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Simple Summary: Acute myeloid leukemia (AML) arises from a stepwise acquisition of multiple genetic alterations in the hematopoietic stem and progenitor cell and is characterized by an accumulation of immature leukemic cells, called blasts, in the bone marrow and tissues. How the single gene alterations mediate the underlying processes is unclear in the majority of cases. IDH1/2 mutations are among the most frequent mutations in AML, accounting for about 15–20%, and are targets of specific small molecule inhibitors. Experimental evidence suggests that they occur early in leukemogenesis. Mostly, murine models of IDH1/2 mutations have been studied. Our study is the first to highlight that—in the human system—IDH1/2 mutants drive a complete block of hematopoietic cell differentiation in vitro, which is completely unleashed by the specific inhibitor, providing a model for early leukemogenesis studies in this setting. How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we study isocitrate dehydrogenase (IDH) gene mutations in the human model of HSPC and discuss the available literature on this topic. IDH1/2 mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on HSPCs, we expressed IDH1-R132H or IDH2-R140Q mutants into human CD34+ healthy donor cells via lentiviral transduction and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by specific inhibitors, confirming that it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed progressive and marked improvements in their fitness over time, in terms of CFU ability and propensity to differentiate. They attained clonal trilinear reconstitution of hematopoiesis and complete hematological remission. [ABSTRACT FROM AUTHOR]

Background: Despite advances in the management of head and neck squamous cell carcinoma (HNSCC), prognostic models and treatment strategies remain inadequate, particularly for HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). The rising incidence of HPV-positive OPSCC highlights an urgent need for innovative therapeutic approaches. Ferroptosis, a regulated form of non-apoptotic cell death, has gained attention for its role in cancer progression, but its potential as a prognostic and therapeutic target in HPV-positive OPSCC remains largely unexplored. This study investigates the role of ferroptosis in HPV-positive OPSCC, aiming to identify prognostic markers and provide insights into potential therapeutic strategies that could improve patient outcomes., Methods: Thirteen ferroptosis gene expression signatures were retrieved from the literature, and their performance and association to the immune microenvironment were validated on a meta-analysis of 267 HPV-positive cases (Metanalysis-HPV267) and 286 samples from the BD2Decide project (BD2-HPV286)., Results: Our analysis revealed that specific ferroptosis-related gene expression signatures, particularly FER3, FER4, FER6, and FER12, are significantly associated ( p -value < 0.05) with high-risk patient groups and adverse tumor microenvironment features, including suppressed immune activity and enhanced stromal involvement. Elevated expression of CAV1, a ferroptosis suppressor, further delineates high-risk profiles., Conclusions: These findings highlight the prognostic significance of ferroptosis in stratifying patients and identifying those with poorer clinical outcomes. Targeting ferroptosis pathways represents a novel and promising approach to addressing the unmet need for effective prognostic and therapeutic strategies in HPV-positive OPSCC. Future research should focus on translating these findings into clinical applications to advance precision oncology and improve outcomes for this growing patient population.

Background and Objectives: Robotic-assisted laparoscopy (RS) has been widely adopted for the management of endometrial cancer (EC) due to favorable perioperative outcomes, especially in the context of obesity, which is an established risk factor for EC. This study retrospectively evaluated the perioperative outcomes of RS versus conventional laparoscopy (LS) in treating EC and atypical endometrial hyperplasia (AH)., Methods: Between November 2021 and October 2023, 138 patients with AH or EC underwent surgery at the Clinic of Obstetric and Gynecological-Azienda Sanitaria Universitaria Friuli Centrale, Udine. All patients had total hysterectomy with bilateral salpingo-oophorectomy, with or without lymphadenectomy or sentinel lymph node biopsy. The study included 62 patients treated with LS and 62 with RS., Results: The median BMI was higher in the RS group (35.5 vs. 24 kg/m 2 , p = 0.001). There was no significant difference in operative time between the laparoscopic group and the robotic console time (median 130 vs. 130 min, p = 0.131). No significant differences were found in terms of blood loss, conversion to laparotomy, intraoperative complications, hospital stay, or early postoperative complications between the two groups., Conclusions: Our data confirm the feasibility of robotic surgery in obese patients, allowing surgical results comparable to those of laparoscopy in normal-weight patients.

Background: Liver resection is the standard treatment for resectable hepatocellular carcinoma (HCC). The advent of robotic surgery has extended its application in liver surgery, reducing post-operative complications without compromising oncological safety. This study is a retrospective series with the aim of analyzing the preoperative patient's and tumor's characteristics and evaluating intraoperative and post-operative data in terms of hospital stay, complications, and oncological radicality., Methods: Data were collected from a multicenter retrospective database that includes 1070 consecutive robotic liver resections (RLRs) performed in nine European hospital centers from 2011 to 2023. Of the entire series, 343 liver resections were performed for HCC., Results: A total of 247 patients (72.3%) had mono-focal lesions. Major hepatectomies and anatomical resections have been perfomed in 87% and 55% of patients, respectively. All 17 conversions (4.95%) were to the open approach. The operative mean time was 239.56 min and the estimated blood loss was 229.45 mL. The overall post-operative complication rate was 22.74%, but severe complications occurred in 4.08% of patients and one of them (0.29%) was reoperated on. The mean hospital stay was 5.82 days with a mean ICU stay of 0.9 days. Twenty-six resections (7.6%) were R1 parenchymal. Forty-six patients (4.08%) were readmitted to the hospital within 90 days after discharge and seventy-eight patients (22.74%) had disease recurrence. Total deaths included 36 (10.5%) patients with a 90-day mortality of 0.9%., Conclusions: Robotic liver resection for HCC is feasible and safe when performed in experienced centers by surgeons who have completed the learning curve.

Immune checkpoint inhibitors (ICIs) have revolutionized oncology, providing a groundbreaking therapeutic option for patients with various advanced-stage cancers. While these treatments can significantly extend survival, they also carry a substantial risk of immune-related adverse events, among which hypophysitis is particularly detrimental to endocrine function. This narrative review synthesizes current knowledge on the pathogenesis, clinical features, diagnosis, and management of ICI-induced hypophysitis (IH) based on an in-depth analysis of the recent literature and clinical trials. The diagnosis of IH presents unique challenges due to its overlap with systemic symptoms commonly associated with the underlying malignancy. These symptoms can include asthenia, anorexia, headache, vomiting, weight loss, hypotension, dizziness, decreased libido, and visual disturbances. Diagnostic evaluation typically combines clinical assessment, hormonal profiling, and findings from magnetic resonance imaging (MRI). Effective management of IH requires a personalized, multidisciplinary approach, focusing on hormone replacement therapy and vigilant monitoring. Long-term care depends on the severity of hypophysitis, and the specific hormonal axes involved. This review aims to enhance awareness of the critical aspects of recognizing and managing IH, underscoring the importance of early diagnosis and timely intervention to reduce its long-term effects on patient quality of life.

Background: Intraoperative ultrasound (ioUS) provides real-time imaging during neurosurgical procedures, with advantages such as portability and cost-effectiveness. Accurate tumor segmentation has the potential to substantially enhance the interpretability of ioUS images; however, its implementation is limited by persistent challenges, including noise, artifacts, and anatomical variability. This study aims to develop a convolutional neural network (CNN) model for glioma segmentation in ioUS images via a multicenter dataset. Methods: We retrospectively collected data from the BraTioUS and ReMIND datasets, including histologically confirmed gliomas with high-quality B-mode images. For each patient, the tumor was manually segmented on the 2D slice with its largest diameter. A CNN was trained using the nnU-Net framework. The dataset was stratified by center and divided into training (70%) and testing (30%) subsets, with external validation performed on two independent cohorts: the RESECT-SEG database and the Imperial College NHS Trust London cohort. Performance was evaluated using metrics such as the Dice similarity coefficient (DSC), average symmetric surface distance (ASSD), and 95th percentile Hausdorff distance (HD95). Results: The training cohort consisted of 197 subjects, 56 of whom were in the hold-out testing set and 53 in the external validation cohort. In the hold-out testing set, the model achieved a median DSC of 0.90, ASSD of 8.51, and HD95 of 29.08. On external validation, the model achieved a DSC of 0.65, ASSD of 14.14, and HD95 of 44.02 on the RESECT-SEG database and a DSC of 0.93, ASSD of 8.58, and HD95 of 28.81 on the Imperial-NHS cohort. Conclusions: This study supports the feasibility of CNN-based glioma segmentation in ioUS across multiple centers. Future work should enhance segmentation detail and explore real-time clinical implementation, potentially expanding ioUS's role in neurosurgical resection.

Background: Accurate prognostic models are essential for optimizing treatment strategies for glioblastoma, the most aggressive primary brain tumor. While other neuroimaging modalities have demonstrated utility in predicting overall survival (OS), intraoperative ultrasound (iUS) remains underexplored for this purpose. This study aimed to evaluate the prognostic potential of iUS radiomics in glioblastoma patients in a multi-institutional cohort., Methods: This retrospective study included patients diagnosed with glioblastoma from the multicenter Brain Tumor Intraoperative (BraTioUS) database. A single 2D iUS slice, showing the largest tumor diameter, was selected for each patient. Radiomic features were extracted and subjected to feature selection, and clinical data were collected. Using a fivefold cross-validation strategy, Cox proportional hazards models were built using radiomic features alone, clinical data alone, and their combination. Model performance was assessed via the concordance index (C-index)., Results: A total of 114 patients met the inclusion criteria, with a mean age of 56.88 years, a median OS of 382 days, and a median preoperative tumor volume of 32.69 cm 3 . Complete tumor resection was achieved in 51.8% of the patients. In the testing cohort, the combined model achieved a mean C-index of 0.87 (95% CI: 0.76-0.98), outperforming the radiomic model (C-index: 0.72, 95% CI: 0.57-0.86) and the clinical model (C-index: 0.73, 95% CI: 0.60-0.87)., Conclusions: Intraoperative ultrasound relies on acoustic properties for tissue characterization, capturing unique features of glioblastomas. This study demonstrated that radiomic features derived from this imaging modality have the potential to support the development of survival models.

Background: thymic basaloid carcinoma (BTC) is an extremely rare tumor, and very little data are available on BTC's biology, clinical behavior, drug sensitivity, and patient outcomes., Methods: We performed a retrospective observational study on patients diagnosed with BTC in 11 referral centers of TYME. All BTC diagnoses were reviewed by the referring pathologist., Results: Twenty-eight patients were identified. A total of 22/28 patients were included. Eighteen patients had TNM stage I-III disease, and all underwent surgery; three patients received preoperative chemotherapy, and 10 patients received adjuvant radiotherapy. With a median follow-up of 46 (1-133) months, median overall survival (mOS) and median relapse-free survival were not reached. At 48 months, OS was 77% (95%CI 43-92), and DFS was 63% (95%CI 30-83). The median OS of the 4 patients diagnosed with metastatic disease was 7 months. Six patients received first-line systemic treatment for metastatic disease, and all showed tumor responses. Anti-tumor activity was also observed with an anti-VEGFR TKI and a multi-TKI inhibitor combined with an anti-PD1 antibody. Next-generation sequencing performed in three tumor samples did not identify actionable alterations or microsatellite instability., Conclusions: BTC is an extremely rare tumor that usually presents as a localized disease. Patients diagnosed with stage I-III disease can achieve long-term DFS, and efforts should be made to perform radical surgical resection combined with perioperative treatment whenever appropriate. Patients with advanced disease progression have a poor prognosis despite a high response rate to systemic treatments.

Background: Vulvar carcinoma is an uncommon gynecological tumor primarily affecting older women. Its treatment significantly impacts the quality of life and, not least, aesthetics because of the mutilating surgery it requires., Objectives: The management requires a multidisciplinary team of specialists who know how to care for the patient in her entirety, not neglecting psychological aspects and reconstructive surgery. How do the guidelines address multidisciplinarity, team surgical management, passing through preoperative diagnosis, and follow-up in such a challenging rare tumor to treat?, Methods: To answer these questions, we compared the main scientific recommendations to identify similarities and differences in diagnostic and therapeutic management to provide an overview of the gaps that there are currently in European and American international recommendations in providing management guidance in a cancer that is both among the rarest and most difficult to manage. In this way, we aim to encourage an update in practices based on the latest scientific evidence., Results: A review of various international guidelines, some dating back to 2014, shows significant variation in approaches, ranging from initial diagnostic procedures to managing relapses. The most recent guidelines also lacked references to the latest literature, indicating that more robust scientific evidence is needed before new treatments, such as electrochemotherapy for palliation and reconstructive surgery post exenteration, can be widely adopted., Conclusions: From the systematic comparison of the main international guidelines, a strong heterogeneity emerged in the diagnostic and therapeutic recommendations as well as for the multidisciplinary approach that today is essential. Our work certainly stimulated an update of the main guidelines.

Background: Boron neutron capture therapy (BNCT) is an innovative binary form of radiation therapy with high selectivity towards cancer tissue based on the neutron capture reaction 10 B(n,α) 7 Li, consisting in the exposition of patients to neutron beams after administration of a boron compound with preferential accumulation in cancer cells. The high linear energy transfer products of the ensuing reaction deposit their energy at the cell level, sparing normal tissue. Although progress in accelerator-based BNCT has led to renewed interest in this cancer treatment modality, in vivo dose monitoring during treatment still remains not feasible and several approaches are under investigation. While Compton imaging presents various advantages over other imaging methods, it typically requires long reconstruction times, comparable with BNCT treatment duration., Methods: This study aims to develop deep neural network models to estimate the dose distribution by using a simulated dataset of BNCT Compton camera images. The models pursue the avoidance of the iteration time associated with the maximum-likelihood expectation-maximization algorithm (MLEM), enabling a prompt dose reconstruction during the treatment. The U-Net architecture and two variants based on the deep convolutional framelets framework have been used for noise and artifact reduction in few-iteration reconstructed images., Results: This approach has led to promising results in terms of reconstruction accuracy and processing time, with a reduction by a factor of about 6 with respect to classical iterative algorithms., Conclusions: This can be considered a good reconstruction time performance, considering typical BNCT treatment times. Further enhancements may be achieved by optimizing the reconstruction of input images with different deep learning techniques.

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.

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.

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.

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.

The tumor necrosis factor (TNF) family, which includes 19 ligands and 29 receptors, influences cellular proliferation, differentiation, and apoptosis. The TNF family plays a crucial role in the pathogenesis of Hodgkin lymphoma (HL), particularly through its influence on the tumor microenvironment (TME). Hodgkin Reed-Sternberg (HRS) cells, the hallmark of classic HL (cHL), exhibit overexpression of TNF receptor family members such as CD30 and CD40. Given the critical roles of CD30 and CD40 in the survival and proliferation of HRS cells within the TME, targeting these TNF receptors represents a promising therapeutic strategy; therapies that target CD30 have already shown efficacy in clinical settings. The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis plays a crucial role in immune evasion by HRS cells, which express PD-L1 that interacts with PD-1 on T cells, leading to T cell exhaustion and a diminished immune response against the tumor. By blocking this interaction, checkpoint inhibitors such as nivolumab and pembrolizumab have demonstrated high response rates in patients with cHL, particularly in those who have not responded to conventional therapies. The integration of immune checkpoint inhibitors (ICIs) with standard chemotherapy regimens has improved outcomes for patients with advanced-stage cHL. By understanding how TNF signaling interacts with immune checkpoints, researchers can design more effective treatment regimens that simultaneously target multiple pathways. Combining TNF inhibitors with checkpoint blockade therapies may enhance the overall anti-tumor response by addressing both direct tumor signaling and the immune evasion mechanisms employed by tumor cells.

According to a modern view, cancer no longer follows a purely mechanistic model. Rather, a tumor is conceived as a more complex structure, composed of cancer cells, the activities of which may interact and reshape the so-called tumor microenvironment (TME), leading to preservation of specific tumoral niches and promoting the survival of tumoral stem cells. Background/Objective : Therapeutic strategies must deal with this unique cancer architecture in the near future by widening their range of activities outside the cancer cells and rewiring a TME to ensure it is hostile to cancer growth. Therefore, an intratumoral therapeutic strategy may open the door to a new type of anticancer activity, one that directly injures the tumoral structure while also eliciting an influence on the TME through local and systemic immunomodulation. This review would like to assess the current situation of intratumoral strategies and their clinical implications. Methods We analyzed data from phase I, II, and III trials, comprehensive reviews and relevant clinical and preclinical research, from robust databases, like PUBMED, EMBASE, Cochrane Library, and clinicaltrials.gov. Results: Intratumoral strategies can be quite variable. It is possible the injection and inhalation of traditional antiblastic agents or immunomodulant agents, or intrapleural administration. Ablation strategy is available, both thermal and photodynamic method. Moreover, TTfields and NPs are analyzed and also brachytherapy is mentioned. Intratumoral therapy can find space in "adjuvant"/perioperative or metastatic settings. Finally, intratumoral strategies allow to synergize their activities with systemic therapies, guaranteeing better local and systemic disease control. Conclusions: Intratumoral strategies are overall promising. Antiblastic/immunomodulant injection and NPs use are especially interesting and intriguing. But, there is generally a lack of phase II and III trials, in particular NPs use need additional experimentation and clinical studies.

Aim: This meta-analysis aims to evaluate the impact of anthracycline chemotherapy on subclinical right ventricular (RV) dysfunction in breast cancer patients, using traditional echocardiographic parameters and strain-based measures, such as the RV global longitudinal strain (RV GLS) and the RV free-wall longitudinal strain (RV FWLS)., Methods and Results: A systematic search was conducted according to PRISMA guidelines, including 15 studies with a total of 1148 breast cancer patients undergoing anthracycline chemotherapy. The primary outcome was the evaluation of changes in RV GLS and RV FWLS pre- and post-chemotherapy. Secondary outcomes included changes in traditional echocardiographic parameters: TAPSE, FAC, and TDI S'. Meta-analysis revealed significant declines in RV function post-chemotherapy across all parameters. RV GLS decreased from 23.99% to 20.35% (SMD: -0.259, p < 0.0001), and RV FWLS from 24.92% to 21.56% (SMD: -0.269, p < 0.0001). Traditional parameters like TAPSE, FAC, and TDI S' also showed reductions, but these were less consistent across studies. A meta-regression analysis showed no significant relationship between post-chemotherapy left ventricular ejection fraction (LVEF) and the changes in RV GLS and RV FWLS, suggesting that RV dysfunction may not be solely a consequence of LV impairment., Conclusions: Anthracycline chemotherapy induces subclinical RV dysfunction in breast cancer patients. RV strain analysis, especially 3D strain, shows greater sensitivity in detecting early dysfunction. However, further research is needed to clarify the clinical significance and prognostic value of these findings, as well as the role of routine RV strain analysis in guiding early interventions.

Introduction: Several studies have described how the restrictive measures due to COVID-19 have delayed melanoma diagnoses, resulting in an increased rate of more severe cases. Summarizing the sparse results in this context might help to understand the real impact of the COVID-19 pandemic on melanoma. We conducted a systematic review and meta-analysis to investigate how the clinical and prognostic factors of new melanoma diagnoses changed after COVID-19., Methods: A literature search in MEDLINE, EMBASE, and Scopus was conducted in September 2023. We included studies published in peer-reviewed journals reporting histopathological data on new diagnoses of cutaneous melanoma in adult patients during and/or after the lockdown compared to those diagnosed before the COVID-19 pandemic. A meta-analysis was conducted utilizing a random effects model. The between-study heterogeneity was assessed via Higgins's I 2 statistic. Publication bias was assessed using the Begg and Egger test. This study adhered to the updated PRISMA guidelines. The primary outcome was a comparison of melanoma thickness between the pre-COVID-19 and post-lockdown periods. The secondary outcomes were evaluations of the histopathological subtype, stage, and presence of ulceration and mitosis in melanomas diagnosed in these two pandemic phases., Results: The study included 45 articles. We found a significantly higher proportion of all factors indicating worse prognosis in the post-lockdown period compared to the pre-COVID-19 phase, including high thickness (SOR = 1.14, 95%CI 1.08-1.20 for 1-2 mm; SOR = 1.62, 95%CI 1.08-2.40, for >2 mm), the presence of ulcerations (SOR = 1.35, 95%CI 1.18-1.54), nodular subtype (SOR = 1.19, 95%CI 1.07-1.32), the presence of mitosis (SOR = 1.57, 95% CI 1.17-2.11), and stage III (SOR = 1.39, 95%CI 1.19-1.52) and IV (SOR = 1.44, 95%CI 1.26-1.63). Limitations include the limited studies' geographical distribution and moderate heterogeneity affecting meta-analysis estimates., Conclusions: Our meta-analysis provided evidence of more advanced melanomas diagnosed in the post-COVID-19 pandemic period, emphasizing the importance of creating and updating pandemic preparedness plans to limit the impact of any future events on oncological care.

Background: The interaction between cancer cells and cancer-associated fibroblasts (CAFs) is a key determinant of the rapid progression, high invasiveness, and chemoresistance of aggressive desmoplastic cancers such as pancreatic ductal adenocarcinoma (PDAC). Tumor cells are known to reprogram fibroblasts into CAFs by secreting transforming growth factor beta (TGF-β), amongst other cytokines. In turn, CAFs produce soluble factors that promote tumor-cell invasiveness and chemoresistance, including TGF-β itself, which has a major role in myofibroblastic CAFs. Such a high level of complexity has hampered progress toward a clear view of the TGFβ signaling loop between stromal fibroblasts and PDAC cells., Methods: Here, we tackled this issue by using co-culture settings that allow paracrine signaling alone (transwell systems) or paracrine and contact-mediated signaling (3D spheroids)., Results: We found that TGF-β is critically involved in the activation of normal human fibroblasts into alpha-smooth muscle actin (α-SMA)-positive CAFs. The TGF-β released by CAFs accounted for the enhanced proliferation and resistance to gemcitabine of PDAC cells. This was accompanied by a partial epithelial-to-mesenchymal transition in PDAC cells, with no increase in their migratory abilities. Nevertheless, 3D heterospheroids comprising PDAC cells and fibroblasts allowed monitoring the pro-invasive effects of CAFs on cancer cells, possibly due to combined paracrine and physical contact-mediated signals., Conclusions: We conclude that TGF-β is only one of the players that mediates the communication between PDAC cells and fibroblasts and controls the acquisition of aggressive phenotypes. Hence, these advanced in vitro models may be exploited to further investigate these events and to design innovative anti-PDAC therapies.

Background : In the last decades, the increasing number of adolescent and young adult (AYA) survivors of breast cancer (BC) has highlighted the cardiotoxic role of cancer therapies, making cardiovascular diseases (CVDs) among the most frequent, although rare, long-term sequalae. Leveraging innovative artificial intelligence (AI) tools and real-world data (RWD), we aimed to develop a causally interpretable model to identify young BC survivors at risk of developing CVDs. Methods : We designed and trained a Bayesian network (BN), an AI model, making use of expert knowledge and data from population-based (1036 patients) and clinical (339 patient) cohorts of female AYA (i.e., aged 18 to 39 years) 1-year survivors of BC, diagnosed in 2009-2019. The performance achieved by the BN model was validated against standard classification metrics, and two clinical applications were proposed. Results: The model showed a very good classification performance and a clear causal semantic. According to the predictions made by the model, focusing on the 25% of AYA BC survivors at higher risk of developing CVDs, we could identify 81% of the patients who would actually develop it. Moreover, a desktop-based app was implemented to calculate the individual patient's risk. Conclusions: In this study, we developed the first causal model for predicting the CVD risk in AYA survivors of BC, also proposing an innovative AI approach that could be useful for all researchers dealing with RWD. The model could be pivotal for clinicians who aim to plan personalized follow-up strategies for AYA BC survivors.

Background/objectives: Solitary fibrous tumors (SFTs) represent a rare mesenchymal malignancy that can occur anywhere in the body. Due to the low prevalence of the disease, there is a lack of contemporary data regarding patient demographics and cancer-control outcomes., Methods: Within the SEER database (2000-2019), we identified 1134 patients diagnosed with malignant SFTs. The distributions of patient demographics and tumor characteristics were tabulated. Cumulative incidence plots and competing risks analyses were used to estimate cancer-specific mortality (CSM) after adjustment for other-cause mortality., Results: Of 1134 SFT patients, 87% underwent surgical resection. Most of the tumors were in the chest (28%), central nervous system (22%), head and neck (11%), pelvis (11%), extremities (10%), abdomen (10%) and retroperitoneum (6%), in that order. Stage was distributed as follows: localized (42%) vs. locally advanced (35%) vs. metastatic (13%). In multivariable competing risks models, independent predictors of higher CSM were stage (locally advanced HR: 1.6; metastatic HR: 2.9), non-surgical management (HR: 3.6) and tumor size (9-15.9 cm HR: 1.6; ≥16 cm HR: 1.9)., Conclusions: We validated the importance of stage and surgical resection as independent predictors of CSM in malignant SFTs. Moreover, we provide novel observations regarding the independent importance of tumor size, regardless of the site of origin, stage and/or surgical resection status.

Background/objectives: Lung cancer remains a global health concern, with substantial variation in patient survival. Despite advances in detection and treatment, the genetic basis for the divergent outcomes is not understood. We investigated germline polymorphisms that modulate overall survival in 1464 surgically resected lung adenocarcinoma patients., Methods: A multivariable Cox proportional hazard model was used to assess the association of more than seven million polymorphisms with overall survival at the 60-month follow-up, considering age, sex, pathological stage, decade of surgery and principal components as covariates. Genes in which variants were identified were studied in silico to investigate functional roles., Results: Six germline variants passed the genome-wide significance threshold. These single nucleotide polymorphisms were mapped to non-coding (intronic) regions on chromosomes 2, 3, and 5. The minor alleles of rs13000315, rs151212827, and rs190923216 (chr. 2, 3 and 5, respectively) were found to be independent negative prognostic factors. All six variants have been reported to regulate the expression of nine genes, seven of which are protein-coding, in different tissues. Survival-associated variants on chromosomes 2 and 3 were already reported to regulate the expression of NT5DC2 and NAGK , with high expression associated with the minor alleles. High NT5DC2 and NAGK expression in lung adenocarcinoma tissue was already shown to correlate with poor overall survival., Conclusions: This study highlights a potential regulatory role of the identified polymorphisms in influencing outcome and suggests a mechanistic link between these variants, gene expression regulation, and lung adenocarcinoma prognosis. Validation and functional studies are warranted to elucidate the mechanisms underlying these associations.

The primary treatment for operable pancreatic cancer (PC) involves surgery followed by adjuvant therapy. Nevertheless, perioperative or neoadjuvant chemotherapy (CT) may be used to mitigate the likelihood of recurrence and mortality. This network meta-analysis (NMA) assesses the comparative efficacy of various treatment approaches for resectable PC. A thorough search was carried out on January 31, 2023, encompassing PubMed/MEDLINE, Cochrane Library, and Embase databases. We incorporated randomized clinical trials (RCTs) that compared surgical interventions with or without (neo)adjuvant or perioperative therapies for operable PC. We conducted a fixed-effects Bayesian NMA. We presented the effect sizes in terms of hazard ratios (HRs) for overall survival (OS) along with 95% credible intervals (95% CrIs). The treatment was deemed statistically superior when the 95% credible interval (CrI) did not encompass a null value (hazard ratio < 1). Treatment rankings were established based on the surface under the cumulative ranking curve (SUCRA). A total of 24 studies were incorporated, comparing 21 treatments with surgery in isolation. Eleven treatments showed superior efficacy compared to surgery alone, with HRs ranging from 0.38 for perioperative treatments to 0.73 for adjuvant 5-fluorouracil. After the exclusion of studies conducted in Asia, it was found that the perioperative regimen of gemcitabine combined with nab-paclitaxel was the most effective regimen (SUCRA, p = 0.99). The findings endorse the utilization of perioperative CT, especially multi-agent CT, as the favored intervention for operable PC in Western nations.

Angiogenesis plays a pivotal role in the growth and metastasis of tumors, including the development and progression of cutaneous lymphomas. The chick embryo CAM model has been utilized in various studies to assess the growth rate, angiogenic potential, and metastatic capability of different tumor types and malignant cell lines. However, the precise mechanisms of angiogenesis in CTCL and the influence of Ruxolitinib or Resminostat on angiogenesis in hematological malignancies and solid tumors are not well understood. Recent in vitro and in vivo data have demonstrated the synergistic inhibition of tumorigenesis and metastasis in experimental models of CTCL when using the combination of Resminostat (HDACi) with Ruxolitinib (JAKi). The present work aims to elucidate the effects of this combination on the tumor microenvironment's vascular components. We investigated the effects of Ruxolitinib (JAKi) in combination with Resminostat (HDACi) treatment in transendothelial migration of CTCL cells (10 6 MyLa and SeAx) by using a transwell-based transendothelial migration assay and tumor angiogenesis in vivo. We used the CTCL chick embryo CAM model with xenografted tumors derived from implanted MyLa and SeAx cells and administered topically 15 μM ruxolitinib and 5 μM Resminostat every two days during a 5-day period. JAKi and HDACi inhibited CTCL cell transendothelial migration by 75% and 82% ( p < 0.05) in both CTCL engrafted cells (MyLa and SeAx, respectively) compared to the untreated group. Moreover, the combination of ruxolitinib with resminostat blocked angiogenesis by significantly reducing the number of blood vessel formation by 49% and 34% in both MyLa and SeAx, respectively ( p < 0.05), indicating that the proposed combination exerted significant anti-angiogenic effects in the CAM CTCL model. Overall, these data provide valuable insights into potential therapeutic strategies targeting angiogenesis in CTCL, paving the way for more effective treatment approaches in the future.

Amide Proton Transfer-weighted (APTw) imaging is a molecular MRI technique used to quantify protein concentrations in gliomas, which have heterogeneous components with varying cellularity and metabolic activity. This study aimed to assess the correlation between the component-specific APT signal of the neoplasm and WHO grade, molecular profile and survival status. Sixty-one patients with adult-type diffuse gliomas were retrospectively analyzed. APT values were semi-automatically extracted from tumor solid and, whenever present, necrotic components. APT values were compared between groups stratified by WHO grade, IDH-mutation, MGMT promoter methylation and 1- and 2-year survival status using Wilcoxon rank-sum test, adjusting for multiple comparisons. Overall survival (OS) was analyzed in the subgroup of 48 patients with grade 4 tumors using Cox proportional-hazards models. Random-effects models were used to assess inter-subject heterogeneity of the mean APT values in each tumor component. APT values of the solid component significantly differed between patients with grades 2-3 and 4 tumors (mean 1.58 ± 0.50 vs. 2.04 ± 0.56, p = 0.028) and correlated with OS after 1 year (1.81 ± 0.58 in survivors vs. 2.17 ± 0.51 in deceased patients, p = 0.030). APT values did not differ by IDH-mutation, MGMT methylation, and 2-year survival status. Within grade 4 glioma patients, higher APT kurtosis of the solid component was a negative prognostic factor (hazard ratio = 1.60, p = 0.040). Mean APT values of the necrosis showed high inter-subject variability, although most necrotic tumors were grade 4 and IDH wildtype. In conclusion, APTw imaging in the solid component provided metrics associated with glioma grade and survival status but showed weak correlation with IDH-mutation and MGMT promoter methylation status, in contrast to previous works. Further research is needed to understand APT signal variability within the necrotic component of high-grade gliomas.

A multitude of exogenous and endogenous processes have the potential to result in DNA damage. While the repair mechanisms are typically capable of correcting this damage, errors in the repair process can result in mutations. The findings of research conducted in 2012 indicate that mutations do not occur randomly but rather follow specific patterns that can be attributed to known or inferred mutational processes. The process of mutational signature analysis allows for the inference of the predominant mutational process for a given cancer sample, with significant potential for clinical applications. A deeper comprehension of these mutational signatures in CRC could facilitate enhanced prevention strategies, facilitate the comprehension of genotoxic drug activity, predict responses to personalized treatments, and, in the future, inform the development of targeted therapies in the context of precision oncology. The efforts of numerous researchers have led to the identification of several mutational signatures, which can be categorized into different mutational signature references. In CRC, distinct mutational signatures are identified as correlating with mismatch repair deficiency, polymerase mutations, and chemotherapy treatment. In this context, a mutational signature analysis offers considerable potential for enhancing minimal residual disease (MRD) tests in stage II (high-risk) and stage III CRC post-surgery, stratifying CRC based on the impacts of genetic and epigenetic alterations for precision oncology, identifying potential therapeutic vulnerabilities, and evaluating drug efficacy and guiding therapy, as illustrated in a proof-of-concept clinical trial.

Cutaneous melanoma still represents a significant health burden worldwide, being responsible for the majority of skin cancer deaths. Key advances in therapeutic strategies have significantly improved patient outcomes; however, most patients experience drug resistance and tumor relapse. Cancer stem cells (CSCs) are a small subpopulation of cells in different tumors, including melanoma, endowed with distinctive capacities of self-renewal and differentiation into bulk tumor cells. Melanoma CSCs are characterized by the expression of specific biomarkers and intracellular pathways; moreover, they play a pivotal role in tumor onset, progression and drug resistance. In recent years, great efforts have been made to dissect the molecular mechanisms underlying the protumor activities of melanoma CSCs to provide the basis for novel CSC-targeted therapies. Herein, we highlight the intricate crosstalk between melanoma CSCs and bystander cells in the tumor microenvironment (TME), including immune cells, endothelial cells and cancer-associated fibroblasts (CAFs), and its role in melanoma progression. Specifically, we discuss the peculiar capacities of melanoma CSCs to escape the host immune surveillance, to recruit immunosuppressive cells and to educate immune cells toward an immunosuppressive and protumor phenotype. We also address currently investigated CSC-targeted strategies that could pave the way for new promising therapeutic approaches for melanoma care.

Introduction: Leukemia history affects some radical prostatectomy (RP) patients. Although its prevalence and effect as an adverse risk factor are well known in cardiac surgery, the number of RP patients with a leukemia history, as well as their rate of adverse in-hospital outcomes, are unknown., Methods: We identified RP patients (National Inpatient Sample 2000-2019), stratified according to the presence or absence of a leukemia history. Descriptive analyses, propensity score matching (PSM, ratio 1:10), and multivariable logistic regression models were used., Results: Of 259,939 RP patients, 416 (0.2%) had a leukemia history. Their proportion increased from 0.1 to 0.2% covering the study span ( p < 0.01). Leukemia history patients were older (median age, 64 vs. 62 years, p < 0.001). After PSM for age, insurance status, ethnicity, pelvic lymph node dissection, and Charlson Comorbidity Index, leukemia history RP patients exhibited higher rates of acute kidney injury (<2.6 vs. 0.9%; Odds Ratio [OR] 2.0, p = 0.02), more frequently underwent dialysis (3.6 vs. 1.9%; OR 1.9, p = 0.03), and more frequently had a length of stay exceeding one week (4.8 vs. 2.5%; OR 2.0, p = 0.006)., Conclusions: Although leukemia history RP patients are rare, their numbers have increased. Renal complications and extended hospital stays are more frequent in those individuals.

The link between neurodegenerative diseases (NDs) and cancer has generated greater interest in biomedical research, with decades of global studies investigating neurodegenerative biomarkers in cancer to better understand possible connections. Tau, amyloid-β, α-synuclein, SOD1, TDP-43, and other proteins associated with nervous system diseases have also been identified in various types of solid and malignant tumors, suggesting a potential overlap in pathological processes. In this review, we aim to provide an overview of current evidence on the role of these proteins in cancer, specifically examining their effects on cell proliferation, apoptosis, chemoresistance, and tumor progression. Additionally, we discuss the diagnostic and therapeutic implications of this interconnection, emphasizing the importance of further research to completely comprehend the clinical implications of these proteins in tumors. Finally, we explore the challenges and opportunities in targeting these proteins for the development of new targeted anticancer therapies, providing insight into how to integrate knowledge of NDs in oncology research.

(1) Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Surgical resection, tumor ablation, and liver transplantation are curative treatments indicated for early-stage HCC. The management of intermediate and advanced stages of pathology is based on the use of systemic therapies which often show important side effects. Vitamin E-derivative tocotrienols (TTs) play antitumoral properties in different tumors. Here, we analyzed the activity of delta-TT (δ-TT) on HCC human cell lines. (2) We analyzed the ability of δ-TT to trigger apoptosis, to induce oxidative stress, autophagy, and mitophagy in HepG2 cell line. We evaluated the correlation between the activation of autophagy with the ability of δ-TT to induce cell death. (3) The data obtained demonstrate that δ-TT exerts an antiproliferative and proapoptotic effect in HCC cells. Furthermore, δ-TT induces the release of mitochondrial ROS and causes a structural and functional alteration of the mitochondria compatible with a fission process. Finally, δ-TT triggers selective autophagy process removing dysfunctional mitochondria. Inhibition of autophagy reversed the cytotoxic action of δ-TT. (4) Our results demonstrate that δ-TT through the activation of autophagy could represent a potential new approach in the treatment of advanced HCC.

Background: Targeted therapies changed the treatment of advanced oncogene-addicted non-small cell lung cancer and could also improve outcomes in resectable disease., Results: The ALINA trial evaluated the clinical benefit of adjuvant alectinib compared with standard chemotherapy and met the primary endpoint with a significant increase in disease-free survival at 2 years among anaplastic lymphoma kinase positive patients with stage IB-IIIA disease; two phase II trials (ALNEO and NAUTIKA1) are currently evaluating perioperative treatment with alectinib, and the results of the case reports published to date are encouraging., Conclusion: In resectable anaplastic lymphoma kinase-positive lung cancer, adjuvant alectinib represents the new standard of care and could soon be used in perioperative treatment.

Background and purpose : Differentiating pediatric posterior fossa (PF) tumors such as medulloblastoma (MB), ependymoma (EP), and pilocytic astrocytoma (PA) remains relevant, because of important treatment and prognostic implications. Diffusion kurtosis imaging (DKI) has not yet been investigated for discrimination of pediatric PF tumors. Estimating diffusion values from whole-tumor-based (VOI) segmentations may improve diffusion measurement repeatability compared to conventional region-of-interest (ROI) approaches. Our purpose was to compare repeatability between ROI and VOI DKI-derived diffusion measurements and assess DKI accuracy in discriminating among pediatric PF tumors. Materials and methods : We retrospectively analyzed 34 children (M, F, mean age 7.48 years) with PF tumors who underwent preoperative examination on a 3 Tesla magnet, including DKI. For each patient, two neuroradiologists independently segmented the whole solid tumor, the ROI of the area of maximum tumor diameter, and a small 5 mm ROI. The automated analysis pipeline included inter-observer variability, statistical, and machine learning (ML) analyses. We evaluated inter-observer variability with coefficient of variation (COV) and Bland-Altman plots. We estimated DKI metrics accuracy in discriminating among tumor histology with MANOVA analysis. In order to account for class imbalances, we applied SMOTE to balance the dataset. Finally, we performed a Random Forest (RF) machine learning classification analysis based on all DKI metrics from the SMOTE dataset by partitioning 70/30 the training and testing cohort. Results : Tumor histology included medulloblastoma (15), pilocytic astrocytoma (14), and ependymoma (5). VOI-based measurements presented lower variability than ROI-based measurements across all DKI metrics and were used for the analysis. DKI-derived metrics could accurately discriminate between tumor subtypes (Pillai's trace: p < 0.001). SMOTE generated 11 synthetic observations (10 EP and 1 PA), resulting in a balanced dataset with 45 instances (34 original and 11 synthetic). ML analysis yielded an accuracy of 0.928, which correctly predicted all but one lesion in the testing set. Conclusions : VOI-based measurements presented improved repeatability compared to ROI-based measurements across all diffusion metrics. An ML classification algorithm resulted accurate in discriminating PF tumors on a SMOTE-generated dataset. ML techniques based on DKI-derived metrics are useful for the discrimination of pediatric PF tumors., Competing Interests: The authors declare no conflicts of interest.

Cervical cancer continues to have a significant incidence, despite global efforts in HPV vaccination campaigns. Managing this condition involves a diverse team of healthcare professionals. Research in this field is undergoing a period of great revolution in multiple areas, and international guidelines will soon have to adapt to new scientific evidence. This could be true mainly in locally advanced stages, and it could also be true for minimal invasive surgery. This paper aims to summarize and compare the most recent recommendations published by international gynecological oncological societies for patients with cervical cancer. From their comparison, common aspects and disagreements emerged, especially in the diagnostic pathway and follow-up strategies. Several issues that remain to be debated in the literature were addressed and compared, highlighting similarities and differences, from the role of the sentinel lymph node in early stages to that of the adjuvant hysterectomy in locally advanced tumors. On the surgical side, for this last subset of patients, currently, a laparotomic approach is recommended. At the same time, the advent of immunotherapy has just opened up new and promising scenarios in systemic treatment for locally advanced cervical cancer, and international guidelines will soon introduce it into their algorithms.