Search

Growing evidence has demonstrated the role of mutations of tumor biomarkers in diagnosing and treating epithelial ovarian cancer. This review aims to analyze recent literature on the correlation between tumor biomarkers and chemotherapy in nonmucinous ovarian cancer, providing suggestions for personalized treatment approaches. An extensive literature search was conducted to identify relevant studies and trials. BRCA1/2 mutations are central in homologous recombination repair deficiency (HRD) in ovarian cancer, but several other genetic mutations also contribute to varying cancer risks. While the role of MMR testing in ovarian cancer is debated, it is more commonly linked to non-serous ovarian cancer, often associated with Lynch syndrome. A significant proportion of ovarian cancer patients have HRD, affecting treatment decisions in both first-line (especially in advanced stages) and second-line therapy due to HRD's connection with platinum-based therapy and PARP inhibitors' response. However, validated genetic tests to identify HRD have not yet been universally implemented. There is no definitive therapeutic algorithm for advanced ovarian cancer, despite ongoing efforts and multiple proposed tools. Future research should focus on expanding the utility of biomarkers, reducing resistance, and increasing the actionable biomarker pool. [ABSTRACT FROM AUTHOR]

Introduction: Radiotherapy (RT) shows potential for improving local control in cases of oligoprogressive metastatic breast cancer (mBC). This retrospective analysis aims to evaluate the advantages of RT in such a clinical scenario. Methods: We conducted a retrospective analysis including patients with mBC who received radiation therapy (RT) for up to three sites of oligoprogression while continuing systemic therapy. The study took place between January 2014 and December 2021. Our endpoints were progression-free survival after radiotherapy (PFS-AR), the rate of discontinuation of systemic therapy (RDT) at three months post-RT, and overall survival (OS). We used Cox regression analysis to perform multivariate analysis for PFS-AR. Results: Fifty-nine patients met the inclusion criteria. The PFS-AR was 13 months (95% CI 8.5–18.8 months). At three months, the RDT was 3% (two patients). A significant difference in median PFS-AR was observed between patients in the first + second-line group and those in the subsequent line group (p = 0.03). In the multivariate analysis conducted for PFS-AR, the biologically effective dose (BED) with α/β = 4 > 100 Gy emerged as the sole significant variable (p = 0.0017). The median overall survival (OS) was 24.4 months (95% CI 17–24.4 months). Conclusions: This study is the first report on the outcomes of radiotherapy in a cohort of over 50 patients with oligoprogressive metastatic breast cancer (mBC). Our findings emphasize the significant relationship between PFS-AR, the number of ongoing lines of systemic therapy, and the BED of radiotherapy. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by irreversible scarring of lung tissue, leading to death. Despite recent advancements in understanding its pathophysiology, IPF remains elusive, and therapeutic options are limited and non-curative. This review aims to synthesize the latest research developments, focusing on the molecular mechanisms driving the disease and on the related emerging treatments. Unfortunately, several phase 2 studies showing promising preliminary results did not meet the primary endpoints in the subsequent phase 3, underlying the complexity of the disease and the need for new integrated endpoints. IPF remains a challenging condition with a complex interplay of genetic, epigenetic, and pathophysiological factors. Ongoing research into the molecular keystones of IPF is critical for the development of targeted therapies that could potentially stop the progression of the disease. Future directions include personalized medicine approaches, artificial intelligence integration, growth in genetic insights, and novel drug targets. [ABSTRACT FROM AUTHOR]

Gliomas' aggressive nature and resistance to therapy make them a major problem in oncology. Gliomas continue to have dismal prognoses despite significant advancements in medical science, and traditional treatments like surgery, radiation (RT), and chemotherapy (CT) frequently prove to be ineffective. After glioma stem cells (GSCs) were discovered, the traditional view of gliomas as homogeneous masses changed. GSCs are essential for tumor growth, treatment resistance, and recurrence. These cells' distinct capacities for differentiation and self-renewal are changing our knowledge of the biology of gliomas. This systematic literature review aims to uncover the molecular mechanisms driving glioma progression associated with GSCs. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. The first literature search was performed on 1 March 2024, and the search was updated on 15 May 2024. Employing MeSH terms and Boolean operators, the search focused on molecular mechanisms associated with GCSs-mediated glioma progression. Inclusion criteria encompassed English language studies, preclinical studies, and clinical trials. A number of 957 papers were initially identified, of which 65 studies spanning from 2005 to 2024 were finally included in the review. The main GSC model distribution is arranged in decreasing order of frequency: U87: 20 studies (32.0%); U251: 13 studies (20.0%); A172: 4 studies (6.2%); and T98G: 2 studies (3.17%). From most to least frequent, the distribution of the primary GSC pathway is as follows: Notch: 8 studies (12.3%); STAT3: 6 studies (9.2%); Wnt/β-catenin: 6 studies (9.2%); HIF: 5 studies (7.7%); and PI3K/AKT: 4 studies (6.2%). The distribution of molecular effects, from most to least common, is as follows: inhibition of differentiation: 22 studies (33.8%); increased proliferation: 18 studies (27.7%); enhanced invasive ability: 15 studies (23.1%); increased self-renewal: 5 studies (7.7%); and inhibition of apoptosis: 3 studies (4.6%). This work highlights GSC heterogeneity and the dynamic interplay within the glioblastoma microenvironment, underscoring the need for a tailored approach. A few key pathways influencing GSC behavior are JAK/STAT3, PI3K/AKT, Wnt/β-catenin, and Notch. Therapy may target these pathways. This research urges more study to fill in knowledge gaps in the biology of GSCs and translate findings into useful treatment approaches that could improve GBM patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: CD44 is a crucial factor in colorectal cancer, with specific isoforms demonstrating their significance in the development, progression, metastasis, and resistance to therapy. Given the clinical and pathological impact of CD44, it represents a promising molecular target for cancer therapy. In this review, we aim to highlight the predictive and prognostic significance of CD44 in various cancer types, with a particular focus on colorectal cancer. Moreover, we evaluate current therapeutic interventions that target CD44 or reduce its expression, thereby highlighting its potential as an effective therapeutic strategy. Cluster of differentiation 44 (CD44) is a non-kinase cell surface glycoprotein. It is overexpressed in several cell types, including cancer stem cells (CSCs). Cells overexpressing CD44 exhibit several CSC traits, such as self-renewal, epithelial–mesenchymal transition (EMT) capability, and resistance to chemo- and radiotherapy. The role of CD44 in maintaining stemness and the CSC function in tumor progression is accomplished by binding to its main ligand, hyaluronan (HA). The HA-CD44 complex activates several signaling pathways that lead to cell proliferation, adhesion, migration, and invasion. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The different functional roles of CD44s and specific CD44v isoforms still need to be fully understood. The clinicopathological impact of CD44 and its isoforms in promoting tumorigenesis suggests that CD44 could be a molecular target for cancer therapy. Furthermore, the recent association observed between CD44 and KRAS-dependent carcinomas and the potential correlations between CD44 and tumor mutational burden (TMB) and microsatellite instability (MSI) open new research scenarios for developing new strategies in cancer treatment. This review summarises current research regarding the different CD44 isoform structures, their roles, and functions in supporting tumorigenesis and discusses its therapeutic implications. [ABSTRACT FROM AUTHOR]

Glioblastoma, the most aggressive and common malignant primary brain tumour, is characterized by infiltrative growth, abundant vascularization, and aggressive clinical evolution. Patients with glioblastoma often face poor prognoses, with a median survival of approximately 15 months. Technological progress and the subsequent improvement in understanding the pathophysiology of these tumours have not translated into significant achievements in therapies or survival outcomes for patients. Progress in molecular profiling has yielded new omics data for a more refined classification of glioblastoma. Several typical genetic and epigenetic alterations in glioblastoma include mutations in genes regulating receptor tyrosine kinase (RTK)/rat sarcoma (RAS)/phosphoinositide 3-kinase (PI3K), p53, and retinoblastoma protein (RB) signalling, as well as mutation of isocitrate dehydrogenase (IDH), methylation of O6-methylguanine-DNA methyltransferase (MGMT), amplification of epidermal growth factor receptor vIII, and codeletion of 1p/19q. Certain microRNAs, such as miR-10b and miR-21, have also been identified as prognostic biomarkers. Effective treatment options for glioblastoma are limited. Surgery, radiotherapy, and alkylating agent chemotherapy remain the primary pillars of treatment. Only promoter methylation of the gene MGMT predicts the benefit from alkylating chemotherapy with temozolomide and it guides the choice of first-line treatment in elderly patients. Several targeted strategies based on tumour-intrinsic dominant signalling pathways and antigenic tumour profiles are under investigation in clinical trials. This review explores the potential genetic and epigenetic biomarkers that could be deployed as analytical tools in the diagnosis and prognostication of glioblastoma. Recent clinical advancements in treating glioblastoma are also discussed, along with the potential of liquid biopsies to advance personalized medicine in the field of glioblastoma, highlighting the challenges and promises for the future. [ABSTRACT FROM AUTHOR]

Background: Pediatric gastroenteropancreatic neuroendocrine tumors are exceedingly rare, resulting in most pediatric treatment recommendations being based on data derived from adults. Trametinib is a kinase inhibitor that targets MEK1/2 and has been employed in the treatment of cancers harboring mutations in the Ras pathway. Methods: We utilized an established human pediatric gastroenteropancreatic neuroendocrine-like tumor patient-derived xenograft (PDX) with a known NRAS mutation to study the effects of MEK inhibition. We evaluated the effects of trametinib on proliferation, motility, and tumor growth in vivo. We created an intraperitoneal metastatic model of this PDX, characterized both the phenotype and the genotype of the metastatic PDX and again, investigated the effects of MEK inhibition. Results: We found target engagement with decreased ERK1/2 phosphorylation with trametinib treatment. Trametinib led to decreased in vitro cell growth and motility, and decreased tumor growth and increased animal survival in a murine flank tumor model. Finally, we demonstrated that trametinib was able to significantly decrease gastroenteropancreatic neuroendocrine intraperitoneal tumor metastasis. Conclusions: The results of these studies support the further investigation of MEK inhibition in pediatric NRAS mutated solid tumors.

Introduction: Molecular and genomic profiling in endometrial cancer is increasing popularity. L1 cell adhesion molecule (L1CAM) is frequently mutated in endometrial cancer. In this paper, we aim to evaluate the prognostic role of L1CAM in patients with stage I endometrial cancer. Methods: We performed a systematic review and meta-analysis searching in PubMed (MEDLINE), EMBASE, and Web of Science database to identify studies reporting the expression of L1CAM in endometrial cancer. The primary endpoint measure was to assess and evaluate the impact of L1CAM on survival outcomes. This study was performed according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) statement. Results: Five studies were included. The pooled results suggested that L1CAM expression influences survival outcomes in stage I endometrial cancer. High L1CAM expression correlated with worse disease-free survival (HR 4.11, 95% CI 1.02–16.59, p = 0.047) and overall survival (HR 3.62, 95% CI 1.32–9.31, p = 0.012). High L1CAM level was also associated with a more aggressive FIGO grade and with older age. Conclusion: This systematic review supported that L1CAM have a prognostic role in stage I endometrial cancer, thus providing a potential useful tool for tailoring the need of adjuvant therapy. [ABSTRACT FROM AUTHOR]

Background: Chondrosarcomas rank as the second most common primary bone malignancy. Characterized by the production of a cartilaginous matrix, these tumors typically exhibit resistance to both radiotherapy (RT) and chemotherapy (CT), resulting in overall poor outcomes: a high rate of mortality, especially among children and adolescents. Due to the considerable resistance to current conventional therapies such as surgery, CT, and RT, there is an urgent need to identify factors contributing to resistance and discover new strategies for optimal treatment. Over the past decade, researchers have delved into the dysregulation of genes associated with tumor development and therapy resistance to identify potential therapeutic targets for overcoming resistance. Recent studies have suggested several promising biomarkers and therapeutic targets for chondrosarcoma, including isocitrate dehydrogenase (IDH1/2) and COL2A1. Molecule-targeting agents and immunotherapies have demonstrated favorable antitumor activity in clinical studies involving patients with advanced chondrosarcomas. In this systematic review, we delineate the clinical features of chondrosarcoma and provide a summary of gene dysregulation and mutation associated with tumor development, as well as targeted therapies as a promising molecular approach. Finally, we analyze the probable role of the tumor microenvironment in chondrosarcoma drug resistance. Methods: A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 10 November 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "chondrosarcomas", "target therapies", "immunotherapies", and "outcomes". The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of target therapies for the treatment of chondrosarcoma in human subjects. Results: Of the initial 279 articles identified, 40 articles were included in the article. The exclusion of 140 articles was due to reasons such as irrelevance, non-reporting of selected results, systematic literature review or meta-analysis, and lack of details on the method/results. Three tables highlighted clinical studies, preclinical studies, and ongoing clinical trials, encompassing 13, 7, and 20 studies, respectively. For the clinical study, a range of molecular targets, such as death receptors 4/5 (DR4 and DR5) (15%), platelet-derived growth factor receptor-alpha or -beta (PDGFR-α, PDGFR-β) (31%), were investigated. Adverse events were mainly constitutional symptoms emphasizing that to improve therapy tolerance, careful observation and tailored management are essential. Preclinical studies analyzed various molecular targets such as DR4/5 (28.6%) and COX-2 (28.6%). The prevalent indicator of antitumoral activity was the apoptotic rate of both a single agent (tumor necrosis factor-related apoptosis-inducing ligand: TRAIL) and double agents (TRAIL-DOX, TRAIL-MG132). Ongoing clinical trials, the majority in Phase II (53.9%), highlighted possible therapeutic strategies such as IDH1 inhibitors and PD-1/PD-L1 inhibitors (30.8%). Conclusions: The present review offers a comprehensive analysis of targeted therapeutics for skull base chondrosarcomas, highlighting a complex landscape characterized by a range of treatment approaches and new opportunities for tailored interventions. The combination of results from molecular research and clinical trials emphasizes the necessity for specialized treatment strategies and the complexity of chondrosarcoma biology. [ABSTRACT FROM AUTHOR]

High-grade glial tumors (HGGs) exhibit aggressive growth patterns and high recurrence rates. The prevailing treatment approach comprises radiation therapy (RT), chemotherapy (CMT), and surgical resection. Despite the progress made in traditional treatments, the outlook for patients with HGGs remains bleak. Tumor metabolism is emerging as a potential target for glioma therapies, a promising approach that harnesses the metabolism to target tumor cells. However, the efficacy of therapies targeting the metabolism of HGGs remains unclear, compelling a comprehensive review. This study aimed to assess the outcome of present trials on HGG therapies targeting metabolism. A comprehensive search of PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted until November 2023. The search method used pertinent Medical Subject Heading (MeSH) terminologies and keywords referring to "high-grade gliomas", "metabolism", "target therapies", "monoclonal antibodies", "overall survival", and "progression-free survival". The review analyzed studies that focused on therapies targeting the metabolism of HGGs in human subjects. These studies included both randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs). Out of 284 articles identified, 23 trials met the inclusion criteria and were thoroughly analyzed. Phase II trials were the most numerous (62%). Targeted metabolic therapies were predominantly used for recurrent HGGs (67%). The most common targeted pathways were the vascular endothelial growth factor (VEGF, 43%), the human epidermal growth factor receptor (HER, 22%), the platelet-derived growth factor (PDGF, 17%), and the mammalian target of rapamycin (mTOR, 17%). In 39% of studies, the subject treatment was combined with CMT (22%), RT (4%), or both (13%). The median OS widely ranged from 4 to 26.3 months, while the median PFS ranged from 1.5 to 13 months. This systematic literature review offers a thorough exploration of the present state of metabolic therapies for HGGs. The multitude of targeted pathways underscores the intricate nature of addressing the metabolic aspects of these tumors. Despite existing challenges, these findings provide valuable insights, guiding future research endeavors. The results serve as a foundation for refining treatment strategies and enhancing patient outcomes within the complex landscape of HGGs. [ABSTRACT FROM AUTHOR]

Craniopharyngiomas present unique challenges in surgical management due to their proximity to critical neurovascular structures. This systematic review investigates genetic and immunological markers as potential targets for therapy in craniopharyngiomas, assessing their involvement in tumorigenesis, and their influence on prognosis and treatment strategies. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. Employing MeSH terms and Boolean operators, the search focused on craniopharyngiomas, targeted or molecular therapy, and clinical outcomes or adverse events. Inclusion criteria encompassed English language studies, clinical trials (randomized or non-randomized), and investigations into adamantinomatous or papillary craniopharyngiomas. Targeted therapies, either standalone or combined with chemotherapy and/or radiotherapy, were examined if they included clinical outcomes or adverse event analysis. Primary outcomes assessed disease response through follow-up MRI scans, categorizing responses as follows: complete response (CR), near-complete response (NCR), partial response, and stable or progressive disease based on lesion regression percentages. Secondary outcomes included treatment type and duration, as well as adverse events. A total of 891 papers were initially identified, of which 26 studies spanning from 2000 to 2023 were finally included in the review. Two tables highlighted adamantinomatous and papillary craniopharyngiomas, encompassing 7 and 19 studies, respectively. For adamantinomatous craniopharyngiomas, Interferon-2α was the predominant targeted therapy (29%), whereas dabrafenib took precedence (70%) for papillary craniopharyngiomas. Treatment durations varied, ranging from 1.7 to 28 months. Positive responses, including CR or NCR, were observed in both types of craniopharyngiomas (29% CR for adamantinomatous; 32% CR for papillary). Adverse events, such as constitutional symptoms and skin changes, were reported, emphasizing the need for vigilant monitoring and personalized management to enhance treatment tolerability. Overall, the data highlighted a diverse landscape of targeted therapies with encouraging responses and manageable adverse events, underscoring the importance of ongoing research and individualized patient care in the exploration of treatment options for craniopharyngiomas. In the realm of targeted therapies for craniopharyngiomas, tocilizumab and dabrafenib emerged as prominent choices for adamantinomatous and papillary cases, respectively. While adverse events were common, their manageable nature underscored the importance of vigilant monitoring and personalized management. Acknowledging limitations, future research should prioritize larger, well-designed clinical trials and standardized treatment protocols to enhance our understanding of the impact of targeted therapies on craniopharyngioma patients. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) still ranks as the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide. Despite the recent progress in the therapeutic algorithm of the advanced disease with the advent of immune checkpoint inhibitors (ICIs) and next-generation HER2-directed therapies, survival rates remain poor, with a median survival hardly exceeding 12 months. Furthermore, only 40% of patients remain eligible for second- and later-line treatments due to the aggressiveness of the disease and the rapid deterioration of performance status (PS). Thus, current research is focusing either on the identification of novel treatment options or the development of personalized strategies to optimize the continuum of care and ultimately improve patients' outcome. In this article, we provide an overview of the current treatment landscape for advanced GC with a particular emphasis on later-line treatments and outline novel perspectives on the horizon. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "glioblastomas," "immunotherapies," and "treatment." The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability. [ABSTRACT FROM AUTHOR]

Atopic dermatitis and psoriasis are traditionally considered diseases that cannot coexist, since they are described as the result of the activation of opposing inflammatory pathways. However, this belief has been debunked, and numerous cases of psoriasis induced by dupilumab, a biologic treatment for atopic dermatitis, have been reported. We report three cases of dupilumab-induced psoriasis and we present a literature review including cases of "de novo" psoriasis and of the relapse of psoriasis that occurred during treatment with dupilumab. In total, 39 publications met the inclusion criteria, including 112 AD patients, 101 of whom developed "de novo" psoriasis, and 11 with a flare of pre-existent psoriasis. In the first group, patients more frequently developed plaque psoriasis on the scalp and extremities, after an average latency period from the initiation of dupilumab of 5 months. In the second group, the incidence of dupilumab-induced relapses of psoriasis was 43%, after an average of 4 months since the first administration. The most common psoriasis type was plaque psoriasis, with the involvement of the scalp and upper extremities. Dupilumab was interrupted in 38% of patients with "de novo" psoriasis and in 50% of relapsed patients, leading, in most cases, to an improvement of psoriasis. In conclusion, atopic dermatitis and psoriasis can definitely co-exist, and biologic drugs used to treat the former can promote the latter. It is thus crucial to perform a careful personal and familiar anamnesis before prescribing any biologic treatment. Moreover, a study of cytokine expression and blood proteomic markers could be considered in these patients. [ABSTRACT FROM AUTHOR]

In carcinogenesis of the gastrointestinal (GI) tract, the deregulation of fibroblast growth factor receptor (FGFR) signaling plays a critical role. The aberrant activity of this pathway is described in approximately 10% of gastric cancers and its frequency increases in intrahepatic cholangiocarcinomas (iCCAs), with an estimated frequency of 10–16%. Several selective FGFR inhibitors have been developed in the last few years with promising results. For example, targeting the FGFR pathway is now a fundamental part of clinical practice when treating iCCA and many clinical trials are ongoing to test the safety and efficacy of anti-FGFR agents in gastric, colon and pancreatic cancer, with variable results. However, the response rates of anti-FGFR drugs are modest and resistances emerge rapidly, limiting their efficacy and causing disease progression. In this review, we aim to explore the landscape of anti-FGFR inhibitors in relation to GI cancer, with particular focus on selective FGFR inhibitors and drug combinations that may lead to overcoming resistance mechanisms and drug-induced toxicities. [ABSTRACT FROM AUTHOR]

Paola Triggianese, Paola Conigliaro, Erica De Martino, Benedetta Monosi, Maria Sole Chimenti Department of Systems Medicine, Rheumatology, Allergology and Clinical Immunology, University of Rome Tor Vergata, Rome, ItalyCorrespondence: Maria Sole Chimenti, Rheumatology, Allergology and Immunology, University of Rome Tor Vergata, Via Montpellier 1, Rome, Italy, Tel +39 6 20900358, Email maria.sole.chimenti@unroma2.itAbstract: Complement system (CS) dysregulation is a key factor in the pathogenesis of different autoimmune diseases playing a central role in many immune innate and adaptive processes. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by ta breach of self-tolerance leading to a synovitis and extra-articular manifestations. The CS is activated in RA and seems not only to mediate direct tissue damage but also play a role in the initiation of RA pathogenetic mechanisms through interactions with citrullinated proteins. Interstitial lung disease (ILD) represents the most common extra-articular manifestation that can lead to progressive fibrosis. In this review, we focused on the evidence of CS dysregulation in RA and in ILD, and highlighted the role of the CS in both the innate and adaptive immune responses in the development of diseases, by using idiopathic pulmonary fibrosis as a model of lung disease. As a proof of concept, we dissected the evidence that several treatments used to treat RA and ILD such as glucocorticoids, pirfenidone, disease modifying antirheumatic drugs, targeted biologics such as tumor necrosis factor (TNF)-inhibitors, rituximab, tocilizumab, and nintedanib may act indirectly on the CS, suggesting that the CS might represent a potential therapeutic target in these complex diseases.Keywords: complement system, rheumatoid arthritis, interstitial lung disease, target therapies

Adenoid cystic carcinoma (ACC) is an aggressive tumor with a high propensity for distant metastasis and perineural invasion. This tumor is more commonly found in regions of the head and neck, mainly the salivary glands. In general, the primary treatment modality for ACC is surgical resection and, in some cases, postoperative radiotherapy. However, no effective systemic treatment is available for patients with advanced disease. Furthermore, this tumor type is characterized by recurrent molecular alterations, especially rearrangements involving the MYB, MYBL1, and NFIB genes. In addition, they also reported copy number alterations (CNAs) that impact genes. One of them is C-KIT, mutations that affect signaling pathways such as NOTCH, PI3KCA, and PTEN, as well as alterations in chromatin remodeling genes. The identification of new molecular targets enables the development of specific therapies. Despite ongoing investigations into immunotherapy, tyrosine kinase inhibitors, and anti-angiogenics, no systemic therapy is approved by the FDA for ACC. In this review, we report the genetic and cytogenetic findings on head and neck ACC, highlighting possible targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) have high cure rates with current treatment options including immuno-polychemotherapy. However, around 30% of cases do not respond or develop relapse disease. For this, it is necessary to search for new therapeutic options. In recent years, therapy using chimeric antigen receptor (CAR) T-cells has been a strategy for those patients with LBDCG in progression or relapse, although only 30-40% of cases achieve durable remissions. The programmed death-1 (PD-1) receptor regulates the T-cell-mediated immune response through binding to its ligands (PD-L1). Some tumor cells present high expression of PD-L1, which down-regulates T-cell activation. The beneficial antitumor activity of PD-1 and PD-L1has been widely demonstrated in certain solid organ malignancies. However, their utility in the treatment of lymphomas is complex. To date, different clinical trials have demonstrated its usefulness as an innovative therapeutic alternative in these tumors. In this review article, we evaluate the literature on the role of the PD-1/PD-L1 pathway in DLBCL and describe future strategies involving these new anticancer agents in this lymphoid neoplasm. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness of the lower limbs. These conditions are caused by lesions in the neuronal pyramidal tract and exhibit clinical and genetic variability. Ongoing research focuses on understanding the underlying mechanisms of HSP onset, which ultimately lead to neuronal degeneration. Key molecular mechanisms involved include axonal transport, cytoskeleton dynamics, myelination abnormalities, membrane trafficking, organelle morphogenesis, ER homeostasis, mitochondrial dysfunction, and autophagy deregulation. This review aims to provide an overview of the shared pathogenetic mechanisms in various forms of HSPs. By examining disease-causing gene products and their associated functional pathways, this understanding could lead to the discovery of new therapeutic targets and the development of treatments to modify the progression of the disease. Investigating gene functionality is crucial for identifying shared pathogenetic pathways underlying different HSP subtypes. Categorizing protein function and identifying pathways aids in finding biomarkers, predicting early onset, and guiding treatment for a better quality of life. Targeting shared mechanisms enables efficient and cost-effective therapies. Prospects involve identifying new disease-causing genes, refining molecular processes, and implementing findings in diagnosis, key for advancing HSP understanding and developing effective treatments. [ABSTRACT FROM AUTHOR]

Adenoid cystic carcinoma (ACC) is an aggressive tumor with a high propensity for distant metastasis and perineural invasion. This tumor is more commonly found in regions of the head and neck, mainly the salivary glands. In general, the primary treatment modality for ACC is surgical resection and, in some cases, postoperative radiotherapy. However, no effective systemic treatment is available for patients with advanced disease. Furthermore, this tumor type is characterized by recurrent molecular alterations, especially rearrangements involving the MYB, MYBL1, and NFIB genes. In addition, they also reported copy number alterations (CNAs) that impact genes. One of them is C-KIT, mutations that affect signaling pathways such as NOTCH, PI3KCA, and PTEN, as well as alterations in chromatin remodeling genes. The identification of new molecular targets enables the development of specific therapies. Despite ongoing investigations into immunotherapy, tyrosine kinase inhibitors, and anti-angiogenics, no systemic therapy is approved by the FDA for ACC. In this review, we report the genetic and cytogenetic findings on head and neck ACC, highlighting possible targets for therapeutic interventions.

Simple Summary: In recent years, the genetic landscape of hepatocellular carcinoma (HCC) has been explored, identifying TERT promoter, CTNNB1, and TP53 as the most frequent mutated genes. Therapies directed against specific targetable genomic alterations are the basis of personalized medicine and represent the cornerstone of systemic treatment for many malignancies, but are not yet available in HCC. Tools such as liquid biopsy and, in particular, circulating tumor DNA (ctDNA) may help in identifying biomarkers of response or resistance to treatment, and their role in HCC is an active field of research. In this review, we summarize the available evidence on the HCC genomic landscape and the potential role of ctDNA in clinical practice. Hepatocellular carcinoma (HCC) accounts for 90% of primary hepatic malignancies and is one of the major causes of cancer-related death. Over the last 15 years, the molecular landscape of HCC has been deciphered, with the identification of the main driver genes of liver carcinogenesis that belong to six major biological pathways, such as telomere maintenance, Wnt/b-catenin, P53/cell cycle regulation, oxidative stress, epigenetic modifiers, AKT/mTOR and MAP kinase. The combination of genetic and transcriptomic data composed various HCC subclasses strongly related to risk factors, pathological features and prognosis. However, translation into clinical practice is not achieved, mainly because the most frequently mutated genes are undruggable. Moreover, the results derived from the analysis of a single tissue sample may not adequately catch the intra- and intertumor heterogeneity. The analysis of circulating tumor DNA (ctDNA) is broadly developed in other types of cancer for early diagnosis, prognosis and monitoring under systemic treatment in order to identify primary and secondary mechanisms of resistance. The aim of this review is to describe recent data about the HCC molecular landscape and to discuss how ctDNA could be used in the future for HCC detection and management. [ABSTRACT FROM AUTHOR]

Despite progress reported in terms of paraclinical tests and imagistic studies, ovarian cancer represents one of the most lethal malignancies affecting women worldwide. Therefore attention was focused on identifying new prognostic markers in order to better identify candidates for primary cytoreductive surgery versus interval debulking surgery. Moreover, the wide introduction of the concept of personalized medicine gave the opportunity to benefit from more targeted treatments according to each patient needs and particularities. This is a literature review of the current status of ovarian cancer worldwide.

The MET gene, known as MET proto-oncogene receptor tyrosine kinase, was first identified to induce tumor cell migration, invasion, and proliferation/survival through canonical RAS-CDC42-PAK-Rho kinase, RAS-MAPK, PI3K-AKT-mTOR, and β-catenin signaling pathways, and its driver mutations, such as MET gene amplification (METamp) and the exon 14 skipping alterations (METex14), activate cell transformation, cancer progression, and worse patient prognosis, principally in lung cancer through the overactivation of their own oncogenic and MET parallel signaling pathways. Because of this, MET driver alterations have become of interest in lung adenocarcinomas since the FDA approval of target therapies for METamp and METex14 in 2020. However, after using MET target therapies, tumor cells develop adaptative changes, favoring tumor resistance to drugs, the main current challenge to precision medicine. Here, we review a link between the resistance mechanism and MET signaling pathways, which is not only limited to MET. The resistance impacts MET parallel tyrosine kinase receptors and signals shared hubs. Therefore, this information could be relevant in the patient's mutational profile evaluation before the first target therapy prescription and follow-up to reduce the risk of drug resistance. However, to develop a resistance mechanism to a MET inhibitor, patients must have access to the drugs. For instance, none of the FDA approved MET inhibitors are registered as such in Chile and other developing countries. Constant cross-feeding between basic and clinical research will thus be required to meet future challenges imposed by the acquired resistance to targeted therapies. [ABSTRACT FROM AUTHOR]

Periodontal disease is a chronic inflammatory condition affecting about 20–50% of people, worldwide, and manifesting clinically through the detection of gingival inflammation, clinical attachment loss, radiographically assessed resorption of alveolar bone, gingival bleeding upon probing, teeth mobility and their potential loss at advanced stages. It is characterized by a multifactorial etiology, including an imbalance of the oral microbiota, mechanical stress and systemic diseases such as diabetes mellitus. The current standard treatments for periodontitis include eliminating the microbial pathogens and applying biomaterials to treat the bone defects. However, periodontal tissue regeneration via a process consistent with the natural tissue formation process has not yet been achieved. Developmental biology studies state that periodontal tissue is composed of neural crest-derived ectomesenchyme. The aim of this review is to discuss the clinical utility of stem cells in periodontal regeneration by reviewing the relevant literature that assesses the periodontal-regenerative potential of stem cells. [ABSTRACT FROM AUTHOR]

Vaccines are a promising therapeutic alternative to monoclonal antibodies against HER-2+ breast cancer. We present the preclinical activity of an ES2B-C001, a VLP-based vaccine being developed for human breast cancer therapy. FVB mice challenged with HER-2+ mammary carcinoma cells QD developed progressive tumors, whereas all mice vaccinated with ES2B-C001+Montanide ISA 51, and 70% of mice vaccinated without adjuvant, remained tumor-free. ES2B-C001 completely inhibited lung metastases in mice challenged intravenously. HER-2 transgenic Delta16 mice developed mammary carcinomas by 4–8 months of age; two administrations of ES2B-C001+Montanide prevented tumor onset for >1 year. Young Delta16 mice challenged intravenously with QD cells developed a mean of 68 lung nodules in 13 weeks, whereas all mice vaccinated with ES2B-C001+Montanide, and 73% of mice vaccinated without adjuvant, remained metastasis-free. ES2B-C001 in adjuvant elicited strong anti-HER-2 antibody responses comprising all Ig isotypes; titers ranging from 1–10 mg/mL persisted for many months. Antibodies inhibited the 3D growth of human HER-2+ trastuzumab-sensitive and -resistant breast cancer cells. Vaccination did not induce cytokine storms; however, it increased the ELISpot frequency of IFN-γ secreting HER-2-specific splenocytes. ES2B-C001 is a promising candidate vaccine for the therapy of tumors expressing HER-2. Preclinical results warrant further development towards human clinical studies. [ABSTRACT FROM AUTHOR]

Primary immunodeficiencies (PID) are rare, complex diseases that can be characterised by a spectrum of phenotypes, from increased susceptibility to infections to autoimmunity, allergy, auto-inflammatory diseases and predisposition to malignancy. With the introduction of genetic testing in these patients and wider use of next-Generation sequencing techniques, a higher number of pathogenic genetic variants and conditions have been identified, allowing the development of new, targeted treatments in PID. The concept of precision medicine, that aims to tailor the medical interventions to each patient, allows to perform more precise diagnosis and more importantly the use of treatments directed to a specific defect, with the objective to cure or achieve long-term remission, minimising the number and type of side effects. This approach takes particular importance in PID, considering the nature of causative defects, disease severity, short- and long-term complications of disease but also of the available treatments, with impact in life-expectancy and quality of life. In this review we revisit how this approach can or is already being implemented in PID and provide a summary of the most relevant treatments applied to specific diseases.

In carcinogenesis of the gastrointestinal (GI) tract, the deregulation of fibroblast growth factor receptor (FGFR) signaling plays a critical role. The aberrant activity of this pathway is described in approximately 10% of gastric cancers and its frequency increases in intrahepatic cholangiocarcinomas (iCCAs), with an estimated frequency of 10–16%. Several selective FGFR inhibitors have been developed in the last few years with promising results. For example, targeting the FGFR pathway is now a fundamental part of clinical practice when treating iCCA and many clinical trials are ongoing to test the safety and efficacy of anti-FGFR agents in gastric, colon and pancreatic cancer, with variable results. However, the response rates of anti-FGFR drugs are modest and resistances emerge rapidly, limiting their efficacy and causing disease progression. In this review, we aim to explore the landscape of anti-FGFR inhibitors in relation to GI cancer, with particular focus on selective FGFR inhibitors and drug combinations that may lead to overcoming resistance mechanisms and drug-induced toxicities.

Simple Summary: In recent years, several agents have been tested in randomized clinical trials in addition to anthracycline and taxane-based neoadjuvant chemotherapy (NACT) in early-stage triple-negative breast cancer (TNBC) to improve pathological complete response rate and, ultimately, survival outcome. Platinum agents, immune checkpoint inhibitors (ICIs), and PARP-inhibitors are the most extensively studied, while established predictors of their efficacy are lacking. Based on the biological features of TNBC, the purpose of this review is to provide an overview of the role of platinum agents, immunotherapy, and novel target therapies in the neoadjuvant setting. Moreover, based on safety issues and financial costs, we provide an overview of potential biomarkers associated with increased likelihood of benefit from the addition of platinum, ICIs, and novel target therapies to NACT. Triple-negative breast cancer (TNBC) is characterized by the absence of hormone receptor and HER2 expression, and therefore a lack of therapeutic targets. Anthracyclines and taxane-based neoadjuvant chemotherapy have historically been the cornerstone of treatment of early TNBC. However, genomic and transcriptomic analyses have suggested that TNBCs include various subtypes, characterized by peculiar genomic drivers and potential therapeutic targets. Therefore, several efforts have been made to expand the therapeutic landscape of early TNBC, leading to the introduction of platinum and immunomodulatory agents into the neoadjuvant setting. This review provides a comprehensive overview of the currently available evidence regarding platinum agents and immune-checkpoint-inhibitors for the neoadjuvant treatment of TNBC, as well as the novel target therapies that are currently being evaluated in this setting. Taking into account the economic issues and the side effects of the expanding therapeutic options, we focus on the potential efficacy biomarkers of the emerging therapies, in order to select the best therapeutic strategy for each specific patient. [ABSTRACT FROM AUTHOR]

Hidradenitis suppurativa, also known as acne inversa, is a chronic, progressive, debilitating, recurrent inflammatory skin disease characterized by the occurrence of very severe, persistent, painful nodules, abscesses, and fistulas, most commonly found in the skin folds of the axilla, groin, gluteal, and perianal areas. Treatment is rather difficult and typically requires the use of multiple modalities. Regardless of the presence of several therapeutic options, treatment often turns out to be ineffective or poorly selected concerning the clinical picture of the disease. Thus, the search for new biologics and other target treatments of hidradenitis suppurativa is ongoing. The safety and efficacy of adalimumab, still the only U.S. Food and Drug Administration approved biologic in the hidradenitis suppurativa treatment, paved the way for new drugs to be compared with it. Several more drugs with new immunological targets are currently under investigation for the treatment of acne inversa. The aim of the article was to present the current and future targets of acne inversa treatment, simultaneously providing insights into the molecular pathomechanisms of the disease. [ABSTRACT FROM AUTHOR]

Background: Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective. Nevertheless, immunocompromised participants were excluded from randomized controlled clinical trials. This study evaluates the efficacy and safety of the Pfizer/BioNTech BNT162b2 (BNT162b2) vaccine in patients with breast and gynecological cancer treated with active anticancer therapy versus a control cohort of healthy participants. Methods: Immune responses to the BNT162b2 vaccine in patients with breast cancer (n = 44) or a gynecological malignancy (n = 6) on active anticancer therapy (28 on chemotherapy, mostly anthracycline- or taxane-based, and 22 on target therapy) and in a control cohort of participants without cancer (n = 67) were investigated by SARS-CoV-2 neutralizing antibody titers measured by S1-binding immunoglobulin G (IgG) concentrations assessed using the LIAISON XL tools (DiaSorin S.p.A.). Response was assessed after a second dose of the BNT162b2 vaccine administered before and at least 3 weeks after the vaccine dose. Results: Overall, 43/50 (86%) patients of the cancer cohort (74% in the breast cancer group and 100% in the gynecological malignancy group) developed IgG antibodies after the second dose of the BNT162b2 vaccine. There were no statistically significant differences in responder rates between patients treated with chemotherapy and those on target therapy. The majority of patients who received chemotherapy with or without target therapy, 21/28 (75%), developed a reliable antibody titer after a vaccine. All seven non-responder patients were undergoing an anthracycline-based regimen. Based on IgG levels (0-400 AU/ml), patients were classified as negative ('non-responders'), weakly positive, or strongly positive ('responders'). No delay in cancer therapy schedule or reported side effects were recorded after BNT162b2 vaccine administration. All healthy participants were strongly positive. Responder rates differed significantly between the two study cohorts (p < 0.001). Conclusions: Most patients develop antibody titers after the second immunization. However, given the persistence of non-responders or weak responders, additional immunization booster seems to be required, along with proactive planning in the vaccination schedule, with vaccine administration spaced out over time with respect to chemotherapy. [ABSTRACT FROM AUTHOR]

BackgroundVaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective. Nevertheless, immunocompromised participants were excluded from randomized controlled clinical trials. This study evaluates the efficacy and safety of the Pfizer/BioNTech BNT162b2 (BNT162b2) vaccine in patients with breast and gynecological cancer treated with active anticancer therapy versus a control cohort of healthy participants.MethodsImmune responses to the BNT162b2 vaccine in patients with breast cancer (n = 44) or a gynecological malignancy (n = 6) on active anticancer therapy (28 on chemotherapy, mostly anthracycline- or taxane-based, and 22 on target therapy) and in a control cohort of participants without cancer (n = 67) were investigated by SARS-CoV-2 neutralizing antibody titers measured by S1-binding immunoglobulin G (IgG) concentrations assessed using the LIAISON XL tools (DiaSorin S.p.A.). Response was assessed after a second dose of the BNT162b2 vaccine administered before and at least 3 weeks after the vaccine dose.ResultsOverall, 43/50 (86%) patients of the cancer cohort (74% in the breast cancer group and 100% in the gynecological malignancy group) developed IgG antibodies after the second dose of the BNT162b2 vaccine. There were no statistically significant differences in responder rates between patients treated with chemotherapy and those on target therapy. The majority of patients who received chemotherapy with or without target therapy, 21/28 (75%), developed a reliable antibody titer after a vaccine. All seven non-responder patients were undergoing an anthracycline-based regimen. Based on IgG levels (0–400 AU/ml), patients were classified as negative (‘non-responders’), weakly positive, or strongly positive (‘responders’). No delay in cancer therapy schedule or reported side effects were recorded after BNT162b2 vaccine administration. All healthy participants were strongly positive. Responder rates differed significantly between the two study cohorts (p < 0.001).ConclusionsMost patients develop antibody titers after the second immunization. However, given the persistence of non-responders or weak responders, additional immunization booster seems to be required, along with proactive planning in the vaccination schedule, with vaccine administration spaced out over time with respect to chemotherapy.

Acute myeloid leukemia (AML) accounts for approximately 15–20% of all childhood leukemia cases. The overall survival of children with acute myeloid leukemia does not exceed 82%, and the 5-year event-free survival rates range from 46% to 69%. Such suboptimal outcomes are the result of numerous mutations and epigenetic changes occurring in this disease that adversely affect the susceptibility to treatment and relapse rate. We describe various molecular-targeted therapies that have been developed in recent years to meet these challenges and were or are currently being studied in clinical trials. First introduced in adult AML, novel forms of treatment are slowly beginning to change the therapeutic approach to pediatric AML. Despite promising results of clinical trials investigating new drugs, further clinical studies involving greater numbers of pediatric patients are still needed to improve the outcomes in childhood AML. [ABSTRACT FROM AUTHOR]

Abstract: Allogeneic stem cell transplantation (allo-SCT) is an increasingly important treatment strategy in fit adults with acute myeloid leukemia (AML). Increased donor availability and a steady reduction in transplant-related mortality (TRM) over the last 2 decades have transformed access to the curative potential of allo-SCT. The identification of patients with AML in first complete remission who will benefit from allo-SCT requires a dynamic assessment of the risk of disease relapse and TRM. Increased accuracy in predicting both relapse risk and transplant toxicity has allowed recommendations for allo-SCT to become increasingly personalized. Notwithstanding its now central position in the treatment algorithm of patients with AML, there, however, has been little progress in reducing the main cause of transplant failure, which remains disease relapse. Novel molecularly targeted therapies have the potential to augment the curative potential of nontransplant therapies, and this may influence the proportion of newly diagnosed fit patients deemed to be allomandatory. At the same time, the ability of such therapies to improve transplant outcomes, either by reducing TRM or the risk of relapse, has the potential to further embed allo-SCT as a key therapeutic modality in AML. [ABSTRACT FROM AUTHOR]

Background: Pediatric gastroenteropancreatic neuroendocrine tumors are exceedingly rare, resulting in most pediatric treatment recommendations being based on data derived from adults. Trametinib is a kinase inhibitor that targets MEK1/2 and has been employed in the treatment of cancers harboring mutations in the Ras pathway., Methods: We utilized an established human pediatric gastroenteropancreatic neuroendocrine-like tumor patient-derived xenograft (PDX) with a known NRAS mutation to study the effects of MEK inhibition. We evaluated the effects of trametinib on proliferation, motility, and tumor growth in vivo. We created an intraperitoneal metastatic model of this PDX, characterized both the phenotype and the genotype of the metastatic PDX and again, investigated the effects of MEK inhibition., Results: We found target engagement with decreased ERK1/2 phosphorylation with trametinib treatment. Trametinib led to decreased in vitro cell growth and motility, and decreased tumor growth and increased animal survival in a murine flank tumor model. Finally, we demonstrated that trametinib was able to significantly decrease gastroenteropancreatic neuroendocrine intraperitoneal tumor metastasis., Conclusions: The results of these studies support the further investigation of MEK inhibition in pediatric NRAS mutated solid tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Bullous pemphigoid is a subepidermal blistering disease associated with autoantibodies (auto-ab) to BP180 and BP230 which affects elderly patients, predominately. Although it is a rare disease, bullous pemphigoid is the most common among the autoimmune bullous skin diseases. Systemic corticosteroids and immunosuppressants represent milestones in the treatment of patients suffering from bullous pemphigoid; however, therapeutic management of patients still represents a clinical challenge, owing to the chronic nature of the disease and to potential adverse effects related to the long-term use of systemic treatments. Recent discoveries on the pathogenesis of bullous pemphigoid have allowed investigation of new target therapies against selective pro-inflammatory mediators. These therapies appear to yield satisfactory results with fewer side effects in cases of refractory disease. The review discusses current evidence on these new therapeutic targets and specific drugs under investigation.

Vaccines are a promising therapeutic alternative to monoclonal antibodies against HER-2+ breast cancer. We present the preclinical activity of an ES2B-C001, a VLP-based vaccine being developed for human breast cancer therapy. FVB mice challenged with HER-2+ mammary carcinoma cells QD developed progressive tumors, whereas all mice vaccinated with ES2B-C001+Montanide ISA 51, and 70% of mice vaccinated without adjuvant, remained tumor-free. ES2B-C001 completely inhibited lung metastases in mice challenged intravenously. HER-2 transgenic Delta16 mice developed mammary carcinomas by 4–8 months of age; two administrations of ES2B-C001+Montanide prevented tumor onset for >1 year. Young Delta16 mice challenged intravenously with QD cells developed a mean of 68 lung nodules in 13 weeks, whereas all mice vaccinated with ES2B-C001+Montanide, and 73% of mice vaccinated without adjuvant, remained metastasis-free. ES2B-C001 in adjuvant elicited strong anti-HER-2 antibody responses comprising all Ig isotypes; titers ranging from 1–10 mg/mL persisted for many months. Antibodies inhibited the 3D growth of human HER-2+ trastuzumab-sensitive and -resistant breast cancer cells. Vaccination did not induce cytokine storms; however, it increased the ELISpot frequency of IFN-γ secreting HER-2-specific splenocytes. ES2B-C001 is a promising candidate vaccine for the therapy of tumors expressing HER-2. Preclinical results warrant further development towards human clinical studies.

BackgroundHepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer-related death. Although the diagnostic scheme of HCC is currently undergoing refinement, the prognosis of HCC is still not satisfactory. In addition to certain factors, such as tumor size and number and vascular invasion displayed on traditional imaging, some histopathological features and gene expression parameters are also important for the prognosis of HCC patients. However, most parameters are based on postoperative pathological examinations, which cannot help with preoperative decision-making. As a new field, radiomics extracts high-throughput imaging data from different types of images to build models and predict clinical outcomes noninvasively before surgery, rendering it a powerful aid for making personalized treatment decisions preoperatively.ObjectiveThis study reviewed the workflow of radiomics and the research progress on magnetic resonance imaging (MRI) radiomics in the diagnosis and treatment of HCC.MethodsA literature review was conducted by searching PubMed for search of relevant peer-reviewed articles published from May 2017 to June 2021.The search keywords included HCC, MRI, radiomics, deep learning, artificial intelligence, machine learning, neural network, texture analysis, diagnosis, histopathology, microvascular invasion, surgical resection, radiofrequency, recurrence, relapse, transarterial chemoembolization, targeted therapy, immunotherapy, therapeutic response, and prognosis.ResultsRadiomics features on MRI can be used as biomarkers to determine the differential diagnosis, histological grade, microvascular invasion status, gene expression status, local and systemic therapeutic responses, and prognosis of HCC patients.ConclusionRadiomics is a promising new imaging method. MRI radiomics has high application value in the diagnosis and treatment of HCC.

Background: Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer-related death. Although the diagnostic scheme of HCC is currently undergoing refinement, the prognosis of HCC is still not satisfactory. In addition to certain factors, such as tumor size and number and vascular invasion displayed on traditional imaging, some histopathological features and gene expression parameters are also important for the prognosis of HCC patients. However, most parameters are based on postoperative pathological examinations, which cannot help with preoperative decision-making. As a new field, radiomics extracts high-throughput imaging data from different types of images to build models and predict clinical outcomes noninvasively before surgery, rendering it a powerful aid for making personalized treatment decisions preoperatively. Objective: This study reviewed the workflow of radiomics and the research progress on magnetic resonance imaging (MRI) radiomics in the diagnosis and treatment of HCC. Methods: A literature review was conducted by searching PubMed for search of relevant peer-reviewed articles published from May 2017 to June 2021.The search keywords included HCC, MRI, radiomics, deep learning, artificial intelligence, machine learning, neural network, texture analysis, diagnosis, histopathology, microvascular invasion, surgical resection, radiofrequency, recurrence, relapse, transarterial chemoembolization, targeted therapy, immunotherapy, therapeutic response, and prognosis. Results: Radiomics features on MRI can be used as biomarkers to determine the differential diagnosis, histological grade, microvascular invasion status, gene expression status, local and systemic therapeutic responses, and prognosis of HCC patients. Conclusion: Radiomics is a promising new imaging method. MRI radiomics has high application value in the diagnosis and treatment of HCC. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) and liquid biopsy are new technologies that can allow overall tumor profiling in a single analysis and play an important role in the implementation of precision oncology. However, the lack of guidelines in this setting has limited the development of precision oncology in Italy. This article summarizes recommendations for the appropriate use of NGS in tumor gene profiling, as well as access to tests and target drugs, that were prepared by a group of key opinion leaders and relevant stakeholders. In particular, the need to create laboratory networks capable of carrying out NGS tests in Italy is highlighted. It also appears necessary to establish an adequate reimbursement system for NGS tests. However, the expert panel recommends that the use of NGS tests in clinical practice should be limited to specific tumor types, based on the number and complexity of biomarkers and the availability of treatments. [ABSTRACT FROM AUTHOR]

The recent identification of rearrangements of neurotrophic tyrosine receptor kinase (NTRK) genes and the development of specific fusion protein inhibitors, such as larotrectinib and entrectinib, have revolutionised the diagnostic and clinical management of patients presenting with tumours with these alterations. Tumours that harbour NTRK fusions are found in both adults and children; and they are either rare tumours with common NTRK fusions that may be diagnostic, or more prevalent tumours with rare NTRK fusions. To assess currently available evidence on this matter, three key Spanish medical societies (the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Pathological Anatomy (SEAP), and the Spanish Society of Paediatric Haematology and Oncology (SEHOP) have brought together a group of experts to develop a consensus document that includes guidelines on the diagnostic, clinical, and therapeutic aspects of NTRK-fusion tumours. This document also discusses the challenges related to the routine detection of these genetic alterations in a mostly public Health Care System. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is a paradigm of tumors that require the interaction between tumor and microenvironment cells to foster their development from initial steps to progression. Recent large-scale genome studies have uncovered multiple genetic alterations of FL that influence the microenvironment in two main directions, promoting tumor cell survival and proliferation and facilitating their evasion from immune antitumor signals. Understanding the crosstalk between tumor B-cells and the microenvironment will facilitate the identification of vulnerabilities that may offer novel targets for treatment of the patients. This review highlights recent findings showing the effect of common genetic mutations modulating the cell composition of the tumor microenvironment and the novel therapeutic perspectives to target these interactions. [ABSTRACT FROM AUTHOR]

Introduction: Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin's lymphoma, characterized by malignant T cells infiltrating the skin. CTCL exhibits vast heterogeneity which complicates diagnosis and therapeutic strategies. Current CTCL treatment includes skin-directed therapies (such as topical corticosteroid, topical mechlorethamine, topical bexarotene, ultraviolet phototherapy and localized radiotherapy), total skin electron beam therapy and systemic therapies. Elucidation of molecular and signaling pathways underlying CTCL pathogenesis leads to identification of innovative and personalized treatment schemes. Areas covered: The authors reviewed the molecular and immunological aspects of CTCL with special focus on Mycosis Fungoides (MF), Sézary Syndrome (SS) and associated systemic treatment. A literature search was conducted in PubMed and Web of Science for peer-reviewed articles published until November 2020. Novel treatment approaches including retinoids, targeted therapies, immune checkpoint and JAK/STAT inhibitors, histones deacetylase (HDAC) and mTOR inhibitors as well as proteasome inhibitors, are discussed as potential therapeutic tools for the treatment of CTCL. Expert opinion: Novel therapeutic agents exhibit potential beneficial effects in CTCL patients of high need for therapy such as refractory early stage cutaneous and advanced stage disease. Therapeutic schemes employing a combination of novel agents with current treatment options may prove valuable for the future management of CTCL patients. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) accounts for approximately 15–20% of all childhood leukemia cases. The overall survival of children with acute myeloid leukemia does not exceed 82%, and the 5-year event-free survival rates range from 46% to 69%. Such suboptimal outcomes are the result of numerous mutations and epigenetic changes occurring in this disease that adversely affect the susceptibility to treatment and relapse rate. We describe various molecular-targeted therapies that have been developed in recent years to meet these challenges and were or are currently being studied in clinical trials. First introduced in adult AML, novel forms of treatment are slowly beginning to change the therapeutic approach to pediatric AML. Despite promising results of clinical trials investigating new drugs, further clinical studies involving greater numbers of pediatric patients are still needed to improve the outcomes in childhood AML.

Background: Galectin-1 (Gal-1) plays major roles in cancer by modulating different processes leading to tumor development and progression. In the last years, it has been suggested as a promising target for anticancer therapy. Recently, aflibercept has shown high affinity for Gal-1. Here, we investigated how aflibercept could exert its antitumor activity via Gal-1-driven pathways in neuroendocrine carcinomas (NECs). Methods and Results: NEC tumor xenografts were used to assess the effect of aflibercept on Gal-1 functions. Aflibercept induced a significant reduction of Gal-1 at epithelial, stromal, and extracellular localizations in lung NEC, whereas this was not observed in colon NECs, which displayed low expression of Gal-1. Additionally, aflibercept significantly reduced p-VEGFR2 protein, extracellular matrix remodeling, epithelial-mesenchymal transition, and activation of cancer-associated fibroblast hampering cell invasion in lung NEC but not in colon NEC. Gal-1 screening in human NECs confirmed that pulmonary and pancreatic tumors displayed higher levels of Gal-1 than colon NECs, becoming good candidates to benefit from aflibercept treatment. Conclusions: The lack of validated predictive markers of aflibercept is a weakness for guaranteeing the best treatment management with this drug. This work provides new mechanistic insight of aflibercept depending on Gal-1. Thus, in tumors overexpressing Gal-1, aflibercept has not only an antiangiogenic effect but also prevents Gal-1-mediated tumor-stroma cross talk. The stronger aflibercept effect in tumors with high levels of Gal-1 points out this protein as a molecular marker to predict the efficacy of this agent not only for NECs but also for other tumors with high levels of this protein. [ABSTRACT FROM AUTHOR]

T-cell acute lymphoblastic leukemia/lymphoma is an aggressive hematological neoplasm whose classification is still based on immunophenotypic findings. Frontline treatment encompass high intensity combination chemotherapy with good overall survival; however, relapsing/refractory patients have very limited options. In the last years, the understanding of molecular physiopathology of this disease, lead to the identification of a subset of patients with peculiar genetic profile, namely “early T-cell precursors” lymphoblastic leukemia, characterized by dismal outcome and indication to frontline allogeneic bone marrow transplant. In general, the most common mutations occur in the NOTCH1/FBXW7 pathway (60% of adult patients), with a positive prognostic impact. Other pathogenic steps encompass transcriptional deregulation of oncogenes/oncosuppressors, cell cycle deregulation, kinase signaling (including IL7R-JAK-STAT pathway, PI3K/AKT/mTOR pathway, RAS/MAPK signaling pathway, ABL1 signaling pathway), epigenetic deregulation, ribosomal dysfunction, and altered expression of oncogenic miRNAs or long non-coding RNA. The insight in the genomic landscape of the disease paves the way to the use of novel targeted drugs that might improve the outcome, particularly in relapse/refractory patients. In this review, we analyse available literature on T-ALL pathogenesis, focusing on molecular aspects of clinical, prognostic, and therapeutic significance.