Publications by authors named "Jacopo Nanni"

11 Publications

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Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations.

Leukemia 2021 Jun 30. Epub 2021 Jun 30.

MLL Munich Leukemia Laboratory, Munich, Germany.

Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.
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http://dx.doi.org/10.1038/s41375-021-01318-xDOI Listing
June 2021

Clinical Efficacy of Ponatinib in Philadelphia-Positive T-Cell Acute Lymphoblastic Leukemia with Extramedullary Involvement.

Acta Haematol 2021 Jun 15:1-5. Epub 2021 Jun 15.

Istituto di Ematologia "Seràgnoli" IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

T-cell acute lymphoblastic leukemia (T-ALL) is a rare entity in the adult acute leukemia setting. Translocation (9;22)(q34;q11) and BCR-ABL1 rearrangement are occasionally found in T-ALL and have been reported in no more than 100 cases in the literature (most of which are chronic myeloid leukemia blast crisis). Here, we report the remarkable effectiveness of third-generation tyrosine-kinase inhibitor ponatinib in obtaining hematological and metabolic remission, in a patient with Philadelphia chromosome-positive de novo T-ALL and outcomes of a therapeutic strategy containing chemotherapy intensification, nelarabine, and allogeneic hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1159/000516003DOI Listing
June 2021

Pharmacological Inhibition of WIP1 Sensitizes Acute Myeloid Leukemia Cells to the MDM2 Inhibitor Nutlin-3a.

Biomedicines 2021 Apr 6;9(4). Epub 2021 Apr 6.

IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"-IRST, 47014 Meldola (FC), Italy.

In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in combinatorial therapies. WIP1, encoded from , is a negative regulator of p53. We evaluated expression and explored the therapeutic efficacy of WIP1 inhibitor (WIP1i) GSK2830371, in association with the MDM2 inhibitor Nutlin-3a (Nut-3a) in AML cell lines and primary samples. transcript levels were higher in young patients compared with older ones and in core-binding-factor AML compared with other cytogenetic subgroups. In contrast, its expression was reduced in -mutated (mut, irrespective of -ITD status) or -mut cases compared with wild-type (wt) ones. Either Nut-3a, and moderately WIP1i, as single agent decreased cell viability of -wt cells (MV-4-11, MOLM-13, OCI-AML3) in a time/dosage-dependent manner, but not of -mut cells (HEL, KASUMI-1, NOMO-1). The drug combination synergistically reduced viability and induced apoptosis in -wt AML cell line and primary cells, but not in -mut cells. Gene expression and immunoblotting analyses showed increased p53, MDM2 and p21 levels in treated -wt cells and highlighted the enrichment of MYC, PI3K-AKT-mTOR and inflammation-related signatures upon WIP1i, Nut-3a and their combination, respectively, in the MV-4-11 -wt model. This study demonstrated that WIP1 is a promising therapeutic target to enhance Nut-3a efficacy in -wt AML.
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http://dx.doi.org/10.3390/biomedicines9040388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067413PMC
April 2021

Safety profile and impact on survival of tyrosine kinase inhibitors versus conventional therapy in relapse or refractory FLT3 positive acute myeloid leukemia patients.

Leuk Res 2021 02 25;101:106497. Epub 2020 Dec 25.

Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy. Electronic address:

Relapsed or refractory (R/R) acute myeloid leukemia (AML) has a poor prognosis, and new therapies are a major clinical need. When mutated, FLT3 drives neoplastic cell proliferation. New drugs (i.e., tyrosine kinase inhibitors, TKIs) showed effectiveness in FLT3-AML and promise to change disease history and outcome. We evaluated the benefit conferred by TKIs in terms of survival, burden of complications and surrogate endpoint of quality of life in a retrospective cohort of 49 FLT3 positive, R/R AML patients. Patients who received TKIs were compared to those treated with conventional chemotherapy. Treatment with TKIs conferred a better OS and wea associated with a lower burden and severity of adverse events. Importantly, patients who received TKIs showed reduced time of hospitalization. In conclusion, treatment with TKI in R/R FLT3-AML was related to a better survival, less and milder AEs, and shorter hospitalization.
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http://dx.doi.org/10.1016/j.leukres.2020.106497DOI Listing
February 2021

Extended Latissimus Dorsi Kite Flap (ELD-K Flap): Revisiting an Old Place for a Total Autologous Breast Reconstruction in Patients with Medium to Large Breasts.

Aesthetic Plast Surg 2021 04 15;45(2):390-401. Epub 2020 Oct 15.

Department of Surgery, "P. Valdoni", Unit of Plastic and Reconstructive Surgery, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

Background: The latissimus dorsi (LD) flap represents one of the most reliable methods for autologous breast reconstruction. However, in many patients, the exclusive use of this technique may not guarantee the restoration of an adequate volume and projection. We report our experience with the extended latissimus dorsi kite flap (ELD-K flap), an alternative surgical approach to maximize the volume of the fleur-de-lis pattern LD flap, for total autologous breast reconstruction.

Methods: Between 2016 and 2018, 23 patients were subjected to mastectomy and immediate autologous reconstruction with "extended latissimus dorsi kite flap" (ELD-K flap), technique that employs an extended version of the LD musculocutaneous flap, based on the skeletonized thoracodorsal pedicle and a trilobate skin incision with an inferiorly based vertical branch. The BREAST-Q questionnaire was administered preoperatively, and one year after surgery to evaluate the quality of life results of the patients. BREAST-Q latissimus dorsi module was also provided.

Results: Average body mass index was 29.7 kg/m (range 25-40 kg/m). Mild complications occurred in only six cases, and eight patients underwent treatment to improve the donor site scar outcome. Patients indicated high scores in quality of life measures with an increase in all BREAST domains from the preoperative to the postoperative period. A statistically significant increase (p < 0.05) was noted in: "overall satisfaction with breasts" (p < 0.05), "psychosocial well-being" (p < 0.05), "physical impact of the surgery" (p < 0.05). Within the LD module, participants reported a mean score of, respectively, 73.8 and 67.9 for "satisfaction with back" and "satisfaction with shoulder and back function" domains.

Conclusions: The extended incision allows the recruitment of additional tissue to provide enough volume to complete the reconstruction without implants. The isolation of the vascular pedicle allows for extreme freedom and mobilization of the flap, ensuring adequate filling of the breast. ELD-K flap may expand the indications for a total autologous LD immediate breast reconstruction, representing an additional and reliable alternative in selected cohorts of patients.

Level Of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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http://dx.doi.org/10.1007/s00266-020-01990-xDOI Listing
April 2021

Reduction of modal noise due to fiber/photodetector misalignment in SSMF links based on 850  nm VCSELs through a low-cost polymer coupling structure.

Appl Opt 2020 Mar;59(8):2329-2336

A low-cost polymer-based structure is proposed to improve the coupling between a fiber end section and photodetector active surface in optical links based on standard single-mode fiber (SSMF), which employs vertical cavity surface emitting lasers operating at 850 nm, i.e., below the SSMF cutoff wavelength. Considering receivers as small-area detectors, which are generally necessary to guarantee high-speed operation but at the same time are particularly subject to power fluctuations due to modal noise (whose impact is in turn enhanced in the presence of fiber-to-photodetector misalignment), significant achievements are demonstrated by employing the presented structure. Indeed, in the presence of a misalignment of $ \pm 4 $±4 to $ \pm 6\;{\unicode{x00B5}{\rm m}} $±6µm, which is nowadays typically achievable, the relative optical power fluctuations due to modal noise reduce in the presented case more than four times (2.5% from more than 10%) with respect to the case of butt-coupling, which implies an increase of the same factor in the output signal-to-noise ratio at the receiver end.
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http://dx.doi.org/10.1364/AO.380976DOI Listing
March 2020

MEC (mitoxantrone, etoposide, and cytarabine) induces complete remission and is an effective bridge to transplant in acute myeloid leukemia.

Eur J Haematol 2020 Jul 7;105(1):47-55. Epub 2020 Apr 7.

Department of Hematology and Oncology, Institute of Hematology L. e A. Seràgnoli, Azienda Ospedaliero-Universitaria S. Orsola Malpighi, Bologna, Italy.

Introduction: Clinical response and chemosensitivity of relapse or refractory AML patients were evaluated after rescue and bridge-to-transplant MEC (mitoxantrone, etoposide, and cytarabine) regimen.

Methods And Patients: Fifty-five consecutive AML patients were treated with MEC from 2009 to 2018. Chemosensitivity was evaluated by WT1 quantification.

Results: 27/55 patients (49.1%) had AML resistant to induction and 28/55 patients (50.9%) had AML relapse. 25/55 patients (45.5%) achieved a CR after one course of MEC, and 12 patients (21.8%) achieved WT1 negativity. In 12 patients, a second MEC was administered. Four out of 12 patients improved significantly their response with the 2nd MEC. MEC was an effective bridge to transplant, 32/55 patients (58.2%) received an allogenic stem cell transplant. Median overall survival (OS) from MEC was 455 days (95% CI 307-602 days.); patient with WT1 negative CR had the best OS (P<.000).

Conclusion: WT1 is a useful marker of chemosensitivity after MEC as rescue and bridge-to-transplant therapy.
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http://dx.doi.org/10.1111/ejh.13406DOI Listing
July 2020

Acute Myeloid Leukemia Mutations: Therapeutic Implications.

Int J Mol Sci 2019 Jun 3;20(11). Epub 2019 Jun 3.

Istituto di Ematologia e Oncologia Medica "L. e A. Seràgnoli", S.Orsola-Malpighi Hospital, 40138 Bologna, Italy.

Acute Myeloid Leukemia (AML) is an extremely heterogeneous group of hematological neoplasms, for which allogeneic stem cell transplantation (HSCT) still represents the only potentially curative option in the majority of cases. However, elderly age and clinically severe comorbidities may often exclude a wide amount of patients from this therapeutic approach, underlying the urgent need for alternative strategies. Thanks to the introduction of advanced high-throughput techniques, light is being shed on the pathogenesis of AML, identifying molecular recurrent mutations as responsible for the onset, as well as progression, of disease. As a consequence, and in parallel, many new compounds, including targeted therapies (FMS-like tyrosine kinase 3 (FLT3) and Isocitrate dehydrogenase 1-2 (IDH1-2) inhibitors), have found a wide room of application in this setting, and are now available in daily practice, or in late phases of clinical development. Moreover, several further innovative molecules are currently under investigation, and promising results for many of them have already been reported. In this review, we will present an update on the most relevant molecular alterations of AML, focusing on the most frequent genomic mutations of the disease, for which compounds have been approved or are still currently under investigation.
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http://dx.doi.org/10.3390/ijms20112721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600275PMC
June 2019

Inotuzumab ozogamicin is effective in relapsed/refractory extramedullary B acute lymphoblastic leukemia.

BMC Cancer 2018 Nov 15;18(1):1117. Epub 2018 Nov 15.

DIMES (Department of Experimental, Diagnostic, and Specialty Medicine), Institute of Hematology "L. and A. Seragnoli", University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.

Background: Extramedullary involvement of B-cell Acute Lymphoblastic Leukemia (EM-ALL) is a rare occurrence, characterized by dismal outcome and the absence of a defined and shared therapeutic approach. In the landscape of innovative compounds, inotuzumab ozogamicin (IO) is a promising drug, whose mechanism of action relies on the killing of CD22 positive leukemic cells, through the delivery, after cell binding, of a molecule of calicheamicin.

Case Presentation: We report two cases of CD22 positive relapsed EM-ALL treated with IO, obtained as compassionate use. Case 1, a 66 years old woman, affected by Philadelphia (Ph) negative B-ALL, relapsed with extramedullary involvement after 6 standard chemotherapy courses, who reached a complete metabolic response with IO treatment. Case 2, a 67 years old man with Ph positive B-ALL, initially treated with ponatinib, a third generation tyrosine-kinase inhibitor (TKI), obtaining a prolonged deep molecular remission. Nevertheless, for skin relapse during TKI treatment, the patient received local radiotherapy and, shortly after, standard chemotherapy, as multiple abdominal sites of relapse were detected too, with no response. The patient then received IO, obtained as compassionate use, with a good metabolic response.

Conclusions: These two cases suggest a possible key role of IO in the setting of advanced CD22 positive ALL, and underline its potential activity also in patients with EM involvement, relapsed after or refractory to conventional chemotherapy. Despite the well known hepatotoxic effect of the compound (Sinusoid Occlusive Syndrome), neither of them had such adverse event, moreover the second patient safely underwent allogeneic bone marrow transplantation.
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http://dx.doi.org/10.1186/s12885-018-5026-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238377PMC
November 2018

Chirp evaluation of semiconductor DFB lasers through a simple Interferometry-Based (IB) technique.

Appl Opt 2016 Oct;55(28):7788-7795

Direct modulation of a laser source is often utilized in realizing optical fiber connections where the cost of the entire system must be kept at a low level. An undesired consequence of this choice is the onset of the laser frequency chirp effect, which is detrimental in the case of either digital or analog links, and must be evaluated with precision in order to perform an accurate design of the whole system. Various methods of evaluation of the chirp parameters have been proposed, and the choice among them is typically made on the basis of the laboratory equipment available at the moment. This paper adds a further element to the set of possible choices, since it presents a method for the evaluation of the adiabatic chirp factor in distributed feedback (DFB) laser sources, which exploits a simple interferometric scheme, guarantees low cost, and shows, at the same time, good accuracy of the results.
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http://dx.doi.org/10.1364/AO.55.007788DOI Listing
October 2016
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