Search Results (146)

Uveal melanoma (UM), the most common primary intraocular malignancy in adults, poses a unique clinical challenge due to its high propensity for liver metastasis and poor responsiveness to conventional therapies. Despite the expanding landscape of immunotherapy in oncology, progress in managing metastatic uveal melanoma (mUM) remains limited, and no universally accepted standard of care has been established. In this review, we examine the current state and evolving strategies in immunotherapy for mUM, focusing on immune checkpoint inhibitors (ICIs), T cell receptor (TCR)-engineered therapies, and tumor-targeted vaccines. We also present a meta-analytical comparison of clinical outcomes between ICI monotherapy and combination regimens, alongside the recently FDA-approved T cell engager tebentafusp. Our analysis indicates that the triple combination of Ipilimumab, anti-PD-1 agents, and tebentafusp significantly enhances objective response rates, disease control rates, 1-year overall survival rates, and median overall survival (mOS) compared to ICI monotherapy alone. However, this enhanced efficacy is accompanied by increased toxicity due to broader immune activation. In contrast, tebentafusp offers superior tumor specificity and a more favorable safety profile in HLA-A*02:01-positive patients, positioning it as a preferred therapeutic option for this genetically defined subset of UM. Additionally, early-phase studies involving dendritic cell-based immunotherapies and peptide vaccines has shown encouraging signs of tumor-specific immune activation, along with improved tolerability. Collectively, this review underscores the urgent need for more precise and effective immunotherapeutic approaches tailored to the unique biology of mUM. Full article

Objective: Lower third impacted molar extraction, despite being a routinary procedure for oral and maxillo-facial surgeons, may often result in a significantly negative impact in patient’s post-operatory quality of life. Among others, treatments based on oxygen-enriched oils have been shown to provide valuable therapeutic benefits in promoting wound healing, and therefore improving the immediate post-operatory symptomatology. The aim of this triple-blinded randomized controlled study is to supplement the existing evidence in the scientific literature by assessing the effectiveness of NovoX^®-Drop (Moss S.p.A., Lesa, Novara), a specific type of oxygen enriched oil-based device in reducing pain and inflammatory stimulus of post-surgical wounds following the extraction of lower third impacted molars. Materials and methods: Seventy-one patients undergoing surgical extraction of a single lower third impacted molar were randomly assigned to receive either NovoX^®-Drop (Group A) or a glycerin-based gel (Group B). Additionally, both patient groups followed the same standard therapy with amoxicillin-clavulanic acid and ibuprofen. Data were collected preoperative (T0) and after three (T3) and seven (T7) days postoperative in order to assess the following outcomes: mean visual analogue scale (VAS) score during the seven days protocol treatment, total duration of nonsteroidal anti-inflammatory drug (NSAID) usage, trismus (maximum mouth opening) and facial oedema. Results: Group A (treatment group) reported significatively lower pain levels at T7 compared to group B (average VAS value during the week: Group A: 3.57 ± 0.39 cm; Group B: 4.47 ± 0.40 cm; p-value = 0.0014) despite a significatively shorter period of NSAID usage (average NSAID usage duration: Group A: 2.43 ± 0.38 days; Group B: 3.38 ± 0.44 days; p-value = 0.00001). Therefore, trismus seems to be better controlled in group A, although the difference between the groups did not reach the threshold for statistical significance. Conclusions: The results of this study suggest that application of NovoX^®-Drop is capable of significantly reducing the post-operatory pain as well as NSAID usage, representing a promising and effective option for third impacted molar extraction surgery management. Full article

Background/Objectives: The tumor microenvironment (TME) plays a critical role in cancer progression by shaping immune responses and influencing patient outcomes. We hypothesized that the relative proximity of specific immune cell pairs to cancer cells within the TME could help predict their pro- or anti-tumor functions and reflect clinically relevant immune dynamics. Methods: We analyzed imaging mass cytometry (IMC) data from lung adenocarcinoma (LUAD) and triple-negative breast cancer (TNBC) cohorts. For each immune cell pair, we calculated a relative distance (RD) score, which quantifies the spatial difference in proximity to cancer cells. We assessed the prognostic and predictive significance of these RD-scores by comparing them with conventional features such as cell fractions, densities, and individual cell distances. To account for variations in cell abundance, we also derived normalized RD-scores (NRD-scores). Results: RD-scores were more strongly associated with overall patient survival than standard immunological metrics. Among all immune cell pairs, the RD-score comparing the proximity of B cells to that of intermediate monocytes showed the most significant association with improved survival. In TNBC, RD-scores also improved the distinction between responders and non-responders to immunochemotherapy and chemotherapy. Normalized RD-scores reinforced these findings by minimizing the influence of cell density and further highlighting the importance of immune cell spatial relationships. Conclusions: RD-scores offer a spatially informed biomarker that outperforms traditional metrics in predicting survival and treatment response. This approach provides a new perspective on immune cell behavior in the TME and has potential utility in guiding personalized cancer therapies and patient stratification. Full article

Background: Local audits of Helicobacter pylori (H. pylori) prescriptions and outcomes are necessary to assess guideline awareness among clinicians and treatment effectiveness. Aims: The aims were to investigate first-line prescriptions and effectiveness over a 10-year period in Ireland and evaluate the influence of the 2017 Irish consensus guidelines on these trends. Methods: Data were collected at e-CRF AEG-REDCap from the European Registry on H. pylori management (Hp-EuReg) and quality reviewed from 2013 to 2022. All treatment-naïve cases were assessed for effectiveness by modified intention-to-treat (mITT) analysis. Multivariate analysis was also performed. Results: Data from 1000 patients (mean age 50 ± 15 years; 54% female) were analyzed. Clarithromycin (C) and amoxicillin (A) triple therapy represented 88% of treatments, followed by sequential C, A, and metronidazole (M) therapy (4.3%) and triple C + M (2.7%). Bismuth quadruple therapy was prescribed in 1.7% of cases. Treatment durations of 14, 10, and 7 days accounted for 87%, 4.5%, and 8.5% of prescriptions, respectively. High-, standard-, and low-dose proton pump inhibitors (PPIs; 80 mg, 40 mg, and 20 mg omeprazole equivalent b.i.d.) were used in 86%, 0.9%, and 13% of cases, respectively. The overall eradication rate was 80%, while it was 81% for triple C + A. Good compliance and high-dose PPI were associated with higher overall mITT eradication rates (OR 4.5 and OR 1.9, respectively) and triple C + A eradication rates (OR 4.2 and OR 1.9, respectively). Overall eradication rates increased from 74% pre-2017 to 82% (p < 0.05) by the end of 2022. Similarly, the triple C + A eradication rates increased from 76% to 83% (p < 0.05). Conclusions: While first-line treatment effectiveness improved in clinical practice over time, cure rates remain below 90%. Alternative first-line strategies are required in Ireland. Full article

Triple-negative breast cancer (TNBC) is a heterogenous group of breast tumors. This type of breast tumor is relatively difficult to manage, due to the lack of expression of Hormone Receptors (HR) and human epidermal growth factor receptor (HER2). Efforts have been made to understand the factors involved in determining how a triple-negative breast tumor responds to therapy. The standard of treatment in most cases today is a combined modality of immune checkpoint inhibitors (ICIs) and chemotherapy with agents such as anti-mitotic (taxanes) or DNA-damaging agents (alkylating agents, cyclophosphamides, platin salts). In this study, we investigated the predictive and prognostic factors for TNBC, in the neoadjuvant setting; understanding each patient’s response before treatment initiation is crucial to guiding the subsequent approach and finally improving patient outcomes. We focused on tumor-infiltrating lymphocytes at the site of the primary tumor (TILs), circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), the mutational status of protein 53 (p53), and Ki-67, investigating the potential roles of these factors in predicting responses to anti-cancer agents. Full article

Triple-negative breast cancer is the most aggressive subtype of breast cancer and is associated with the worst prognosis. Conventional chemotherapy remains the gold standard treatment for this disease but is associated with a high relapse rate, highlighting the urgent need for effective targeted therapies. The PI3K/Akt/mTOR pathway, dysregulated in nearly 60% of these cancers, appears to be a prime target. It involves a signaling cascade beginning with PI3K activation followed by activating phosphorylation of Akt and then mTOR complex, which activates oncogenic processes by enhancing protein synthesis, inhibiting apoptosis, dysregulating autophagy and promoting DNA repair that supports tumor cell survival. Moreover, the PI3K/Akt/mTOR pathway plays a central role in the development of chemoresistance. Numerous alterations (activating the mutation of PIK3CA or the loss of tumor suppressor PTEN) may lead to its overactivation. Targeted inhibitors of PI3K, Akt and mTOR have been developed to counteract this dysregulation. However, numerous cancer resistance mechanisms have emerged, reducing their efficacy, for example, reactivation of Akt following mTOR blockade, reactivation of the pathway by insulin signaling or activation of compensatory pathways such as the MAPK pathway, thus limiting their integration into routine practice. To counteract these resistances, combination therapies currently being investigated in clinical trials aim to improve clinical outcomes of PI3K/Akt/mTOR pathway inhibition. The aim of this review was to summarize current therapies developed to target this pathway in TNBC, with a focus on the resistance mechanisms that limit their effectiveness. Full article

Background: Anti-EGFR therapy, combined with chemotherapy, represents the standard therapeutic approach for triple wild-type (KRAS/NRAS and BRAF), left-sided, microsatellite stable (MSS) metastatic colorectal cancer (mCRC). However, acquired resistance develops in approximately 50% of patients. This study evaluated the efficacy of anti-EGFR therapy re-challenge and analyzed circulating tumor DNA (ctDNA) for potential resistance mechanisms. Methods: Eleven patients with triple wild-type, MSS, HER2-negative, left-sided mCRC were included. All patients received Cetuximab with chemotherapy as the first-line treatment, with three patients subsequently receiving Cetuximab re-challenge. Twenty-one plasma samples were collected at baseline and at each response assessment for retrospective ctDNA analysis using next-generation sequencing with a 16-gene panel. Results: Genetic alterations were detected in only 14.2% of ctDNA samples. In one re-challenge patient, the KRAS: c.35G>A mutation appeared during progression. No RAS mutations were identified in four patients who progressed on first-line Cetuximab treatment. Conclusions: This preliminary study suggests that clinically based anti-EGFR re-challenge may benefit selected mCRC patients. The low detection rate of resistance-conferring mutations indicates potential alternative resistance mechanisms beyond RAS pathway alterations. Our findings, while limited by sample size and the retrospective design of ctDNA testing, contribute to the growing evidence supporting anti-EGFR re-challenge strategies in mCRC management. Full article

Immunotherapy with antibodies targeting immune checkpoints, in combination with standard therapies, is one of the areas with the most significant clinical research, particularly in aggressive tumors such as triple-negative breast cancer, where there have been relevant advances with antibodies against PD-1/PD-L1. However, it is essential to define the biological and molecular factors that influence survival and response to immunotherapy, as other immune control points, such as CTLA-4, TIM-3, LAG-3, TIGIT, and VISTA, also play a role. The immune checkpoints were studied by microarrays and immunohistochemistry in 243 samples from patients with breast cancer, according to the molecular subtype. Significant differences in PD-1, PL-1, CTLA-4, and TIGIT expression were observed between triple-negative and Her-2 tumors compared to Luminal A and Luminal B tumors. No differences in VISTA expression were observed between the different molecular subtypes. Patients with high-grade tumors showed higher PD-1, PD-L1, LAG-3, and VISTA expression than low and intermediate-grade tumors. We observed a significant difference in PD-L1/TIGIT co-expression in tumor-infiltrating cells from patients with triple-negative tumors compared to patients with Luminal A, Luminal B, and Her2+ tumors. These results are relevant in the context of clinical application. Full article

Background/Objectives: Chondrosarcoma (CS), the most common malignant bone tumor in adults, exhibits a poor prognosis due to high rates of post-surgical recurrence and metastasis, and resistance to chemotherapy. CS’s abundant expression of aspartyl-asparaginyl-β-hydroxylase (ASPH), which drives invasive tumor growth via Notch and PI3K/mTOR activation, opens opportunities for treatment in combination with standard Doxorubicin (DOX) chemotherapy. We hypothesized that the small molecule inhibitor SMI1182, which targets the catalytic domain of ASPH, and BEZ235, which targets PI3K/mTOR, could enhance the chemotherapeutic effects of DOX. Human CS1 (Grade 3) and CDS11 (Grade 2) conventional CS cell lines were treated with broad dose ranges of DOX, BEZ235, or SMI1182 as mono- or combination therapy to assess their anti-tumor effects on cell viability, toxicity, and motility. Methods: Mechanistic studies included the analysis of ASPH expression, Notch signaling, and insulin/IGF/IRS pathway activation through mTOR. DOX, BEZ235, or SMI1182 treatments caused dose-dependent cell loss and cytotoxicity. Results: SMI1182 and BEZ235, with or without DOX, significantly reduced directional motility. Combined treatments had additive cytotoxic effects linked to the reduced expression of ASPH, Notch transcription factors, and insulin receptor substrate type I, which positively regulates both ASPH and Notch. Conclusions: Triple-drug treatment with DOX, SMI1182, and BEZ235 could potentially improve disease-free survival with CS by the simultaneous targeting of multiple upstream mediators of aggressive malignant tumor cell behavior. Full article

In triple-negative (TNBC) and human epidermal growth factor receptor 2-positive (HER2+) breast cancer patients, neoadjuvant systemic therapy is the standard recommendation for tumors larger than 2 cm. Monitoring the response to primary systemic therapy allows for the assessment of treatment effects, the need for breast-conserving surgery (BCS), and the achievement of pathological complete responses (pCRs). In estrogen receptor-positive/HER2-negative (ER+/HER2-) breast cancer, the benefit of neoadjuvant strategies is controversial, as they have shown lower tumor downstaging and pCR rates compared to other breast cancers. In recent decades, several gene expression assays have been developed to tailor adjuvant treatments in ER+/HER2- early breast cancer (EBC) to identify the patients that will benefit the most from adjuvant chemotherapy (CT) and those at low risk who could be spared from undergoing CT. It is still a challenge to identify patients who will benefit from neoadjuvant systemic treatment (CT or endocrine therapy (ET)). Here, we review the published data on the most common gene expression signatures (MammaPrint (MP), BluePrint (BP), Oncotype Dx, PAM50, the Breast Cancer Index (BCI), and EndoPredict (EP)) and their ability to predict the response to neoadjuvant treatment, as well as the possibility of using them on core needle biopsies. Additionally, we review the changes in the gene expression signatures after neoadjuvant treatment, and the ongoing clinical trials related to the utility of gene expression signatures in the neoadjuvant setting. Full article

Background: In 2022, there were an estimated 20 million new cancer cases and 9.7 million deaths. The number of new cancer cases is expected to rise to over 35 million by 2050, marking a 75% increase from 2022 levels. Twenty to eighty-six percent of cancer patients suffer from taste disorders (TD), which are associated with an increased risk of malnutrition. Cachectic syndrome is linked to the presence and growth of tumors and leads to systemic inflammation. Synsepalum dulcificum is a plant whose berries contain miraculin, a glycoprotein that transforms sour tastes into sweet and can ameliorate TD. Objectives: To evaluate the effect of the regular intake of dried miracle berries (DMBs), a novel food containing miraculin, on biomarkers of inflammation and cachexia in malnourished patients with cancer and TD receiving systemic antineoplastic therapy. Methods: we conducted a triple-blind, randomized, placebo-controlled pilot clinical trial. Thirty-one patients with cancer of various etiologies who received chemotherapy were enrolled in this pilot study and divided into three groups. The first group received a tablet containing 150 mg of DMB (standard dose), the high-dose group received a tablet of 300 mg of DMB, and the third group received a tablet with 300 mg of the placebo for three months before each main meal. The plasma levels of several molecules associated with inflammation and cancer cachexia were measured using the X-MAP Luminex multiplexing platform. Results: We found decreased plasma levels of IFN-γ in the standard-dose group. In addition, our results suggest a downtrend of IL-1β levels in the three groups after three months of intervention (p = 0.093). Moreover, the three groups showed a reduction in tumor-derived molecule proteolysis-inducing factor/dermcidin (p = 0.021). It is important to highlight the positive correlation between IL-6 and IL-10 in the standard group, which suggests a better balance between proinflammatory and anti-inflammatory cytokines. Regardless of DMB consumption, soluble TNF receptor type II tended to decrease with treatment in patients who responded well to the antineoplastic treatment (p = 0.011). We did not find significant correlations between cytokines and sensory variables or dietary and nutritional status. Conclusions: Our results suggest that the regular consumption of a standard dose of DMB along with a systemic antineoplastic treatment could contribute to reducing inflammation and cachexia biomarkers in malnourished patients with cancer exhibiting TD. In this sense, nutritional support is crucial in the treatment of cancer cachexia. In our view, it should be considered a coadjuvant of therapeutics. Future studies on the molecular signaling pathways and specific mechanisms of action of bioactive compounds within food supplements, such as miraculin, will allow them to be used to target pathogenic mechanisms of cancer cachexia and malnutrition: NCT05486260. Full article

Breast cancer is the most common and deadly female-specific malignancy in the world. Four immunohistochemical subtypes are distinguished: luminal A, luminal B, HER2-positive, and triple-negative. In turn, the HER2-positive subtype presents two variants depending on the status of the hormone receptors. The variant that expresses them can benefit from both anti-HER2 and anti-hormonal therapy. Today, MCTP finds application in maintenance therapy after standard of care and in advanced breast cancer when the patient’s clinical condition is already seriously compromised by metastatic disease; in this context, it is used as a first-line treatment, in pre-treated subjects, or as a rescue treatment. Here, the use of adjuvant oral MCTP after surgery at an early stage in HER-2 and hormone-positive local breast cancer is proposed, where effective treatment options are available, such as anti-HER2 therapy (e.g., trastuzumab, pertuzumab), anti-hormonal therapy (e.g., tamoxifen, letrozole), radiotherapy, and, in case of strong PD-1 positivity, immunotherapy. Full article

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with high metastatic potential, poor prognosis, and the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2). The lack of these receptors limits the standard treatments, such as hormone therapies and HER2-targeted antibodies like trastuzumab. These challenges highlight the critical need for novel therapeutic strategies. CD147, a transmembrane glycoprotein overexpressed in TNBC, promotes tumor progression, metastasis, and chemoresistance, making it a promising therapeutic target. This study evaluates the antibody-dependent cellular cytotoxicity (ADCC) of HuM6-1B9, a humanized anti-CD147 antibody, against MDA-MB-231 cells, a TNBC model. Methods: CFSE-labelled MDA-MB-231 cells were co-cultured with PBMCs as effector cells (E:T ratio 80:1) in the presence of HuM6-1B9 and incubated for 4 h. Cells were then collected and stained with PI, and CFSE+/PI+ dead target cells were analyzed by flow cytometry. Results: Co-culturing MDA-MB-231 cells with peripheral blood mononuclear cells (PBMCs) in the presence of HuM6-1B9 demonstrated effective ADCC induction without direct cytotoxicity. HuM6-1B9 induced 54.01% cancer cell death via ADCC, significantly outperforming trastuzumab (26.14%) while sparing PBMCs. Conclusion: These findings support HuM6-1B9 as a prospective TNBC therapeutic and warrant further investigation into its clinical potential. Full article

Background/Objectives: Accurately identifying residual disease in the breast following neoadjuvant systemic therapy (NST) is a critical aspect of treatment planning. While surgery remains the standard treatment, its omission may be considered in exceptional responders. However, this strategy is still under investigation and carries local and distant recurrence risks. No definitive method currently exists to confirm pathologic complete response (pCR) after NST. This study evaluates the reliability of ultrasound-guided 14G Tru-Cut biopsy in assessing post-NST disease status. Methods: Data from 204 breast cancer patients who underwent ultrasound-guided 14G Tru-Cut biopsy before surgery at Istanbul University Oncology Institute (March 2015–May 2024) were analyzed. Concordance between Tru-Cut biopsy and final pathology was assessed, along with diagnostic accuracy parameters, including false-negative rate (FNR), accuracy, negative predictive value (NPV), and positive predictive value (PPV). Results: The median patient age was 45 years (range: 26–86). The median initial tumor size was 32 mm, reducing to 10 mm post-treatment. Pathologic complete response (pCR) was 33.8% in surgical specimens and 40.7% in biopsy samples. Biopsy misdiagnosed 15 patients, with an overall FNR of 11.1% and accuracy of 92.2% (95% CI, 7.1–18.1%; 95% CI, 87.6–95.5%). Among patients with radiologic complete response (rCR) (n = 99), FNR was 25.8%, and accuracy was 92.1%. The best outcomes were in the rCR and Tru-Cut pCR subgroup, with an FNR of 5.9% and accuracy of 95.6%. In triple-negative breast cancer patients, FNR was 5%, and an accuracy was 97.4%. Conclusions: Although obtaining eight or more samples with a 14G Tru-Cut biopsy after NST is insufficient to alter clinical practice for detecting residual disease, the promising results observed in the rCR and Tru-Cut pCR subgroups suggest its potential role in guiding treatment strategies. Full article

Primary cervical dystonia (PCD), or spasmodic torticollis, is a focal dystonia characterized by involuntary and often painful muscle contractions, leading to abnormal cervical movements and postures. While botulinum toxin injections are the first-line treatment, additional therapies, such as segmental muscle vibration (SMV), remain underexplored. SMV, a non-invasive neuromodulation technique, may enhance motor cortex excitability and promote neuroplasticity, offering potential benefits in PCD management. This single-center triple-blinded randomized controlled trial evaluates SMV’s efficacy in reducing dystonic pain and improving quality of life in PCD patients undergoing standardized rehabilitation after botulinum toxin treatment. Participants with a pain level of ≥3 on the Numerical Rating Scale will be randomized into two groups. The experimental group will receive 80 Hz SMV during a 10-session rehabilitation program, while the control group will undergo sham SMV. Both groups will follow identical physiotherapy and occupational therapy protocols. The primary outcomes include changes in pain intensity and function, assessed at baseline, mid-treatment, and post-treatment using validated scales. The secondary outcomes will evaluate quality of life and patient satisfaction. This study hypothesizes that SMV will significantly reduce dystonic pain and enhance quality of life, supporting its integration into multidisciplinary rehabilitation for dystonic disorders. Trial registration number: NCT06748846. Full article