Paola Alberti

Her main expertise is related to peripheral nervous system diseases, especially Chemotherapy-Induced Peripheral Neurotoxicity (CIPN). She is an active member of the Toxic Neuropathy Consortium (TNC), part of the Peripheral Nervous System (PNS) society. During the Residency in Neurology, she was a visiting fellow at Johns Hopkins University (Prof. D.R. Cornblath, MD) to refine her knowledge of neurophysiological techniques. Since 2015 she has been pursuing an interest for preclinical research and joined the Experimental Neurology Unit (ENU, University of Milano-Bicocca) team, where she completed the PhD program in Neuroscience (2019). Her PhD project was focused on Oxaliplatin Induced Peripheral Neurotoxicity in preclinical models: she introduced advanced neurophysiological techniques, nerve excitability testing, to ENU after having learnt them from Prof H. Bostock, (UCL, London). She was a visiting fellow at University of Baltimore (Prof. S.G. Dorsey and Prof C. Renn) where learned DRG

EDUCATION

EDUCATION AND TRAINING

July 2010: Degree: MD – 110/110 cum laude – University of Milano-Bicocca (Monza, Italy)

June 2016 – Degree: Board in Neurology – 70/70 cum laude – University of Milano-Bicocca (Monza, Italy)

February 2019 – Degree: PhD in Neuroscience – University of Milano-Bicocca (Monza, Italy)

RESEARCH, TEACHING, or OTHER INTERESTS

Medicine, Anatomy, Neurology (clinical)

FUTURE PROJECTS

Scopus Publications

Patient-reported strategies for prevention and treatment of chemotherapy-induced peripheral neuropathy
Daniel L. Hertz, Mary Tanay, Cindy Tofthagen, Emanuela Rossi, Davide Paolo Bernasconi, Katharine E. Sheffield, Martha Carlson, Larissa Nekhlyudov, Lisa Grech, Diane Von Ah,et al.
Springer Science and Business Media LLC



Paclitaxel alters the microvascular network in the central and peripheral nervous system of rats with chemotherapy-induced painful peripheral neuropathy
Antonio Giuliano Zippo, Virginia Rodriguez‐Menendez, Eleonora Pozzi, Annalisa Canta, Alessia Chiorazzi, Elisa Ballarini, Laura Monza, Paola Alberti, Cristina Meregalli, Alberto Bravin,et al.
Wiley
AbstractBackground and AimsChemotherapy‐induced peripheral neurotoxicity (CIPN), with paraesthesia, numbness, dysesthesia and neuropathic pain ranks among the most common dose‐limiting toxicity of several widely used anticancer drugs. Recent studies revealed the microvascular angiogenesis as a new important actor, beside peripheral neurons, in the neurotoxicity and neuropathic pain development and chronicisation. The aim of this work is to elucidate the role of vascular alterations in CIPN.MethodsWe evaluated the severity of CIPN with neurophysiological, behavioural and neuropathological analysis together with the microvascular network in central and peripheral nervous systems of rats in order to correlate the features of the CIPN and the vascular abnormalities. The vascular network was quantitatively evaluated through synchrotron radiation‐based X‐ray phase‐contrast micro‐tomography imaging, measuring four specific parameters: vascular density, vessel diameter, vessel tortuosity and branching.ResultsRats exposed to paclitaxel and affected by a severe painful sensory axonopathy showed an increased vascular density (putative sprouting angiogenesis) in the crucial districts of the central (somatosensory cortex and lumbar spinal cord) and peripheral nervous system (lumbar dorsal root ganglia). In addition, the complexity of the vascular network and the size of neo‐formed vessels were significantly decreased in specific regions. On the other hand, less significant changes were observed in rats exposed to cisplatin, affected by a painless peripheral neuropathy, suggesting a specific involvement of neo‐angiogenesis in the development of severe neurotoxicity and neuropathic pain.InterpretationsThese new ground‐breaking results can shed light on new pathogenetic mechanisms and potential novel therapeutic approaches for painful‐CIPN.


Repurposing chemotherapy-induced peripheral neuropathy grading
Roser Velasco, Andreas A. Argyriou, David R. Cornblath, Pere Bruna, Paola Alberti, Emanuela Rossi, Ingemar S. J. Merkies, Dimitri Psimaras, Chiara Briani, Roy I. Lalisang,et al.
Wiley
AbstractBackground and PurposeChemotherapy‐induced peripheral neuropathy (CIPN) is perceived differently by patients and physicians, complicating its assessment. Current recommendations advocate combining clinical and patient‐reported outcomes measures, but this approach can be challenging in patient care. This multicenter European study aims to bridge the gap between patients' perceptions and neurological impairments by aligning both perspectives to improve treatment decision‐making.MethodsData were pooled from two prospective studies of subjects (n = 372) with established CIPN. Patient and physician views regarding CIPN were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE), Total Neuropathy Scale–clinical version (TNSc) items, and the disease‐specific quality of life ‐ Chemotherapy‐Induced Peripheral Neuropathy questionnaire (QLQ‐CIPN20) from the European Organization for Research and Treatment of Cancer (EORTC). To identify inherent neurotoxic severity patterns, we employed hierarchical cluster analysis optimized with k‐means clustering and internally validated by discriminant functional analysis.ResultsBoth NCI‐CTCAE and TNSc demonstrated a significant difference in the distribution of severity grades in relation to QLQ‐CIPN20 scores. However, a proportion of subjects with different neurotoxic severity grades exhibited overlapping QLQ‐CIPN20 scores. We identified three distinct clusters classifying subjects as having severely impaired, intermediately impaired, and mildly impaired CIPN based on TNSc and QLQ‐CIPN20 scores. No differences in demographics, cancer type distribution, or class of drug received were observed.ConclusionsOur results confirm the heterogeneity in CIPN perception between patients and physicians and identify three well‐differentiated subgroups of patients delineated by degree of CIPN impairment based on scores derived from TNSc and QLQ‐CIPN20. A more refined assessment of CIPN could potentially be achieved using the calculator tool derived from the cluster equations in this study. This tool, which facilitates individual patient classification, requires prospective validation.


Molsidomine provides neuroprotection against vincristine-induced peripheral neurotoxicity through soluble guanylyl cyclase activation
Irina Utkina-Sosunova, Alessia Chiorazzi, Mariangels de Planell-Saguer, Hai Li, Cristina Meregalli, Eleonora Pozzi, Valentina Alda Carozzi, Annalisa Canta, Laura Monza, Paola Alberti,et al.
Springer Science and Business Media LLC



Translation of paclitaxel-induced peripheral neurotoxicity from mice to patients: The importance of model selection
Guido Cavaletti, Paola Alberti, Annalisa Canta, Valentina Carozzi, Laura Cherchi, Alessia Chiorazzi, Luca Crippa, Paola Marmiroli, Cristina Meregalli, Eleonora Pozzi,et al.
Ovid Technologies (Wolters Kluwer Health)
Abstract Paclitaxel-induced peripheral neurotoxicity (PIPN) is a potentially dose-limiting side effect in anticancer chemotherapy. Several animal models of PIPN exist, but their results are sometimes difficult to be translated into the clinical setting. We compared 2 widely used PIPN models characterized by marked differences in their methodologies. Female C57BL/6JOlaHsd mice were used, and they received only paclitaxel vehicle (n = 38) or paclitaxel via intravenous injection (n = 19, 70 mg/kg) once a week for 4 weeks (Study 1) or intraperitoneally (n = 19, 10 mg/kg) every 2 days for 7 times (Study 2). At the end of treatment and in the follow-up, mice underwent behavioral and neurophysiological assessments of PIPN. At the same time points, some mice were killed and dorsal root ganglia, skin, and sciatic and caudal nerve samples underwent pathological examination. Serum neurofilament light levels were also measured. The differences in the neurotoxicity parameters were analyzed using a nonparametric Mann-Whitney test, with significance level set at P < 0.05. Study 1 showed significant and consistent behavioral, neurophysiological, pathological, and serological changes induced by paclitaxel administration at the end of treatment, and most of these changes were still evident in the follow-up period. By contrast, study 2 evidenced only a transient small fiber neuropathy, associated with neuropathic pain. Our comparative study clearly distinguished a PIPN model recapitulating all the clinical features of the human condition and a model showing only small fiber neuropathy with neuropathic pain induced by paclitaxel.


Supportive care 2030 movement: towards unifying ambitions for global excellence in supportive cancer care—an international Delphi study
Raymond Javan Chan, Reegan Knowles, Fredrick D. Ashbury, Joanne Bowen, Alexandre Chan, Melissa Chin, Ian Olver, Carolyn Taylor, Stacey Tinianov, Paola Alberti,et al.
Elsevier BV



Ion Channel and Transporter Involvement in Chemotherapy-Induced Peripheral Neurotoxicity
Eleonora Pozzi, Giulia Terribile, Laura Cherchi, Sara Di Girolamo, Giulio Sancini, and Paola Alberti
MDPI AG
The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN.


Correction to: Considerations for establishing and maintaining international research collaboration: the example of chemotherapy-induced peripheral neurotoxicity (CIPN)—a white paper (Supportive Care in Cancer, (2024), 32, 2, (117), 10.1007/s00520-023-08301-5)
Paola Alberti, Andreas A. Argyriou, Jordi Bruna, M. Imad Damaj, Sara Faithfull, Alice Harding, Ahmet Hoke, Robert Knoerl, Noah Kolb, Tiffany Li,et al.
Springer Science and Business Media LLC



Effect of age on metabolomic changes in a model of paclitaxel-induced peripheral neurotoxicity
Roberta Bonomo, Annalisa Canta, Alessia Chiorazzi, Valentina Alda Carozzi, Cristina Meregalli, Eleonora Pozzi, Paola Alberti, Cecile F. Frampas, Daan R. Van der Veen, Paola Marmiroli,et al.
Wiley
AbstractBackground and AimsChemotherapy‐induced peripheral neurotoxicity (CIPN) is one of the most common dose‐limiting side effects of paclitaxel (PTX) treatment. Many age‐related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated.MethodsTwenty‐four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2‐week follow‐up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis.ResultsAt the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p < .05) in the caudal nerve of young PTX‐animals, and in both the digital and caudal nerve of adult PTX‐animals (p < .05). A significant decrease in the mechanical threshold was observed only in young PTX‐animals (p < .001), but not in adult PTX‐ones. Nevertheless, both young and adult PTX‐rats had reduced IENF density (p < .0001), which persisted at the end of follow‐up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX‐animals developing peripheral neuropathy and age‐matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration.InterpretationOur study identifies for the first time multiple related metabolic axes involved in PTX‐induced peripheral neurotoxicity, and suggests age‐related differences in CIPN manifestations and in the metabolic profile.


Morphofunctional characterisation of axonal damage in different rat models of chemotherapy-induced peripheral neurotoxicity: The role of nerve excitability testing
Alessia Chiorazzi, Annalisa Canta, Valentina Alda Carozzi, Cristina Meregalli, Eleonora Pozzi, Elisa Ballarini, Virginia Rodriguez‐Menendez, Paola Marmiroli, Guido Cavaletti, and Paola Alberti
Wiley
AbstractBackground and AimsChemotherapy‐induced peripheral neurotoxicity (CIPN) is a common and long‐lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage.MethodsWe tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density.ResultsNET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement.InterpretationNET after the first administration demonstrated the ongoing OHP‐related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.


Considerations for establishing and maintaining international research collaboration: the example of chemotherapy-induced peripheral neurotoxicity (CIPN)—a white paper
Paola Alberti, Andreas A. Argyriou, Jordi Bruna, M. Imad Damaj, Sara Faithfull, Alice Harding, Ahmet Hoke, Robert Knoerl, Noah Kolb, Tiffany Li,et al.
Springer Science and Business Media LLC
Abstract Purpose This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. Methods An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. Results Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. Conclusion Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. Relevance to inform research policy Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.


3D Digital tools in neuro-anatomy teaching: from peer-to-peer tutoring to clinically oriented approaches
Paola Alberti
Firenze University Press
Neuroanatomy knowledge is pivotal due to the constantly increased use of neuroimaging in everyday clinical practice, even in the emergency setting as it is for patients potentially affected by stroke. To empower our students, we are relying on innovative 3D digital tools to teach human anatomy, exploiting several approaches among which Anatomage TableTM, also fostering a peer-to-peer tutor program. We present here the results of a pilot phase of these initiatives. First year med students from the Italian and International Course used Anatomage TableTM under the supervision of fourth-, fifth-, or sixth-year med students, as peer-to-peer tutors. Participants were divided into groups (10-12 people each). Three sessions lasting 2 hours were planned with a predefined topic: thorax (topic 1), abdomen/pelvis (topic 2), neuroanatomy (topic 3). A questionnaire was filled at the end of each session rating satisfaction/impact. One-hundred-thirty students (105 from the Italian course and 25 from the international course) participated. More than 90% of students rated the neuroanatomy session as highly satisfactory and more than 95% as highly useful, and 100% of them would suggest others participate. Based on these results, a further implementation is planned for the next year, also exploiting DICOM data to present the students with real clinical cases bearing a highly didactive anatomical content. Specifically, in the international course, based on a vertical track approach, we are also strongly relying on flipped-classroom approach. Digital tools to teach neuroanatomy are also being implemented for clinically oriented teaching for residents/consultants.


In vitro neurotoxicity testing: lessons from chemotherapy-induced peripheral neurotoxicity
Olga Tarasiuk, Chiara Invernizzi, and Paola Alberti
Informa UK Limited
INTRODUCTION Chemotherapy induced peripheral neurotoxicity (CIPN) is a long-lasting, or even permanent, late toxicity caused by largely used anticancer drugs. CIPN affects a growing population of cancer survivors and diminishes their quality of life since there is no curative/preventive treatment. Among several reasons for this unmet clinical need, there is an incomplete knowledge on mechanisms leading to CIPN. Therefore, bench side research is still greatly needed: in vitro studies are pivotal to both evaluate neurotoxicity mechanisms and potential neuroprotection strategies. AREAS COVERED Advantages and disadvantages of in vitro approaches are addressed with respect to their applicability to the CIPN field. Different cell cultures and techniques to assess neurotoxicity/neuroprotection are described. PubMed search-string: (chemotherapy-induced) AND (((neuropathy) OR neurotoxicity) OR neuropathic pain) AND (in vitro) AND (((((model) OR SH-SY5Y) OR PC12) OR iPSC) OR DRG neurons); (chemotherapy-induced) AND (((neuropathy) OR neurotoxicity) OR neuropathic pain) AND (model) AND (((neurite elongation) OR cell viability) OR morphology). No articles published before 1990 were selected. EXPERT OPINION CIPN is an ideal experimental setting to test axonal damage and, in general, peripheral nervous system mechanisms of disease and neuroprotection. Therefore, starting from robust preclinical data in this field, potentially, relevant biological rationale can be transferred to other human spontaneous diseases of the peripheral nervous system.


Patient perceptions of altering chemotherapy treatment due to peripheral neuropathy
Daniel L Hertz, Cindy Tofthagen, Emanuela Rossi, Davide Paolo Bernasconi, Jiyoon Lim, Martha Carlson, Katharine E. Sheffield, Larissa Nekhlyudov, Lisa Grech, Diane Von Ah,et al.
Springer Science and Business Media LLC



Inhibition of NHE1 transport activity and gene transcription in DRG neurons in oxaliplatin-induced painful peripheral neurotoxicity
Marianna Dionisi, Beatrice Riva, Marta Delconti, Cristina Meregalli, Alessia Chiorazzi, Annalisa Canta, Paola Alberti, Valentina Carozzi, Eleonora Pozzi, Dmtry Lim,et al.
Springer Science and Business Media LLC
AbstractOxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN), one of the major dose-limiting side effects of colorectal cancer treatment, is characterized by both acute and chronic syndromes. Acute exposure to low dose OHP on dorsal root ganglion (DRG) neurons is able to induce an increase in intracellular calcium and proton concentration, thus influencing ion channels activity and neuronal excitability. The Na+/H+ exchanger isoform-1 (NHE1) is a plasma membrane protein that plays a pivotal role in intracellular pH (pHi) homeostasis in many cell types, including nociceptors. Here we show that OHP has early effects on NHE1 activity in cultured mouse DRG neurons: the mean rate of pHi recovery was strongly reduced compared to vehicle-treated controls, reaching levels similar to those obtained in the presence of cariporide (Car), a specific NHE1 antagonist. The effect of OHP on NHE1 activity was sensitive to FK506, a specific calcineurin (CaN) inhibitor. Lastly, molecular analyses revealed transcriptional downregulation of NHE1 both in vitro, in mouse primary DRG neurons, and in vivo, in an OIPN rat model. Altogether, these data suggest that OHP-induced intracellular acidification of DRG neurons largely depends on CaN-mediated NHE1 inhibition, revealing new mechanisms that OHP could exert to alter neuronal excitability, and providing novel druggable targets.


Axonal degeneration in chemotherapy-induced peripheral neurotoxicity: clinical and experimental evidence
Susanna B Park, Aysel Cetinkaya-Fisgin, Andreas A Argyriou, Ahmet Höke, Guido Cavaletti, and Paola Alberti
BMJ
Multiple pathological mechanisms are involved in the development of chemotherapy-induced peripheral neurotoxicity (CIPN). Recent work has provided insights into the molecular mechanisms underlying chemotherapy-induced axonal degeneration. This review integrates evidence from preclinical and clinical work on the onset, progression and outcome of axonal degeneration in CIPN. We review likely triggers of axonal degeneration in CIPN and highlight evidence of molecular pathways involved in axonal degeneration and their relevance to CIPN, including SARM1-mediated axon degeneration pathway. We identify potential clinical markers of axonal dysfunction to provide early identification of toxicity as well as present potential treatment strategies to intervene in axonal degeneration pathways. A greater understanding of axonal degeneration processes in CIPN will provide important information regarding the development and progression of axonal dysfunction more broadly and will hopefully assist in the development of successful interventions for CIPN and other neurodegenerative disorders.


Gait analysis in chemotherapy-induced peripheral neurotoxicity rodent models
Maria Lopez-Garzon, Annalisa Canta, Alessia Chiorazzi, and Paola Alberti
Elsevier BV



Toxic medications in Charcot–Marie–Tooth patients: A systematic review
Guido Cavaletti, Katherine Forsey, and Paola Alberti
Wiley
AbstractBackground and AimsSeveral widely used medications, with a relevant efficacy profile, are toxic to the peripheral nervous system and an even larger number of agents are suspected to be neurotoxic. There are concerns about the use of these drugs in patients with Charcot–Marie–Tooth disease (CMT), a hereditary motor and sensory neuropathy. This review provides evidence‐based updated recommendations on this clinically relevant topic.MethodsA systematic review of the available studies/reports written in English was performed from July to September 2022 including in the search string all reported putative neurotoxic drugs.ResultsThe results of our systematic review provide evidence‐based support for the statement that use of vincristine, and possibly paclitaxel, can occasionally induce an atypical, and more severe, course of drug‐related peripheral neurotoxicity in CMT patients. It is therefore reasonable to recommend caution in the use of these compounds in CMT patients. However, no convincing evidence for a similar recommendation could be found for all other drugs.InterpretationIt is important that patients with CMT are not denied effective treatments that may prolong life expectancy for cancer or improve their health status if affected by non‐oncological diseases. Accurate monitoring of peripheral nerve function in CMT patients treated with any neurotoxic agent remains mandatory to detect the earliest signs of neuropathy worsening and atypical clinical courses. Neurologists monitoring CMT patients as part of their normal care package or for natural history studies should keep detailed records of exposures to neurotoxic medications and support reporting of accelerated neuropathy progression if observed.


Framework to leverage physical therapists for the assessment and treatment of chemotherapy-induced peripheral neurotoxicity (CIPN)
Stefanie Stoller, Scott Capozza, Paola Alberti, Maryam Lustberg, and Ian R. Kleckner
Springer Science and Business Media LLC



Paclitaxel, but Not Cisplatin, Affects Satellite Glial Cells in Dorsal Root Ganglia of Rats with Chemotherapy-Induced Peripheral Neurotoxicity
Eleonora Pozzi, Elisa Ballarini, Virginia Rodriguez-Menendez, Annalisa Canta, Alessia Chiorazzi, Laura Monza, Mario Bossi, Paola Alberti, Alessio Malacrida, Cristina Meregalli,et al.
MDPI AG
Chemotherapy-induced peripheral neurotoxicity is one of the most common dose-limiting toxicities of several widely used anticancer drugs such as platinum derivatives (cisplatin) and taxanes (paclitaxel). Several molecular mechanisms related to the onset of neurotoxicity have already been proposed, most of them having the sensory neurons of the dorsal root ganglia (DRG) and the peripheral nerve fibers as principal targets. In this study we explore chemotherapy-induced peripheral neurotoxicity beyond the neuronocentric view, investigating the changes induced by paclitaxel (PTX) and cisplatin (CDDP) on satellite glial cells (SGC) in the DRG and their crosstalk. Rats were chronically treated with PTX (10 mg/Kg, 1qwx4) or CDDP (2 mg/Kg 2qwx4) or respective vehicles. Morpho-functional analyses were performed to verify the features of drug-induced peripheral neurotoxicity. Qualitative and quantitative immunohistochemistry, 3D immunofluorescence, immunoblotting, and transmission electron microscopy analyses were also performed to detect alterations in SGCs and their interconnections. We demonstrated that PTX, but not CDDP, produces a strong activation of SGCs in the DRG, by altering their interconnections and their physical contact with sensory neurons. SGCs may act as principal actors in PTX-induced peripheral neurotoxicity, paving the way for the identification of new druggable targets for the treatment and prevention of chemotherapy-induced peripheral neurotoxicity.


Morpho-Functional Characterisation of the Rat Ventral Caudal Nerve in a Model of Axonal Peripheral Neuropathy
Eleonora Pozzi, Laura Monza, Elisa Ballarini, Mario Bossi, Virginia Rodriguez-Menendez, Annalisa Canta, Alessia Chiorazzi, Valentina Alda Carozzi, Luca Crippa, Paola Marmiroli,et al.
MDPI AG
Peripheral Neuropathies (PN) are common conditions whose treatment is still lacking in most cases. Animal models are crucial, but experimental procedures should be refined in some cases. We performed a detailed characterization of the ventral caudal nerve to contribute to a more effective assessment of axonal damage in future PN studies. PN was induced via weekly systemic injection of a neurotoxic drug (paclitaxel); we compared the control and PN-affected rats, performing serial neurophysiological evaluations of the caudal nerve for its entire length. On the same nerve portions, we performed light microscopy and ultrastructural pathological observations to assess the severity of damage and verify the integrity of the surrounding structures. Neurophysiological and morphological analyses confirmed that a severe axonopathy had ensued in the PN group, with a length-dependent modality, matching morphological observations. The site of neurophysiological recording (e.g., distance from the base of the tail) was critical for achieving useful data. A flexible experimental paradigm should be considered in animal studies investigating axonal PN, particularly if the expected severity is relevant; the mid-portion of the tail might be the most appropriate site: there damage might be remarkable but neither as extreme as at the tip of the tail nor as mild as at the base of the tail.


Neurological Complications of Conventional and Novel Anticancer Treatments
Paola Alberti, Alessandro Salvalaggio, Andreas A. Argyriou, Jordi Bruna, Andrea Visentin, Guido Cavaletti, and Chiara Briani
MDPI AG
Various neurological complications, affecting both the central and peripheral nervous system, can frequently be experienced by cancer survivors after exposure to conventional chemotherapy, but also to modern immunotherapy. In this review, we provide an overview of the most well-known adverse events related to chemotherapy, with a focus on chemotherapy induced peripheral neurotoxicity, but we also address some emerging novel clinical entities related to cancer treatment, including chemotherapy-related cognitive impairment and immune-mediated adverse events. Unfortunately, efficacious curative or preventive treatment for all these neurological complications is still lacking. We provide a description of the possible mechanisms involved to drive future drug discovery in this field, both for symptomatic treatment and neuroprotection.


Sodium-Calcium Exchanger 2: A Pivotal Role in Oxaliplatin Induced Peripheral Neurotoxicity and Axonal Damage?
Elisa Ballarini, Alessio Malacrida, Virginia Rodriguez-Menendez, Eleonora Pozzi, Annalisa Canta, Alessia Chiorazzi, Laura Monza, Sara Semperboni, Cristina Meregalli, Valentina Alda Carozzi,et al.
MDPI AG
Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a frequent adverse event of colorectal cancer treatment. OIPN encompasses a chronic and an acute syndrome. The latter consists of transient axonal hyperexcitability, due to unbalance in Na+ voltage-operated channels (Na+VOC). This leads to sustained depolarisation which can activate the reverse mode of the Na+/Ca2+ exchanger 2 (NCX2), resulting in toxic Ca2+ accumulation and axonal damage (ADa). We explored the role of NCX2 in in vitro and in vivo settings. Embryonic rat Dorsal Root Ganglia (DRG) organotypic cultures treated with SEA0400 (SEA), a NCX inhibitor, were used to assess neuroprotection in a proof-of-concept and pilot study to exploit NCX modulation to prevent ADa. In vivo, OHP treated mice (7 mg/Kg, i.v., once a week for 8 weeks) were compared with a vehicle-treated group (n = 12 each). Neurophysiological and behavioural testing were performed to characterise acute and chronic OIPN, and morphological analyses were performed to detect ADa. Immunohistochemistry, immunofluorescence, and western blotting (WB) analyses were also performed to demonstrate changes in NCX2 immunoreactivity and protein expression. In vitro, NCX inhibition was matched by ADa mitigation. In the in vivo part, after verifyingboth acute and chronic OIPN had ensued, we confirmed via immunohistochemistry, immunofluorescence, and WB that a significant NCX2 alteration had ensued in the OHP group. Our data suggest NCX2 involvement in ADa development, paving the way to a new line of research to prevent OIPN.


Neurons: The Interplay between Cytoskeleton, Ion Channels/Transporters and Mitochondria
Paola Alberti, Sara Semperboni, Guido Cavaletti, and Arianna Scuteri
MDPI AG
Neurons are permanent cells whose key feature is information transmission via chemical and electrical signals. Therefore, a finely tuned homeostasis is necessary to maintain function and preserve neuronal lifelong survival. The cytoskeleton, and in particular microtubules, are far from being inert actors in the maintenance of this complex cellular equilibrium, and they participate in the mobilization of molecular cargos and organelles, thus influencing neuronal migration, neuritis growth and synaptic transmission. Notably, alterations of cytoskeletal dynamics have been linked to alterations of neuronal excitability. In this review, we discuss the characteristics of the neuronal cytoskeleton and provide insights into alterations of this component leading to human diseases, addressing how these might affect excitability/synaptic activity, as well as neuronal functioning. We also provide an overview of the microscopic approaches to visualize and assess the cytoskeleton, with a specific focus on mitochondrial trafficking.


Prospectively assessing serum neurofilament light chain levels as a biomarker of paclitaxel-induced peripheral neurotoxicity in breast cancer patients
Sofia Karteri, Jordi Bruna, Andreas A. Argyriou, Sara Mariotto, Roser Velasco, Montse Alemany, Foteini Kalofonou, Paola Alberti, Alessandro Dinoto, Dimitrios Velissaris,et al.
Wiley
AbstractOur aim was to assess the significance of measuring serum neurofilament light chain (sNfL) levels as a biomarker of paclitaxel‐induced peripheral neurotoxicity (PIPN). We longitudinally measured sNfL in breast cancer patients, scheduled to receive the 12‐weekly paclitaxel‐based regimen. Patients were clinically examined by means of the Total Neuropathy Score‐clinical version (TNSc), while sNfL were quantified, using the highly sensitive Simoa technique, before starting chemotherapy (baseline), after 2 (week 2) and 3 (week 3) weekly courses, and at the end of chemotherapy (week 12). Among 59 included patients (mean age: 53.1 ± 11.5 years), 33 (56%) developed grade 0‐1 and 26 (44%) grade 2‐3 PIPN at week 12. A significant longitudinal increase of sNfL levels from baseline to week‐12 was determined, whereas patients with TNSc grade 2‐3 PIPN had significantly increased sNfL levels at week 12, compared to those with grade 0‐1. receiver‐operated characteristics (ROC) analysis defined a value of NfL of >85 pg/mL at week 3 as the best discriminative determination to predict the development of grade 2‐3 PIPN at week 12 (sensitivity 46.2%, specificity 84.8%). The logistic binary regression analysis revealed that age > 50 years and the cutoff of >85 pg/mL of sNfL levels at week 3 independently predicted the development of grade 2‐3 PIPN at week 12 with a sensitivity of 46%, a specificity of 91%, and a positive and negative predictive values of 75% and 67%, respectively. sNfL levels seem to be a valuable biomarker of neuro‐axonal injury in PIPN. An early increase of this biomarker after a 3‐weekly chemotherapy course can be a predictive marker of final PIPN severity.

RECENT SCHOLAR PUBLICATIONS

Patient-reported strategies for prevention and treatment of chemotherapy-induced peripheral neuropathy
DL Hertz, M Tanay, C Tofthagen, E Rossi, DP Bernasconi, KE Sheffield, ...
Supportive Care in Cancer 33 (2), 142 2025



Paclitaxel alters the microvascular network in the central and peripheral nervous system of rats with chemotherapy‐induced painful peripheral neuropathy
AG Zippo, V Rodriguez‐Menendez, E Pozzi, A Canta, A Chiorazzi, ...
Journal of the Peripheral Nervous System 29 (4), 537-554 2024



Repurposing chemotherapy‐induced peripheral neuropathy grading
R Velasco, AA Argyriou, DR Cornblath, P Bruna, P Alberti, E Rossi, ...
European Journal of Neurology 31 (12), e16457 2024



In vitro neurotoxicity testing: lessons from chemotherapy-induced peripheral neurotoxicity
O Tarasiuk, C Invernizzi, P Alberti
Expert Opinion on Drug Metabolism & Toxicology 20 (11-12), 1037-1052 2024



Supportive care 2030 movement: towards unifying ambitions for global excellence in supportive cancer care—an international Delphi study
RJ Chan, R Knowles, FD Ashbury, J Bowen, A Chan, M Chin, I Olver, ...
EClinicalMedicine 76 2024



Association between multimorbidity and postoperative mortality in patients undergoing major surgery: a prospective study in 29 countries across Europe
STARSurg Collaborative, EuroSurg Collaborative, SK Kamarajah, O Kouli, ...
Anaesthesia 79 (9), 945-956 2024



Molsidomine provides neuroprotection against vincristine-induced peripheral neurotoxicity through soluble guanylyl cyclase activation
I Utkina-Sosunova, A Chiorazzi, M de Planell-Saguer, H Li, C Meregalli, ...
Scientific reports 14 (1), 19341 2024



CHEMOTHERAPY-INDUCED PERIPHERAL NEUROTOXICITY: SOCIO-ECONOMICAL COSTS
P Alberti, E Lucchese
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM 29, S175-S175 2024



REFINEMENT OF DORSAL ROOT GANGLIA NEURONS MORPHOMETRY
C Invernizzi, C Capelli, E Pozzi, A Canta, A Chiorazzi, E Ballarini, ...
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM 29, S72-S72 2024



MOLECULAR CHARACTERIZATION OF OXALIPLATIN-INDUCED PERIPHERAL NEUROTOXICITY
P Alberti, E Pozzi, MP Serra, M Trucas, M Boi, C Capelli, C Invernizzi, ...
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM 29, S69-S70 2024



INVESTIGATING LOSS OF REPLICATION FACTOR COMPLEX SUBUNIT 1 (RFC1) FUNCTION IN CANVAS PATIENTS AND HETEROZYGOUS AAGGG EXPANSION CARRIERS
R Curro, N Dominik, C Perini, S Facchini, R Ronco, B Rugginini, A Ghia, ...
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM 29, S156-S156 2024



Impact of postoperative cardiovascular complications on 30‐day mortality after major abdominal surgery: an international prospective cohort study
STARSurg Collaborative, EuroSurg Collaborative, O Kouli, D Chaudhry, ...
Anaesthesia 79 (7), 715-724 2024



Ion Channel and transporter involvement in chemotherapy-induced peripheral neurotoxicity
E Pozzi, G Terribile, L Cherchi, S Di Girolamo, G Sancini, P Alberti
International Journal of Molecular Sciences 25 (12), 6552 2024



Morphofunctional characterisation of axonal damage in different rat models of chemotherapy‐induced peripheral neurotoxicity: The role of nerve excitability testing
A Chiorazzi, A Canta, VA Carozzi, C Meregalli, E Pozzi, E Ballarini, ...
Journal of the Peripheral Nervous System 29 (1), 47-57 2024



Effect of age on metabolomic changes in a model of paclitaxel‐induced peripheral neurotoxicity
R Bonomo, A Canta, A Chiorazzi, VA Carozzi, C Meregalli, E Pozzi, ...
Journal of the peripheral nervous system 29 (1), 58-71 2024



Correction to: Considerations for establishing and maintaining international research collaboration: the example of chemotherapy‑induced peripheral neurotoxicity (CIPN)—a
P Alberti, AA Argyriou, J Bruna, MI Damaj, S Faithfull, A Harding, A Hoke, ...
Supportive Care in Cancer 32 (3), 175 2024



Considerations for establishing and maintaining international research collaboration: the example of chemotherapy-induced peripheral neurotoxicity (CIPN)—a white paper
P Alberti, AA Argyriou, J Bruna, MI Damaj, S Faithfull, A Harding, A Hoke, ...
Supportive Care in Cancer 32 (2), 117 2024



MORPHOLOGICAL AND METABOLOMIC CHANGES IN PIPN
R Bonomo, A Canta, A Chiorazzi, V Carozzi, C Meregalli, E Pozzi, ...
EUROPEAN JOURNAL OF HISTOCHEMISTRY 68 (supplement 2), 10-10 2024



In vivo study of Carfilzomib-Induced Neuropathy
F Iseppon, A Chiorazzo, A Canta, P Alberti, V Carozzi, E Pozzi, L Cherchi, ...
EUROPEAN JOURNAL OF HISTOCHEMISTRY 68 (S2), 10-11 2024



Irina Utkina‑Sosunova, Alessia Chiorazzi 4, 10, Mariangels de Planell‑Saguer, Hai Li 5, 6, Cristina Meregalli 4, Eleonora Pozzi 4, Valentina Alda Carozzi 4, Annalisa Canta 4
L Monza, P Alberti, G Fumagalli, C Karan, Y Moayedi, S Przedborski, ...
Scientific Reports 14, 19341 2024

MOST CITED SCHOLAR PUBLICATIONS

Guillain-Barr syndrome related to COVID-19 infection
P Alberti, S Beretta, M Piatti, A Karantzoulis, ML Piatti, P Santoro, ...
Neurology: Neuroimmunology & Neuroinflammation 7 (4), e741 2020
Citations: 442



The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings
G Cavaletti, DR Cornblath, ISJ Merkies, TJ Postma, E Rossi, B Frigeni, ...
Annals of Oncology 24 (2), 454-462 2013
Citations: 368



Chemotherapy-induced peripheral neurotoxicity assessment: a critical revision of the currently available tools
G Cavaletti, B Frigeni, F Lanzani, L Mattavelli, E Susani, P Alberti, ...
European journal of cancer 46 (3), 479-494 2010
Citations: 334



Clinical pattern and associations of oxaliplatin acute neurotoxicity: a prospective study in 170 patients with colorectal cancer
AA Argyriou, G Cavaletti, C Briani, R Velasco, J Bruna, M Campagnolo, ...
Cancer 119 (2), 438-444 2013
Citations: 272



Understanding the quality of life (QOL) issues in survivors of cancer: towards the development of an EORTC QOL cancer survivorship questionnaire
M Van Leeuwen, O Husson, P Alberti, JI Arraras, OL Chinot, A Costantini, ...
Health and quality of life outcomes 16, 1-15 2018
Citations: 269



Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin
P Alberti, E Rossi, DR Cornblath, ISJ Merkies, TJ Postma, B Frigeni, ...
Annals of oncology 25 (1), 257-264 2014
Citations: 196



Early predictors of oxaliplatin-induced cumulative neuropathy in colorectal cancer patients
R Velasco, J Bruna, C Briani, AA Argyriou, G Cavaletti, P Alberti, B Frigeni, ...
Journal of Neurology, Neurosurgery & Psychiatry 85 (4), 392-398 2014
Citations: 173



Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics
G Cavaletti, P Alberti, P Marmiroli
The lancet oncology 12 (12), 1151-1161 2011
Citations: 150



Voltage‐gated sodium channel polymorphisms play a pivotal role in the development of oxaliplatin‐induced peripheral neurotoxicity: Results from a prospective multicenter study
AA Argyriou, G Cavaletti, A Antonacopoulou, AA Genazzani, C Briani, ...
Cancer 119 (19), 3570-3577 2013
Citations: 140



Chemotherapy-induced neuropathy
G Cavaletti, P Alberti, B Frigeni, M Piatti, E Susani
Current treatment options in neurology 13, 180-190 2011
Citations: 138



Peripheral neurotoxicity of oxaliplatin in combination with 5-fluorouracil (FOLFOX) or capecitabine (XELOX): a prospective evaluation of 150 colorectal cancer patients
AA Argyriou, R Velasco, C Briani, G Cavaletti, J Bruna, P Alberti, ...
Annals of oncology 23 (12), 3116-3122 2012
Citations: 125



Efficacy of a novel sigma-1 receptor antagonist for oxaliplatin-induced neuropathy: a randomized, double-blind, placebo-controlled phase IIa clinical trial
J Bruna, S Videla, AA Argyriou, R Velasco, J Villoria, C Santos, C Nadal, ...
Neurotherapeutics 15 (1), 178-189 2018
Citations: 119



Long‐term course of oxaliplatin‐induced polyneuropathy: a prospective 2‐year follow‐up study
C Briani, AA Argyriou, C Izquierdo, R Velasco, M Campagnolo, P Alberti, ...
Journal of the Peripheral Nervous System 19 (4), 299-306 2014
Citations: 114



Neurophysiological, nerve imaging and other techniques to assess chemotherapy-induced peripheral neurotoxicity in the clinical and research settings
AA Argyriou, SB Park, B Islam, S Tamburin, R Velasco, P Alberti, J Bruna, ...
Journal of Neurology, Neurosurgery & Psychiatry 90 (12), 1361-1369 2019
Citations: 101



Chemotherapy‐induced peripheral neurotoxicity can be misdiagnosed by the National Cancer Institute Common Toxicity scale
B Frigeni, M Piatti, F Lanzani, P Alberti, P Villa, C Zanna, M Ceracchi, ...
Journal of the peripheral nervous system 16 (3), 228-236 2011
Citations: 87



Chemotherapy‐induced peripheral neurotoxicity: A multifaceted, still unsolved issue
G Cavaletti, P Alberti, AA Argyriou, M Lustberg, NP Staff, S Tamburin, ...
Journal of the Peripheral Nervous System 24, S6-S12 2019
Citations: 86



Overview and critical revision of clinical assessment tools in chemotherapy‐induced peripheral neurotoxicity
SB Park, P Alberti, NA Kolb, JS Gewandter, A Schenone, AA Argyriou
Journal of the Peripheral Nervous System 24, S13-S25 2019
Citations: 84



Bortezomib and other proteosome inhibitors—induced peripheral neurotoxicity: From pathogenesis to treatment
R Velasco, P Alberti, J Bruna, D Psimaras, AA Argyriou
Journal of the Peripheral Nervous System 24, S52-S62 2019
Citations: 79



Neurofilament light chain as disease biomarker in a rodent model of chemotherapy induced peripheral neuropathy
C Meregalli, G Fumagalli, P Alberti, A Canta, VA Carozzi, A Chiorazzi, ...
Experimental neurology 307, 129-132 2018
Citations: 79



OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity
AF Leblanc, JA Sprowl, P Alberti, A Chiorazzi, WD Arnold, AA Gibson, ...
The Journal of clinical investigation 128 (2), 816-825 2018
Citations: 76