA use across multiple cancer types compared to matched controls. Notable risk reductions were observed in gastrointestinal (HR 0.67, 95% CI 0.59–0.75), skin (HR 0.62, 95% CI 0.55–0.70), breast (HR 0.72, 95% CI 0.64–0.82), female genital (HR 0.61, 95% CI 0.53–0.71), prostate (HR 0.68, 95% CI 0.58–0.80), and lymphoid/hematopoietic cancers (HR 0.69, 95% CI 0.60–0.80). Semaglutide demonstrated superior protective effects, particularly in gastrointestinal cancers (HR 0.45, 95% CI 0.37–0.53). Conversely, liraglutide showed increased risks for thyroid (HR 1.70, 95% CI 1.03–2.82) and respiratory cancers (HR 1.62, 95% CI 1.13–2.32). Conclusions: This research provides compelling evidence for GLP-1RA’s potential role in cancer-risk reduction, with semaglutide showing particularly promising results. The differential effects observed among GLP-1RA agents emphasize the importance of personalized medicine approaches. These findings suggest significant implications for clinical practice and future research in both obesity management and cancer prevention.

Cancers doi: 10.3390/cancers17010076

Authors: Alberto Savino Alberto Rossi Stefano Fagiuoli Pietro Invernizzi Alessio Gerussi Mauro Viganò

Cancer immunotherapy, particularly immune checkpoint inhibitors, has positively impacted oncological treatments. Despite its effectiveness, immunotherapy is associated with immune-related adverse events (irAEs) that can affect any organ, including the liver. Hepatotoxicity primarily manifests as immune-related hepatitis and, less frequently, cholangitis. Several risk factors, such as pre-existing autoimmune and liver diseases, the type of immunotherapy, and combination regimens, play a role in immune-related hepatotoxicity (irH), although reliable predictive markers or models are still lacking. The severity of irH ranges from mild to severe cases, up to, in rare instances, acute liver failure. Management strategies require regular monitoring for early diagnosis and interventions, encompassing strict monitoring for mild cases to the permanent suspension of immunotherapy for severe forms. Corticosteroids are the backbone of treatment in moderate and high-grade damage, alone or in combination with additional immunosuppressive drugs for resistant or refractory cases. Given the relatively low number of events and the lack of dedicated prospective studies, much uncertainty remains about the optimal management of irH, especially in the most severe cases. This review presents the main features of irH, focusing on injury patterns and mechanisms, and provides an overview of the management landscape, from standard care to the latest evidence.

Cancers doi: 10.3390/cancers17010075

Authors: Siddhant Bhoir Arrigo De Benedetti

For nearly a century, fundamental observations that prostate cancer (PCa) cells nearly always require AR stimulation for sustained proliferation have led to a unidirectional quest to abrogate such a pathway. Similarly focused have been efforts to understand AR-driven processes in the context of elevated expression of its _target genes, and much less so on products that become overexpressed when AR signaling is suppressed. Treatment with ARSI results in an increased expression of the TLK1B splice variant via a ‘translational’ derepression driven by the compensatory mTOR activation and consequent activation of the TLK1 > NEK1 > ATR > Chk1 and NEK1 > YAP axes. In due course, this results first in a pro-survival quiescence and then adaptation to ADT and CRPC progression. This constitutes a novel liability for PCa that we have _targeted for several years and novel approaches.

Cancers doi: 10.3390/cancers17010073

Authors: Evelin Kiss Zsófia Simon Árpád Illés Ádám Jóna

Introduction: Follicular lymphoma (FL) is a heterogeneous disease, and identifying high-risk patients early is crucial for optimal management. This study aimed to evaluate the prognostic significance of interim positron emission tomography/computed tomography (PET/CT) in newly diagnosed FL patients undergoing first-line treatment. Methods: This single-center, retrospective study included 103 patients with newly diagnosed FL who underwent interim PET/CT. The primary endpoint was progression-free survival (PFS). The prognostic value of positive interim PET/CT, Deauville scores, and maximum standardized uptake values (SUVmax) were analyzed among other clinical features. Results: A total of 30 patients (29.1%) were deemed interim PET/CT-positive. The interim PET/CT-positive group demonstrated a significantly shorter median PFS compared to the interim PET/CT-negative group (17 months vs. not reached, respectively; p < 0.0001). Similarly, patients with Deauville scores of 1–3 had better PFS, with median survival not yet reached, while those with higher Deauville scores exhibited poorer progression-free survival and a median survival of 18 months. Notably, patients with an interim PET/CT SUVmax exceeding 3.365 experienced significantly shorter median survival compared to those with lower values. Discussion: Our findings support the use of interim PET/CT as a prognostic tool in FL. These results are consistent with other studies, although some debate exists regarding the optimal PET/CT metric. Further research is needed to validate these findings and explore personalized treatment strategies based on interim PET/CT results.

Cancers doi: 10.3390/cancers17010074

Authors: Dandan Song Guoguang Fan Miao Chang

Magnetic resonance imaging (MRI) currently serves as the primary diagnostic method for glioma detection and monitoring. The integration of neurosurgery, radiation therapy, pathology, and radiology in a multi-disciplinary approach has significantly advanced its diagnosis and treatment. However, the prognosis remains unfavorable due to treatment resistance, inconsistent response rates, and high recurrence rates after surgery. These factors are closely associated with the complex molecular characteristics of the tumors, the internal heterogeneity, and the relevant external microenvironment. The complete removal of gliomas presents challenges due to their infiltrative growth pattern along the white matter fibers and perivascular space. Therefore, it is crucial to comprehensively understand the molecular features of gliomas and analyze the internal tumor heterogeneity in order to accurately characterize and quantify the tumor invasion range. The multi-parameter quantitative MRI technique provides an opportunity to investigate the microenvironment and aggressiveness of glioma tumors at the cellular, blood perfusion, and cerebrovascular response levels. Therefore, this review examines the current applications of advanced multi-parameter quantitative MRI in glioma research and explores the prospects for future development.

Cancers doi: 10.3390/cancers17010071

Authors: Chiara Gaudino Andrea Cassoni Martina Lucia Pisciotti Resi Pucci Chiara Veneroso Cira Rosaria Tiziana Di Gioia Francesca De Felice Patrizia Pantano Valentino Valentini

Backgrounds: Imaging of parotid tumors is crucial for surgery planning, but it cannot distinguish malignant from benign lesions with absolute reliability. The aim of the study was to establish a diagnostic MRI algorithm to differentiate parotid tumors. Methods: A retrospective study was conducted including all patients with parotid tumors, who underwent 3T-MRI and surgery. Morphological characteristics and normalized T2 and late postcontrast T1 signal intensities (SI) were assessed. “Ghosting sign” on late postcontrast T1 sequence was defined as indistinguishability of the tumor except for a thin peripheral enhancement. Patients were divided according to histology and imaging data were compared. A diagnostic MRI algorithm was established. Results: Thirty-six patients were included. The combination of normalized late T1 postcontrast SI, normalized T2 SI and “ghosting sign” allowed for the distinguishing of malignant from benign parotid tumors with high sensitivity (100%), specificity (93%), positive predictive value (80%), negative predictive value, (100%) and accuracy (94%). Moreover, pleomorphic adenomas often showed a homogeneous T2 signal and a complete capsule (p < 0.01), Warthin tumors protein-rich cysts and calcifications (p < 0.005 and p < 0.05), and malignant tumors an inhomogeneous contrast enhancement (p < 0.01). Conclusions: High field MRI represents a promising tool in parotid tumors, allowing for an accurate differentiation of malignant and benign lesions.

Cancers doi: 10.3390/cancers17010072

Authors: Marianne Ayoub Santos A. Susin Brigitte Bauvois

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of neoplastic CD5+/CD19+ B lymphocytes in the blood. These cells migrate to and proliferate in the bone marrow and lymphoid tissues. Despite the development of new therapies for CLL, drug resistance and disease relapse still occur; novel treatment approaches are therefore still needed. Inhibition of the angiogenesis involved in the progression of CLL might be a relevant therapeutic strategy. The literature data indicate that vascular endothelial growth factor, angiopoietin-2, and matrix metalloproteinase-9 are pro-angiogenic factors in CLL. A number of other CLL factors might have pro-angiogenic activity: fibroblast growth factor-2, certain chemokines (such as CXCL-12 and CXCL-2), tumor necrosis factor-α, insulin-like growth factor-1, neutrophil gelatinase-associated lipocalin, and progranulin. All these molecules contribute to the survival, proliferation, and migration of CLL cells. Here, we review the literature on these factors’ respective expression profiles and roles in CLL. We also summarize the main results of preclinical and clinical trials of novel agents _targeting most of these molecules in a CLL setting. Through the eradication of leukemic cells and the inhibition of angiogenesis, these therapeutic approaches might alter the course of CLL.

Cancers doi: 10.3390/cancers17010070

Authors: Efthymios Ladoukakis Tim Oliver Mark Wilks Emily F. Lane Frank Chinegwundoh Greg Shaw Belinda Nedjai

Background/Objectives: Several independent studies have associated prostate cancer (PCa) with specific groups of bacteria, most of them reporting the presence of anaerobic or microaerophilic species such as Cutibacterium acnes (C. acnes). Such findings suggest a prostate cancer-related bacterial dysbiosis, in a manner similar to the association between Helicobacter pylori infection and gastric cancer. In an earlier exploratory study looking for such dysbiosis events, using a culturomics approach, we discovered that the presence of obligate anaerobes (OAs) along with C. acnes was associated with increased prostate-specific antigen (PSA) levels in 39 participants. Methods: Building on this, in this study, we analyzed 89 post-rectal examination urine samples, from men with prostate cancer attending the PROVENT trial, using 16S rDNA sequencing. Our investigation focused on the impact of six previously identified OA genera (Finegoldia, Fusobacterium, Prevotella, Peptoniphilus_A, Peptostreptococcus, and Veillonella_A) on PSA levels. However, an additional data-driven approach was followed to uncover more taxa linked to increased PSA. Results: Our analysis revealed a statistically significant association between Peptostreptococcus and elevated PSA levels. Additionally, there were potential interactions between Prevotella and Fusobacterium. Interestingly, we also found that an aerobe, Ochrobactrum_A,was significantly linked to higher PSA levels. Conclusions: These findings suggest that OA-related dysbiosis may contribute to elevated PSA levels through prostate cell damage even before prostate cancer develops, possibly playing a role in chronic inflammation and the hypervascular changes seen in precancerous lesions. Future clinical trials with larger cohorts are needed to further evaluate the role of OA in prostate cancer development and progression.

Cancers doi: 10.3390/cancers17010069

Authors: Theofilos Kanavos Effrosyni Birbas Theodoros P. Zanos

Background: Positron emission tomography (PET) is a valuable tool for the assessment of lymphoma, while artificial intelligence (AI) holds promise as a reliable resource for the analysis of medical images. In this context, we systematically reviewed the applications of deep learning (DL) for the interpretation of lymphoma PET images. Methods: We searched PubMed until 11 September 2024 for studies developing DL models for the evaluation of PET images of patients with lymphoma. The risk of bias and applicability concerns were assessed using the prediction model risk of bias assessment tool (PROBAST). The articles included were categorized and presented based on the task performed by the proposed models. Our study was registered with the international prospective register of systematic reviews, PROSPERO, as CRD42024600026. Results: From 71 papers initially retrieved, 21 studies with a total of 9402 participants were ultimately included in our review. The proposed models achieved a promising performance in diverse medical tasks, namely, the detection and histological classification of lesions, the differential diagnosis of lymphoma from other conditions, the quantification of metabolic tumor volume, and the prediction of treatment response and survival with areas under the curve, F1-scores, and R2 values of up to 0.963, 87.49%, and 0.94, respectively. Discussion: The primary limitations of several studies were the small number of participants and the absence of external validation. In conclusion, the interpretation of lymphoma PET images can reliably be aided by DL models, which are not designed to replace physicians but to assist them in managing large volumes of scans through rapid and accurate calculations, alleviate their workload, and provide them with decision support tools for precise care and improved outcomes.

Cancers doi: 10.3390/cancers17010068

Authors: Magdalena Hoellwerth Matthias Brandlmaier Peter Koelblinger

Basal cell carcinoma (BCC) accounts for 80% of skin cancer cases. Although mostly curable by simple excision, the treatment of advanced disease can be challenging, as curative surgery or radiotherapy may not always be feasible. The scope of this review is to summarize current knowledge on molecular mechanisms in BCC pathogenesis, to elaborate on the definition of advanced/difficult-to-treat BCC, and to outline systemic treatment options. Particularly, pivotal trial data of the approved hedgehog inhibitors (HHI) sonidegib and vismodegib are compared. Concluding, we provide an overview of novel, particularly neoadjuvant and combined treatment approaches, both with hedgehog and immune-checkpoint inhibitors.

Cancers doi: 10.3390/cancers17010067

Authors: María Criado-Otero María Navedo-de las Heras Elia Samaniego-González

Cutaneous melanoma is a malignant neoplasm with local and distant metastatic potential. When feasible, surgery is the first line of treatment in locoregionally advanced disease. Topical and intralesional treatments can be an alternative second-line treatment. The aim of this article was to perform a narrative review of the most widely used topical and intralesional treatments for locoregionally advanced melanoma. Diphenciprone, imiquimod and 5-florouracil were included as topical treatments and bacillus Calmette-Guerin, interleukin 2, rose bengal, talimogene laherparepvec and electrochemotherapy were included as intralesional treatments. Brief comments on other alternatives in development such as interferon-alpha, interleukin-12, ipilimumab and intralesional daromun are presented. Topical treatments generally have higher response rates in epidermal metastases than in deeper metastases. In addition, the larger the lesions, the worse they tend to respond to local treatments. Some reports show that combining certain systemic treatments and topical or intralesional therapies can improve response rates. It has also been described in a few papers that non-injected lesions may respond after the application of a local therapy in distant skin-metastases. Many of these intralesional treatments are being combined in different investigations with systemic immunotherapies, with the aim of obtaining synergic responses in those patients with refractory disease.

Cancers doi: 10.3390/cancers17010066

Authors: Mahmoud Singer Zhuoli Zhang Farshid Dayyani Zigeng Zhang Vahid Yaghmai April Choi Jennifer Valerin David Imagawa Nadine Abi-Jaoudeh

Hepatocellular carcinoma (HCC) is a major global health issue characterized by poor prognosis and complex tumor biology. One of the critical components of the HCC tumor microenvironment (TME) is tumor-associated macrophages (TAMs), which play a pivotal role in modulating tumor growth, immune evasion, and metastasis. Macrophages are divided into two major subtypes: pro-inflammatory M1 and anti-inflammatory M2, both of which may exist in TME with altered function and proportion. The anti-inflammatory M2 macrophages are further subdivided into four distinct immune suppressive subsets. TAMs are generally counted as M2-like macrophages with altered immune suppressive functions that exert a significant influence on both cancer progression and the ability of tumors to escape immune surveillance. Their involvement in modulating immune responses via different mechanisms at the local and systemic levels has made them a key _target for therapeutic interventions seeking to enhance treatment outcomes. How TAMs’ depletion influences immune responses in cancer is the primary interest in cancer immunotherapies. The purpose of this review is to delve into the recent progress made in TAM-_targeting therapies. We will explore the current theories, benefits, and challenges associated with TAMs’ depletion or inhibition. The manuscript concludes with future directions and potential implications for clinical practice.

Cancers doi: 10.3390/cancers17010065

Authors: Irene Russo Emma Sartor Rocco Cappellesso Roberto Salmaso Paolo Del Fiore Gino Sartor Antonella Vecchiato Mauro Alaibac Simone Mocellin

Background: Diagnosis of nevoid melanoma (NeM) is often difficult because NeM closely resembles a common nevus clinically and histologically. Methods: A retrospective study was conducted on 110 patients diagnosed with and/or treated for primary nevoid melanoma at the Veneto Institute of Oncology and at the University Hospital of Padua from August 1999. Results: Mean Breslow thickness was of 1.4 mm. Sentinel lymph node biopsy was conducted in nearly half of the patients, and positivity was detected in 16.7% of them. Twenty-four clinical and 23 dermoscopic pictures were collected. Papular and macular lesions prevailed over nodular and plaque-type lesions. Different hues of brown, pink, and red color were most represented. Twenty nevus-like NeMs and four multicomponent-pattern NeMs were observed. The Most frequent dermoscopic patterns for nevus-like NeM were atypical pigmented reticulum, irregular globules and dots, and hyperpigmented blotches. Atypical vessels, asymmetric peripheric striae, blue-white veil, and areas of regression were less frequent and prevailed in multicomponent pattern NeM. A structureless pattern was also featured. Many patients in the series had multiple melanomas. However, none of them had numerous multiple nevoid melanomas. Conclusions: NeM should not be regarded as a separate biological entity from classical melanoma, and the same histological and clinical prognostic factors apply to NeM. Clinically and dermoscopically, it often resembles benign nevi, although some clues such as evolution and some dermoscopic patterns could suggest malignancy. Clinical suspicion might prove crucial to further pathological analysis and recognition.

Cancers doi: 10.3390/cancers17010064

Authors: Shervin Hosseingholi Nouri Vijay Nitturi Elizabeth Ledbetter Collin W. English Sean Lau Tiemo J. Klisch Akash J. Patel

Background/Objectives: With the rise in prevalence of diagnostic genetic techniques like RNA sequencing and whole exome sequencing (WES), as well as biological treatment regiments for cancer therapy, several genes have been implicated in carcinogenesis. This review aims to update our understanding of the Neurofibromatosis 2 (NF2) gene and its role in the pathogenesis of various cancers. Methods: A comprehensive search of five online databases yielded 43 studies that highlighted the effect of sporadic NF2 mutations on several cancers, including sporadic meningioma, ependymoma, schwannoma, mesothelioma, breast cancer, hepatocellular carcinoma, prostate cancer, glioblastoma, thyroid cancer, and melanoma. Of note were key biological pathways implicated in cancer formation resulting from sporadic NF2 mutations. Results: NF2 gene mutations are implicated in over 11 different cancers, including several CNS tumors, soli-organ tumors, and skin cancer. NF2 acts as a driver mutation in some cancers, as a non-driver mutation in some cancers, and has simple associated mutations with other cancers. In terms of biological pathway involvement, 8 of the 11 cancers with NF2 mutations show evidence of Hippo signaling cascade involvement. Conclusions: Several cancers characterized by mutations in the NF2 gene have associations with the Hippo signaling pathway. However, future studies remain to be done to further elucidate the role of the Hippo signaling pathway in the carcinogenesis of human NF2-mutant tumors. The findings of this review provide insights into the role of NF2 mutations in cancers, Hippo signaling in NF2-mutant cancers, and current gaps in our knowledge regarding the two.

Cancers doi: 10.3390/cancers17010063

Authors: Raquel Ibáñez Esther Roura Francisca Morey Miguel Andújar Miquel Ángel Pavón Amelia Acera Laia Bruni Silvia de Sanjosé

Background: Implementing self-sampling (SS) in cervical cancer screening requires comparable results to clinician-collected samples (CCS). Agreement measures are essential for evaluating HPV test performance. Previous studies on non-paired samples have reported higher viral cycle threshold (Ct) values in SS compared to CCS, affecting sensitivity for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Objectives: We aimed to evaluate the agreement of high-risk (hr)HPV testing results between SS and CCS using paired samples and to explore differences in Ct values. Methods: Women aged 30 to 65 years attending cervical cancer screening in two regions of Spain were invited to participated in this study. For each woman there was: CCS collected during the screening visit using liquid-based cytology and cytobrush, and a SS using a brush at home one month later. A PCR-based assay was used for hrHPV detection. Agreement in hrHPV results among both samples, Ct value differences, and their association with screening outcomes were analyzed. Results: This study included 981 women with paired samples. SS had a higher hrHPV prevalence than CCS (overall ratio of 1.3). Positive agreement for all hrHPV genotypes, HPV16, HPV18, and other hrHPV types were 85%, 91.3%, 66.7%, and 83.3%, respectively. Negative agreement was >95% for all results. Median Ct values was slightly higher in SS than in CSS (32.9 vs. 30.6, p = 0.02). Seven CIN2+ cases HPV positive were detected by both methods. One CIN3 case was missed by SS. Conclusions: This study showed a good agreement between SS and CCS for hrHPV testing in a routine screening in Spain. Despite the slightly higher Ct values for SS, no significant impact on sensitivity could be determined due to the low incidence of CIN2+ cases. Further research on larger paired samples is needed to assess the implications of Ct values on test sensitivity.

Cancers doi: 10.3390/cancers17010062

Authors: Akinari Yamano Masahide Matsuda Eiichi Ishikawa

Skull base tumors such as meningiomas and schwannomas are often pathologically benign. However, surgery for these tumors poses significant challenges because of their proximity to critical structures such as the brainstem, cerebral arteries, veins, and cranial nerves. These structures are compressed or encased by the tumor as they grow, increasing the risk of unintended injury to these structures, which can potentially lead to severe neurological deficits. Preoperative imaging is crucial for assessing the tumor size, location, and its relationship with adjacent vital structures. This study reviews advanced imaging techniques that allow detailed visualization of vascular structures and cranial nerves. Contrast-enhanced computed tomography and digital subtraction angiography are optimal for evaluating vascular structures, whereas magnetic resonance imaging (MRI) with high-resolution T2-weighted images and diffusion tensor imaging are optimal for evaluating cranial nerves. These methods help surgeons plan tumor resection strategies, including surgical approaches, more precisely. An accurate preoperative assessment can contribute to safe tumor resection and preserve neurological function. Additionally, we report the MRI contrast defect sign in skull base meningiomas, which suggests cranial nerve penetration through the tumor. This is an essential finding for inferring the course of cranial nerves completely encased within the tumor. These preoperative imaging techniques have the potential to improve the outcomes of patients with skull base tumors. Furthermore, this study highlights the importance of multimodal imaging approaches and discusses future directions for imaging technology that could further develop preoperative surgical simulations and improve the quality of complex skull base tumor surgeries.

Cancers doi: 10.3390/cancers17010060

Authors: Ernesto Fasulo Ferdinando D’Amico Alessandra Zilli Federica Furfaro Clelia Cicerone Tommaso Lorenzo Parigi Laurent Peyrin-Biroulet Silvio Danese Mariangela Allocca

Patients with inflammatory bowel disease (IBD) face an elevated risk of developing colorectal cancer (CRC). Endoscopic surveillance is a cornerstone in CRC prevention, enabling early detection and intervention. However, despite recent advancements, challenges persist. Chromoendoscopy (CE), considered the gold standard for dysplasia detection, remains underutilized due to logistical constraints, prolonged procedural times, and the need for specialized training. New technologies, such as endomicroscopy, confocal laser endomicroscopy (CLE), and molecular endoscopy (ME), promise unprecedented precision in lesion characterization but are limited to specialized centers. Artificial intelligence (AI) can transform the field; however, barriers to widespread AI adoption include the need for robust datasets, real-time video integration, and seamless incorporation into existing workflows. Beyond technology, patient adherence to surveillance protocols, including bowel preparation and repeat procedures, remains a critical hurdle. This review aims to explore the advancements, ongoing challenges, and future prospects in CRC prevention for IBD patients, focusing on improving outcomes and expanding the implementation of advanced surveillance technologies.

Cancers doi: 10.3390/cancers17010061

Authors: Ramya Muddasani Helena T. Wu Shwe Win Arya Amini Badri Modi Ravi Salgia Vijay Trisal Edward W. Wang Miguel Angel Villalona-Calero Aaron Chan Yan Xing

Background: This study addresses the lack of research on Medicaid expansion’s impact on melanoma staging, treatment utilization, and outcomes by evaluating its effects under the Affordable Care Act (ACA), particularly focusing on staging at diagnosis, treatment use, and 3-year mortality outcomes. The objective is to determine whether Medicaid expansion led to earlier melanoma diagnosis and improved survival rates among non-elderly adults (ages 40–64) by analyzing data from the National Cancer Database (NCDB). Methods: A total of 12,667 patients, aged 40–64, diagnosed with melanoma from 2010 to 2020 were identified using the NCDB. Difference-in-difference (DID) analysis was performed to analyze tumor staging at presentation between Medicaid expansion states and non-Medicaid expansion states both prior to the expansion and after the expansion. Results: Of the total patients, 2307 were from the pre-expansion time period residing in Medicaid expansion states (MES) and 1804 in non-Medicaid expansion states. In the post-expansion time period there were 5571 residing in the MES and 2985 in the non-MES. DID analysis revealed a decrease in stage IV melanoma at diagnosis (DID −0.222, p < 0.001) between MES and non-MES before and after Medicaid expansion. After expansion, in stage IV, the occurrence of primary surgery was 0.42 in non-MES and 0.44 (difference 0.02); DID analysis was not statistically significant. The use of immunotherapy in MES was significantly higher than in non-MES after expansion (p < 0.001), although DID analysis did not reveal a statistically significant difference. DID analysis showed a statistically significant decrease in 3-year mortality (DID −0.05, p = 0.001) between MES and non-MES before and after Medicaid expansion. Conclusions: This study revealed the positive impact of the ACA’s Medicaid expansion on melanoma stage at presentation, highlighting the importance of public health policies in reducing disparities in mortality rates and early-stage diagnoses. Future research should explore additional barriers to care and evaluate the long-term outcomes of Medicaid expansion to optimize cancer care for vulnerable populations.

Cancers doi: 10.3390/cancers17010059

Authors: Giuseppe Nardo Pan Pantziarka Matteo Conti

Intratumoral microbiota, the diverse community of microorganisms residing within tumor tissues, represent an emerging and intriguing field in cancer biology. These microbial populations are distinct from the well-studied gut microbiota, offering novel insights into tumor biology, cancer progression, and potential therapeutic interventions. Recent studies have explored the use of certain antibiotics to modulate intratumoral microbiota and enhance the efficacy of cancer therapies, showing promising results. Antibiotics can alter intratumoral microbiota’s composition, which may have a major role in promoting cancer progression and immune evasion. Certain bacteria within tumors can promote immunosuppression and resistance to therapies. By _targeting these bacteria, antibiotics can help create a more favorable environment for chemotherapy, _targeted therapy, and immunotherapy to act effectively. Some bacteria within the tumor microenvironment produce immunosuppressive molecules that inhibit the activity of immune cells. The combination of antibiotics and other cancer therapies holds significant promise for creating a synergistic effect and enhancing the immune response against cancer. In this review, we analyze several preclinical studies that have been conducted to demonstrate the synergy between antibiotics and other cancer therapies and discuss possible clinical implications.

Cancers doi: 10.3390/cancers17010058

Authors: Ian Janzen Cheryl Ho Barbara Melosky Qian Ye Jessica Li Gang Wang Stephen Lam Calum MacAulay Ren Yuan

Background/Objectives: Pembrolizumab monotherapy is approved in Canada for first-line treatment of advanced NSCLC with PD-L1 ≥ 50% and no EGFR/ALK aberrations. However, approximately 55% of these patients do not respond to pembrolizumab, underscoring the need for the early intervention of non-responders to optimize treatment strategies. Distinguishing the 55% sub-cohort prior to treatment is a real-world dilemma. Methods: In this retrospective study, we analyzed two patient cohorts treated with pembrolizumab monotherapy (training set: n = 97; test set: n = 17). The treatment response was assessed using baseline and follow-up CT scans via RECIST 1.1 criteria. Results: A logistic regression model, incorporating pre-treatment CT radiomic features of lung tumors and clinical variables, achieved high predictive accuracy (AUC: 0.85 in training; 0.81 in testing, 95% CI: 0.63–0.99). Notably, radiomic features from the peritumoral region were found to be independent predictors, complementing the standard CT evaluations and other clinical characteristics. Conclusions: This pragmatic model offers a valuable tool to guide first-line treatment decisions in NSCLC patients with high PD-L1 expression and has the potential to advance personalized oncology and improve timely disease management.

Cancers doi: 10.3390/cancers17010057

Authors: Won Ku Hwang Seon Beom Jo Da Eun Han Sun Tae Ahn Mi Mi Oh Hong Seok Park Du Geon Moon Insung Choi Zepa Yang Jong Wook Kim

Background/Objectives: Cystoscopy is necessary for diagnosing bladder cancer, but it has limitations in identifying ambiguous lesions, such as carcinoma in situ (CIS), which leads to a high recurrence rate of bladder cancer. With the significant advancements in deep learning in the medical field, several studies have explored its application in cystoscopy. This study aimed to utilize the VGG19 and Deeplab v3+ deep learning models to classify and segment cystoscope images, respectively. Methods: We classified cystoscope images obtained from 772 patients based on morphology (normal, papillary, flat, mixed) and biopsy results (normal, Ta, T1, T2, CIS, etc.). Experienced urologists annotated and labeled the lesion areas and image categories. The classification model for bladder cancer lesion, annotated with pathological results, was developed using VGG19 with an additional fully connected layer, utilizing sparse categorical cross-entropy as the loss function. The Deeplab v3+ model was used for segmenting each morphological type of bladder cancer in the cystoscope images, employing the dice coefficient loss function. The classification model was evaluated using validation accuracy and correlation with biopsy results, while the segmentation model was assessed using the Intersection over Union (IoU) combined with binary accuracy. Results: The dataset was split into training and validation sets with a 4:1 ratio. The VGG19 classification model achieved an accuracy score of 0.912. The Deeplab v3+ segmentation model achieved an IoU of 0.833 and a binary accuracy of 0.951. Visual analysis revealed a high similarity between the lesions identified by Deeplab v3+ and those labeled by experts. Conclusions: In this study, we applied two deep learning models using well-annotated datasets of cystoscopic images. Both VGG19 and Deeplab v3+ demonstrated high performance in classification and segmentation, respectively. These models can serve as valuable tools for bladder cancer research and may aid in the diagnosis of bladder cancer.

Cancers doi: 10.3390/cancers17010056

Authors: Sarah Krieg Sven H. Loosen Christoph Roderburg Andreas Krieg Karel Kostev

Background: Discharge against medical advice (DAMA) disrupts continuity of care and is associated with increased readmission rates, morbidity, and mortality. While extensively studied in general hospital populations, its prevalence and associated factors in cancer patients, where treatment adherence is critical for outcomes, remain underexplored. Methods: This multicenter, cross-sectional study analyzed anonymized data from the IQVIA hospital database, including cancer patients hospitalized in 36 German hospitals between January 2019 and December 2023. Multivariate logistic regression assessed associations between DAMA and factors such as age, sex, cancer type, metastases, and comorbidities. Results: Among 51,505 cancer patients, DAMA occurred in 0.9% of hospitalizations. The highest rates were observed in cancers of the lip, oral cavity, and pharynx (2.1%), larynx (2.0%), and liver (1.8%). DAMA was more frequent in younger patients (≤50 years) (OR: 1.73; 95% CI: 1.30–2.14) and males (OR: 1.46; 95% CI: 1.23–1.72). Distant metastases showed no significant association (OR: 0.96; 95% CI: 0.81–1.13). Conclusions: The findings suggest that DAMA in cancer patients is more strongly associated with demographic and social factors than with disease severity. These results provide a basis for exploring strategies that address underlying psychosocial and economic challenges during hospitalization, particularly in younger and male patients. Further research is needed to better understand these associations and their implications for clinical practice.

Cancers doi: 10.3390/cancers17010055

Authors: Salvatore Audia Carolina Brescia Vincenzo Dattilo Naomi Torchia Francesco Trapasso Rosario Amato

IL-23R (interleukin-23 receptor), found on the surface of several immune cells, plays a key role in the immune system. Indeed, this process is not limited to the inflammatory response but also plays a role in the adaptive immune response. The binding between IL-23R and its specific ligand, the interleukin 23, initiates a number of specific signals by modulating both properties and behavior of immune cells. In particular, it is critical for the regulation of T helper 17 cells (Th17). Th17s are a subset of T cells involved in autoimmune and inflammatory diseases, as well as in cancer. The clinical relevance of IL-23R is underscored by its association with an elevated susceptibility or diminished vulnerability to a spectrum of diseases, including psoriasis, ankylosing spondylitis, and inflammatory bowel disease (IBD). Evidence has emerged that suggests it may also serve to predict both tumor progression and therapeutic responsiveness. It is noteworthy that the IL-23/IL-23R pathway is emerging as a promising therapeutic _target. A number of biologic drugs, such as monoclonal antibodies, are currently developing with the aim of blocking this interaction, thus reducing inflammation. This represents a significant advancement in the field of medicine, offering new hope for pursuing more effective and personalized treatments. Recent studies have also investigated the role of such a pathway in autoimmune diseases, and its potential impact on infections as well as in carcinogenesis. The aim of this review is to focus on the role of IL-23R in immune genetics and its potential for modulating the natural history of neoplastic disease.

Cancers doi: 10.3390/cancers17010054

Authors: Francesco Fiorica Umberto Tebano Giuseppe Napoli Antonella Franceschetto Marco Muraro Carlotta Giorgi Paolo Pinton

From a cancer-centric perspective, radiotherapy has been primarily viewed as a localised treatment modality, _targeting cancer tissues with ionising radiation to induce DNA damage and cell death [...]

Cancers doi: 10.3390/cancers17010053

Authors: Juan Morote Ana Celma María E. Semidey Andreu Antolín Berta Miró Olga Méndez Enrique Trilla

Background. Inflammatory features can mimic PCa in suspicious MRI-lesions. Objectives: To assess the incidence of inflammatory features in _targeted biopsies to suspicious lesions. Methods. A prospective analysis was conducted of 531 MRI-suspicious lesions with Prostate Imaging-Reporting and Data System (PI-RADS) scores of 3 to 5 in 364 men suspected of having PCa. Results. The incidence of inflammatory features in the MRI-suspicious lesions without PCa was 69.6%, compared to 48.1% in those with PCa (p < 0.001). Among the suspicious lesions without PCa, the incidence of inflammatory features ranged from 68.6% to 71.2% across the PI-RADS categories (p = 0.870). Mild chronic prostatitis increased with higher PI-RADS scores, while acute prostatitis decreased, and granulomatous prostatitis was exclusively observed in patients with PI-RADS scores of 4 and 5. The incidence of inflammatory features in the lesions with insignificant PCa (grade group 1) was 66.7%, compared to 42.7% in those with significant PCa (grade group 2 to 5; p = 0.027). The detection of inflammatory features in MRI-suspicious lesions was identified as an independent predictor of a lower likelihood of significant PCa detection, with an odds ratio (OR) of 0.326 (95% CI 0.196–0.541). Mild chronic prostatitis was the only type of prostatitis which was an independent predictor of a lower likelihood of significant PCa, with an OR of 0.398 (95% CI 0.268–0.590). Conclusions. These data suggest that inflammatory features may be considered mimickers of significant PCa on MRI.

Cancers doi: 10.3390/cancers17010052

Authors: Ali Ramouz Ali Adeliansedehi Elias Khajeh Keno März Dominik Michael Martin Wagner Beat Peter Müller-Stich Arianeb Mehrabi Ali Majlesara

Background: Despite the significant advancements of liver surgery in the last few decades, the survival rate of patients with liver and pancreatic cancers has improved by only 10% in 30 years. Precision medicine offers a patient-centered approach, which, when combined with machine learning, could enhance decision making and treatment outcomes in surgical management of ihCC. This study aims to develop a decision support model to optimize treatment strategies for patients with ihCC, a prevalent primary liver cancer. Methods: The decision support model, named MedMax, was developed using three data sources: studies retrieved through a systematic literature review, expert opinions from HPB surgeons, and data from ihCC patients treated at Heidelberg University Hospital. Expert opinions were collected via surveys, with factors rated on a Likert scale, while patient data were used to validate the model’s accuracy. Results: The model is structured into four decision-making phases, assessing diagnosis, treatment modality, surgical approach, and prognosis. Prospectively, 44 patients with ihCC were included for internal primary validation of the model. MedMax could predict the appropriate treatment considering the resectability of the lesions in 100% of patients. Also, MedMax could predict a decent surgical approach in 77% of the patients. The model proved effective in making decisions regarding surgery and patient management, demonstrating its potential as a clinical decision support tool. Conclusions: MedMax offers a transparent, personalized approach to decision making in HPB surgery, particularly for ihCC patients. Initial results show high accuracy in treatment selection, and the model’s flexibility allows for future expansion to other liver tumors and HPB surgeries. Further validation with larger patient cohorts is required to enhance its clinical utility.

Cancers doi: 10.3390/cancers17010051

Authors: Benedikt Slusny Vanessa Zimmer Elena Nasiri Veronika Lutz Magdalena Huber Malte Buchholz Thomas M. Gress Katrin Roth Christian Bauer

Background: Most spheroid models use size measurements as a primary readout parameter; some models extend analysis to T cell infiltration or perform caspase activation assays. However, to our knowledge, T cell motility analysis is not regularly included as an endpoint in imaging studies on cancer spheroids. Methods: Here, we intend to demonstrate that motility analysis of macrophages and T cells is a valuable functional endpoint for studies on molecular interventions in the tumor microenvironment. In particular, T cell migration analysis represents the final step of effector function, as T cells engage with _targets cells upon cytotoxic interaction, which is represented by an arrest within the spheroid volume. Therefore, T cell arrest is a novel readout parameter of T cell effector function in spheroids. Results: Here, we demonstrate that incubation of macrophages with nigericin for NLRP3 activation increases T cell velocity, but results in decreased T cellular arrest. This is paralleled by reduced rejection kinetics of pancreatic cancer spheroids in the presence of antigen-dependent T cells and nigericin-treated macrophages. Our model demonstrates consistent changes in T cell motility upon coculturing of T cells and tumors cells with macrophages, including influences of molecular interventions such as NLRP3 activation. Conclusions: Motility analysis using a spheroid model of pancreatic cancer is a more sophisticated alternative to in vitro cytotoxicity assays measuring spheroid size. Ultimately, an optimized spheroid model might replace at least some aspects of animal experiments investigating T cell effector function.

Cancers doi: 10.3390/cancers17010050

Authors: Len De Nys Anita Barzegar-Fallah Katrien Lanckmans Stephane Steurbaut David Beckwée Amy de Haar-Holleman Steven Provyn Elke Gasthuys Sofie Vande Casteele Pieter-Jan De Sutter An Vermeulen Jan Van Bocxlaer Stephanie C. M. Wuyts Nele Adriaenssens

Background/Objectives: Paclitaxel (PTX), a commonly used chemotherapy for breast cancer (BC), is associated with dose-limiting toxicities (DLTs) such as peripheral neuropathy and neutropenia. These toxicities frequently lead to dose reductions, treatment delays, or therapy discontinuation, negatively affecting patients’ quality of life and clinical outcomes. Current dosing strategies based on body surface area (BSA) fail to account for individual variations in body composition (skeletal muscle mass (SMM) and adipose tissue (AT) mass) and physical activity (PA), which can influence drug metabolism and toxicity. This study aims to explore the relationships between PTX pharmacokinetics, body composition, and PA to predict DLTs. Methods: This single-group observational cohort study will recruit 40 female BC patients undergoing PTX treatment. Data collection will include plasma PTX concentrations, body composition assessments (using dual X-ray absorptiometry and bioelectrical impedance analysis), PA measurements (via accelerometers), and questionnaires to assess BC-related health-related quality of life, chemotherapy-induced peripheral neuropathy, and neutropenia during the PTX schedule using validated questionnaires. Dose-limiting toxicities will be graded according to the Common Terminology Criteria for Adverse Events v5.0 (grade 3 or higher). This protocol is designed to develop a population-based PK-PD model that predicts the occurrence of chemotherapy-induced peripheral neuropathy and neutropenia in women with stage II or III BC undergoing PTX therapy, focusing on explanatory outcomes related to SMM, AT mass, and PA.

Cancers doi: 10.3390/cancers17010049

Authors: Martine Berliere Fabienne Roelants François P. Duhoux Amandine Gerday Nathan Piette Camille Lacroix Marie-Agnes Docquier Vasiliki Samartzi Maude Coyette Jennifer Hammer Nassim Touil Houda Azzouzi Philippe Piette Christine Watremez

Background: Hypnosis sedation has recently been used for anesthesia in breast oncologic surgery. Methods: Between January 2017 and October 2019, 284 patients from our Breast Clinic (Cliniques Universitaires Saint-Luc, Université Catholique de Louvain) and from the Jolimont Hospital were prospectively included in an interventional non-randomized study approved by our two local ethics committees and registered on clinicaltrials.gov (NCT03330117). Ninety-three consecutive patients underwent surgery while on general anesthesia (GA group). Ninety-two consecutive patients underwent surgery while on general anesthesia preceded by a hypnorelaxation session (GAVRH group). Ninety-five consecutive patients underwent surgery while exclusively on hypnosis sedation (HYPS group). Clinical parameters (pain score, anxiety and distress score) were measured on days 0, 1 and 8 for all patients. All evaluable patients underwent NLR (neutrophil-to-lymphocyte ratio) and CRP (C-reactive protein) dosage on days 0, 1 and 8. Results: Pain scores and anxiety scores were statistically lower in the HYPS group on days 1 and 8, as was the duration of NSAID consumption. NLR and CRP values were significantly inferior on day 1 for all patients who benefited from hypnosis sedation. Conclusions: Some benefits of hypnosis sedation (reduction in postoperative pain, decrease in NSAID consumption) are correlated with a significant reduction in inflammatory parameters in the perioperative process.

Cancers doi: 10.3390/cancers17010048

Authors: Anusha Abdullah Jörg Kumbrink Paris Liokatis Andreas Mock Ahdiya Abdullah Ina Dewenter Katharina Theresa Obermeier

Skin cancer is one of the most prevalent malignancies in the world, with increasing incidence. In 2022, the World Health Organization estimated over 1.5 million new diagnoses of skin malignancies, primarily affecting the older population. Surgical excision, particularly in the head and neck area, can cause aesthetic deficits and significantly impair patients’ quality of life. There are limited therapeutic options for advanced skin malignancies, and the development of resistance to _targeted therapy further restricts treatment choices. Cancer metabolism may offer a novel approach to overcome these challenges. The pentose phosphate pathway, along with its rate-limiting enzyme, glucose-6-phosphate dehydrogenase, is essential for both the antioxidative response and the synthesis of ribonucleotides and may play a critical role in the proliferation and growth of cancer cells. This review examines current knowledge on the correlation between altered glucose-6-phosphate dehydrogenase expression and activity and skin cancer progression, with the aim of identifying a potential therapeutic _target for treating advanced skin cancer.

Cancers doi: 10.3390/cancers17010047

Authors: Roksana Duszkiewicz Janusz Strzelczyk Elżbieta Chełmecka Joanna Katarzyna Strzelczyk

Introduction: Neuroendocrine tumors are a diverse group of tumors predominantly found in the gastrointestinal tract or respiratory system. Methods: This retrospective study aimed to measure the serum concentrations of LRP6 (low-density lipoprotein receptor-related protein 6), SFRP3 (secreted frizzled-related protein 3), and DVL1 (segment polarity protein dishevelled homolog) using the ELISA method in patients with NETs (N = 80) and a control group (N = 62). We evaluated the results against various demographic, clinicopathological, and biochemical characteristics. Results: Our analyses revealed that the concentration of SFRP3 in patients with neuroendocrine tumors was significantly elevated (p < 0.001) compared to the control group. Additionally, DVL1 concentrations were significantly higher (p < 0.01) in patients with BP-NETs compared to GEP-NETs. Furthermore, DVL1 analysis showed a moderate negative correlation with chromogranin A (p < 0.001) and weak negative correlations with serotonin (p < 0.05) and 5-HIAA (p < 0.05). Significant negative correlations were also observed between DVL1 and age in the control group (p < 0.01), and between LRP6 and Ki-67 in the study group. Conclusions: These results suggest that changes in the SFRP3 and DVL1 pathways play a key role in NET development. Elevated levels of these proteins highlight their importance in tumor biology, with SFRP3 and DVL1 potentially being crucial in NET molecular mechanisms. Further research is needed to explore their roles and potential in diagnosis and treatment.

Cancers doi: 10.3390/cancers17010046

Authors: Salih Tünbekici Haydar cagatay Yuksel Caner Acar Gökhan Sahin Seval Orman Nargiz Majidova Alper Coskun Mustafa Seyyar Mehmet sıddık Dilek Mahmut Kara Ahmet Kursat Dıslı Teyfik Demir Nagihan Kolkıran Mustafa Sahbazlar Erkut Demırcıler Fatih Kuş Ali Aytac Serkan Menekse Hakan Yucel Sedat Biter Tolga Koseci Ahmet Unsal Ahmet Ozveren Alper Sevınc Erdem Goker Pınar Gürsoy

Background/Objectives: In the REGOMA trial, regorafenib demonstrated an overall survival advantage over lomustine, and it has become a recommended treatment for recurrent glioblastoma in guidelines. This study aimed to evaluate the effectiveness and safety of regorafenib as a third-line treatment for patients with recurrent glioblastoma who progressed while taking bevacizumab-based therapy. Methods: This retrospective, multicenter study in Turkey included 65 patients treated between 2021 and 2023 across 19 oncology centers. The main inclusion criteria were histologically confirmed isocitrate dehydrogenase (IDH)-wildtype glioblastoma, progression after second-line bevacizumab-based treatment, and an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2. Patients received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. Results: The median age of the patients was 53 years (18–67 years), with a median progression-free survival of 2.5 months (95% Confidence Interval: 2.23–2.75) and a median overall survival of 4.1 months (95% CI: 3.52–4.68). The median overall survival was improved in patients who received subsequent therapy after regorafenib treatment compared with those who did not (p = 0.022). Progression-free survival was longer in patients with ECOG 0–1 than in those with ECOG 2 (p = 0.042). The safety profile was consistent with that of the REGOMA trial, with no drug-related deaths observed. Conclusions: Regorafenib shows good efficacy and safety as a third-line treatment for recurrent glioblastoma after bevacizumab-based therapy. This study supports the use of regorafenib and emphasizes the need for further randomized studies to validate its role and optimize treatment strategies.

Cancers doi: 10.3390/cancers17010045

Authors: Matthew J. Goldman Bin S. Teh Simon S. Lo E. Brian Butler David S. Baskin

Radiation has been used to treat meningiomas since the mid-1970s. Traditionally, radiation was reserved for patients unfit for major surgery or those with surgically inaccessible tumors. With an increased quantity and quality of imaging, and an aging population, there has been a rise in incidentally diagnosed meningiomas with smaller tumors at diagnosis time. Deciding if, how, and when to intervene must be determined on a case-by-case basis. Anatomical location and adjacent vital structures are crucial for decision-making. Prior review articles have detailed outcomes of radiosurgery in broad anatomical regions such as the skull base, but a recent deluge of research on increasingly specific anatomical subregions deserves attention. This narrative review synthesizes information regarding specific anatomical subregions, including anatomical challenges, radiosurgical outcomes, and unique considerations. Via MEDLINE and ascendancy search, we utilized evidence available for each anatomical region and herein discuss details of published research and explore future directions. Meningioma management remains individualized based on patient comorbidities, tumor location/characteristics, symptomatic burden, and patient age. In addition to stereotactic radiosurgery’s established role for surgically inaccessible, recurrent, and high-grade meningiomas, its use as upfront management for small asymptomatic meningiomas is increasingly investigated. For all subregions reported, radiosurgical intervention resulted in high tumor control rates and acceptably low adverse radiation events.

Cancers doi: 10.3390/cancers17010044

Authors: Akanksha Patel Aishwarya Saraswat Harsh Patel Zhe-Sheng Chen Ketan Patel

In the original publication [...]

Cancers doi: 10.3390/cancers17010043

Authors: Bukuru Dieu-Donne Nturubika Jessica Logan Ian R. D. Johnson Courtney Moore Ka Lok Li Jingying Tang Giang Lam Emma Parkinson-Lawrence Desmond B. Williams James Chakiris Madison Hindes Robert D. Brooks Mark A. Miles Stavros Selemidis Philip Gregory Roberto Weigert Lisa Butler Mark P. Ward David J. J. Waugh John J. O’Leary Douglas A. Brooks

Prostate cancer remains a significant global health concern, with over 1.4 million new cases diagnosed and more than 330,000 deaths each year. The primary clinical challenge that contributes to poor patient outcomes involves the failure to accurately predict and treat at the onset of metastasis, which remains an incurable stage of the disease. This review discusses the emerging paradigm that prostate cancer metastasis is driven by a dysregulation of critical molecular machinery that regulates endosome-lysosome homeostasis. Endosome and lysosome compartments have crucial roles in maintaining normal cellular function but are also involved in many hallmarks of cancer pathogenesis, including inflammation, immune response, nutrient sensing, metabolism, proliferation, signalling, and migration. Here we discuss new insight into how alterations in the complex network of trafficking machinery, responsible for the microtubule-based transport of endosomes and lysosomes, may be involved in prostate cancer progression. A better understanding of endosome-lysosome dynamics may facilitate the discovery of novel strategies to detect and manage prostate cancer metastasis and improve patient outcomes.

Cancers doi: 10.3390/cancers17010042

Authors: Arkadiusz Kacała Mateusz Dorochowicz Adrian Korbecki Michał Sobański Agata Zdanowicz-Ratajczak Dariusz Patrzałek Dariusz Janczak Maciej Guziński

Introduction: Giant hepatic hemangiomas are challenging to manage, requiring effective therapeutic approaches. Transarterial bleomycin–lipiodol embolization (TACE) has shown promise as a treatment option, yet predictive factors for its success are not well defined. This study aimed to assess the efficacy of TACE for giant hepatic hemangiomas and identify factors influencing treatment outcomes. Methods: A retrospective analysis of 31 adult patients who underwent TACE with bleomycin and lipiodol between December 2014 and October 2022 was conducted. Clinical parameters including age, sex, hemangioma location, lesion size, bleomycin dose, number of TACE sessions, and follow-up duration were evaluated. The primary outcome was hemangioma volume reduction, with statistical analyses identifying factors associated with significant lesion regression. Results: Higher bleomycin doses and longer intervals from procedure to follow-up were positively correlated with hemangioma volume reduction, while variables such as patient sex and lesion location showed no statistically significant impact on clinical success. The findings suggest that increased bleomycin dosage and extended follow-up periods may enhance treatment efficacy. Conclusions: The study identifies bleomycin dose and follow-up duration as predictive factors for TACE success in treating giant hepatic hemangiomas, underscoring their role in optimizing therapeutic strategies. These insights contribute to improved treatment personalization for patients with giant hepatic hemangiomas and highlight the need for further prospective studies to validate and expand upon these findings.

Cancers doi: 10.3390/cancers17010041

Authors: Yenpo Lin Khulan Khurelsukh I-Gung Li Chen-Te Wu Yi-Ming Wu Gigin Lin Cheng-Hong Toh Yung-Liang Wan

The affiliation for K [...]

Cancers doi: 10.3390/cancers17010040

Authors: Ivan Yanev Armen G. Aprikian Brendan L. Raizenne Alice Dragomir

Background/Objectives: Through phase III clinical trials, PARP inhibitors have demonstrated outcome improvements in mCRPC patients with alterations in BRCA1/2 genes who have progressed on a second-generation androgen receptor pathway inhibitor (ARPI). While improving outcomes, PARP inhibitors contribute to the ever-growing economic burden of PCa. The objective of this project is to evaluate the cost-effectiveness of PARP inhibitors (olaparib, rucaparib, or talazoparib) versus the SOC (docetaxel or androgen receptor pathway inhibitors (ARPI)) for previously progressed mCRPC patients with BRCA1/2 mutations from the Canadian healthcare system perspective. Methods: Partitioned survival models were created to represent mCRPC disease after progression until death. Survival inputs for BRCA1/2-mutated patients were extracted from the PROfound, TRITON3, and TALAPRO-1 clinical trials, while Canadian-specific costs are presented in 2023 dollars. Upon progression, patients were treated with chemotherapy. The considered time horizon was 5 years and outcomes were discounted at 1.5% per year. Results: PARP inhibitors provide an additional survival of 0.19 quality-adjusted life years (QALY) when compared to the current standard of care, with additional costs of CAD 101,679 resulting in an incremental cost-utility ratio (ICUR) of CAD 565,383/QALY. The results were most sensitive to PARP inhibitors’ acquisition costs and health-state utilities. PARP inhibitors required price reductions of up to 83% to meet the CAD 50,000/QALY willingness-to-pay threshold (WTP). Conclusions: While providing survival benefits to previously progressed mCRPC patients presenting deleterious BRCA1/2 gene mutations, PARP inhibitors are not cost-effective and require major price reductions to reach local WTP thresholds.

Cancers doi: 10.3390/cancers17010039

Authors: Răzvan Mihail Pleșea Anca-Lelia Riza Ana Maria Ahmet Ionuț Gavrilă Andreea Mituț Georgiana-Cristiana Camen Cristian Virgil Lungulescu Ștefania Dorobanțu Adina Barbu Andra Grigorescu Cecil Sorin Mirea Michael Schenker Florin Burada Ioana Streață

Background: Conditions associated with BRCA1/2 pathogenic (PVs) or likely pathogenic variants (LPVs) are often severe. The early detection of carrier status is ideal, as it provides options for effective case management. Materials and Methods: The study involved 58 patients with a personal and familial history of breast cancer (BC) who underwent genetic testing at the Regional Centre for Medical Genetics Dolj over a three-year period. An immunohistochemical panel (HER2, ER, PR, and Ki-67) was used to define the molecular subtypes of breast tumors. The AmpliSeq for Illumina BRCA Panel was used to evaluate germline variants in the BRCA1 and BRCA2 genes in patients with BC. The χ2 test and Fisher’s exact test were used to compare the different parameters studied. Results: Our findings revealed that 15.5% of the patients carried either BRCA1 or BRCA2 PVs or LPVs. BRCA1 carriers had aggressive tumors whereas BRCA2 carriers had rather low-grade tumors. Conclusions: The study revealed that PVs in both BRCA genes have a significant frequency among BC patients in our region, and BRCA1 carriers tend to develop more aggressive tumors than carriers of BRCA2 PVs and patients with no germline PVs in either of the two genes. These observations could provide new epidemiologic data for this disease in our region and contribute further to the development of national screening strategies.

Cancers doi: 10.3390/cancers17010038

Authors: João Casanova Alexandru Babiciu Gonçalo S. Duarte Ana Gomes da Costa Sofia Silvério Serra Teresa Costa Ana Catarino Mário M. Leitão Jorge Lima

Objective: Our primary objective was to evaluate the oncologic outcomes of patients with abnormal p53 FIGO grade 3 (high-grade) endometrioid endometrial cancer. As secondary objectives, we determined the global prevalence of abnormal p53 in grade 3 endometrioid endometrial carcinomas and the geographical variations. Methods: The following electronic databases were searched: PubMed/Medline, EMBASE, Cochrane Library, Scopus, and Web of Science. We followed the Meta-Analysis for Observational Studies in Epidemiology guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. This review was preregistered with PROSPERO (no: CRD42023495192). Bias was assessed using the Quality in Prognosis Studies tool. For time-to-event data, the effect of p53 status on grade 3 endometrial cancer was described using hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Overall survival and progression-free survival were analyzed using one- and two-stage approaches, the Kaplan–Meier method, and Cox proportional hazards models. Results: Fifty-seven studies with 2528 patients were included. Patients with abnormal p53 had an increased risk of death (HR, 1.29 (95% CI, 1.11–1.48); I2 = 88%) and disease progression (HR, 1.63; 95% CI, 1.42–1.88; I2 = 2%) compared with patients with wildtype p53 G3 endometrial cancer. The global pooled prevalence of abnormal p53 was 30% (95% CI, 25–34%; tau2 = 0.02; I2 = 74%), with the highest prevalence being found in studies conducted in Asia (95% CI, 27–41%; tau2 = 0.01; I2 = 52%). Conclusions: Abnormal p53 grade 3 endometrioid endometrial cancer is more common in Asia, and it is associated with decreased overall survival and progression-free survival.

Cancers doi: 10.3390/cancers17010037

Authors: Mustafa Murat Midik Damla Gunenc Pınar Fatma Acar Burcak Saziye Karaca

Background: Although immune checkpoint inhibitors (ICIs) have significantly improved cancer treatment, a substantial proportion of patients do not benefit from these therapies, revealing the crucial need to identify reliable biomarkers. Inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), pan-immune inflammation value (PIV), systemic inflammation response index (SIRI), lactate dehydrogenase (LDH), and C-reactive protein (CRP), may provide insights into treatment outcomes. Objectives: This study aimed to evaluate the prognostic value of multiple inflammatory markers in patients with cancer receiving ICI-based therapies. Methods: A retrospective analysis was performed on 226 patients treated with ICI-based therapies at a single center between 2012 and 2023. The inflammatory markers NLR, PIV, SII, SIRI, LDH, CRP, and albumin were assessed. Cut-off values were determined using maximally selected rank statistics, and overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan–Meier method and Cox regression analysis. Results: High NLR, PIV, SII, SIRI, LDH, and CRP, as well as low albumin levels, were associated with worse OS and PFS (p < 0.001). In the multivariate analysis, high CRP, LDH, NLR, PIV, and SII independently predicted worse OS. Conclusions: Our findings confirm the prognostic utility of several inflammatory biomarkers in patients with cancer receiving ICIs, highlighting their potential for treatment stratification. Further studies are necessary to standardize cut-off values and validate these findings across broader, more diverse populations.

Cancers doi: 10.3390/cancers17010036

Authors: Mario Leporace Ferdinando F. Calabria Roberto Siciliano Carlo Capalbo Dimitrios K. Filippiadis Roberto Iezzi

The growing interest in minimal and non-invasive therapies, especially in the field of cancer treatment, highlights a significant shift toward safer and more effective options. Ablative therapies are well-established tools in cancer treatment, with known effects including locoregional control, while their role as modulators of the systemic immune response against cancer is emerging. The HIFU developed with magnetic resonance imaging (MRI) guidance enables treatment precision, improves real-time procedural control, and ensures accurate outcome assessment. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) induces deep coagulation necrosis within an elliptical focal area, effectively encompassing the entire tumor site and allowing for highly _targeted radical ablation. The applications of MRgFUS in oncology are rapidly expanding, offering pain relief and curative treatment options for bone metastatic lesions. Additionally, the MRgFUS plays an effective role in _targeted optional therapies for early prostate and breast cancers. Emerging research also focuses on the potential uses in treating abdominal cancers and harnessing capabilities to stimulate immune responses against tumors or to facilitate the delivery of anticancer drugs. This evolving landscape presents exciting opportunities for improving patient outcomes and advancing cancer treatment methodologies. In neuro-oncology, MRgFUS utilizes low-intensity focused ultrasound (LIFU) along with intravenous microbubbles to open the blood-brain barrier (BBB) and enhance the intra-tumoral delivery of chemotherapy drugs.

Cancers doi: 10.3390/cancers17010035

Authors: Spencer M. Erickson Benjamin M. Manning Akhilesh Kumar Manish R. Patel

Thoracic malignancies (lung cancers and malignant pleural mesothelioma) are prevalent worldwide and are associated with high morbidity and mortality. Effective treatments are needed for patients with advanced disease. Cell therapies are a promising approach to the treatment of advanced cancers that make use of immune effector cells that have the ability to mediate antitumor immune responses. In this review, we discuss the prospect of chimeric antigen receptor-T (CAR-T) cells, natural killer (NK) cells, T cell receptor-engineered (TCR-T) cells, and tumor-infiltrating lymphocytes (TILs) as treatments for thoracic malignancies. CAR-T cells and TILs have proven successful in several hematologic cancers and advanced melanoma, respectively, but outside of melanoma, results have thus far been unsuccessful in most other solid tumors. NK cells and TCR-T cells are additional cell therapy platforms with their own unique advantages and challenges. Obstacles that must be overcome to develop effective cell therapy for these malignancies include selecting an appropriate _target antigen, combating immunosuppressive cells and signaling molecules present in the tumor microenvironment, persistence, and delivering a sufficient quantity of antitumor immune cells to the tumor. Induced pluripotent stem cells (iPSCs) offer great promise as a source for both NK and T cell-based therapies due to their unlimited expansion potential. Here, we review clinical trial data, as well as recent basic scientific advances that offer insight into how we may overcome these obstacles, and provide an overview of ongoing trials testing novel strategies to overcome these obstacles.

Cancers doi: 10.3390/cancers17010034

Authors: Giuseppe Corazzelli Sergio Corvino Valentina Cioffi Ciro Mastantuoni Maria Rosaria Scala Salvatore Di Colandrea Luigi Sigona Antonio Bocchetti Raffaele de Falco

Background: Although its validity has recently been questioned since its introduction, the Simpson grade has remained one of the most relevant factors in estimating the recurrence risk of intracranial meningiomas. This study aims to assess its role in spinal meningiomas through a retrospective analysis of a mono-institutional surgical series and literature meta-analysis. Methods: We conducted a systematic review and meta-analysis of the literature from 1980 to 2023, complemented by a mono-institutional series of 74 patients treated at “Santa Maria delle Grazie” hospital. Demographic, clinical, neuroradiological, pathological, surgical, and outcome data of case series were analyzed. For the meta-analysis, studies were selected based on predefined inclusion criteria, and a fixed-effects model was used to synthesize data due to assumed homogeneity among included studies. Statistical analyses included odds ratios (OR) for recurrence risk and assessment of publication bias using Peter’s test. Results: Mono-institutional sample included 74 patients, most of whom were women (85%) with a median age of 61.9 years. The thoracic spine was the most common tumor location (81%). Recurrences occurred in patients with Simpson grade II and III resections. The meta-analysis involved 2142 patients from 25 studies and revealed a significantly higher recurrence rate for Simpson grades III–V compared to grades I–II (OR 0.10; CI95 0.06–0.16). Additionally, Simpson grade II had a higher recurrence risk than grade I (OR 0.42; CI95 0.20–0.90). Conclusions: The Simpson grading remains a valid predictor of recurrence also for spinal meningiomas. Our findings revealed a significant increase in recurrence rate with higher Simpson grades. These results support the need to strive for Simpson grade I resection when feasible.

Cancers doi: 10.3390/cancers17010033

Authors: Lucy Pu Rajeev Dhupar Xin Meng

Background: Surgical resection remains the standard treatment for early-stage lung cancer. However, the recurrence rate after surgery is unacceptably high, ranging from 30% to 50%. Despite extensive efforts, accurately predicting the likelihood and timing of recurrence remains a significant challenge. This study aims to predict postoperative recurrence by identifying novel image biomarkers from preoperative chest CT scans. Methods: A cohort of 309 patients was selected from 512 non-small-cell lung cancer patients who underwent lung resection. Cox proportional hazards regression analysis was employed to identify risk factors associated with recurrence and was compared with machine learning (ML) methods for predictive performance. The goal is to improve the ability to predict the risk and time of recurrence in seemingly “cured” patients, enabling personalized surveillance strategies to minimize lung cancer recurrence. Results: The Cox hazards analyses identified surgical procedure, TNM staging, lymph node involvement, body composition, and tumor characteristics as significant determinants of recurrence risk, both for local/regional and distant recurrence, as well as recurrence-free survival (RFS) and overall survival (OS) (p < 0.05). ML models and Cox models exhibited comparable predictive performance, with an area under the receiver operative characteristic (ROC) curve (AUC) ranging from 0.75 to 0.77. Conclusions: These promising findings demonstrate the feasibility of predicting postoperative lung cancer recurrence and survival time using preoperative chest CT scans. However, further validation using larger, multisite cohort is necessary to ensure robustness and facilitate integration into clinical practice for improved cancer management.

Cancers doi: 10.3390/cancers17010032

Authors: Michele Salati Marco Andolfi Alberto Roncon Gian Marco Guiducci Francesco Xiumè Michela Tiberi Anna Chiara Nanto Sara Cingolani Eleonora Ricci Majed Refai

Objectives: The purpose of the present study was to verify if performance in the 6-min walking test (6MWT) during the preoperative evaluation phase is associated with the development of cardiopulmonary postoperative complications in patients who underwent uniportal VATS (U-VATS) for lung cancer. Methods: This retrospective, monocentric study included patients submitted to U-VATS anatomical lung resections (March 2022–December 2023). The patients were enrolled in a preoperative rehabilitation program carried out 15 days before surgery. The 6MWT was performed at counseling (T0) and after pre-habilitation (T1). Univariate analysis followed by logistic regression verified the association of baseline patients’ characteristics and performance in the 6MWT (meters walked during T0 and T1 and the difference between T1 and T0—T1-T0 variation) with postoperative cardiopulmonary complications (CPCs). Youde’s index was used to establish the optimal cut-offs for ergometric parameters significantly correlated with CPCs. Results: We enrolled 212 patients scheduled to undergo U-VATS lung resection (lobectomies: 177; bilobectomies: 2; segmentectomies: 33). Twenty-three (10.8%) patients developed CPCs. None of the baseline patients’ characteristics were associated with CPCs. Complicated patients showed more significant differences compared to non-complicated ones for meters walked during the 6MWT T1 (6MWT-T1-complicated: 450 vs. 6MWT-T1-non-complicated: 517; p: 0.01) and for variation-T1-T0 (variation-T1-T0-complicated: 4 m vs. variation-T1-T0-non-complicated: 20 m; p: 0.02). The best cut-offs for discriminating between patients with CPCs and those with uneventful courses were 458 m for 6MWT-T1 and 31 m for variation-T1-T0. After multivariate analysis, 6MWT-T1 < 458 m and variation-T1-T0 < 31 m were the unique parameters independently correlated with CPCs (p: 0.03 and p: 0.05, respectively). Conclusions: The 6MWT results (in particular, 6MWT-T1 < 458 m and variation-T1-T0 < 31 m) in the context of a pre-habilitation program are associated with the development of CPCs after U-VATS lung resection.

Cancers doi: 10.3390/cancers17010031

Authors: Iva Perić Boris Brkljačić Tade Tadić Kristian Jerković Krešimir Dolić Matija Borić Marija Ćavar

Objectives: This study aimed to investigate whether the apparent diffusion coefficient (ADC) maps values of breast lesions presenting as non-mass enhancement (NME) on MRI could predict benign or malignant pathohistological findings. Materials and Methods: This retrospective single-center study included 136 female patients with NME and corresponding ultrasound correlate and a subsequent ultrasound-guided core needle biopsy. The patients were subdivided into benign or malignant subgroups based on pathology reports, which served as the gold standard. Blinded to the pathological results, two radiologists independently measured the ADC values of the depicted NME using punctate, 10 mm and whole tumor regions of interest (ROIs) wherever applicable. The mean of all measurements was also analyzed and compared with the pathologic subdivision. Results: The sensitivity of whole tumor ROI in detecting benign NME is 91% compared to 74% for 10 mm ROI and 78% for punctate ROI. No significant differences in ADC values were observed when comparing fatty breast tissue and dense breast tissue. Conclusions: There were differences in ADC values between benign and malignant findings using all types of measurements, where the whole tumor ROI was the most sensitive.

Cancers doi: 10.3390/cancers17010030

Authors: Seong Uk Kang Seung-Joo Nam Oh Beom Kwon Inhyeok Yim Tae-Hoon Kim Na Young Yeo Myoung Nam Lim Woo Jin Kim Sang Won Park

Background/Objectives: Gastric cancer is a leading cause of cancer-related mortality, particularly in East Asia, with a notable burden in Republic of Korea. This study aimed to construct and develop machine learning models for the prediction of gastric cancer mortality and the identification of risk factors. Methods: All data were acquired from the Korean Clinical Data Utilization for Research Excellence by multiple medical centers in South Korea. A total of 23,717 gastric cancer patients were divided into two groups by cause of mortality (all-cause of 2664 and disease-specific of 1620) and investigated. We used comprehensive data integrating clinical, pathological, lifestyle, and socio-economic factors. Cox proportional hazards analysis was conducted to estimate hazard ratios for mortality. Five machine learning models (random forest, gradient boosting machine, XGBoost, light GBM, and cat boosting) were developed to predict mortality. The models were interpreted by SHAP, one of the explainable AI techniques. Results: For all-cause mortality, the gradient-boosting machine learning model demonstrated the highest performance with an AUC-ROC of 0.795. For disease-specific mortality, the light GBM model outperformed others, achieving an AUC-ROC of 0.867. Significant predictors included the AJCC7 stage, tumor size, lymph node count, and lifestyle factors such as smoking, drinking, and diabetes. Conclusions: This study underscores the importance of integrating both clinical and lifestyle data to enhance mortality prediction accuracy in gastric cancer patients. The findings highlight the need for personalized treatment approaches in the Korean population and emphasize the role of demographic-specific data in predictive modeling.

Cancers doi: 10.3390/cancers17010029

Authors: Joe Hasei Ryuichi Nakahara Yujiro Otsuka Yusuke Nakamura Kunihiro Ikuta Shuhei Osaki Tamiya Hironari Shinji Miwa Shusa Ohshika Shunji Nishimura Naoaki Kahara Aki Yoshida Tomohiro Fujiwara Eiji Nakata Toshiyuki Kunisada Toshifumi Ozaki

Background/Objectives: Developing high-performance artificial intelligence (AI) models for rare diseases is challenging owing to limited data availability. This study aimed to evaluate whether a novel three-class annotation method for preparing training data could enhance AI model performance in detecting osteosarcoma on plain radiographs compared to conventional single-class annotation. Methods: We developed two annotation methods for the same dataset of 468 osteosarcoma X-rays and 378 normal radiographs: a conventional single-class annotation (1C model) and a novel three-class annotation method (3C model) that separately labeled intramedullary, cortical, and extramedullary tumor components. Both models used identical U-Net-based architectures, differing only in their annotation approaches. Performance was evaluated using an independent validation dataset. Results: Although both models achieved high diagnostic accuracy (AUC: 0.99 vs. 0.98), the 3C model demonstrated superior operational characteristics. At a standardized cutoff value of 0.2, the 3C model maintained balanced performance (sensitivity: 93.28%, specificity: 92.21%), whereas the 1C model showed compromised specificity (83.58%) despite high sensitivity (98.88%). Notably, at the 25th percentile threshold, both models showed identical false-negative rates despite significantly different cutoff values (3C: 0.661 vs. 1C: 0.985), indicating the ability of the 3C model to maintain diagnostic accuracy at substantially lower thresholds. Conclusions: This study demonstrated that anatomically informed three-class annotation can enhance AI model performance for rare disease detection without requiring additional training data. The improved stability at lower thresholds suggests that thoughtful annotation strategies can optimize the AI model training, particularly in contexts where training data are limited.

Cancers doi: 10.3390/cancers17010028

Authors: Magdalini Kreouzi Nikolaos Theodorakis Georgios Feretzakis Evgenia Paxinou Aikaterini Sakagianni Dimitris Kalles Athanasios Anastasiou Vassilios S. Verykios Maria Nikolaou

Background/Objectives: Melanoma, an aggressive form of skin cancer, accounts for a significant proportion of skin-cancer-related deaths worldwide. Early and accurate differentiation between melanoma and benign melanocytic nevi is critical for improving survival rates but remains challenging because of diagnostic variability. Convolutional neural networks (CNNs) have shown promise in automating melanoma detection with accuracy comparable to expert dermatologists. This study evaluates and compares the performance of four CNN architectures—DenseNet121, ResNet50V2, NASNetMobile, and MobileNetV2—for the binary classification of dermoscopic images. Methods: A dataset of 8825 dermoscopic images from DermNet was standardized and divided into training (80%), validation (10%), and testing (10%) subsets. Image augmentation techniques were applied to enhance model generalizability. The CNN architectures were pre-trained on ImageNet and customized for binary classification. Models were trained using the Adam optimizer and evaluated based on accuracy, area under the receiver operating characteristic curve (AUC-ROC), inference time, and model size. The statistical significance of the differences was assessed using McNemar’s test. Results: DenseNet121 achieved the highest accuracy (92.30%) and an AUC of 0.951, while ResNet50V2 recorded the highest AUC (0.957). MobileNetV2 combined efficiency with competitive performance, achieving a 92.19% accuracy, the smallest model size (9.89 MB), and the fastest inference time (23.46 ms). NASNetMobile, despite its compact size, had a slower inference time (108.67 ms), and slightly lower accuracy (90.94%). Performance differences among the models were statistically significant (p < 0.0001). Conclusions: DenseNet121 demonstrated a superior diagnostic performance, while MobileNetV2 provided the most efficient solution for deployment in resource-constrained settings. The CNNs show substantial potential for improving melanoma detection in clinical and mobile applications.

Cancers doi: 10.3390/cancers17010027

Authors: Silvia Strocchi Giacomo Santandrea Eleonora Zanetti Giulio Verna Vincenza Ylenia Cusenza Davide Nicoli Valentina Fantini Alessandra Grieco Massimiliano Paci Alessia Ciarrocchi Valentina Sancisi

Background/Objectives: Despite the introduction of innovative therapeutics, lung cancer is still the leading cause of cancer-related death. For this reason, lung cancer still requires deep characterization to identify cellular and molecular _targets that can be used to develop novel therapeutic strategies. Three-dimensional cellular models, including patient-derived organoids (PDOs), represent useful tools to study lung cancer biology and may be employed in the future as predictive tools in therapeutic decisions. However, the successful establishment of lung cancer organoids cultures that faithfully represent the respective patient tissues is still challenging due to low success rate and/or overgrowth of normal airway epithelial cells. Methods: We set up a two-step protocol that allows for establishing both short-term and long-term 3D cultures, with different characteristics and success rates. Results: Cancer tissue-originated spheroids (CTOSs) show a 100% success rate and allow for the concomitant isolation of autologous tumor infiltrating leukocytes (TILs). On the contrary, PDOs can be expanded for a medium-long term and bio-banked but retain a lower success rate and the possibility of contamination with normal airway epithelial cells. To overcome these problems, we set up an optimal medium formulation and we implemented rigorous quality controls, leading to a substantial improvement in the success rate of tumoral PDO establishment. Conclusions: Overall, this protocol guarantees flexibility and reliability, also providing useful guidelines for quality control checks to support different experimental settings. The setting up of a robust protocol for lung cancer PDO culture establishment and expansion is a key requirement for their employment both in cancer research and as predictive tools in clinical practice.

Cancers doi: 10.3390/cancers17010025

Authors: Mohammad H. Hussein Eman Toraih Jessan A. Jishu Tessa Lavorgna Ahmed Abdelmaksoud Ryan Craig Emad Kandil

Background: Radioactive iodine (RAI) ablation therapy is a common minimally invasive treatment for patients diagnosed with differentiated thyroid cancer (DTC). Although previous studies have identified a link between RAI and the mortality from secondary solid cancers, the connection between RAI and leukemia remains under-researched. This study investigated the differential risk of leukemia and its subtypes in DTC patients following RAI treatment. Methods: DTC patients from the Surveillance, Epidemiology, and End Results (SEER) Registry 17 (2000–2019) were analyzed. The standard incidence ratio (SIR) and excess risk (ER) compared to the reference population were calculated. Results: Out of 196,569 DTC patients, 1381 patients developed various types of hematological malignancies. Leukemia was diagnosed in 508 of these patients, and it had the highest risk among the malignancies studied, with an SIR of 1.74 (95%CI: 1.59–1.9). The RAI group had an SIR of 2.12 (95%CI: 1.87–2.39), while the non-RAI group had an SIR was 1.45 (95%CI: 1.37–1.52) (p < 0.001). Those diagnosed before the age of 55 years had a conspicuously elevated risk (SIR 2.74) compared to those diagnosed at 55 years or older (SIR 1.53). American Indian/Alaska Native survivors manifested a pronounced leukemia risk with an SIR of 7.63 (95%CI: 2.46–17.8). Conclusions: RAI treatment increased the risk of developing leukemia when serving as adjuvant therapy in surgical patients (SIR 2.12). There exists a significant association between RAI treatment in DTC patients and the incidence of leukemia. This susceptibility seems to be modulated by factors including time since diagnosis, age, gender, and racial background.

Cancers doi: 10.3390/cancers17010026

Authors: Sandra Viridiana Salgado-Hernández Lucero Martínez-Retamoza Rodolfo Ocadiz-Delgado Salvador Pérez-Mora Gladys Edith Cedeño-Arboleda María del Consuelo Gómez-García Patricio Gariglio David Guillermo Pérez-Ishiwara

Prostate pathologies, including chronic prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa), are strongly associated with chronic inflammation, which is a key risk factor and hallmark of these diseases [...]

Cancers doi: 10.3390/cancers17010024

Authors: Tzu-Rong Peng Chao-Chuan Wu Jong-Kai Hsiao Yi-Chun Chou Yuan-Ling Liao Yen-Chih Chen Pei-Jung Shao Ta-Wei Wu Ching-Sheng Hsu

Background: Muscle depletion (MD) is a critical factor that influences clinical outcomes in patients with hepatocellular carcinoma (HCC). Although its role in cancer prognosis is recognized, its integration into widely used prognostic systems remains underexplored. This study aimed to evaluate the prognostic impact of MD on overall survival (OS) in HCC patients and to improve existing noninvasive prognostic models by incorporating MD-related metrics. Methods: A retrospective analysis was conducted on 1072 HCC patients treated at Taipei Tzu Chi Hospital between January 2006 and December 2016. All patients had follow-up data and computed tomography (CT) scans at vertebral level L3 for MD evaluation. Independent prognostic factors for OS were identified using Cox proportional hazards models, and the predictive performance of various prognostic models was assessed through the area under the receiver operating characteristic curve (AUROC). Results: The key independent predictors of OS in HCC patients included hepatitis B virus infection, hepatitis C virus infection, liver cirrhosis, tumor size, serum alpha-fetoprotein levels, and MD-related metrics (psoas muscle-to-spine ratio, psoas muscle-to-vertebral ratio, and myosteatosis). Among existing models, the Barcelona Clinic Liver Cancer (BCLC) stage, the Child–Turcotte–Pugh (CTP) class, and the albumin–bilirubin (ALBI) grade demonstrated robust predictive performance for OS. However, incorporating MD significantly improved the predictive accuracy of these models, with the MD–BCLC model showing the highest AUROC (0.804, 95% CI: 0.777–0.832, p < 0.001). Conclusions: MD is an independent and significant prognostic predictor for patients with HCC. Integrating MD metrics into established systems, particularly the BCLC staging system, markedly improves OS prediction, providing a more comprehensive tool for clinical decision-making in the management of HCC.

Cancers doi: 10.3390/cancers17010023

Authors: Felix J. M. Schoonhoven Johanna W. M. Aarts Guus Fons Lukas J. A. Stalpers Luc R. C. W. van Lonkhuijzen Jacobus van der Velden Constantijne H. Mom

Background: Guidelines recommend the extension of the pelvic radiotherapy volume to the para-aortic region in locally advanced cervical cancer and ≥3 suspicious pelvic lymph nodes (PLN) on imaging. Whether this recommendation is also valid for clinically early stages is uncertain. The objective of this study was to investigate the para-aortic (PAO) lymph node recurrence rate in patients with early-stage cervical cancer, ≥3 metastatic PLN, and negative common iliac nodes after a radical hysterectomy followed by pelvic (chemo)radiotherapy without extension to the PAO region. Methods: Consecutive patients, surgically treated between 2000 and 2020, with FIGO 2009 stage IB2-IIA1 and positive PLN, were included in this retrospective cohort study. The frequency of PAO recurrences, disease-free survival, and overall survival were analyzed in patients with <3 versus ≥3 positive PLN. Results: In 127 patients, the isolated PAO recurrence rate was 2/88 (2.3%) versus 1/39 (2.6%) for patients with <3 versus ≥3 positive PLNs, respectively (p = 0.671). The 5-year disease-free survival (87.3% versus 73.7%; p = 0.088) and the overall survival (90.7% versus 76.5%; p = 0.355) between patients with <3 versus ≥3 positive PLN was not significantly different. Conclusions: Isolated PAO nodal recurrence rate in women with early-stage cervical cancer after radical hysterectomy and pelvic lymphadenectomy, with positive PLN but negative common iliac nodes, followed by pelvic (chemo)radiotherapy, is low and did not differ between the groups with <3 versus ≥3 positive PLN. This makes it unlikely that the inclusion of the PAO region in the adjuvant radiotherapy volume would result in a better oncological outcome.

Cancers doi: 10.3390/cancers17010022

Authors: Jie-Zeng Yu Zsofia Kiss Weijie Ma Ruqiang Liang Tianhong Li

Patient-centered precision oncology strives to deliver individualized cancer care. In lung cancer, preclinical models and technological innovations have become critical in advancing this approach. Preclinical models enable deeper insights into tumor biology and enhance the selection of appropriate systemic therapies across chemotherapy, _targeted therapies, immunotherapies, antibody–drug conjugates, and emerging investigational treatments. While traditional human lung cancer cell lines offer a basic framework for cancer research, they often lack the tumor heterogeneity and intricate tumor–stromal interactions necessary to accurately predict patient-specific clinical outcomes. Patient-derived xenografts (PDXs), however, retain the original tumor’s histopathology and genetic features, providing a more reliable model for predicting responses to systemic therapeutics, especially molecularly _targeted therapies. For studying immunotherapies and antibody–drug conjugates, humanized PDX mouse models, syngeneic mouse models, and genetically engineered mouse models (GEMMs) are increasingly utilized. Despite their value, these in vivo models are costly, labor-intensive, and time-consuming. Recently, patient-derived lung cancer organoids (LCOs) have emerged as a promising in vitro tool for functional precision oncology studies. These LCOs demonstrate high success rates in growth and maintenance, accurately represent the histology and genomics of the original tumors and exhibit strong correlations with clinical treatment responses. Further supported by advancements in imaging, spatial and single-cell transcriptomics, proteomics, and artificial intelligence, these preclinical models are reshaping the landscape of drug development and functional precision lung cancer research. This integrated approach holds the potential to deliver increasingly accurate, personalized treatment strategies, ultimately enhancing patient outcomes in lung cancer.

Cancers doi: 10.3390/cancers17010021

Authors: Toshimi Chiba Airi Ota Taifu Hirano Tadashi Kawai Atsushi Ogawa Hiroyuki Yamada

Narrow band imaging (NBI) magnification endoscopy for the diagnosis of early-stage oral cavity-related cancer and precancerous lesions can recognize oral lesions as brownish areas, and can observe intraepithelial papillary capillary loops (IPCLs) in the mucosa and submucosa to make a qualitative diagnosis of the lesion and highlight the mucosal surface microstructure to facilitate appropriate diagnosis and early treatment. IPCLs are classified from Type 0 to IV: Type 0 is normal mucosa or no blood vessels observed, e.g., in keratinization; Type I is mainly normal mucosa; Type II is mainly inflammatory sites or non-malignant lesions; Type III is mainly precancerous or suspected malignant lesions; and Type IV is cancerous or malignant lesions. NBI magnification endoscopy is a useful noninvasive method for identifying the malignant transformation of oral potentially malignant disorders (OPMDs). Oral lesions classified as IPCL Type II or higher are atypical epithelial or oral squamous cell carcinoma (OSCC); oral biopsy is recommended for early and accurate diagnosis, and is an indicator of the appropriate biopsy site in the follow-up for OPMDs. In the future, the accuracy of NBI magnification endoscopy for malignant transformation of OPMDs and OSCC will be further confirmed.

Cancers doi: 10.3390/cancers17010020

Authors: Valerio Santarelli Dalila Carino Roberta Corvino Stefano Salciccia Ettore De Berardinis Wojciech Krajewski Łukasz Nowak Jan Łaszkiewicz Tomasz Szydełko Rajesh Nair Muhammad Shamim Khan Ramesh Thurairaja Mohamed Gad Benjamin I. Chung Alessandro Sciarra Francesco Del Giudice

Background/Objectives: Robot-assisted radical prostatectomy (RARP) for the treatment of prostate cancer (PCa) has been standardized over the last 20 years. At our institution, only n = 3 rob arms are used for RARP. In addition, n = 2, 12 mm lap trocars are placed for the bedside assistant symmetrically at the midclavicular lines, which allows for direct pelvic triangulation and greater involvement of the assisting surgeon. The aim of our study was to compare surgical and perioperative outcomes of RARP performed using our alternative trocar placement with no fourth robotic arm in the subgroups of experienced attending surgeons and post-graduate residents as bedside assistants. Residents’ satisfaction was also explored. Methods: RARPs performed within the urology residency program between 2019 and 2024 were retrospectively analyzed. Only rob procedures performed using our 3+2 trocars configuration were included. Intra- and postoperative outcomes, as well as long-term functional outcomes including continence recovery and potency, were assessed, stratified by the level of expertise of the bedside assistant, i.e., an experienced attending or post-graduate Year I–III resident. Satisfaction of residents assigned to the two groups during their robotic rotation was evaluated considering three domains with a score from 1 to 10: insight into surgical procedure, confidence level, and gratification level. Results: Out of n = 281 RARP procedures, the bedside assistant was an attending in 104 cases and a resident in 177. Operative time was found to be slightly longer in cases where the second operator was a resident (attendings vs. residents: 134 ± 40 vs. 152 ± 24; p < 0.001). Postoperative hospitalization time was longer in patients in the resident group (attendings vs. residents: 3.9 ± 1.6 vs. 4.3 ± 1 days; p = 0.025). However, cases where the second operator was a resident had a lower rate of positive surgical margins, with rates of 19.7% in the resident and 43.3% in the attending surgeon cohorts (OR = 0.32; 95% CI 0.18–0.55). This difference remained significant in multivariate analysis. There was no significant difference in postoperative blood transfusion rates (attendings vs. residents: 1.9% vs. 1.2%; p = 0.6). Similarly, long-term functional outcomes in terms of erectile dysfunction and urinary incontinence rates mostly overlapped between groups. The mean score in all three domains evaluating residents’ satisfaction was significantly higher when residents actively participated in the surgical procedure as bedside assistants (p = 0.02, p = 0.004, and p < 0.001, respectively, for insights into surgical procedure, confidence level, and gratification level). Conclusions: These findings provide insight into how an alternative port positioning during RARP could improve the involvement of the bedside assistant, particularly residents, without compromising perioperative outcomes or surgical safety.

Cancers doi: 10.3390/cancers17010019

Authors: Adam Merenstein Loiy Obeidat Apostolos Zaravinos Benjamin Bonavida

The treatment of cancers with immunotherapies has yielded significant milestones in recent years. Amongst these immunotherapeutic strategies, the FDA has approved several checkpoint inhibitors (CPIs), primarily Anti-Programmed Death-1 (PD-1) and Programmed Death Ligand-1/2 (PDL-1/2) monoclonal antibodies, in the treatment of various cancers unresponsive to immune therapeutics. Such treatments resulted in significant clinical responses and the prolongation of survival in a subset of patients. However, not all patients responded to CPIs, due to various mechanisms of immune resistance. One such mechanism is that, in addition to PD-1 expression on CD8 T cells, other inhibitory receptors exist, such as Lymphocyte Activation Gene 3 (LAG-3), T cell Immunoglobulin Mucin 3 (TIM3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors might be active in the presence of the above approved CPIs. Clearly, it is clinically challenging to block all such inhibitory receptors simultaneously using conventional antibodies. To circumvent this difficulty, we sought to _target a potential transcription factor that may be involved in the molecular regulation of more than one inhibitory receptor. The transcription factor Yin Yang1 (YY1) was found to regulate the expression of PD-1, LAG-3, and TIM3. Therefore, we hypothesized that _targeting YY1 in CD8 T cells should inhibit the expression of these receptors and, thus, prevent the inactivation of the anti-tumor CD8 T cells by these receptors, by corresponding ligands to tumor cells. This strategy should result in the prevention of immune evasion, leading to the inhibition of tumor growth. In addition, this strategy will be particularly effective in a subset of cancer patients who were unresponsive to approved CPIs. In this review, we discuss the regulation of LAG-3 by YY1 as proof of principle for the potential use of _targeting YY1 as an alternative therapeutic approach to preventing the immune evasion of cancer. We present findings on the molecular regulations of both YY1 and LAG-3 expressions, the direct regulation of LAG-3 by YY1, the various approaches to _targeting YY1 to evade immune evasion, and their clinical challenges. We also present bioinformatic analyses demonstrating the overexpression of LAG-3, YY1, and PD-L1 in various cancers, their associations with immune infiltrates, and the fact that when LAG-3 is hypermethylated in its promoter region it correlates with a better overall survival. Hence, _targeting YY1 in CD8 T cells will result in restoring the anti-tumor immune response and tumor regression. Notably, in addition to the beneficial effects of _targeting YY1 in CD8 T cells to inhibit the expression of inhibitory receptors, we also suggest _targeting YY1 overexpressed in the tumor cells, which will also inhibit PD-L1 expression and other YY1-associated pro-tumorigenic activities.

Cancers doi: 10.3390/cancers17010017

Authors: Kumari Alka Jacob F. Oyeniyi Ghulam Mohammad Yi Zhao Stephen Marcus Prakash Chinnaiyan

Pancreatic cancer is the third leading cause of cancer-related mortality in the United States, with rising incidence and mortality. The receptor for advanced glycation end products (RAGE) and its ligands significantly contribute to pancreatic cancer progression by enhancing cell proliferation, fostering treatment resistance, and promoting a pro-tumor microenvironment via activation of the nuclear factor-kappa B (NF-κB) signaling pathways. This study validated pathway activation in human pancreatic cancer and evaluated the therapeutic efficacy of TTP488 (Azeliragon), a small-molecule RAGE inhibitor, alone and in combination with radiation therapy (RT) in preclinical models of pancreatic cancer. Human (Panc1) and murine (Pan02) pancreatic cancer cell lines exhibited elevated levels of RAGE and its ligands compared to normal pancreatic tissue. In vitro, Azeliragon inhibited RAGE-mediated NF-κB activation and ligand-mediated cell proliferation in pancreatic cancer cell lines. _target engagement of Azeliragon was confirmed in vivo, as determined by decreased NF-κB activation. Azeliragon demonstrated significant growth delay in mouse models of pancreatic cancer and additive effects when combined with RT. Additionally, Azeliragon modulated the immune suppressive tumor microenvironment in pancreatic cancer by reducing immunosuppressive cells, including M2 macrophages, regulatory T cells, and myeloid-derived suppressor cells, while enhancing CD8+ T cell infiltration. These findings suggest that Azeliragon, by inhibiting RAGE-mediated signaling and modulating immune response, may serve as an effective anti-cancer agent in pancreatic cancer.

Cancers doi: 10.3390/cancers17010018

Authors: Daniel J. Landsburg

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) and high-grade B cell lymphoma (HGBL) comprise the majority of large B-cell lymphomas (LBCL), and approximately two-thirds of patients diagnosed with these LBCLs are cured following treatment with first-line immunochemotherapy. While the International Prognostic Index (IPI) score is a validated prognostic tool used for patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), there is a growing body of evidence that suggests that LBCL tumor features, which can be detected by clinical laboratory testing, can predict patient survival following first-line immunochemotherapy. Conclusions: Clinical laboratory testing may also allow for rational identification of _targeted agents that can be added to first-line immunochemotherapy for high-risk, pathologically defined subsets of LBCL patients, and this approach may result in better survival outcomes for the entire LBCL patient population as compared with adding pathologically “agnostic” agents for those defined as high risk by IPI score.

Cancers doi: 10.3390/cancers17010016

Authors: Liu Liu Stephanie L. Graff Yihong Wang

In hormone receptor-positive and HER2-negative breast cancers, a growing number of revolutionary personalized therapies are in clinical use or trials, such as CDK4/6 inhibitors, immune checkpoint inhibitors, and PIK3CA inhibitors. Those treatment options are largely driven by the presence or absence of genomic alterations in the tumor. Therefore, molecular profiling is often performed during disease progression. The most encountered genomic alterations are in the PI3K/AKT/mTOR/PTEN pathway. This review discusses the genetic alterations associated with the PI3K/AKT/mTOR/PTEN pathway to help clinicians understand drug selection, resistance, or interaction from a molecular pathologist’s perspective.

Cancers doi: 10.3390/cancers17010015

Authors: Irene Salazar-Saura María Pinilla-Sala Javier Megías Lara Navarro Esther Roselló-Sastre Teresa San-Miguel

Glioblastoma IDH wild type (GB), the most common malignant primary brain tumor, is characterized by rapid proliferation, extensive infiltration into surrounding brain tissue, and significant resistance to current therapies. Median survival is only 15 months despite extensive clinical efforts. The tumor microenvironment (TME) in GB is highly specialized, supporting the tumor’s aggressive behavior and its ability to evade conventional treatments. One critical component is the aberrant vascular network that complicates the delivery of chemotherapy across the blood–brain barrier. Antiangiogenic therapies emerged as a promising option but have shown limited efficacy in extending the survival of these patients. Comprehension of the complex vascular network of GB may be a key to overcoming the limitations of current therapies. Pericytes are gaining recognition within the context of the TME. These mural cells are essential for vascular integrity and may contribute to tumor progression and therapeutic resistance. Although their role has been evidenced in other tumors, they remain underexplored in GB. Pericytes are known to respond to tumor hypoxia and interact with vascular endothelia, influencing responses to DNA damage and antiangiogenic treatments. They actively regulate not only angiogenesis but also the different vasculogenic strategies for tumor neovascularization. Additionally, they affect leukocyte trafficking and tumor-associated macrophages. This review aims to integrate the various functions controlled by pericytes to favor deeper investigation into their actionable potential. Pericytes may represent a promising _target for novel therapeutic strategies in order to improve patient outcomes.

Cancers doi: 10.3390/cancers17010014

Authors: Vittorio Rampinelli Davide Mattavelli Daniele Borsetto Robert Kennedy Marco Ferrari Mattia Savardi Alberto Deganello Piero Nicolai Francesco Doglietto Cesare Piazza Alberto Signoroni

Background/Objectives Successful surgical outcomes in head and neck cancer depend on the accurate identification of resection margins. Effective communication between surgeons and pathologists is critical, but is often jeopardised by challenges in sampling and orienting anatomically complex specimens. This pilot study aims to evaluate the use of 3D scanning of surgical specimens as a tool to improve communication and optimise the pathology sampling process. Methods Two structured light 3D scanners, Cronos Dual and Optor Lab, were used to acquire 3D models of anatomical specimens in both preclinical (cadaver specimens) and clinical contexts (fresh surgical specimens). Surgical margins and critical points were annotated on the digital models. Acquisition quality, operating times and subjective feedback from surgeons and pathologists were evaluated. Results The Optor Lab scanner demonstrated superior image quality, shorter processing times and a more user-friendly interface than the Cronos Dual. Key challenges identified included specimen geometry, surface reflectivity and tissue stability. Feedback from both surgeons and pathologists was positive, highlighting the potential of 3D models to improve the surgical-pathology workflow. Conclusions 3D scanning of surgical specimens provides accurate, detailed digital models that can significantly enhance communication between surgeons and pathologists. This technology shows promise in improving pathological staging and clinical decision making, with further studies required to validate its integration into routine practice.

Cancers doi: 10.3390/cancers17010013

Authors: Rixt S. Bruinsma Caroline W. M. Lekkerkerker Marta Fiocco Miranda P. Dierselhuis Karin P. S. Langenberg Godelieve A. M. Tytgat Max M. van Noesel Marc H. W. A. Wijnen Alida F. W. van der Steeg Ronald R. de Krijger

Background: The 5-year prognosis of non-high-risk neuroblastomas is generally good (>90%). However, a proportion of patients show progression and succumb to their disease. We aimed to identify molecular aberrations (not incorporated in the current risk stratification) associated with overall survival (OS) and/or event-free survival (EFS) in patients diagnosed with non-high-risk neuroblastoma. Methods: We conducted a systematic search in PubMed, Embase, Cochrane and Google Scholar. Two reviewers independently and blindly screened titles/abstracts, references of protocols/reviews and full texts. Risk of bias was assessed using a customized Quality in Prognostic Studies tool. Applicability was assessed using a tool designed by the researchers. GRADE criteria were used to determine quality of evidence. Results: Sixteen studies (4718 patients) were included. A segmental chromosomal aberration (SCA) profile was associated with lower survival. 1p loss of heterozygosity (LOH) and 17q gain were associated with lower OS and EFS. 1p deletion and 2p gain were associated with lower OS, but this was not the same for EFS. 3p deletion was not associated with worse outcome. Quality of evidence was downgraded because of imprecision and publication bias and upgraded because of moderate/large effect, resulting in a moderate quality of evidence. Conclusion: The association of 1p LOH, 1p deletion, 2p gain and 17q gain with OS and EFS suggests that these SCAs may be added to the risk stratification to identify non-high-risk neuroblastomas with worse prognosis.

Cancers doi: 10.3390/cancers17010012

Authors: Litika Vermani Alicja Wolk Annika Lindblom

Background: Antibiotics have recently been suggested to increase the risk of colorectal cancer. Here, we aimed to investigate the association of frequent antibiotic use and genetic susceptibility with the increased risk of the development of colorectal cancer. Therefore, a genome-wide association study was conducted in colorectal cancer patients with frequent antibiotic use and controls to identify potential chromosomal regions that could indicate an increased risk of colorectal cancer associated with antibiotic use. The results were replicated with a case-case analysis. Methods: A genome-wide case-control study involving 143 colorectal cancer cases with frequent exposure to antibiotics and 1642 healthy individuals with unknown antibiotic use was undertaken. A logistic regression model was used to identify associations between certain chromosomal regions (loci) and the risk of colorectal cancer in cases with frequent antibiotic use. The results were replicated in a follow-up association case-case study comparing the frequent users to those with a more modest use of antibiotics. Results: Six chromosomal regions were associated with colorectal cancer in patients exposed to frequent antibiotic use. Two of the six regions contained genes already suggested to be associated with colorectal cancer tumorigenesis, epithelial-mesenchymal transition and colorectal cancer recurrence. The results for the six chromosomal regions were further replicated in a case-case analysis where all the chromosomal regions were confirmed with high odds ratios (ORs) supporting the hypothesis that frequent antibiotic use is associated with an increased risk of colorectal cancer development. Conclusions: The study suggested that genetic modifiers could influence the risk of colorectal cancer associated with the frequent use of antibiotics.

Cancers doi: 10.3390/cancers17010011

Authors: Luca Nicosia Luciano Mariano Carmen Mallardi Adriana Sorce Samuele Frassoni Vincenzo Bagnardi Cristian Gialain Filippo Pesapane Claudia Sangalli Enrico Cassano

Background: Contrast-enhanced mammography (CEM) has recently gained recognition as an effective alternative to breast magnetic resonance imaging (MRI) for assessing breast lesions, offering both morphological and functional imaging capabilities. However, the phenomenon of background parenchymal enhancement (BPE) remains a critical consideration, as it can affect the interpretation of images by obscuring or mimicking lesions. While the impact of BPE has been well-documented in MRI, limited data are available regarding the factors influencing BPE in CEM and its relationship with breast cancer (BC) characteristics. Materials: This retrospective study included 116 patients with confirmed invasive BC who underwent CEM prior to biopsy and surgery. Data collected included patient age, breast density, receptor status, tumor grading, and the Ki-67 proliferation index. BPE was evaluated by two radiologists using the 2022 ACR BI-RADS lexicon for CEM. Statistical analyses were conducted to assess the relationship between BPE, patient demographics, and tumor characteristics. Results: The study found a significant association between higher levels of BPE and specific patient characteristics. In particular, increased BPE was more commonly observed in patients with higher breast density (p < 0.001) and those who were pre-menopausal (p = 0.029). Among patients categorized under density level B, the majority exhibited minimal BPE, while those in categories C and D showed progressively higher levels of BPE, indicating a clear trend correlating higher breast density with increased enhancement. Additionally, pre-menopausal patients demonstrated a higher likelihood of moderate to marked BPE compared to post-menopausal patients. Despite these significant associations, the analysis did not reveal a meaningful correlation between BPE intensity and tumor subtypes (p = 0.77) or tumor grade (p = 0.73). The inter-reader agreement for BPE assessment was substantial, as indicated by a weighted kappa of 0.78 (95% CI: 0.68–0.89), demonstrating consistent evaluation between radiologists. Conclusions: These findings suggest that BPE in CEM is influenced by factors like breast density and age, aligning with patterns observed in MRI studies. However, BPE intensity was not associated with tumor subtypes or grades, indicating a poorer prognosis. These insights highlight the potential of BPE as a risk biomarker in preventive follow-up, particularly for patients with high breast density and pre-menopausal status. Further multicentric and prospective studies are needed to validate these results and deepen the understanding of BPE’s role in CEM diagnostics.

Cancers doi: 10.3390/cancers17010010

Authors: Leonidas Mavroeidis Andrea Napolitano Paul Huang Robin L. Jones

There has been noteworthy progress in molecular characterisation and therapeutics in soft tissue sarcomas. Novel agents have gained regulatory approval by the FDA. Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab in alveolar soft part tissue sarcoma, the γ-secretase inhibitor nirogacestat in desmoid tumours, the NTRK inhibitors larotrectinib and entrectinib in tumours with NTRK fusions, the mTOR inhibitor nab-sirolimus in PEComa, and the EZH-2 inhibitor tazemetostat in epithelioid sarcoma. The FDA has also recently granted accelerated approval for autologous T-cell therapy with afami-cel in patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. There are other promising treatments that are still investigational, such as MDM2 and CDK4/6 inhibitors in well-/dedifferentiated liposarcoma, immune checkpoint inhibitors in the head and neck angiosarcoma and a subset of patients with undifferentiated pleomorphic sarcoma, and PARP inhibitors in leiomyosarcoma. The challenges in drug development in soft tissue sarcoma are due to the rarity and the molecular heterogeneity of the disease and the fact that many subtypes are associated with complex karyotypes or non-_targetable molecular alterations. We believe that progress maybe possible with a better understanding of the complex biology, the development of novel compounds for difficult _targets such as proteolysis _targeting chimeras (Protacs), the utilisation of modern clinical trial designs, and enhanced collaboration of academia with industry to develop treatments with a strong biologic rationale.

Cancers doi: 10.3390/cancers17010009

Authors: Michelle G. M. H. Florie Monse W. M. Wieland Walmari Pilz Rosanne Partoens Bjorn Winkens Ann Hoeben Nathalie Rommel Laura W. J. Baijens

Background: Head-and-neck cancer (HNC) can cause oropharyngeal dysphagia (OD). Early identification of OD in newly diagnosed HNC patients is important to better prepare patients for their cancer treatment trajectory. The aim of this study is (1) to assess the prevalence of OD in HNC patients within three weeks before the start of cancer treatment and (2) to investigate which demographic and oncological characteristics may be risk factors associated with the risk of OD at baseline. Methods: Patients (N = 225) completed the Eating Assessment Tool-10 (EAT-10) and Short Nutritional Assessment Questionnaire (SNAQ). Logistic regression analysis was conducted to examine the association between OD versus demographic and oncological characteristics. Results: A total of 21.3% (proportion 0.213; 95% CI 0.163–0.274) of the patients were at risk for OD. After correction for age, Charlson Comorbidity Index (CCI) grade, and primary tumor location, a significant association was found between advanced-stage cancer versus the risk of OD. Additionally, post hoc analysis revealed a significant association between the risk of malnutrition versus the risk of OD. Conclusions: Approximately one-fifth of all newly diagnosed HNC patients are at risk of OD, with advanced-stage cancer and malnutrition emerging as significant risk factors of OD. These findings empower health professionals toward more effective screening and management of a patient’s risk profile before the start of HNC treatment.

Cancers doi: 10.3390/cancers17010008

Authors: Joshua Zhi Chien Tan Zewen Zhang Hui Xuan Goh Joanne Ngeow

Background: Identifying patients with gBRCAm is crucial to facilitate screening strategies, preventive measures and the usage of _targeted therapeutics in their management. This review examines the evidence for the latest predictive and therapeutic approaches in BRCA-associated cancers. Clinical Description: Data supports the use of adjuvant olaparib in patients with gBRCAm high-risk HER2-negative breast cancer. In advanced gBRCAm HER2-negative breast cancer, the PARPis talazoparib and olaparib have demonstrated benefit over standard chemotherapy. In ovarian cancer, olaparib, niraparib or rucaparib can be used as monotherapy in frontline maintenance. Olaparib and bevacizumab as a combination can also be used as frontline maintenance. In the relapsed platinum-sensitive setting, olaparib, niraparib and rucaparib are effective maintenance options in BRCAm patients who are PARPi naive. Both olaparib and rucaparib are effective options in BRCAm metastatic castrate-resistant prostate cancer (mCRPC). Evidence also exists for the benefit of PARPi combinations in mCRPC. In metastatic pancreatic cancer, olaparib can be used in gBRCAm patients who are responding to platinum chemotherapy. However, there may be a development of PARPi resistance. Understanding the pathophysiology that contributes to such resistance may allow the development of novel therapeutics. Combination therapy appears to have promising results in emerging trials. Seeking avenues for subsidised genetic testing can reduce the total costs of cancer management, leading to improve detection rates. Conclusion: Identifying breast, ovarian, pancreatic and prostate cancer patients with gBRCAm plays a crucial predictive role in selecting those who will benefit significantly from PARPi therapy. The use of PARPi in gBRCAm HBOC-related cancers has resulted in significant survival benefits. Beyond BRCA1/2, HRR gene assessment and the consideration of other cancer predisposition syndromes may allow more patients to be eligible for and benefit from _targeted therapies.

Cancers doi: 10.3390/cancers17010007

Authors: Jack Kollmar Junmei Xu Diego Gonzalves Joseph A. Baur Lin Z. Li Julia Tchou He N. Xu

Background/Objectives: Cancer cells rely on metabolic reprogramming that is supported by altered mitochondrial redox status and an increased demand for NAD+. Over expression of Nampt, the rate-limiting enzyme of the NAD+ biosynthesis salvage pathway, is common in breast cancer cells, and more so in triple negative breast cancer (TNBC) cells. _targeting the salvage pathway has been pursued for cancer therapy. However, TNBC cells have heterogeneous responses to Nampt inhibition, which contributes to the diverse outcomes. There is a lack of imaging biomarkers to differentiate among TNBC cells under metabolic stress and identify which are responsive. We aimed to characterize and differentiate among a panel of TNBC cell lines under NAD-deficient stress and identify which subtypes are more dependent on the NAD salvage pathway. Methods: Optical redox imaging (ORI), a label-free live cell imaging microscopy technique was utilized to acquire intrinsic fluorescence intensities of NADH and FAD-containing flavoproteins (Fp) thus the mitochondrial redox ratio Fp/(NADH + Fp) in a panel of TNBC cell lines. Various fluorescence probes were then added to the cultures to image the mitochondrial ROS, mitochondrial membrane potential, mitochondrial mass, and cell number. Results: Various TNBC subtypes are sensitive to Nampt inhibition in a dose- and time-dependent manner, they have differential mitochondrial redox responses; furthermore, the mitochondrial redox indices linearly correlated with mitochondrial ROS induced by various doses of a Nampt inhibitor. Moreover, the changes in the redox indices correlated with growth inhibition. Additionally, the redox state was found fully recovered after removing the Nampt inhibitor. Conclusions: This study supports the utility of ORI in rapid metabolic phenotyping of TNBC cells under NAD-deficient stress to identify responsive cells and biomarkers of treatment response, facilitating combination therapy strategies.

Cancers doi: 10.3390/cancers17010005

Authors: Lilah Khoja Manar Zoulfikar Layla Hak Sabrina Yousif Manar Aljebori Matthew Stiffler Madiha Tariq Sarah Burgard Nancy L. Fleischer Lauren P. Wallner Celeste Leigh Pearce

Background: Understanding why Arab American women have lower adherence to cervical cancer screening compared to other racial/ethnic groups is important. The study aimed to understand attitudes and knowledge of cervical cancer prevention and HPV vaccination among Arab American women. Methods: A mixed-method approach was employed, including nine focus groups and an online questionnaire. Demographic characteristics, medical history, screening practices, and attitudes towards HPV vaccination and HPV self-sampling for cervical cancer screening were assessed. Results: Focus group participants (n = 22) demonstrated varying levels of knowledge about cervical cancer and HPV, including limited awareness of the Papanicolaou (Pap) test. Participants expressed mixed feelings about HPV self-sampling. Among questionnaire respondents (n = 25), who on average had a higher socioeconomic status than focus group participants, 73.9% had undergone a Pap test, with 94% up to date on screening. While 59% preferred self-sampling at home, almost two in five cited concerns about sample accuracy. Conclusions: Our study demonstrates the variability in attitudes and experiences towards cervical cancer screening among Arab American women, potentially driven by socioeconomic disparities. Our qualitative results suggest the need for _targeted, culturally tailored health education in the Arab American community. Further research should explore effective strategies to engage this underserved group and enhance adherence to prevention programs.