Immune checkpoint inhibitors and neurotoxicity: a focus on diagnosis and management for a multidisciplinary approach.

INTRODUCTION: Despite immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, the consequential over activation of the immune system is often complicated by adverse events that can affect several organs and systems including the nervous system. The precise pathophysiology underlying neurological irAEs (n-irAEs) is not completely known. Around 3.8% of patients receiving anti-CTLA-4 agents, 6.1% of patients receiving anti-PD-1/PD-L1, and 12% of patients receiving combination therapies have n-irAEs. Most n-irAEs are low-grade, while severe toxicities have been rarely reported.In this article we performed an updated literature search on immuno-related neurotoxicity on main medical research database, from February 2017 to December 2023. AREAS COVERED: We have also compared the latest national and international guidelines on n-irAEs management with each other in order to better define patient management. EXPERT OPINION: A multidisciplinary approach appears necessary in the management of the oncological patient during immunotherapy. Therefore, in order to better manage these toxicities, we believe that it is essential to collaborate with neurologists specialized in the diagnosis and treatment of n-irAEs, and that a global neurological assessment, both central and peripheral, is necessary before starting immunotherapy, with regular reassessment during treatment.

Circulating biomarkers as predictors of response to immune checkpoint inhibitors in NSCLC: Are we on the right path?

Immune checkpoints inhibitors (ICIs) have markedly improved the therapeutic management of advanced NSCLC and, more recently, they have demonstrated efficacy also in the early-stage disease. Despite better survival outcomes with ICIs compared to standard chemotherapy, a large proportion of patients can derive limited clinical benefit from these agents. So far, few predictive biomarkers, including the programmed death-ligand 1 (PD-L1), have been introduced in clinical practice. Therefore, there is an urgent need to identify novel biomarkers to select patients for immunotherapy, to improve efficacy and avoid unnecessary toxicity. A deeper understanding of the mechanisms involved in antitumor immunity and advances in the field of liquid biopsy have led to the identification of a wide range of circulating biomarkers that could potentially predict response to immunotherapy. Herein, we provide an updated overview of these circulating biomarkers, focusing on emerging data from clinical studies and describing modern technologies used for their detection.

Immune escape of multiple myeloma cells results from low miR29b and the ensuing epigenetic silencing of proteasome genes.

BACKGROUND: Activation of CD28 on multiple myeloma (MM) plasma cells, by binding to CD80 and CD86 on dendritic cells, decreases proteasome subunit expression in the tumor cells and thereby helps them evade being killed by CD8+ T cells. Understanding how CD28 activation leads to proteasome subunit downregulation is needed to design new MM therapies. METHODS: This study investigates the molecular pathway downstream of CD28 activation, using an in vitro model consisting of myeloma cell lines stimulated with anti-CD28-coated beads. RESULTS: We show that CD28 engagement on U266 and RPMI 8226 cells activates the PI3K/AKT pathway, reduces miR29b expression, increases the expression of DNA methyltransferase 3B (DNMT3B, a target of miR29b), and decreases immunoproteasome subunit expression. In vitro transfection of U266 and RPMI 8226 cells with a miR29b mimic downregulates the PI3K/AKT pathway and DNMT3B expression, restores proteasome subunit levels, and promotes myeloma cell killing by bone marrow CD8+ T cells from MM patients. Freshly purified bone marrow plasma cells (CD138+) from MM patients have lower miR29b and higher DNMT3B (mRNA and protein) than do cells from patients with monoclonal gammopathy of undetermined significance. Finally, in MM patients, high DNMT3B levels associate with shorter overall survival. CONCLUSIONS: Altogether, this study describes a novel molecular pathway in MM. This pathway starts from CD28 expressed on tumor plasma cells and, through the PI3K-miR29b-DNMT3B axis, leads to epigenetic silencing of immunoproteasome subunits, allowing MM plasma cells to elude immunosurveillance. This discovery has implications for the design of innovative miR29b-based therapies for MM.

Atherosclerosis and the Bidirectional Relationship between Cancer and Cardiovascular Disease: From Bench to Bedside-Part 1.

Atherosclerosis, a complex metabolic-immune disease characterized by chronic inflammation driven by the buildup of lipid-rich plaques within arterial walls, has emerged as a pivotal factor in the intricate interplay between cancer and cardiovascular disease. This bidirectional relationship, marked by shared risk factors and pathophysiological mechanisms, underscores the need for a comprehensive understanding of how these two formidable health challenges intersect and influence each other. Cancer and its treatments can contribute to the progression of atherosclerosis, while atherosclerosis, with its inflammatory microenvironment, can exert profound effects on cancer development and outcomes. Both cancer and cardiovascular disease involve intricate interactions between general and personal exposomes. In this review, we aim to summarize the state of the art of translational data and try to show how oncologic studies on cardiotoxicity can broaden our knowledge of crucial pathways in cardiovascular biology and exert a positive impact on precision cardiology and cardio-oncology.

Endocrine-metabolic assessment checklist for cancer patients treated with immunotherapy: A proposal by the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE) and Italian Society of Pharmacology (SIF) multidisciplinary group.

Immunotherapy with immune checkpoint inhibitors (ICI) is increasingly employed in oncology. National and international endocrine and oncologic scientific societies have provided guidelines for the management of endocrine immune-related adverse events. However, guidelines recommendations differ according to the specific filed, particularly pertaining to recommendations for the timing of endocrine testing. In this position paper, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) offers a critical multidisciplinary consensus for a clear, simple, useful, and easily applicable endocrine-metabolic assessment checklist for cancer patients on immunotherapy.

Holistic exploration of CHGA and hsa-miR-137 in colorectal cancer via multi-omic data Integration.

Colorectal cancer (CRC) ranks among the most widespread malignancies globally, with early detection significantly influencing prognosis. Employing a systems biology approach, we aimed to unravel the intricate mRNA-miRNA network linked to CRC pathogenesis, potentially yielding diagnostic biomarkers. Through an integrative analysis of microarray, Bulk RNA-seq, and single-cell RNA-seq data, we explored CRC-related transcriptomes comprehensively. Differential gene expression analysis uncovered crucial genes, while Weighted Gene Co-expression Network Analysis (WGCNA) identified key modules closely linked to CRC. Remarkably, CRC manifested its strongest correlation with the turquoise module, signifying its pivotal role. From the cohort of genes showing high Gene Significance (GS) and Module Membership (MM), and Differential Expression Genes (DEGs), we highlighted the downregulated Chromogranin A (CHGA) as a notable hub gene in CRC. This finding was corroborated by the Human Protein Atlas database, which illustrated decreased CHGA expression in CRC tissues. Additionally, CHGA displayed elevated expression in primary versus metastatic cell lines, as evidenced by the CCLE database. Subsequent RT-qPCR validation substantiated the marked downregulation of CHGA in CRC tissues, reinforcing the significance of our differential expression analysis. Analyzing the Space-Time Gut Cell Atlas dataset underscored specific CHGA expression in epithelial cell subclusters, a trend persisting across developmental stages. Furthermore, our scrutiny of colon and small intestine Enteroendocrine cells uncovered distinct CHGA expression patterns, accentuating its role in CRC pathogenesis. Utilizing the WGCNA algorithm and TargetScan database, we validated the downregulation of hsa-miR-137 in CRC, and integrated assessment highlighted its interplay with CHGA. Our findings advocate hsa-miR-137 and CHGA as promising CRC biomarkers, offering valuable insights into diagnosis and prognosis. Despite proteomic analysis yielding no direct correlation, our multifaceted approach contributes comprehensive understanding of CRC's intricate regulatory mechanisms. In conclusion, this study advances hsa-miR-137 and CHGA as promising CRC biomarkers through an integrated analysis of diverse datasets and network interactions.

The Italian Rare Biliary tract Cancer initiative (IRaBiCa): A multicentric observational study of Gruppo Oncologico dell'Italia Meridionale (GOIM) in collaboration with Gruppo Italiano Colangiocarcinoma (GICO).

INTRODUCTION: About 90% of cholangiocarcinomas are adenocarcinomas with glandular or tubular structures lined by epithelial cells, with no bile production and with a variable degree of differentiation, arising in the background of desmoplastic stroma. The remaining 10% is represented by rarer histological variants of which there is little knowledge regarding the biological behavior, molecular characterization, and sensitivity to the various possible therapies, including molecular-based treatments. Such rare tumors are described only in case reports or small retrospective series because of their exclusion from clinical trials. This national initiative, here presented, aims to address the following knowledge gap: a) how much does histological diversity translate into clinical manifestation variety? b) are those chemotherapy regimens, recommended for conventional biliary tract cancers, potentially active in rare variants?Therefore, epidemiological, pathological, and clinical characterization of series of rare biliary histotypes/variants, for which therapeutic and follow-up data are available, will be collected. METHODS: An Italian task force on rare tumors of the biliary tract (IRaBiCa) has been created, whose initiative is a multicenter retrospective study involving 34 Italian cancer centers.Clinical data from approximately 100 patients will be collected and analyzed. Continuous variables will be presented as median ± standard deviation, while categorical variables will be expressed in terms of frequency. Kaplan-Maier analyses will be used to compare disease free, progression free and overall survival, according to the different histotypes. CONCLUSIONS: We expect to gather novel data on rare histotypes of biliary tract cancer that will be useful to support their molecular and immunological characterization.

Challenges and pitfalls in the management of endocrine toxicities from immune checkpoint inhibitors: a case presentation of synchronous thyrotoxicosis and primary adrenal insufficiency in a melanoma patient.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the therapeutic approach to several solid tumors, becoming the standard of care for cancer treatment in different disease settings. Despite the fact that these agents are better tolerated than conventional chemotherapy, their use is associated with a specific toxicity profile, so-called immune-related adverse events (irAEs), that can involve several organs. Endocrine irAEs are among the most frequent toxicities (around 10 to 16%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Some of them may be life-threatening if not promptly recognized (such as diabetic ketoacidosis and acute adrenal crisis). CASE PRESENTATION: A 55-year-old woman with a personal history of euthyroid Hashimoto's thyroiditis was diagnosed with a metastatic melanoma, BRAF wild type. Under treatment with anti-PD-1 pembrolizumab, she developed thyrotoxicosis followed by hypothyroidism due to destructive thyroiditis and concurrent primary adrenal insufficiency due to adrenalitis. CONCLUSIONS: The simultaneous occurrence of adrenal and thyroid autoimmune diseases, resembling autoimmune polyendocrine syndrome type 2, may occur as a rare but serious side effect of ICI treatment. It often presents with abrupt onset and rapid evolution towards polyglandular insufficiency. Physicians should be aware of the potential association of two or more endocrine disorders and careful monitoring of endocrine function is needed during ICI therapy.

HSV1 microRNAs in glioblastoma development: an in silico study.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor. Recent findings highlighted the significance of viral microRNAs (miRs) in regulating post-transcriptional mRNA expression in various human conditions. Although HSV1 encodes viral miRs and affects the central nervous system, no study investigated the roles of HSV1-encoding miRs in GBM development. This study applied in silico approaches to investigate whether HSV1-encoding miRs are involved in GBM development and, if so, how they regulate tumor-suppressive/oncogenes expression in GBM. This study leveraged bioinformatics approaches to identify the potential effect of HSV1 miRs in GBM development. The GSE158284, GSE153679, and GSE182109 datasets were analyzed to identify differentially expressed genes in GBM tissues and cell lines using the limma package in the R software. The GSE182109 dataset was analyzed to determine gene expression at the single-cell levels using the Seurat package in the R software. The TCGA-GTEX, GDSC, CTRP, immunogenetic, and enrichment analyses were performed to study the impact of identified viral HSV1 miRs targets in GBM development. hsv1-miR-H6-3p is upregulated in GBM and can be responsible for EPB41L1 and SH3PXD2A downregulation in GBM tissues. Also, hsv1-miR-H1-5p is upregulated in GBM and can decrease the expression of MELK, FZD2, NOVA1, TMEM97, PTPRZ1, and PDGFC in GBM development. The single-cell RNA sequencing analyses have demonstrated that MELK, FZD2, NOVA1, TMEM97, PTPRZ1, and PDGFC are expressed in astrocytes residing in the GBM microenvironment. This study provides novel insights into the potential roles of HSV1 miRs in GBM pathogenesis and offers a reference for further studies on the significance of HSV1 miRs in GBM development.

Italian oncologists and vaccinations against infectious diseases: Results of a survey of the Italian Association of Medical Oncology.

BACKGROUND: Patients with cancer present a higher risk of vaccine-preventable diseases. Recommended vaccinations are the most cost-effective measure to reduce the risk of transmission and related complications. Nevertheless, vaccination rates are inadequate. Oncologists have a central role in tailored vaccine communication to their patients. We present the results of a survey conducted by AIOM in 2022, focusing on the perception of the problem by oncologists. MATERIALS AND METHODS: An anonymous 31-item online questionnaire was shared on 15 September 2022 on the AIOM website. The objectives of this survey were to examine the perception of Italian oncologists on vaccine-preventable diseases and the main available vaccines, their attitude towards recommending vaccines and the COVID-19 pandemic impact on their habits regarding vaccine-preventable diseases. RESULTS: Between September 2022 and January 2023, 114 medical oncologists (5% of the members) completed the anonymous questionnaire. At the first oncological visit, only 30% of respondents usually propose a vaccination schedule to all their patient, 41% do not usually discuss vaccinations at the first visit and 29% recommend vaccines exclusively to specific categories of patients. For 56% of respondents, patients are more aware of the benefits of vaccines, whereas 36% reported that patients are worried of receiving too many vaccines. CONCLUSION: This is the first survey conducted among Italian oncologists to better understand the perception and attitudes towards the vaccination. It highlights the urgent issues of educating and training oncologists in vaccine-preventable diseases and vaccine awareness and the need to build (or implement) a network of multidisciplinary collaborations.

Deciphering the immune landscape of head and neck squamous cell carcinoma: A single-cell transcriptomic analysis of regulatory T cell responses to PD-1 blockade therapy.

Immunotherapy is changing the Head and Neck Squamous Cell Carcinoma (HNSCC) landscape and improving outcomes for patients with recurrent or metastatic HNSCC. A deeper understanding of the tumor microenvironment (TME) is required in light of the limitations of patients' responses to immunotherapy. Here, we aimed to examine how Nivolumab affects infiltrating Tregs in the HNSCC TME. We used single-cell RNA sequencing data from eight tissues isolated from four HNSCC donors before and after Nivolumab treatment. Interestingly, the study found that Treg counts and suppressive activity increased following Nivolumab therapy. We also discovered that changes in the CD44-SSP1 axis, NKG2C/D-HLA-E axis, and KRAS signaling may have contributed to the increase in Treg numbers. Furthermore, our study suggests that decreasing the activity of the KRAS and Notch signaling pathways, and increasing FOXP3, CTLA-4, LAG-3, and GZMA expression, may be mechanisms that enhance the killing and suppressive capacity of Tregs. Additionally, the result of pseudo-temporal analysis of the HNSCC TME indicated that after Nivolumab therapy, the expression of certain inhibitory immune checkpoints including TIGIT, ENTPD1, and CD276 and LY9, were decreased in Tregs, while LAG-3 showed an increased expression level. The study also found that Tregs had a dense communication network with cluster two, and that certain ligand-receptor pairs, including SPP1/CD44, HLA-E/KLRC2, HLA-E/KLRK1, ANXA1/FPR3, and CXCL9/FCGR2A, had notable changes after the therapy. These changes in gene expression and cell interactions may have implications for the role of Tregs in the TME and in response to Nivolumab therapy.

siRNA-Mediated B7H7 Knockdown in Gastric Cancer Lysate-Loaded Dendritic Cells Amplifies Expansion and Cytokine Secretion of Autologous T Cells.

BACKGROUND: Gastric cancer, ranked as the fifth most common cancer worldwide, presents multiple treatment challenges. These obstacles often arise due to cancer stem cells, which are associated with recurrence, metastasis, and drug resistance. While dendritic cell (DC)-based immunotherapy has shown promise as a therapeutic strategy, its efficacy can be limited by the tumor microenvironment and certain inhibitory immune checkpoint molecules, such as B7H7. SiRNA-medicated knockdown of B7H7 in tumor cell lysate-pulsed DCs can increase cytokine secretion and autologous T lymphocyte expansion. This study aimed to evaluate the impact of B7H7 suppression in gastric cancer cell lysate-pulsed DCs on the stimulatory potential of autologous CD3+ T lymphocytes. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated and monocytes were obtained; then, they were differentiated to immature DCs (iDCs) by GM-CSF and IL-4. Tumor cell lysates from human gastric cancer cell lines were harvested, and iDCs were transformed into mature DCs (mDCs) by stimulating iDCs with tumor cell lysate and lipopolysaccharide. B7H7-siRNA was delivered into mDCs using electroporation, and gene silencing efficiency was assessed. The phenotypic characteristics of iDCs, mDCs, and B7H7-silenced mDCs were evaluated using specific surface markers, an inverted light microscope, and flow cytometry. CD3+ T cells were isolated via magnetically activated cell sorting. They were labeled with CFSE dye and co-cultured with mDCs and B7H7-silenced mDCs to evaluate their ability to induce T-cell proliferation. T-cell proliferation was assessed using flow cytometry. The concentration of TGF-ß, IL-4, and IFN-γ secreted from CD3+ T cells in the co-cultured supernatant was evaluated to investigate the cytokine secretory activity of the cells. RESULTS: Transfection of B7H7 siRNA into mDCs was performed in optimal conditions, and the siRNA transfection effectively reduced B7H7 mRNA expression in a dose-dependent manner. SiRNA-mediated B7H7 knockdown in mDCs enhanced maturation and activation of the DCs, as demonstrated by an increased surface expression of CD11c, CD86, and CD40. Co-culture experiments revealed that B7H7-silenced mDCs had more capacity to induce T cell proliferation compared to non-transfected mDCs. The cytokine production patterns of T cells were also altered. Upon examining the levels of TGF-ß, IL-4, and IFN-γ released by CD3+ T cells in the co-culture supernatant, we found that silencing B7H7 in mDCs resulted in a rise in IL-4 secretion and a reduction in TGF-ß levels compared to mDCs that were not transfected. CONCLUSIONS: The study found that suppressing B7H7 expression in DCs significantly enhances their maturation and stimulatory activity when exposed to gastric cancer cell lysate. These B7H7-silenced DCs can substantially increase cytokine production and promote co-cultured T-cell expansion. Consequently, inhibiting B7H7 in DCs may offer a practical strategy to enhance the ability of DCs to initiate T lymphocyte responses and improve the effectiveness of DC-based cell therapy for cancer patients.

Neuropsychiatric adverse drug reactions with oral tyrosine kinase inhibitors in metastatic colorectal cancer: an analysis from the FDA Adverse Event Reporting System.

Introduction: New oral tyrosine kinase inhibitors (TKIs) are approved for metastatic colorectal cancer (mCRC). The aim of this study was to assess the neuropsychiatric adverse drug reactions (ADRs) of these drugs reported in the FDA Adverse Event Reporting System (FAERS) database. Methods: All reports with regorafenib (REG) and encorafenib (ENC) as the primary suspect, and reported in the FAERS between 2012 and 2022, were collected. A descriptive and disproportionality analyses were conducted. Results: Out of 4,984 cases, 1,357 (30.2%) reported at least one neuropsychiatric ADR. New potential signals for REG included neuropathy peripheral (n = 265; reporting odds ratio, ROR = 19.48, 95% confidence interval, CI 95% = 17.52-22.47; information component, IC = 2.89, IC025-IC075 = 2.77-3.02), hyperesthesia (n = 18; ROR = 12.56, CI 95% = 7.90-19.96; IC = 2.25, IC025-IC075 = 1.79-2.72), taste disorder (n = 41; ROR = 9.91, CI 95% = 7.29-13.49; IC = 2.18, IC025-IC075 = 1.88-2.49), poor quality sleep (n = 18; ROR = 6.56, CI 95% = 4.13-10.42; IC = 1.74, IC025-IC075 = 1.27-2.20), altered state of consciousness (n = 15; ROR = 5.50, CI 95% = 3.31-9.14; IC = 1.57, IC025-IC075 = 1.06-2.07), depressed mood (n = 13; ROR = 1.85, CI 95% = 1.07-3.19; IC = 0.58, IC025-IC075 = 0.04-1.13) and insomnia (n = 63; ROR = 1.48, CI 95% = 1.15-1.89; IC = 0.38, IC025-IC075 = 0.13-0.63). For ENC comprised depressed mood (n = 4; ROR = 5.75, CI 95% = 2.15-15.39; IC = 1.74, IC025-IC075 = 0.76-2.73) and cognitive disorders (n = 3; ROR = 4.71, CI 95% = 1.51-14.66; IC = 1.54, IC025-IC075 = 0.41-2.68). Discussion: This study identified new unknown potential neuropsychiatric ADRs. Further investigations are required to better define the neurotoxicity of TKIs in mCRC patients.

Corrigendum: Cancer survivorship at heart: a multidisciplinary cardio-oncology roadmap for healthcare professionals.

[This corrects the article DOI: 10.3389/fcvm.2023.1223660.].

Cancer survivorship at heart: a multidisciplinary cardio-oncology roadmap for healthcare professionals.

In cancer, a patient is considered a survivor from the time of initial diagnosis until the end of life. With improvements in early diagnosis and treatment, the number of cancer survivors (CS) has grown considerably and includes: (1) Patients cured and free from cancer who may be at risk of late-onset cancer therapy-related cardiovascular toxicity (CTR-CVT); (2) Patients with long-term control of not-curable cancers in whom CTR-CVT may need to be addressed. This paper highlights the importance of the cancer care continuum, of a patient-centered approach and of a prevention-oriented policy. The ultimate goal is a personalized care of CS, achievable only through a multidisciplinary-guided survivorship care plan, one that replaces the fragmented management of current healthcare systems. Collaboration between oncologists and cardiologists is the pillar of a framework in which primary care providers and other specialists must be engaged and in which familial, social and environmental factors are also taken into account.

Polybrominated Diphenyl Ethers (PBDEs) and Human Health: Effects on Metabolism, Diabetes and Cancer.

There is increasing evidence of the role of endocrine disruptors (EDs) derived from commonly employed compounds for manufacturing and processing in altering hormonal signaling and function. Due to their prolonged half-life and persistence, EDs can usually be found not only in industrial products but also in households and in the environment, creating the premises for long-lasting exposure. Polybrominated diphenyl ethers (PBDEs) are common EDs used in industrial products such as flame retardants, and recent studies are increasingly showing that they may interfere with both metabolic and oncogenic pathways. In this article, a multidisciplinary panel of experts of the Italian Association of Medical Diabetologists (AMD), the Italian Society of Diabetology (SID), the Italian Association of Medical Oncology (AIOM), the Italian Society of Endocrinology (SIE) and the Italian Society of Pharmacology (SIF) provides a review on the potential role of PBDEs in human health and disease, exploring both molecular and clinical aspects and focusing on metabolic and oncogenic pathways.

Potential predictive role of gut microbiota to immunotherapy in HCC patients: a brief review.

The recent evolution of immunotherapy has revolutionised the treatment of hepatocellular carcinoma (HCC) and has led to new therapeutic standards. The advances in immunotherapy have been accompanied by the recognition of the role of the gut-liver axis in the progression of HCC but also of the clinical relevance of the gut microbiota, which influences host homeostasis but also cancer development and the response to treatment. Dysbiosis, by altering the tumour microenvironment, favours the activation of intracellular signalling pathways and promotes carcinogenesis. The gut microbiota, through their composition and immunomodulatory role, are thus strong predictors of the response to immune checkpoint inhibitor (ICI) treatment as well as an available target to improve ICI efficacy and reduce drug toxicities. In this review we examine the novel role of the gut microbiota as biomarkers in both the diagnosis of HCC and the clinical response to immunotherapy as well as its potential impact on clinical practice in the future.

Renal Disorders with Oral Tyrosine Kinase Inhibitors in Metastatic Colorectal Cancer: An Analysis from the FDA Adverse Event Reporting System Database.

BACKGROUND: this study assessed the nephrotoxicity of regorafenib (REG) and encorafenib (ENC) in metastatic colorectal cancer (mCRC) through an analysis of reports from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) database. METHODS: descriptive and disproportional analyses were performed for all reports using ENC and REG as the primary suspect. RESULTS: A total of 379 reports had at least one renal adverse drug reaction (ADR), and these ADRs were mainly related to REG (93.1%). Potential safety signals for REG included chromaturia (n = 44; ROR = 12.00, CI 95% = 8.92-16.16; IC = 2.36, IC025-IC075 = 2.06-2.66), hydronephrosis (10; 8.70, 4.67-16.19; 1.85, 1.23-2.47), nephrotic syndrome (7; 5.73, 2.73-12.03; 1.47, 0.73-2.21), renal impairment (53; 4.16, 3.17-5.45; 1.39, 1.12-1.66), dysuria (19; 3.06, 1.95-4.81; 1.06, 0.61-1.52), renal failure (38; 1.66, 1.20-2.28; 0.49, 0.17-0.81), and acute kidney injury (AKI) (43; 1.46, 1.08-1.97; 0.37, 0.07-0.67). For ENC, consistent disproportionalities were observed for AKI (n = 11; ROR = 3.79, CI 95% = 2.09-6.90; IC = 1.32, IC025-IC075 = 0.72-1.91) and dysuria (4; 6.50, 2.43-17.39; 1.86, 0.88-2.85). CONCLUSIONS: these findings highlight some not extensively reported renal ADRs that require further investigations to better characterize the safety profiles of REG and ENC in patients with mCRC.

Low and Ultra-Low HER2 in Human Breast Cancer: An Effort to Define New Neoplastic Subtypes.

HER2-low and ultra-low breast cancer (BC) have been recently proposed as new subcategories of HER2 BC, supporting a re-consideration of immunohistochemical negative scores of 0, 1+ and the 2+/in situ hybridization (ISH) negative phenotype. In the present review, we outline the criteria needed to exactly distinguish HER2-low and ultra-low BC. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating these groups of tumors. In particular, trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC, has been recently approved by the US Food and Drug Administration as the first targeted therapy to treat HER2-low BC. Furthermore, ongoing trials, such as the DESTINY-Breast06 trial, are currently evaluating ADCs in patients with HER2-ultra low BC. Finally, we hope that new guidelines may help to codify HER2-low and ultra-low BC, increasing our knowledge of tumor biology and improving a targetable new therapeutical treatment.