Publications by authors named "Stefano Sacchi"

55 Publications

Improving the international prognostic index score using peripheral blood counts: Results of a large multicenter study involving 520 patients with diffuse large B cell lymphoma.

Hematol Oncol 2020 Oct 17;38(4):439-445. Epub 2020 Jun 17.

Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto, Università di Modena e Reggio Emilia, Modena, Italy.

The main purpose of this study was to assess whether it is possible to improve the prognostic impact of international prognostic index (IPI) score by combining it with peripheral blood counts. Thus, we evaluated the prognostic power of lymphocyte, neutrophil, and monocyte counts in 520 patients with diffuse large B cell lymphoma treated with R-CHOP, confirming that these parameters have a strong impact on overall survival (OS). Using revised IPI (R-IPI), 44% of patients were categorized as poor-risk and showed an OS at 5 years of 46%. As OS at 5 years of the 520 patients is 67%, it is clearly evident that R-IPI tends to overestimate the proportion of patients with poor prognosis. Accordingly, in an attempt to improve the discriminating power of R-IPI, we evaluated and compared three different scores by combining the neutrophil lymphocyte ratio (NLR) and absolute monocyte count (AMC) with the following values: (a) IPI score 3-5, (b) age > 60 years and performance status, (c) age  ≥ 65 years and LDH > ULN. The three indexes studied, had a similar 5 years OS for the high-risk group (46%-52%), but the proportion of patients classified as poor-risk were 37%, 20%, and 32%, respectively, which are lower than 44% identified with R-IPI. Thus, while R-IPI overestimates the number of high-risk patients, after applying our models, it is possible to recognize patients who are truly at high-risk. Of the three scores, the most accurate appears to be that based on NLR, AMC, LDH > ULN and age ≥ 65 years, which identifies 32% of high-risk patients, correlating well with what is seen in clinical practice.
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http://dx.doi.org/10.1002/hon.2757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687198PMC
October 2020

Citarinostat and Momelotinib co-target HDAC6 and JAK2/STAT3 in lymphoid malignant cell lines: a potential new therapeutic combination.

Apoptosis 2020 06;25(5-6):370-387

Unit of Oncohematology and Osteoncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Histone deacetylase (HDAC) inhibitors represent an encouraging class of antitumor drugs. HDAC inhibitors induce a series of molecular and biological responses and minimal toxicity to normal cells. Citarinostat (Acy-241) is a second generation, orally administered, HDAC6-selective inhibitor. Momelotinib (CYT387) is an orally administered inhibitor of Janus kinase/signal transducer of transcription-3 (JAK/STAT3) signaling. Momelotinib showed efficacy in patients with myelofibrosis. We hypothesized that both HDAC and JAK/STAT pathways were important in lymphoproliferative disorders, and that inhibiting JAK/STAT3 and HDAC simultaneously might enhance the efficacy of momelotinib and citarinostat without increasing toxicity. Accordingly, we tested the citarinostat + momelotinib combination in lymphoid cell lines. Citarinostat + momelotinib showed strong cytotoxicity; it significantly reduced mitochondrial membrane potential, down-regulated Bcl-2 and Bcl-xL, and activated caspases 9 and 3. Caspase-8 was upregulated in only two lymphoid cell lines, which indicated activation of the extrinsic apoptotic pathway. We identified a lymphoid cell line that was only slightly sensitive to the combination treatment. We knocked down thioredoxin expression by transfecting with small interfering RNA that targeted thioredoxin. This knockdown increased cell sensitivity to the combination-induced cell death. The combination treatment reduced Bcl-2 expression, activated caspase 3, and significantly inhibited cell viability and clonogenic survival.
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http://dx.doi.org/10.1007/s10495-020-01607-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244621PMC
June 2020

The classic prognostic factors in advanced Hodgkin's lymphoma patients are losing their meaning at the time of Pet-guided treatments.

Ann Hematol 2020 Feb 23;99(2):277-282. Epub 2019 Dec 23.

Policlinico S.Orsola-Malpighi, Istituto di Ematologia "Seragnoli", Bologna, Italy.

The International Prognostic Score (IPS) is the most commonly used risk stratification tool for patients with advanced Hodgkin lymphoma (HL). It incorporates seven clinical parameters independently associated with a poorer outcome: male sex, age, stage IV, hemoglobin level, white blood cell and lymphocyte counts, and albumin level. Since the development of the IPS, there have been significant advances in therapy and supportive care. Recent studies suggest that the IPS is less discriminating due to improved outcomes with ABVD therapy. The aim of the present study was to asses if classic prognostic factors maintain their prognostic meaning at the time of response-adapted treatment based on interim PET scans. We evaluated the prognostic significance of IPS in the 520 advanced stage HL patients enrolled in the PET-guided, HD0801 trial in which PET2-positive patients underwent a more intense treatment with an early stem-cell transplantation after 2 cycles of ABVD. We observed that in these patients, the IPS completely loses its prognostic value together with all the single parameters that contribute to the IPS. Furthermore, neutrophils, monocytes, lymphocytes, and the ratio among them also no longer had any predictive value. We believe that the substantial improvement in survival outcomes in PET2-positive patients treated with early autologous transplantation could explain the complete disappearance of the residual prognostic significance of the IPS.
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http://dx.doi.org/10.1007/s00277-019-03893-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976582PMC
February 2020

Nail StrainStress Meter NM 100: A novel in vivo method to characterize biomechanical properties of nails.

Skin Res Technol 2020 May 5;26(3):422-430. Epub 2019 Dec 5.

Department of Drug Sciences, University of Pavia, Pavia, Italy.

Background: Nowadays, nail care products are extremely important both in medical and cosmetic fields. Actually, there are only a very few "in vivo" methods to evaluate the safety and the efficacy of nail products.

Methods: The new apparatus, based on a recently patented technology, is developed for the "in vivo" evaluation of nails in terms of thickness, structural firmness, flattening, and bending properties. The device analyzes nails by an "in vivo" non-invasive methodology in a timely way and with high accuracy. The assessment of the resistance to compression measures the cohesion of the nail matrix (nail firmness), while the evaluation of the resistance to transversal deformation detects the elasticity of the nail plate. Furthermore, the apparatus is able to assess the nail thickness and the flexibility of their distal edge.

Results: The instrument provides nail thickness and several parameters reflecting mechanical properties of nail plate: Viscoelasticity expressed as viscoelasticity index (VI), structural strength/ firmness expressed as Firmness Index (FI), and viscoelasticity of the distal edge expressed as Bending Index (BI).

Conclusions: The instruments described in this work represent an innovative apparatus for the safety and efficacy evaluation of nail products in several fields: cosmetics, pharmaceuticals, and medical devices.
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http://dx.doi.org/10.1111/srt.12818DOI Listing
May 2020

The prognostic role of end of treatment FDG-PET-CT in patients with diffuse large B cell lymphoma can be improved by considering it with absolute monocyte count at diagnosis.

Leuk Lymphoma 2019 08 28;60(8):1958-1964. Epub 2019 Jan 28.

e Sant'Andrea Hospital , Rome , Italy.

It is well established that some patients with diffuse large B-cell lymphoma (DLBCL) and the negative end of treatment PET-CT (EOT-PET-CT) will relapse, while a proportion with positive uptake can still obtain long-term EFS. We reviewed data of 200 consecutive, previously untreated patients with DLBCL recorded in Italy and Israel between 2007 and 2015. We found that patients with negative EOT-PET-CT with AMC > 630/mmc have a 3-years EFS of 72%, compared to those with AMC ≤ 630/mmc that have an EFS of 84%. Furthermore, considering patients with positive EOT-PET-CT, those with AMC > 630/mmc have a 3-years EFS of 8%, while those with AMC ≤ 630/mmc have an EFS of 38%. Thus, it appears that combining the gold standard for response evaluation EOT-PET-CT with a simple and inexpensive parameter like AMC at diagnosis, further improves prognostication in DLBCL. Applying this simple method can be useful for all doctors working in lymphoma clinical practice.
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http://dx.doi.org/10.1080/10428194.2018.1564049DOI Listing
August 2019

Cell-Penetrating CaCO₃ Nanocrystals for Improved Transport of NVP-BEZ235 across Membrane Barrier in T-Cell Lymphoma.

Cancers (Basel) 2018 Jan 25;10(2). Epub 2018 Jan 25.

Dipartimento di Scienze e Tecnologie Biologiche e Ambientali, Università del Salento & UdR INSTM di Lecce, Campus Universitario, Via Monteroni, 73100 Lecce, Italy.

Owing to their nano-sized porous structure, CaCO₃ nanocrystals (CaCO₃NCs) hold the promise to be utilized as desired materials for encapsulating molecules which demonstrate wide promise in drug delivery. We evaluate the possibility to encapsulate and release NVP-BEZ235, a novel and potent dual PI3K/mTOR inhibitor that is currently in phase I/II clinical trials for advanced solid tumors, from the CaCO₃NCs. Its chemical nature shows some intrinsic limitations which induce to administer high doses leading to toxicity; to overcome these problems, here we proposed a strategy to enhance its intracellular penetration and its biological activity. Pristine CaCO₃ NCs biocompatibility, cell interactions and internalization in in vitro experiments on T-cell lymphoma line, were studied. Confocal microscopy was used to monitor NCs-cell interactions and cellular uptake. We have further investigated the interaction nature and release mechanism of drug loaded/released within/from the NCs using an alternative approach based on liquid chromatography coupled to mass spectrometry. Our approach provides a good loading efficiency, therefore this drug delivery system was validated for biological activity in T-cell lymphoma: the anti-proliferative test and western blot results are very interesting because the proposed nano-formulation has an efficiency higher than free drug at the same nominal concentration.
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http://dx.doi.org/10.3390/cancers10020031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836063PMC
January 2018

Ruxolitinib combined with vorinostat suppresses tumor growth and alters metabolic phenotype in hematological diseases.

Oncotarget 2017 Nov 23;8(61):103797-103814. Epub 2017 Oct 23.

Department of Diagnostic, Clinical, and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

JAK-2 dysregulation plays an important role as an oncogenic driver, and is thus a promising therapeutic target in hematological malignancies. Ruxolitinib is a pyrrolo[2.3-d]pyrimidine derivative with inhibitory activity against JAK1 and JAK2, moderate activity against TYK2, and minor activity against JAK3. Vorinostat is an HDAC inhibitor that reduces JAK-2 expression, thus affecting JAK-2 mRNA expression and increasing JAK-2 proteasomal deterioration. Here we hypothesized that the combination of ruxolitinib and vorinostat could have synergistic effects against hematological disease. We tested combinations of low doses of ruxolitinib and vorinostat in 12 cell lines, and observed highly synergistic cytotoxic action in six cell lines, which was maintained for up to 120 h in the presence of stromal cells. The sensitivity of the six cell lines may be explained by the broad effects of the drug combination, which can affect various targets. Treatment with the combination of ruxolitinib and vorinostat appeared to induce a possible reversal of the Warburg effect, with associated ROS production, apoptotic events, and growth inhibition. Decreased glucose metabolism may have markedly sensitized the six more susceptible cell lines to combined treatment. Therapeutic inhibition of the JAK/STAT pathway seems to offer substantial anti-tumor benefit, and combined therapy with ruxolitinib and vorinostat may represent a promising novel therapeutic modality for hematological neoplasms.
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http://dx.doi.org/10.18632/oncotarget.21951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732767PMC
November 2017

Hexamermis popilliae n. sp. (Nematoda: Mermithidae) parasitizing the Japanese beetle Popillia japonica Newman (Coleoptera: Scarabaeidae) in Italy.

Syst Parasitol 2017 10 16;94(8):915-926. Epub 2017 Aug 16.

Department of Integrative Biology, Oregon State University, Corvallis, OR, 97331, USA.

A new species of mermithid nematode, Hexamermis popilliae n. sp. (Nematoda: Mermithidae) is described from the Japanese beetle Popillia japonica Newman in Italy, an area of new introduction for this invasive pest. The combination of the following characters separates H. popilliae from other members of the genus Hexamermis Steiner, 1924: adult head obtuse; amphidial pouches slightly posterior to lateral head papillae in female but adjacent to lateral head papillae in males; amphidial openings large, well developed; amphidial pouches elliptical in females and oblong in males; cuticular vulvar cone well developed, vulvar lips greatly reduced or lacking, vagina curved at tip where meeting uteri, without reverse bend (not S-shaped), spicules slightly curved, with a slight bend in the basal portion, approximately equal to body width at cloaca. This is the first record of a species of Hexamermis parasitizing the Japanese beetle Popillia japonica. The only previous mention of mermithid nematodes from P. japonica was an undescribed species of Psammomermis in North America. Hexamermis popilliae will be evaluated as a potential biological control agent in an integrated control program of the Japanese beetle in Italy.
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http://dx.doi.org/10.1007/s11230-017-9746-0DOI Listing
October 2017

Ricolinostat, a selective HDAC6 inhibitor, shows anti-lymphoma cell activity alone and in combination with bendamustine.

Apoptosis 2017 06;22(6):827-840

Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Via del Pozzo, 71, 41124, Modena, Italy.

Histone deacetylase inhibitors (HDACis) have emerged as a new class of anticancer agents, targeting the biological process including cell cycle and apoptosis. We investigated and explained the anticancer effects of an HDAC6 inhibitor, ricolinostat alone and in combination with bendamustine in lymphoma cell lines. Cell viability was measured by MTT assay. Apoptosis, reactive oxygen species (ROS) generation, Bcl-2 protein expression, cell cycle progression and tubuline expression were determined by flow cytometry. The effects of ricolinostat alone and in combination on the caspases, PI3K/Akt, Bcl-2 pathways, ER stress and UPR were assessed by immunoblotting. Ricolinostat shows anti lymphoma activity when used as single agent and its capability to induce apoptosis is synergistically potentiated by the bendamustine in lymphoma cell lines. Drug combination reduced the proportion of cells in the G/G and S phases and caused an increase of "sub-G/G" peak. The synergistic effect accompanied with the increased ROS, activation of caspase-8, -9, and -3, the cleavage of PARP and modulated by Bcl-2 proteins family. In addition, the exposure of ricolinostat induced the acetylation level of α-tubulin, the extend of which was not further modified by bendamustine. Finally, the apoptosis effect of ricolinostat/bendamustine may be mediated by a corresponding effect on microtubule stabilization. Our data suggest that ricolinostat in combination with bendamustine may be a novel combination with potential for use as an antitumor agent in lymphoma.
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http://dx.doi.org/10.1007/s10495-017-1364-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401712PMC
June 2017

A Multicenter Phase II Study of Twice-Weekly Bortezomib plus Rituximab in Patients with Relapsed Follicular Lymphoma: Long-Term Follow-Up.

Acta Haematol 2017 4;137(1):7-14. Epub 2016 Nov 4.

Program of Innovative Therapy in Oncology and Hematology, Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy.

Single-agent bortezomib (B) has shown activity in heavily pretreated patients with relapsed/refractory indolent lymphoma. On the basis of these findings, we performed a phase II study of B combined with rituximab (R) in patients with relapsed follicular lymphoma (FL). Forty-five patients with fairly good prognostic profiles were enrolled from 2007 to 2011 and received a total of 6 cycles of the B+R combination. The endpoints were the overall response rate (ORR), progression-free survival (PFS), duration of remission (DoR), overall survival (OS), and toxicity evaluation. When considering all the enrolled patients the ORR was 64%. At 5 years, the estimated PFS, DoR, and OS were 34, 49, and 70%, respectively. After excluding the 7 R-naïve patients, the ORR was 58%, with a PFS of 19 months. The most common grade >2 toxicities were thrombocytopenia (18%), peripheral neuropathy (13%), and neutropenia (2%). Our study shows the feasibility, long-term efficacy, and excellent tolerability of the B+R combination. We are aware that our study has specific limitations, such as the small sample size consisting of patients with a relatively good prognostic profile. However, because FL patients will be treated with subsequent chemotherapy regimens, a well-tolerated and effective chemotherapy-free therapy could be considered an additional tool for long-term disease control.
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http://dx.doi.org/10.1159/000449052DOI Listing
February 2017

Neutrophil-lymphocyte ratio at diagnosis is an independent prognostic factor in patients with nodular sclerosis Hodgkin lymphoma: results of a large multicenter study involving 990 patients.

Hematol Oncol 2017 Dec 28;35(4):561-566. Epub 2016 Oct 28.

Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

Several studies have demonstrated the prognostic value of neutrophil-lymphocyte ratio (NLR) in patients with solid tumors and non-Hodgkin lymphoma. In contrast, there is only sparse data on its prognostic role in patients with classical Hodgkin lymphoma (cHL). The aim of our study was to establish whether NLR could serve as an independent prognostic factor in a cohort of 990 patients with nodular sclerosis (NS)-cHL. After analysis of the log hazard ratio (HR) as a function of NLR, we chose the value 6 as cutoff. Patients with NLR >6 had a worse progression-free survival and overall survival compared to those with NLR ≤6; 84% vs 75% and 92% vs 88%, at 5 years, with an HR of 1.65 and 1.82, respectively. Multivariate analysis showed that the risk remained high with HR 1.44 and HR 1.54 in progression-free survival and overall survival, respectively. In summary, our study shows that NLR is a robust and independent prognostic parameter in NS-cHL, both in early and advanced disease. It is inexpensive and simple to apply. Thus, we conclude that NLR, possibly in combination with the international prognostic score and absolute monocyte count, is a useful guide for physicians treating NS-cHL patients.
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http://dx.doi.org/10.1002/hon.2359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763313PMC
December 2017

The histone deacetylase inhibitor romidepsin synergizes with lenalidomide and enhances tumor cell death in T-cell lymphoma cell lines.

Cancer Biol Ther 2016 Oct 22;17(10):1094-1106. Epub 2016 Sep 22.

a Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine , University of Modena and Reggio Emilia , Modena , Italy.

We investigated the cytotoxic interactions of romidepsin, a histone deacetylase inhibitor, and lenalidomide, an immunomodulatory agent, in a T-cell lymphoma preclinical model. Hut-78 and Karpas-299 cells were treated with romidepsin and lenalidomide alone and in combination. The interaction between romidepsin and lenalidomide was evaluated by the Chou-Talalay method, and cell viability and clonogenicity were also evaluated. Apoptosis, reactive oxygen species (ROS) levels, and cell cycle distribution were determined by flow cytometry. ER stress, caspase activation, and the AKT, MAPK/ERK, and STAT-3 pathways were analyzed by Western blot. Combination treatment with romidepsin and lenalidomide had a synergistic effect in Hut-78 cells and an additive effect in Karpas-299 cells at 24 hours and did not decrease the viability of normal peripheral blood mononuclear cells. This drug combination induced apoptosis, increased ROS production, and activated caspase-8, -9, -3 and PARP. Apoptosis was associated with increased hallmarks of ER stress and activation of UPR sensors and was mediated by dephosphorylation of the AKT, MAPK/ERK, and STAT3 pathways.The combination of romidepsin and lenalidomide shows promise as a possible treatment for T-cell lymphoma. This work provides a basis for further studies.
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http://dx.doi.org/10.1080/15384047.2016.1219820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079402PMC
October 2016

Bendamustine, Low-dose dexamethasone, and lenalidomide (BdL) for the treatment of patients with relapsed/refractory multiple myeloma confirms very promising results in a phase I/II study.

Leuk Lymphoma 2017 03 21;58(3):552-559. Epub 2016 Jul 21.

b Department of Hemato-Oncology , Cosenza Hospital , Cosenza , Italy.

Lenalidomide and dexamethasone are an effective treatment for naïve and relapsed multiple myeloma (MM) patients. Bendamustine is a good option for B-cell malignancies showing only partial cross resistance with alkylating agents used in MM patients. Based on these considerations, we proposed a phase I/II study testing escalating doses of bendamustine and lenalidomide and fixed low doses of dexamethasone (BdL). Fifteen patients were enrolled in phase I study. Maximum tolerated dose was established at dose "level 0": bendamustine 40 mg/m days 1,2; lenalidomide 10 mg days 1-21; d 40 mg days 1,8,15,22 every 28-day cycle, for six cycles. We enrolled 23 patients in the phase II study. BdL combination showed mainly hematological toxicities, fever and infections. Overall response rate was 47%. After median follow up of 22 months, median PFS was 10 months. Two-years OS rate was 65%. BdL combination confirmed to be a promising treatment for patients with relapsed/refractory MM.
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http://dx.doi.org/10.1080/10428194.2016.1205741DOI Listing
March 2017

Risk of Second Primary Malignancy in Breast Cancer Survivors: A Nested Population-Based Case-Control Study.

J Breast Cancer 2015 Dec 23;18(4):378-85. Epub 2015 Dec 23.

Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

Purpose: Evolving therapies have improved the prognoses of patients with breast cancer; and currently, the number of long-term survivors is continuously increasing. However, these patients are at increased risk of developing a second cancer. Thus, late side effects are becoming an important issue. In this study, we aimed to investigate whether patient and tumor characteristics, and treatment type correlate with secondary tumor risk.

Methods: This case-control study included 305 patients with a diagnosed second malignancy after almost 6 months after the diagnosis of primary breast cancer and 1,525 controls (ratio 1:5 of cases to controls) from a population-based cohort of 6,325 women. The control patients were randomly selected from the cohort and matched to the cases according to age at diagnosis, calendar period of diagnosis, disease stage, and time of follow-up.

Results: BRCA1 or BRCA2 mutation, human epidermal growth factor receptor 2 (HER2)+ status, chemotherapy, and radiotherapy were related to increased risk of developing a second cancer, whereas hormonotherapy showed a protective effect. Chemotherapy, radiotherapy, and estrogenic receptor level <10% increased the risk of controlateral breast cancer. HER2+ status increased the risk of digestive system and thyroid tumors, while BRCA1 or BRCA2 mutation increased the risk of cancer in the genital system.

Conclusion: Breast cancer survivors are exposed to an excess of risk of developing a second primary cancer. The development of excess of malignancies may be related either to patient and tumor characteristics, such as BRCA1 or BRCA2 mutation and HER2+ status, or to treatments factors.
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http://dx.doi.org/10.4048/jbc.2015.18.4.378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705090PMC
December 2015

Activity of BKM120 and BEZ235 against Lymphoma Cells.

Biomed Res Int 2015 18;2015:870918. Epub 2015 Oct 18.

Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic and Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Italy.

Non-Hodgkin lymphomas encompass a heterogeneous group of cancers, with 85-90% arising from B lymphocytes and the remainder deriving from T lymphocytes or NK lymphocytes. These tumors are molecularly and clinically heterogeneous, showing dramatically different responses and outcomes with standard therapies. Deregulated PI3K signaling is linked to oncogenesis and disease progression in hematologic malignancies and in a variety of solid tumors and apparently enhances resistance to antineoplastic therapy, resulting in a poor prognosis. Here, we have evaluated and compared the effects of the pan-PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitor BEZ235 on mantle, follicular, and T-cell lymphomas. Our results suggest that BKM120 and BEZ235 can effectively inhibit lymphoma cell proliferation by causing cell cycle arrest and can lead to cell death by inducing apoptosis and autophagy mediated by ROS accumulation. Despite great advances in lymphoma therapy after the introduction of monoclonal antibodies, many patients still die from disease progression. Therefore, novel treatment approaches are needed. BKM120 and BEZ235 alone and in combination are very effective against lymphoma cells in vitro. If further studies confirm their effectiveness in animal models, they may be promising candidates for development as new drugs.
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http://dx.doi.org/10.1155/2015/870918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628710PMC
August 2016

Absolute Monocyte Count and Lymphocyte-Monocyte Ratio Predict Outcome in Nodular Sclerosis Hodgkin Lymphoma: Evaluation Based on Data From 1450 Patients.

Mayo Clin Proc 2015 Jun;90(6):756-64

Department of Hematology, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel.

Objective: To verify whether absolute monocyte count (AMC) and lymphocyte- monocyte ratio (LMR) at diagnosis are valid prognostic parameters in classical Hodgkin lymphoma (cHL).

Patients And Methods: Data were collected from 1450 patients with cHL treated in Israel and Italy from January 1, 1988, through December 31, 2007.

Results: The median age of the patients was 33 years (range, 17-72 years), and 70% (1017) of the patients had nodular sclerosis (NS); the median follow-up duration was 87 months. The best cutoff value for AMC was 750 cells/mm(3), and the best ratio for LMR was 2.1. The adverse prognostic impact of an AMC of more than 750 cells/mm(3) was confirmed for the entire cohort, and its clinical significance was particularly evident in patients with NS histology. The progression-free survival (PFS) at 10 years for an AMC of more than 750 cells/mm(3) was 65% (56%-72%), and the PFS at 10 years for an AMC of 750 cells/mm(3) or less was 81% (76%-84%; P<.001). The overall survival (OS) at 10 years for an AMC of more than 750 cells/mm(3) was 78% (70%-85%), and the OS at 10 years for an AMC of 750 cells/mm(3) or less was 88% (84%-90%; P=.01). In multivariate analysis, both AMC and LMR maintained prognostic significance for PFS (hazard ratio [HR], 1.54, P=.006, and HR, 1.50, P=.006) after adjusting for the international prognostic score, whereas the impact on OS was confirmed (HR, 1.56; P=.04) only in patients with NS and an AMC of more than 750 cells/mm(3).

Conclusion: This study confirms that AMC has prognostic value in cHL that is particularly significant in patients with NS subtype histology. This finding links the known impact of macrophages and monocytes in Hodgkin lymphoma with routine clinical practice.
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http://dx.doi.org/10.1016/j.mayocp.2015.03.025DOI Listing
June 2015

The combination of bortezomib with enzastaurin or lenalidomide enhances cytotoxicity in follicular and mantle cell lymphoma cell lines.

Hematol Oncol 2015 Dec 13;33(4):166-75. Epub 2014 Nov 13.

Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

We analyzed the combination of a proteasome inhibitor (bortezomib) with enzastaurin (PKC/AKT-inhibitor) or lenalidomide (immunomodulatory agent) for the inhibition of proliferation and induction of apoptosis in B-cell lymphoma cell lines and primary malignant cells. The effects of bortezomib, enzastaurin or lenalidomide, alone or in combinations, on cell viability and apoptosis were evaluated using the Cell Proliferation Kit and flow cytometry analysis. The interaction between drugs was examined by the Chou-Talalay method. Cell cycle analysis was performed by flow cytometry. The PI3K/AKT, PKC and MAPK/ERK signaling pathways were analyzed using western blot. Bortezomib with either enzastaurin or lenalidomide synergistically induced anti-proliferative and pro-apoptotic effects in B-cell lymphoma cells, even in the presence of the bone marrow microenvironment. The direct cytotoxicity is mediated by signaling events involving the PI3K/AKT, PKC and MAPK/ERK pathways leading to cell death. The significant increase of apoptosis was mediated by an increased ratio of pro-apoptotic proteins (Bax, Bad and Bim) to anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1), triggering the cleavage of caspases -3, -9, -8 and PARP. Further evaluation of the combination of bortezomib with enzastaurin or lenalidomide for the treatment of B-cell lymphoma is warranted, with the goal to improve the quality of life and survival of patients.
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http://dx.doi.org/10.1002/hon.2179DOI Listing
December 2015

The potential of pralatrexate as a treatment of peripheral T-cell lymphoma.

Expert Opin Investig Drugs 2014 May 25;23(5):711-8. Epub 2014 Mar 25.

University of Modena and Reggio Emilia, Medical Oncology, Department of Diagnostic, Clinical and Public Health Medicine , Modena , Italy.

Introduction: Peripheral T-cell lymphomas (PTCLs) are a group of rare malignancies originating from clonal proliferation of mature, post-thymic T cells that represent 10 - 15% of all non-Hodgkin's lymphomas with poor prognosis and median survival of 1 - 3 years. The standard treatment for PTCL has not yet been identified. Many patients with PTCL are refractory to first-line therapy. The complete response rate ranges from 36 to 66% according to different PTCL subtypes. Furthermore, those who reached a complete or partial response often have a shorter progression-free survival.

Areas Covered: This paper discusses the potential of pralatrexate , a methotrexate analogue, as a treatment of PTCL. The authors report on the efficacy and safety data of controlled studies and describe the end points of ongoing trials. Pralatrexate was the first drug to obtain FDA approval for the treatment of patients with relapsed or refractory PTCL. However, the European Medicines Agency has refused marketing authorization.

Expert Opinion: None of the treatments commonly used today have given satisfactory results. Pralatrexate seems to be one of the most promising agents in the treatment of patients with PTCL. Future efforts should be focused on better understanding the molecular pathogenesis of PTCL and on specific trials for different PTCL subtypes using rational drug combinations that include pralatrexate.
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http://dx.doi.org/10.1517/13543784.2014.902050DOI Listing
May 2014

Dialysis-dependent renal failure at diagnosis continues to be associated with very poor outcome in multiple myeloma--response to Murphy et al.

Br J Haematol 2014 Jun 6;165(6):892. Epub 2014 Mar 6.

Programme of Innovative Therapy in Oncology and Haematology, Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

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http://dx.doi.org/10.1111/bjh.12816DOI Listing
June 2014

Monocyte count at diagnosis is a prognostic parameter in diffuse large B-cell lymphoma: results from a large multicenter study involving 1191 patients in the pre- and post-rituximab era.

Haematologica 2014 Jan 9;99(1):125-30. Epub 2013 Aug 9.

In this study we assessed the prognostic significance of absolute monocyte count and selected the best cut-off value at diagnosis in a large cohort of patients with diffuse large B-cell lymphoma. Data were retrieved for therapy-naïve patients with diffuse large B-cell lymphoma followed in Israel and Italy during 1993-2010. A final cohort of 1017 patients was analyzed with a median follow up of 48 months and a 5-year overall survival rate of 68%. The best absolute monocyte count cut-off level was 630/mm(3) and the 5-year overall survival for patients with counts below this cut-off was 71%, whereas it was 59% for those with a count >630 mm(3) (P=0.0002). Of the 1017 patients, 521 (51%) were treated with chemo-immunotherapy, and in this cohort, using multivariate analysis, elevated monocyte count retained a negative prognostic value even when adjusted for International Prognostic Index (HR1.54, P=0.009). This large study shows that a simple parameter such as absolute monocyte count (>630/mm(3)) can easily be used routinely in the evaluation of newly diagnosed diffuse large B-cell lymphoma to identify high-risk patients with a worse survival in the rituximab era.
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http://dx.doi.org/10.3324/haematol.2013.088161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007925PMC
January 2014

Survival of multiple myeloma patients in the era of novel therapies confirms the improvement in patients younger than 75 years: a population-based analysis.

Br J Haematol 2013 Oct 27;163(1):40-6. Epub 2013 Jul 27.

Programme of Innovative Therapy in Oncology and Haematology, Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

Novel treatments for multiple myeloma (MM) have shown promising results in clinical trials, but the advantage in unselected patients is still unclear. In order to evaluate whether novel therapies impact survival of MM patients, we performed a population-based analysis on data collected by the Modena Cancer Registry from 1989 to 2009. The analysis evaluated 1206 newly diagnosed MM patients collected in the years 1988-96 (conventional therapy), 1997-05 (high dose melphalan and autologous transplant), and 2006-09 (novel agents era). Both relative survival (RS) and overall survival (OS) improved over the years, but not equally in the three groups. For patients aged <65 years, RS improved in 1997-05 and 2006-09 compared with previous years and a trend to improvement was observed from 1997-05 to 2006-09. For patients aged 65-74 years, RS improved significantly in 2006-09 compared with 1988-96 and 1997-05. No amelioration was observed for patients 75+ years old. OS confirmed RS. In conclusion, the survival of MM patients aged <65 and, in particular, 65-74 years, has improved over time, especially after 2006. This observation provides circumstantial evidence that novel therapies might impact patient survival. Despite the limits of this study, these data refer to an unselected population, giving a picture of every day clinical practice.
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http://dx.doi.org/10.1111/bjh.12465DOI Listing
October 2013

R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi.

J Clin Oncol 2013 Apr 25;31(12):1506-13. Epub 2013 Mar 25.

Dipartimento di Oncologia ed Ematologia, Centro Oncologico Modenese, Clinica e di Sanità Pubblica, Università di Modena e Reggio Emilia, Modena, Italy.

Purpose: Although rituximab (R) is commonly used for patients with advanced follicular lymphoma (FL) requiring treatment, the optimal associated chemotherapy regimen has yet to be clarified.

Patients And Methods: We conducted an open-label, multicenter, randomized trial among adult patients with previously untreated stages II to IV FL to compare efficacy of eight doses of R associated with eight cycles of cyclophosphamide, vincristine, and prednisone (CVP) or six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or six cycles of fludarabine and mitoxantrone (FM). The principal end point of the study was time to treatment failure (TTF).

Results: There were 534 patients enrolled onto the study. Overall response rates were 88%, 93%, and 91% for R-CVP, R-CHOP, and R-FM, respectively (P=.247). After a median follow-up of 34 months, 3-year TTFs were 46%, 62%, and 59% for the respective treatment groups (R-CHOP v R-CVP, P=.003; R-FM v R-CVP, P=.006; R-FM v R-CHOP, P=.763). Three-year progression-free survival (PFS) rates were 52%, 68%, and 63% (overall P=.011), respectively, and 3-year overall survival was 95% for the whole series. R-FM resulted in higher rates of grade 3 to 4 neutropenia (64%) compared with R-CVP (28%) and R-CHOP (50%; P< .001). Overall, 23 second malignancies were registered during follow-up: four in R-CVP, five in R-CHOP, and 14 in R-FM.

Conclusion: In this study, R-CHOP and R-FM were superior to R-CVP in terms of 3-year TTF and PFS. In addition, R-CHOP had a better risk-benefit ratio compared with R-FM.
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http://dx.doi.org/10.1200/JCO.2012.45.0866DOI Listing
April 2013

Monocytosis has adverse prognostic significance and impacts survival in patients with T-cell lymphomas.

Leuk Res 2013 Jun 8;37(6):619-23. Epub 2013 Feb 8.

Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

In this retrospective study we evaluated the prognostic impact of peripheral blood monocytosis in patients with T-cell non Hodgkin lymphomas with "aggressive-typically nodal presentation". In this dataset monocytes >0.8 × 10(9)/L had a strong and statistically significant negative impact on overall survival (OS). In univariate analysis several parameters, including age >60 years, advanced stage, bone marrow involvement, ECOG PS >1, high LDH level, monocytes >0.8 × 10(9)/L, hemoglobin<120 g/L, albumin<35 g/L) had a negative influence on outcome, but in multivariate analysis, monocytosis alone had a stronger association with poor OS.
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http://dx.doi.org/10.1016/j.leukres.2013.01.009DOI Listing
June 2013

NVP-BEZ235 alone and in combination in mantle cell lymphoma: an effective therapeutic strategy.

Expert Opin Investig Drugs 2012 Nov 25;21(11):1597-606. Epub 2012 Aug 25.

University of Modena, 1-Program of Innovative Therapies in Oncology and Haematology, Centro Oncologico Modenese, Department of Oncology and Haematology, Largo del Pozzo 71, 41100 Modena, Italy.

Objectives: Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma; the complete response rate for standard therapies in use today is 85 - 90%. NVP-BEZ235 inhibits the PI3K/Akt/mTOR signaling axis at the level of both PI3K and mTOR. In this study, we analyzed the inhibitory effects of NVP-BEZ235 on mantle cell lines and its effects in combination with enzastaurin, everolimus and perifosine.

Methods: The effects of NVP-BEZ235 on cell proliferation and apoptosis were evaluated using MTT assay and flow cytometry analysis. The cell cycle analysis was performed applying BrdU incorporation. Western blot analysis was utilized for phosphorylation status evaluation of protein kinases. The interaction between NVP-BEZ235 and enzastaurin, everolimus and perifosine was examined by Chou-Talalay method.

Results: NVP-BEZ235 induced significant increase of apoptosis, both via intrinsic and extrinsic pathways. We found that NVP-BEZ235 inhibited mantle cells growth by induction of G1 arrest. NVP-BEZ235 exerts its antitumor activity even when mantle cells were in contact with bone marrow microenvironment. Enzastaurin, everolimus and perifosine enhanced the cytotoxicity triggered by NVP-BEZ235.

Conclusions: The above results encourage clinical development of NVP-BEZ235 in combination and the possible inclusion of patients with mantle lymphoma in Phase I/II clinical trials.
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http://dx.doi.org/10.1517/13543784.2012.719871DOI Listing
November 2012

Combination of low doses of enzastaurin and lenalidomide has synergistic activity in B-non-Hodgkin lymphoma cell lines.

Ann Hematol 2012 Oct 24;91(10):1613-22. Epub 2012 May 24.

Program of Innovative Therapies in Oncology and Haematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Largo del Pozzo 71, 41124 Modena, Italy.

Less toxic and more active treatments are needed for indolent lymphomas as there is no curative treatment, and patients eventually die due to complications related to their disease. The purpose of the present study was to assess the antitumour activity of the combination of low doses of Enzastaurin and Lenalidomide (Revlimid) on B-lymphoma cell lines. The combination of Enzastaurin and Lenalidomide, at doses as low as 1 μM, showed strong synergism against indolent lymphomas by reducing cell growth, producing an increase in G0-G1 phase followed by significant decrease in S phase, increasing apoptosis, and inhibiting PI3K/AKT, PKC and MAPK/ERK pathways. These preclinical findings, together with promising results obtained with Lenalidomide for the treatment of non-Hodgkin lymphoma, suggest that further evaluation of the combination of Enzastaurin and Lenalidomide for the treatment of indolent lymphomas is warranted. These compounds, with a favourable toxicity profile, are not classic chemotherapeutic agents, causing severe side effects, and could be considered an example of a new innovative attempt of an anti-cancer 'soft treatment'.
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http://dx.doi.org/10.1007/s00277-012-1490-6DOI Listing
October 2012

Therapy-related myeloid neoplasm in non-hodgkin lymphoma survivors.

Mediterr J Hematol Infect Dis 2011 20;3(1):e2011065. Epub 2011 Dec 20.

Program of Innovative Therapy in Oncology and Hematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy.

Relatively little data on secondary cancers is available regarding patients treated for non-Hodgkin lymphoma (NHL), compared with those treated for Hodgkin lymphoma. Evolving treatment regimens have improved survival outcomes for NHL patients. As a result of this improvement, secondary malignancies are becoming an important issue in NHL survivors. This review aims to report data on this topic previously published by our group, adding unpublished results from the Modena Cancer Registry (MCR). We recently performed four studies about secondary neoplasms in NHL survivors: two studies analysing the risk of secondary neoplasms in patients treated for indolent and aggressive NHL; a meta-analysis of 23 studies investigating the risk of secondary malignant neoplasm (SMN) after NHL treatment; and a still-unpublished study evaluating the incidence of therapy-related myeloid neoplasm (t-MN) in patients treated for NHL (from the MCR database). The first two studies analysed 563 patients with indolent NHL and 1280 patients with diffuse large B-cell lymphoma (DLBCL) enrolled in the Gruppo Italiano Studio Linfomi (GISL) trials. Results showed that the cumulative incidence of secondary tumours was 10.5% at 12 years for indolent NHL and 8.2% at 15 years for DLBCL. Results of the meta-analysis indicated that NHL patients experienced a 1.88-fold increased risk for SMN compared with the general population; the standardized incidence risk (SIR) for secondary acute myeloid leukaemia (AML) was 11.07. Based on data from the MCR from 2000 through 2008, we found that the SIR was 1.63 for developing a secondary malignancy after NHL, and 1.99 for developing secondary haematological malignancies. Regarding myelodysplastic syndrome and/or AML incidence, nine NHL patients developed t-MN with a higher risk than expected (SIR 8.8, 95% CI: 4.0-16.6). In conclusion, patients treated for NHL are at increased risk of developing SMN. Regarding t-MN, data from the meta-analysis and the MCR demonstrate an excessive risk of developing AML (SIR 11.07 and 5.7, respectively) compared with solid SMN after treatment for NHL. Thus long-term monitoring should be considered for NHL survivors.
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http://dx.doi.org/10.4084/MJHID.2011.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248342PMC
October 2012