Imperial College London

ProfessorLucaMagnani

Faculty of MedicineDepartment of Surgery & Cancer

Honorary Principal Research Fellow
 
 
 
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Contact

 

+44 (0)20 7594 2808l.magnani CV

 
 
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Location

 

137ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

134 results found

Magnani L, Rosano D, Dhiman H, ivanoiu D, Canale E, Dewhurst H, Saha D, Slaven N, Rehman Fet al., 2024, Long-term multi-modal recording reveals epigenetic adaptation routes in dormant breast cancer cells, Cancer Discovery, ISSN: 2159-8274

Journal article

Hedayat S, Cascione L, Cunningham D, Schirripa M, Lampis A, Hahne JC, Tunariu N, Hong SP, Marchetti S, Khan K, Fontana E, Angerilli V, Delrieux M, Nava Rodrigues D, Procaccio L, Rao S, Watkins D, Starling N, Chau I, Braconi C, Fotiadis N, Begum R, Guppy N, Howell L, Valenti M, Cribbes S, Kolozsvari B, Kirkin V, Lonardi S, Ghidini M, Passalacqua R, Elghadi R, Magnani L, Pinato DJ, Di Maggio F, Ghelardi F, Sottotetti E, Vetere G, Ciraci P, Vlachogiannis G, Pietrantonio F, Cremolini C, Cortellini A, Loupakis F, Fassan M, Valeri Net al., 2024, Circulating microRNA analysis in a prospective co-clinical trial identifies MIR652-3p as a response biomarker and driver of regorafenib resistance mechanisms in colorectal cancer., Clin Cancer Res

BACKGROUND: The multi-kinase inhibitor regorafenib has demonstrated efficacy in chemo-refractory metastatic colorectal cancer (mCRC) patients. However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice. METHODS: Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemo-refractory mCRC patients treated with regorafenib in a phase II clinical trial (PROSPECT-R n=40; NCT03010722) and in a multicentric validation cohort (n=241). Tissue biopsies collected at baseline, after 2 months and at progression in the PROSPECT-R trial were used to establish Patient-Derived Organoids (PDOs) and for molecular analyses. MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform and results were validated by digital droplet PCR and/or In Situ Hybridization in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses. RESULTS: Large-scale microRNA expression analysis in longitudinal matched liquid and tissue biopsies from the PROSPECT-R trial identified MIR652-3p as a biomarker of clinical benefit to regorafenib. These findings were confirmed in an independent validation cohort and in a "control" group of 100 patients treated with lonsurf. Using ex vivo co-culture assays paired with single-cell RNA-sequencing of PDO established pre- and post-treatment, we modelled regorafenib response observed in vivo and in patients, and showed that MIR652-3p controls resistance to regorafenib by impairing regorafenib-induced lethal autophagy and by orchestrating the switch from neo-angiogenesis to vessel co-option. CONCLUSIONS: Our results identify MIR652-3p as potential biomarker and as a driver of cell and non-cell autonomous mechanisms of resistance to regorafenib.

Journal article

Riccieri V, Pellegrino G, Cipolletta E, Giuggioli D, Bajocchi G, Bellando-Randone S, Dagna L, Zanframundo G, Foti R, Cacciapaglia F, Cuomo G, Ariani A, Rosato E, Lepri G, Girelli F, Zanatta E, Bosello SL, Cavazzana I, Ingegnoli F, De Santis M, Murdaca G, Abignano G, Romeo N, Della Rossa A, Caminiti M, Iuliano A, Ciano G, Beretta L, Bagnato G, Lubrano E, De Andres I, Giollo A, Saracco M, Agnes C, Lumetti F, Spinella A, Magnani L, Campochiaro C, De Luca G, Codullo V, Visalli E, Di Vico C, Gigante A, Saccon F, Grazia Lazzaroni M, Franceschini F, Generali E, Mennillo G, Barsotti S, Pagano Mariano G, Calabrese F, Furini F, Vultaggio L, Parisi S, Peroni CL, Bianchi G, Conti F, Cozzi F, DAngelo S, Doria A, Fusaro E, Govoni M, Guiducci S, Iannone F, Salvarani C, Sebastiani GD, Ferri C, Matucci-Cerinic M, De Angelis Ret al., 2024, Practice pattern for the use of intravenous iloprost for the treatment of peripheral vasculopathy in systemic sclerosis: A case–control study from the Italian national multicenter “SPRING” (Systemic Sclerosis Progression InvestiGation) Registry, Journal of Scleroderma and Related Disorders, Vol: 9, Pages: 38-49, ISSN: 2397-1983

Background: Intravenous iloprost has been widely used for the treatment of systemic sclerosis peripheral vasculopathy. No agreement has been found on the regimen and the dosage of intravenous iloprost in different scleroderma subset conditions. This study aimed to evaluate the modalities of intravenous iloprost administration within a large cohort of systemic sclerosis patients from the SPRING Registry and to identify any associated clinical-demographic, instrumental or therapeutic data. Patients and Methods: Data of systemic sclerosis patients treated with intravenous iloprost for at least 1 year (case group) were retrospectively analyzed, including different timing and duration of intravenous iloprost session, and compared with those of untreated patients (control group). Results: Out of 1895 analyzed patients, 937 (49%) received intravenous iloprost treatment, while 958 (51%) were assigned to the control group. Among cases, about 70% were treated every 4 weeks, 24% with an interval of more than 4 weeks, and only 6% of less than 4 weeks. Most patients receiving the treatment every 4 weeks, or less, underwent infusion cycle for 1 day only, while if it was scheduled with an interval of more than 4 weeks, a total number of 5 consecutive days of infusions was the preferred regimen. The comparison between the two groups revealed that patients treated with intravenous iloprost had a higher frequency of DUs (p < 0.001), pitting scars (p < 0.001), diffuse cutaneous involvement (p < 0.001), interstitial lung disease (p < 0.002), as well as higher rates of anti-topoisomerase I, “late” scleroderma pattern at nailfold videocapillaroscopy. These findings were confirmed by multivariate analysis. Conclusion: Our data provide a picture on the Italian use of intravenous iloprost among systemic sclerosis patients and showed that it was usually employed in patients with a more aggressive spectrum of the disease. The disparity of intravenous iloprost treatment

Journal article

Ciriello G, Magnani L, Aitken SJ, Akkari L, Behjati S, Hanahan D, Landau DA, Lopez-Bigas N, Lupiáñez DG, Marine J-C, Martin-Villalba A, Natoli G, Obenauf AC, Oricchio E, Scaffidi P, Sottoriva A, Swarbrick A, Tonon G, Vanharanta S, Zuber Jet al., 2024, Cancer Evolution: A Multifaceted Affair., Cancer Discov, Vol: 14, Pages: 36-48

UNLABELLED: Cancer cells adapt and survive through the acquisition and selection of molecular modifications. This process defines cancer evolution. Building on a theoretical framework based on heritable genetic changes has provided insights into the mechanisms supporting cancer evolution. However, cancer hallmarks also emerge via heritable nongenetic mechanisms, including epigenetic and chromatin topological changes, and interactions between tumor cells and the tumor microenvironment. Recent findings on tumor evolutionary mechanisms draw a multifaceted picture where heterogeneous forces interact and influence each other while shaping tumor progression. A comprehensive characterization of the cancer evolutionary toolkit is required to improve personalized medicine and biomarker discovery. SIGNIFICANCE: Tumor evolution is fueled by multiple enabling mechanisms. Importantly, genetic instability, epigenetic reprogramming, and interactions with the tumor microenvironment are neither alternative nor independent evolutionary mechanisms. As demonstrated by findings highlighted in this perspective, experimental and theoretical approaches must account for multiple evolutionary mechanisms and their interactions to ultimately understand, predict, and steer tumor evolution.

Journal article

Chen B, Ramazzotti D, Heide T, Spiteri I, Fernandez-Mateos J, James C, Magnani L, Graham TA, Sottoriva Aet al., 2023, Contribution of pks+ E. coli mutations to colorectal carcinogenesis., Nat Commun, Vol: 14

The dominant mutational signature in colorectal cancer genomes is C > T deamination (COSMIC Signature 1) and, in a small subgroup, mismatch repair signature (COSMIC signatures 6 and 44). Mutations in common colorectal cancer driver genes are often not consistent with those signatures. Here we perform whole-genome sequencing of normal colon crypts from cancer patients, matched to a previous multi-omic tumour dataset. We analyse normal crypts that were distant vs adjacent to the cancer. In contrast to healthy individuals, normal crypts of colon cancer patients have a high incidence of pks + (polyketide synthases) E.coli (Escherichia coli) mutational and indel signatures, and this is confirmed by metagenomics. These signatures are compatible with many clonal driver mutations detected in the corresponding cancer samples, including in chromatin modifier genes, supporting their role in early tumourigenesis. These results provide evidence that pks + E.coli is a potential driver of carcinogenesis in the human gut.

Journal article

Magnani L, Ariani A, Lo Monaco A, Girelli F, Spinella A, Lumetti F, Reta M, Arrigoni E, Ursini F, Bezzi A, Cataleta P, Montaguti L, Trevisani M, Colina M, Bernardi S, De Pinto M, Galoppini G, Testoni S, Becciolini A, Pignataro F, Ciaffi J, Bravi E, Focherini M, Moscatelli S, Sambo P, Fusconi M, Corvaglia S, Bajocchi G, Conti D, Salvarani C, Giuggioli Det al., 2023, Real life use of prostacyclin analog (iloprost), a multi-centric survey data from the Scleroderma study group Emilia Romagna (Sclero-RER) and review of the literature., Acta Biomed, Vol: 94

BACKGROUND AND AIM: Iloprost is recommend worldwide for the treatment of RP and the healing of DUs. The aim of this study is to report the regimens of Iloprost administered in different rheumatological centers within the same regional Health System Methods: A questionnaire exploring different items related to the use of Iloprost was developed and reviewed by three expert rheumatologists. The questionnaire was distributed as an online survey to all local SSc referral centers in Emilia-Romagna (Italy). Data are reported as percentage or median with interquartile range (IQR), as appropriate. An updated review of world literature on this topic was also carried out. RESULTS: All the invited centers completed the survey. There were both local (8) and university hospitals (4). The majority (58%) had a rheumatologist as head physician. All centers used Iloprost: a single monthly administration was the most common treatment (75%). The cycle lasted 1 [IQR 1-2] days with a 0.5-2.0 ng/Kg/min dose according to the drug tolerance of the patients. There were overall 68 spots (beds, reclining armchair, or simple armchair); 2.0 [1.5-4.0] patients were able to receive Iloprost at the same time. University Hospitals had more physicians at their disposal than local hospitals but less paramedic personnel (respectively: 1.8 vs 1.2 physicians, 1.5 vs 2.1 nurses). CONCLUSIONS: These observations were in line with the majority of previous studies reporting different regimens, comparing similar (but not identical) dose and schedule administration, however, despite differences being at times substantial, no standard infusion method is yet available.

Journal article

Magnani L, Spinella A, Testoni S, Lumetti F, Scelfo C, Dardani L, Bajocchi G, Clini E, Salvarani C, Giuggioli Det al., 2023, One-year clinical experience on the use of Nintedanib in systemic sclerosis, Respirology Case Reports, Vol: 11

We reviewed 11 patients with systemic sclerosis-related ILD who were referred to our Scleroderma Unit from January 2020 to January 2021 and started Nintedanib. Non-specific interstitial pneumonia (NSIP) was prevalent (45%), usual interstitial pneumonia (UIP) and UIP/NSIP pattern were both 27%. Only one patient had a history of smoking. Eight patients were on mycophenolate mofetil (MMF), eight were treated with corticosteroids (mean dose 5 mg/day of Prednisone or equivalent), and three were on Rituximab. The mean modified British Council Medical Questionnaire (mmRC) decreased from 3 to 2.5. Two patients had to reduce their daily dose to 200 mg/day for severe diarrhoea. Nintedanib was generally well tolerated.

Journal article

Rossi S, Statello R, Pelà G, Leonardi F, Cabassi A, Foresti R, Rozzi G, Lo Muzio FP, Carnevali L, Sgoifo A, Magnani L, Callegari S, Pastori P, Tafuni A, Corradi D, Miragoli M, Macchi Eet al., 2023, Age-related increases in cardiac excitability, refractoriness and impulse conduction favor arrhythmogenesis in male rats, Pflugers Archiv European Journal of Physiology, Vol: 475, Pages: 731-745, ISSN: 0031-6768

The effects of excitability, refractoriness, and impulse conduction have been independently related to enhanced arrhythmias in the aged myocardium in experimental and clinical studies. However, their combined arrhythmic effects in the elderly are not yet completely understood. Hence, the aim of the present work is to relate relevant cardiac electrophysiological parameters to enhanced arrhythmia vulnerability in the in vivo senescent heart. We used multiple-lead epicardial potential mapping in control (9-month-old) and aged (24-month-old) rat hearts. Cardiac excitability and refractoriness were evaluated at numerous epicardial test sites by means of the strength-duration curve and effective refractory period, respectively. During sinus rhythm, durations of electrogram intervals and waves were prolonged in the senescent heart, compared with control, demonstrating a latency in tissue activation and recovery. During ventricular pacing, cardiac excitability, effective refractory period, and dispersion of refractoriness increased in the aged animal. This scenario was accompanied by impairment of impulse propagation. Moreover, both spontaneous and induced arrhythmias were increased in senescent cardiac tissue. Histopathological evaluation of aged heart specimens revealed connective tissue deposition and perinuclear myocytolysis in the atria, while scattered microfoci of interstitial fibrosis were mostly present in the ventricular subendocardium. This work suggests that enhanced arrhythmogenesis in the elderly is a multifactorial process due to the joint increase in excitability and dispersion of refractoriness in association with enhanced conduction inhomogeneity. The knowledge of these electrophysiological changes will possibly contribute to improved prevention of the age-associated increase in cardiac arrhythmias.

Journal article

Chang E, Wang Y, Zhu R, Wu L, Yang Y, Zeng S, Li N, Ruan X, Sun M, Zhang W, Zhou J, Miao M, Zhi H, Zhao H, Chen Q, Sun Q, Chang E, Chang A, Zhang T, He X, Liu K, Ma S, Zhu W, Zhang Y, Magnani L, Ma D, Zhang Jet al., 2023, General anesthetic action profile on the human prefrontal cortex cells through comprehensive single-cell RNA-seq analysis, iScience, Vol: 26, Pages: 1-19, ISSN: 2589-0042

The cellular and molecular actions of general anesthetics to induce anesthesia state and also cellular signaling changes for subsequent potential "long term" effects remain largely elusive. General anesthetics were reported to act on voltage-gated ion channels and ligand-gated ion channels. Here we used single-cell RNA-sequencing complemented with whole-cell patch clamp and calcium transient techniques to examine the gene transcriptome and ion channels profiling of sevoflurane and propofol, both commonly used clinically, on the human fetal prefrontal cortex (PFC) mixed cell cultures. Both propofol and sevoflurane at clinically relevant dose/concentration promoted "microgliosis" but only sevoflurane decreased microglia transcriptional similarity. Propofol and sevoflurane each extensively but transiently (<2 h) altered transcriptome profiling across microglia, excitatory neurons, interneurons, astrocytes and oligodendrocyte progenitor cells. Utilizing scRNA-seq as a robust and high-through put tool, our work may provide a comprehensive blueprint for future mechanistic studies of general anesthetics in clinically relevant settings.

Journal article

De Angelis R, Ferri C, Giuggioli D, Bajocchi G, Dagna L, Bellando-Randone S, Zanframundo G, Foti R, Cacciapaglia F, Cuomo G, Ariani A, Rosato E, Lepri G, Girelli F, Riccieri V, Zanatta E, Bosello SL, Cavazzana I, Ingegnoli F, De Santis M, Murdaca G, Abignano G, Romeo N, Della Rossa A, Caminiti M, Iuliano AM, Ciano G, Beretta L, Bagnato G, Lubrano E, De Andres I, Giollo A, Saracco M, Agnes C, Cipolletta E, Lumetti F, Spinella A, Magnani L, Campochiaro C, De Luca G, Codullo V, Visalli E, Di Vico C, Gigante A, Pellagrino G, Pigatto E, Lazzaroni M-G, Franceschini F, Generali E, Mennillo G, Barsotti S, Mariano GP, Furini F, Vultaggio L, Parisi S, Peroni CL, Rozza D, Zanetti A, Carrara G, Landolfi G, Scirè CA, Bianchi G, Fusaro E, Sebastiani GD, Govoni M, D'Angelo S, Cozzi F, Guiducci S, Doria A, Salvarani C, Iannone F, Matucci-Cerinic M, SPRING-SIR Systemic Sclerosis PRogression INvestiGation group of the Italian Society of Rheumatologyet al., 2023, Systemic sclerosis sine scleroderma: clinical and serological features and relationship with other cutaneous subsets in a large series of patients from the national registry 'SPRING' of the Italian Society for Rheumatology., RMD Open, Vol: 9

OBJECTIVE: To describe demographic, clinical and laboratory features of systemic sclerosis sine scleroderma (ssSSc) in a large multicentre systemic sclerosis (SSc) cohort. METHODS: Data involving 1808 SSc patients from Italian Systemic sclerosis PRogression INvestiGation registry were collected. The ssSSc was defined by the absence of any cutaneous sclerosis and/or puffy fingers. Clinical and serological features of ssSSc were compared with limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subsets. RESULTS: Among patients with SSc, only 61 (3.4%) were classified as having ssSSc (F/M=19/1). Time from Raynaud's phenomenon (RP) onset to diagnosis was longer in ssSSc (3 years, IQR 1-16.5) than lcSSc (2 years, IQR 0-7), and dcSSc (1 year, IQR 0-3) (p<0.001). Clinical ssSSc phenotype was comparable to lcSSc, except for digital pitting scars (DPS) (19.7% vs 42%, p=0.01), but significantly milder than dcSSc, particularly for digital ulcers (DU) (6.6% vs 35.7%, p<0.001), oesophagus (46.2% vs 63.5%, p=0.009), lung (mean diffusion capacity for carbon monoxide 72.2±19.6 vs 62.4±22.8, p=0.009; mean forced vital capacity 105.6±21.7 vs 89.2±20.9, p<0.001) and major videocapillaroscopic alterations (late pattern 8.6% vs 47.6%, p<0.001). Moreover, in ssSSc the percentages of anticentromere and antitopoisomerase were comparable to lcSSc (40% and 18.3% vs 36.7% and 26.6%), but divergent respect to dcSSc (8.6% and 67.4%, p<0.001). CONCLUSION: The ssSSc is a quite rare disease variant characterised by clinico-serological features comparable to lcSSc, but significantly different from dcSSc. Overall, longer RP duration, low percentages of DPS and peripheral microvascular abnormalities, and increased anti-centromere seropositivity distinguish ssSSc. Further investigations based on national registries might provide useful insights on the actual relevance of the ssSSc within the scleroderma spectrum.

Journal article

Ferrando L, Vingiani A, Garuti A, Vernieri C, Belfiore A, Agnelli L, Dagrada G, Ivanoiu D, Bonizzi G, Munzone E, Lippolis L, Dameri M, Ravera F, Colleoni M, Viale G, Magnani L, Ballestrero AJ, Zoppoli GJ, Pruneri GJet al., 2023, <i>ESR1</i> gene amplification and <i>MAP3K</i> mutations are selected during adjuvant endocrine therapies in relapsing Hormone Receptor-positive, HER2-negative breast cancer (HR+HER2-BC), PLOS GENETICS, Vol: 19, ISSN: 1553-7404

Journal article

Househam J, Heide T, Cresswell GD, Spiteri I, Kimberley C, Zapata L, Lynn C, James C, Mossner M, Fernandez-Mateos J, Vinceti A, Baker A-M, Gabbutt C, Berner A, Schmidt M, Chen B, Lakatos E, Gunasri V, Nichol D, Costa H, Mitchinson M, Ramazzotti D, Werner B, Iorio F, Jansen M, Caravagna G, Barnes CP, Shibata D, Bridgewater J, Rodriguez-Justo M, Magnani L, Sottoriva A, Graham TAet al., 2022, Phenotypic plasticity and genetic control in colorectal cancer evolution, NATURE, Vol: 611, Pages: 744-+, ISSN: 0028-0836

Journal article

Casalini E, Piro R, Fontana M, Rossi L, Ghinassi F, Taddei S, Mengoli MC, Magnani L, Beghè B, Facciolongo Net al., 2022, Diagnosis of Organizing Pneumonia with an Ultrathin Bronchoscope and Cone-Beam CT: A Case Report, Diagnostics, Vol: 12

Organizing pneumonia (OP) is a pulmonary disease histopathologically characterized by plugs of loose connective tissue in distal airways. The clinical and radiological presentations are not specific and they usually require a biopsy confirmation. This paper presents the case of a patient with a pulmonary opacity sampled with a combined technique of ultrathin bronchoscopy and cone-beam CT. A 64-year-old female, a former smoker, was admitted to the hospital of Reggio Emilia (Italy) for exertional dyspnea and a dry cough without a fever. The history of the patient included primary Sjögren Syndrome interstitial lung disease (pSS-ILD) characterized by a non-specific interstitial pneumonia (NSIP) radiological pattern; this condition was successfully treated up to 18 months before the new admission. The CT scan showed the appearance of a right lower lobe pulmonary opacity of an uncertain origin that required a histological exam for the diagnosis. The lung lesion was difficult to reach with traditional bronchoscopy and a percutaneous approach was excluded. Thus, cone-beam CT, augmented fluoroscopy and ultrathin bronchoscopy were chosen to collect a tissue sample. The histopathological exam was suggestive of OP, a condition occurring in 4–11% of primary Sjögren Syndrome cases. This case showed that, in the correct clinical and radiological context, even biopsies taken with small forceps can lead to a diagnosis of OP. Moreover, it underlined that the combination of multiple advanced technologies in the same procedure can help to reach difficult target lesions, providing proper samples for a histological diagnosis.

Journal article

Heide T, Househam J, Cresswell GD, Spiteri I, Lynn C, Mossner M, Kimberley C, Fernandez-Mateos J, Chen B, Zapata L, James C, Barozzi I, Chkhaidze K, Nichol D, Gunasri V, Berner A, Schmidt M, Lakatos E, Baker A-M, Costa H, Mitchinson M, Piazza R, Jansen M, Caravagna G, Ramazzotti D, Shibata D, Bridgewater J, Rodriguez-Justo M, Magnani L, Graham TA, Sottoriva Aet al., 2022, The co-evolution of the genome and epigenome in colorectal cancer, Nature, Vol: 611, Pages: 733-743, ISSN: 0028-0836

Colorectal malignancies are a leading cause of cancer-related death1 and have undergone extensive genomic study2,3. However, DNA mutations alone do not fully explain malignant transformation4,5,6,7. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.

Journal article

Spinella A, de Pinto M, Galluzzo C, Testoni S, Macripò P, Lumetti F, Parenti L, Magnani L, Sandri G, Bajocchi G, Starnoni M, De Santis G, Salvarani C, Giuggioli Det al., 2022, Photobiomodulation Therapy: A New Light in the Treatment of Systemic Sclerosis Skin Ulcers, Rheumatology and Therapy, Vol: 9, Pages: 891-905, ISSN: 2198-6576

Introduction: Skin ulcers (SU) represent one of the most frequent manifestations of systemic sclerosis (SSc), occurring in almost 50% of scleroderma patients. SSc-SU are often particularly difficult to treat with conventional systemic and local therapies. In this study, a preliminary evaluation of the role and effectiveness of blue light photobiomodulation (PBM) therapy with EmoLED® in the treatment of scleroderma skin ulcers (SSc-SU) was performed. Methods: We retrospectively analyzed 12 consecutive SSc patients with a total of 15 SU on finger hands. All patients were treated with adequate systemic therapy and local treatment for SU; after a standard skin ulcer bed preparation with debridement of all lesions, EmoLED® was performed. All patients were locally treated every week during 2 months of follow-up; SU data were collected after 4 weeks (T4) and 8 weeks (T8). Eight SSc patients with comparable SU were also evaluated as controls. Results: The application of EmoLED® in addition to debridement apparently produced faster healing of SU. Complete healing of SU was recorded in 41.6% cases during EmoLED® treatment. Significant improvements in SU area, length, and width, wound bed, and related pain were observed in EmoLED® patients from T0 to T8. Control subjects treated with standard systemic/local therapies merely showed an amelioration of SU area and width at the end of the follow-up. No procedural or post-procedural adverse events were reported. Conclusions: The positive clinical results and the absence of side effects suggest that EmoLED® could be a promising tool in the management of SSc-SU, with an interesting role to play in the healing process in addition to conventional systemic and local treatments.

Journal article

Househam J, Heide T, Cresswell GD, Lynn C, Spiteri I, Mossner M, Kimberley C, Gabbutt C, Lakatos E, Fernandez-Mateos J, Chen B, Zapata L, James C, Berner A, Schmidt M, Baker AM, Nichol D, Costa H, Mitchinson M, Jansen M, Caravagna G, Shibata D, Bridgewater J, Rodriguez-Justo M, Magnani L, Sottoriva A, Graham TAet al., 2022, Phenotypic Plasticity Limits Subclonal Selection in Colorectal Cancer, Virtual 4th Joint Winter Meeting of the Pathological-Society-of-Great-Britain-and-Ireland and the Royal-Society-of-Medicine, Publisher: WILEY, Pages: S7-S7, ISSN: 0022-3417

Conference paper

Trasanidis N, Katsarou A, Ponnusamy K, Shen Y-A, Kostopoulos I, Bergonia B, Keren K, Reema P, Xiao X, Szydlo RM, Sabbattini PMR, Roberts IAG, Auner HW, Naresh KN, Chaidos A, Wang T-L, Magnani L, Caputo VS, Karadimitris Aet al., 2022, Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma, BLOOD, Vol: 139, Pages: 1939-1953, ISSN: 0006-4971

Journal article

Magnani L, 2022, Genetic and epigenetic driven variation in regulatory regions activity contribute to adaptation and evolution under endocrine treatment

<jats:title>Abstract</jats:title> <jats:p>Comprehensive profiling of hormone-dependent breast cancer (HDBC) has identified hundreds of protein-coding alterations contributing to cancer initiation1,2, but only a handful have been linked to endocrine therapy resistance, potentially contributing to 40% of relapses1,3–9. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ integrative functional genomics to dissect the contribution of cis-regulatory elements (CREs) to cancer evolution by focusing on 12 megabases of non-coding DNA, including clonal enhancers10, gene promoters, and boundaries of topologically associating domains11. Massive parallel perturbation in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance12,13 and endocrine therapy resistance9. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies non-coding changes involved in therapy resistance. Overall, our data uncover actionable transient transcriptional programs critical for dormant persister cells and unveil new regulatory nodes driving evolutionary trajectories towards disease progression</jats:p>

Journal article

Magnani L, 2022, Long-term multi-modal recording reveals unpredictable nongenetic adaptation routes in dormant breast cancer cells.

<jats:title>Abstract</jats:title> <jats:p>Patients diagnosed with hormone dependent breast cancer (HDBC) receive five or more years of adjuvant endocrine therapies (ET). Adjuvant treatment delays relapse1,2 by targeting hidden micro-metastatic deposits, yet up to 50% of treated patients experience recurrent disease, often many years after surgery1. The mechanisms driving these subtype-specific clinical dynamics are largely unknown but likely involve dormancy2. We developed two approaches to study the long-term fate of dormant cells in unprecedented details. Firstly, we took advantage of a rare cohort of patients treated upfront with first line ETs until progression to dissect the contribution of genomic events to tumour awakening. Next, we developed a first of its kind in vitro evolutionary study to systematically record adaptive strategies of individual clonal lineages in parallel unperturbed systems during a period of several months. Collectively our data suggest that ETs induce an inherently unstable persister dormant state in a stochastically selected fraction of lineages. Over time, single cells spontaneously escape dormancy and divergently adapt via heritable transcriptional reprogramming, often developing distinct collateral resistance. Overall, this study uncovers previously unsuspected roles for non-genetic plasticity during dormancy with profound clinical implications for breast cancer.</jats:p>

Journal article

De Angelis R, Giuggioli D, Bajocchi G, Dagna L, Zanframundo G, Foti R, Cacciapaglia F, Cuomo G, Ariani A, Rosato E, Guiducci S, Girelli F, Riccieri V, Zanatta E, Bosello S, Cavazzana I, Ingegnoli F, Santis MD, Murdaca G, Abignano G, Romeo N, Della Rossa A, Caminiti M, Iuliano A, Ciano G, Beretta L, Bagnato G, Lubrano E, De Andres I, Giollo A, Saracco M, Agnes C, Lumetti F, Spinella A, Magnani L, Campochiaro C, De Luca G, Codullo V, Visalli E, Masini F, Gigante A, Bellando-Randone S, Pellegrino G, Pigatto E, Dall'Ara F, Lazzaroni MG, Generali E, Mennillo G, Barsotti S, Mariano GP, Calabrese F, Furini F, Vultaggio L, Parisi S, Peroni CL, Risa AM, Rozza D, Zanetti A, Carrara G, Landolfi G, Scirè CA, Bianchi G, Fusaro E, Sebastiani GD, Govoni M, D'Angelo S, Cozzi F, Doria A, Iannone F, Salvarani C, Matucci-Cerinic M, Ferri C, Systemic sclerosis PRogression INvestiGation group SPRINGet al., 2022, Sex-related Differences in Systemic Sclerosis: A Multicenter Cross-sectional Study From the National Registry of the Italian Society for Rheumatology., J Rheumatol, Vol: 49, Pages: 176-185

OBJECTIVE: There is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics. METHODS: A multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared. RESULTS: The overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs. CONCLUSION: Our study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.

Journal article

Trasanidis N, Katsarou A, Ponnusamy K, Shen Y-A, Kostopoulos IV, Bergonia B, Keren K, Reema P, Xiao X, Szydlo RM, Sabbattini PMR, Roberts IAG, Auner HW, Naresh KN, Chaidos A, Wang T-L, Magnani L, Caputo VS, Karadimitris Aet al., 2021, Systems medicine dissection of chromosome 1q amplification reveals oncogenic regulatory circuits and informs targeted therapy in cancer

<jats:title>Abstract</jats:title><jats:p>Understanding the biological and clinical impact of copy number aberrations (CNA) in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several cancers, including the blood cancer, multiple myeloma (MM). Although several chr1q genes portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here we integrate patient multi-omics datasets with genetic variables to identify 103 adverse prognosis genes in chr1q-amp MM. Amongst these, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways, whilst in co-operation with FOXM1, activates a proliferative gene signature which predicts adverse prognosis across multiple cancers. Notably, pharmacological disruption of the PBX1-FOXM1 axis, including with a novel PBX1 inhibitor is selectively toxic against chr1q-amp cancer cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in cancer.</jats:p><jats:sec><jats:title>Significance</jats:title><jats:p>We provide a comprehensive systems medicine strategy to unveil oncogenic circuitries and inform novel precision therapy decisions against CNA in cancer. This first clinical multi-omic analysis of chr1q-amp in MM identifies a central PBX1-FOXM1 regulatory axis driving high-risk prognosis, as a novel therapeutic target against chr1q-amp in cancer.</jats:p></jats:sec>

Journal article

Toss A, Spinella A, Isca C, Vacchi C, Ficarra G, Fabbiani L, Iannone A, Magnani L, Castrignanò P, Macripò P, Gasparini E, Piana S, Cortesi L, Maiorana A, Salvarani C, Dominici M, Giuggioli Det al., 2021, Clinical and pathological features of breast cancer in systemic sclerosis: Results from the sclero-breast study, Journal of Personalized Medicine, Vol: 11

Systemic Sclerosis (SSc) is a chronic disease associated with a 1.5-fold increase in cancer risk, including lung cancer, hematological malignancies, and breast cancer (BC). This is a retrospective study aiming to explore the clinical and pathological features of BC developed by SSc patients. A total of 54.5% of patients developed BC before SSc (median interval: 5 years), whereas 45.5% of patients developed BC after SSc (median delay: 8 years). A total of 93.1% of patients were diagnosed with an early stage tumor. Among invasive carcinomas, 70.8% presented with a low Mib1, 8.3% with a tubular histotype, and 42.8% with a Luminal A-like phenotype. A total of 66.6% of patients underwent breast-conserving surgery and 55.5% RT. A total of 40% of patients developed interstitial lung disease after RT and 20% diffuse cutaneous SSc. The cause of death of the six deceased patients was PAH. A significant association was observed between the use of immunosuppressive therapy and diffuse skin extension, negative ACA, positive Anti-Scl-70, and interstitial lung disease, but not BC status. SSc patients developed BC at a good prognosis, suggesting a de-escalation strategy of cancer therapies. In particular, ionizing radiation and chemotherapeuticals should be limited to higher-risk cases. Finally, proper screening is mandatory in order to allow for early cancer detection in SSc patients.

Journal article

De Santis F, Fuca G, Schadendorf D, Mantovani A, Magnani L, Lisanti M, Pettitt S, Bellone M, Del Sal G, Minucci S, Eggermont A, Bruzzi P, Bicciato S, Conte P, Noberini R, Hiscott J, De Braud F, Del Vecchio M, Di Nicola Met al., 2021, Anticancer innovative therapy congress: Highlights from the 10th anniversary edition, CYTOKINE & GROWTH FACTOR REVIEWS, Vol: 59, Pages: 1-8, ISSN: 1359-6101

Journal article

Ciriello G, Magnani L, 2021, The many faces of cancer evolution, ISCIENCE, Vol: 24

Journal article

Rosano D, Sofyali E, Dhiman H, Ivanoiu D, Slaven N, Hong SP, Rocca A, Bravaccini S, Ravaioli S, Noberini R, Bonaldi T, Magnani Let al., 2021, Unperturbed dormancy recording reveals stochastic awakening strategies in endocrine treated breast cancer cells

<jats:title>Abstract</jats:title><jats:p>Hormone dependent breast cancer (HDBC) is the most commonly diagnosed tumor type in women. Adjuvant endocrine therapies (ET) have been the cornerstone in the clinical management of HDBC patients for over forty years. A vast proportion of HDBC patients incur long periods of clinical dormancy following ET, with tumour awakening appearing at a steady pace for up to 25 years (Pan et al., 2017). Extensive genomic studies have demonstrated that 15-30% of clinical relapses develop recurrent genomic changes which contribute to drug resistance (i.e. ESR1 activating mutations) (Bertucci et al., 2019; Magnani et al., 2017; Razavi et al., 2018). However, even in these cases, there is no conclusive evidence around the pre-existence vs. <jats:italic>de novo</jats:italic> nature of these events. We previously showed that ETs can trigger and select for dormancy in subpopulations of breast cancer (Hong et al., 2019). In this work we took two novel approaches to investigate the dormancy and awakening roadmap of HDBC cells at unprecedented detail. Firstly, we leveraged a rare cohort of n=5 patients which were treated with primary adjuvant ETs in the absence of surgery (TRACING-HT) to dissect the contribution of genomic aberrations to tumor awakening. Next, we developed a first of its kind evolutionary study <jats:italic>in vitro</jats:italic> to systematically annotate cancer cells adaptive strategies at single cell level in unperturbed systems during a period of several months (TRADITIOM). Collectively our data suggest that ETs steer HDBC cells into an inherently unstable dormant state. Over time, routes to awakening emerge sporadically and spontaneously in single lineages. Each dormant cell retains an intrinsic awakening probability which we propose is a function of epigenetic decay. Awakening occurs without an external trigger and involves multiple apparent endpoint phenotypes that cannot be fully ex

Journal article

Serban T, Allara R, Azzolini V, Bellintani C, Belloli L, Belai Beyene N, Bucci R, Caporali R, Cappelli A, Corbelli V, DE Gennaro F, Fusaro E, Giusti A, Govoni M, Magnani L, Manzo C, Romano C, Rossini M, Santilli D, Saviola G, Sinigaglia L, Bianchi G, MARTE study groupet al., 2021, Long-term methotrexate use in rheumatoid arthritis patients: real-world data from the MARTE study., Minerva Med, Vol: 112, Pages: 246-254

BACKGROUND: The MARTE study investigated the demographic, clinical, and therapeutic characteristics of rheumatoid arthritis (RA) patients ongoing methotrexate (MTX) treatment for longer than 8 years. METHODS: This cross-sectional, observational study considered 587 RA patients from 67 Rheumatology Units across Italy. Data collected included demographic, clinical, and therapeutic characteristics, focusing on MTX prescription patterns (route of administration, dosing regimens, treatment duration, and discontinuation). RESULTS: As initial therapy, 90.6% of patients received one conventional synthetic Disease Modifying Anti Rheumatic Drug (csDMARD), with treatment started within the first 3 months from diagnosis in half of the patients. MTX was the first csDMARD in 46.2% of patients. The prevalent route of administration at diagnosis was the intramuscular (60.5%), while at study entry (baseline) 57.6% were receiving subcutaneous MTX. Patients who required a higher MTX dose at study entry were those who received a significantly lower starting MTX dose (P<0.001). Significantly higher MTX doses were currently required in men (P<0.001), current smokers (P=0.013), and overweight patients (P=0.028), whereas patients on oral therapy received significantly lower doses of MTX (P<0.001). CONCLUSIONS: The MARTE study confirms once again the potential of the proper use of MTX in the treatment of RA. Data from our study suggest that a higher dose of MTX should be used since the first stages in overweight patients, men, and smokers.

Journal article

Spinella A, Magnani L, De Pinto M, Marvisi C, Parenti L, Bajocchi G, Salvarani C, Mascia MT, Giuggioli Det al., 2021, Management of Systemic Sclerosis Patients in the COVID-19 Era: The Experience of an Expert Specialist Reference Center, Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine, Vol: 15

Objective: COVID-19 pandemic represents a serious health emergency that severely compromised our Public Health system, resulting in a rapid and forced reorganization and involved the management of chronic diseases too. The Scleroderma Unit of Modena and Reggio Emilia follows more than 600 patients suffering from systemic sclerosis (SSc) and recently became the referral center (HUB) in Emilia-Romagna for this rare connective tissue disease. The aim of the present study was to evaluate the extent by which the lockdown and the pandemic has impacted the activity of admissions to Scleroderma Unit of Modena and Reggio Emilia. Methods: Our daily clinical activity is characterized by outpatient visits, videocapillaroscopy exam, ulcers treatment, therapeutic infusions in day hospital regimen, multidisciplinary visits following our dedicated SSc care pathway, and clinical trials. Our activity has been quickly rescheduled to ensure the proper assistance to our SSc patients during the COVID-19 pressure. Results: The use of telemedicine has certainly assured a robust continuity of health care. Furthermore, telephone pre-triage, nurse/medical triage, proper physical distancing and use of PPE/DPI allowed us to re-organize and continue SSc daily activity. Specifically, therapeutic infusions in day hospital regimen and outpatient visits, including ulcers treatment, was guaranteed and maximized. Conclusion: The management of scleroderma patients by an expert specialist reference center is crucial in order to ensure continuity of care and pursue the best SSc practice.

Journal article

Giuggioli D, Magnani L, Spinella A, Bajocchi G, Palermo A, Lumetti F, Cocchiara E, Salvarani Cet al., 2021, Infections of scleroderma digital ulcers: A single center cohort retrospective study, Dermatology Reports, Vol: 13, ISSN: 2036-7392

Systemic sclerosis (SSc) is a complex autoimmune and up to 50% of patients develop digital ulcers. We revised fifty consecutive patients with SSc-related digital ulcers (DUs) who referred to our Scleroderma Unit. Thirty-five of them who showed clear signs of DUs infection underwent to cutaneous swab and microbiological data collection. We performed 87 cutaneous swabs overall. DUs were recurrent in 58% of the patients and multiple in 60% of patients. Fourty-four swabs (53%) were positive for Staphylococcus aureus (13% Methicillin-Resistant), 9 (10%) were positive for Pseudomonas aeruginosa, and then the others less frequently isolated. Nine patients (25%) needed hospitalization. Our data support a patient-tailored approached to DUs, particularly those infected. Self-hygiene and asepsis during dressing procedures are mandatory. Patient must be trained to avoid dangerous behaviors and reduce the risk of infection.

Journal article

Borgoni S, Sofyali E, Soleimani M, Wilhelm H, Mueller-Decker K, Will R, Noronha A, Beumers L, Verschure PJ, Yarden Y, Magnani L, van Kampen AHC, Moerland PD, Wiemann Set al., 2020, Time-Resolved Profiling Reveals ATF3 as a Novel Mediator of Endocrine Resistance in Breast Cancer, CANCERS, Vol: 12

Journal article

Callegari S, Macchi E, Monaco R, Magnani L, Tafuni A, Croci S, Nicastro M, Garrapa V, Banchini A, Becchi G, Corradini E, Goldoni M, Rocchio F, Sala R, Benussi S, Ferrara D, Alfieri O, Corradi Det al., 2020, Clinicopathological Bird's-Eye View of Left Atrial Myocardial Fibrosis in 121 Patients With Persistent Atrial Fibrillation: Developing Architecture and Main Cellular Players., Circ Arrhythm Electrophysiol, Vol: 13

BACKGROUND: Scientific research on atrial fibrosis in atrial fibrillation (AF) has mainly focused on quantitative or molecular features. The purpose of this study was to perform a clinicoarchitectural/structural investigation of fibrosis to provide one key to understanding the electrophysiological/clinical aspects of AF. METHODS: We characterized the fibrosis (amount, architecture, cellular components, and ultrastructure) in left atrial biopsies from 121 patients with persistent/long-lasting persistent AF (group 1; 59 males; 60±11 years; 91 mitral disease-related AF, 30 nonmitral disease-related AF) and from 39 patients in sinus rhythm with mitral valve regurgitation (group 2; 32 males; 59±12 years). Ten autopsy hearts served as controls. RESULTS: Qualitatively, the fibrosis exhibited the same characteristics in all cases and displayed particular architectural scenarios (which we arbitrarily subdivided into 4 stages) ranging from isolated foci to confluent sclerotic areas. The percentage of fibrosis was larger and at a more advanced stage in group 1 versus group 2 and, within group 1, in patients with rheumatic disease versus nonrheumatic cases. In patients with AF with mitral disease and no rheumatic disease, the percentage of fibrosis and the fibrosis stages correlated with both left atrial volume index and AF duration. The fibrotic areas mainly consisted of type I collagen with only a minor cellular component (especially fibroblasts/myofibroblasts; average value range 69-150 cells/mm2, depending on the areas in AF biopsies). A few fibrocytes-circulating and bone marrow-derived mesenchymal cells-were also detectable. The fibrosis-entrapped cardiomyocytes showed sarcolemmal damage and connexin 43 redistribution/internalization. CONCLUSIONS: Atrial fibrosis is an evolving and inhomogeneous histological/architectural change that progresses through different stages ranging from isolated foci to confluent sclerotic zones which-seemingly-constrain impulse

Journal article

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