Publications by authors named "Roberto Ria"

97 Publications

Short-Term Variations in Neutrophil-to-Lymphocyte and Urea-to-Creatinine Ratios Anticipate Intensive Care Unit Admission of COVID-19 Patients in the Emergency Department.

Front Med (Lausanne) 2020 20;7:625176. Epub 2021 Jan 20.

Guido Baccelli Unit of Internal Medicine, Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, Bari, Italy.

Timely assessment of COVID-19 severity is crucial for the rapid provision of appropriate treatments. Definitive criteria for the early identification of severe COVID-19 cases that require intensive care unit admission are lacking. This was a single-center, retrospective case-control study of 95 consecutive adults admitted to the intensive care unit (cases) or a medical ward (controls) for laboratory-confirmed COVID-19. Clinical data were collected and changes in laboratory test results were calculated between presentation at the emergency department and admission. Univariate and multivariable logistic regression was performed to calculate odds ratios for intensive care unit admission according to changes in laboratory variables. Of the 95 adults with COVID-19, 25 were admitted to intensive care and 70 to a medical ward after a median 6 h stay in the emergency department. During this interval, neutrophil counts increased in cases and decreased in controls (median, 934 vs. -295 × 10/L; = 0.006), while lymphocyte counts decreased in cases and increased in controls (median, -184 vs. 109 × 10/L; < 0.001). In cases, the neutrophil-to-lymphocyte ratio increased 6-fold and the urea-to-creatinine ratio increased 20-fold during the emergency department stay, but these ratios did not change in controls ( < 0.001 for both comparisons). By multivariable logistic regression, short-term increases in the neutrophil-to-lymphocyte ratio (OR = 1.43; 95% CI, 1.16-1.76) and urea-to-creatinine ratio (OR = 1.72; 95% CI, 1.20-2.66) were independent predictors of intensive care unit admission. Short-time changes in neutrophil-to-lymphocyte ratio and urea-to-creatinine ratio emerged as stand-alone parameters able to identify patients with aggressive disease at an early stage.
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http://dx.doi.org/10.3389/fmed.2020.625176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854700PMC
January 2021

Thrombopoietin Promotes Angiogenesis and Disease Progression in Patients with Multiple Myeloma.

Am J Pathol 2021 04 29;191(4):748-758. Epub 2021 Jan 29.

Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, Bari, Italy. Electronic address:

Multiple myeloma (MM) progression closely depends on bone marrow (BM) angiogenesis. Several factors sustain angiogenesis, including cytokines, growth factors, and cell-to-cell interactions. Herein, BM thrombopoietin (TPO) was shown to support angiogenesis and disease progression in MM. Patients with MM at different progression phases had higher levels of BM and circulating TPO than monoclonal gammopathy of undetermined significance/smoldering MM patients, suggesting that TPO correlates with disease progression and prognosis. Endothelial cells from patients with monoclonal gammopathy of undetermined significance (MGECs) and endothelial cells from MM (MMECs) expressed TPO receptor, and the TPO treatment triggered their angiogenic capabilities in vitro. Indeed, TPO-treated MGECs and MMECs showed enhanced angiogenesis on Matrigel and spontaneous cell migration and chemotaxis by acting as a chemotactic agent. TPO also had an angiogenic activity in vivo in the chorioallantoic membrane assay system. Finally, TPO treatment increased the release of active matrix metalloproteinase (MMP)-9 and MMP-2 in MGECs and of MMP-2 in MMECs and affected the balance between angiogenic/antiangiogenic factors in the MM BM. Our results support the angiogenic activity of TPO, and suggest that it may have a critical role in promoting the angiogenic switch during MM progression. Accordingly, TPO may be envisaged as a new angiogenic and prognostic factor in patients with MM.
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http://dx.doi.org/10.1016/j.ajpath.2020.12.016DOI Listing
April 2021

Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus.

Eur J Haematol 2021 Apr 2;106(4):439-449. Epub 2021 Feb 2.

Département de Recherche Clinique, Avicenne Hospital, Sorbonne Paris Nord University, Bobigny, France.

Objectives: Secondary antibody deficiency (SAD), associated with severe, recurrent or persistent infections, is common in patients with haematological malignancies (HM), but unifying guidance on immunoglobulin replacement therapy (IgRT) in these patients is lacking. We aimed to develop consensus statements for the use of IgRT in patients with HM.

Methods: A Delphi exercise was employed to test the level of agreement on statements developed by a Task Force based on available data and their clinical experience. In Round 1, an Expert Panel, comprising specialist EU physicians caring for patients with HM, helped to refine the statements. In Round 2, experts rated their agreement with the statements. In Round 3, experts who had scored their agreement as ≤4 were invited to review their agreement based on the overall feedback.

Results: Three definitions and 20 statements were formulated and tested for consensus, covering measurement of IgG levels, initiation and discontinuation of IgRT, dosing, and the use of subcutaneous IgG. Consensus (agreement ≥70% on Likert-type scale) was reached for all three definitions and 18 statements.

Conclusions: Recommendations have been developed with the aim of providing guidance for the use of IgRT to prevent severe, recurrent or persistent infections in patients with HM and SAD.
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http://dx.doi.org/10.1111/ejh.13580DOI Listing
April 2021

Response to letter: "Effect of thyroidectomy on circulating angiogenic cytokines in papillary thyroid carcinoma and benign goiter: Potential for new biomarkers?"

Surgery 2021 04 5;169(4):996-997. Epub 2020 Dec 5.

Academic Unit of General Surgery, Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro" Medical School, Bari, (BA), Italy.

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http://dx.doi.org/10.1016/j.surg.2020.10.030DOI Listing
April 2021

TOP2A expression predicts responsiveness to carfilzomib in myeloma and informs novel combinatorial strategies for enhanced proteasome inhibitor cell killing.

Leuk Lymphoma 2021 02 31;62(2):337-347. Epub 2020 Oct 31.

Myeloma Research Group, Australian Centre for Blood Diseases, The Alfred Hospital/Monash University, Melbourne, Australia.

Microarray was utilized to determine if a genetic signature associated with resistance to carfilzomib (CFZ) could be identified. Twelve human myeloma (MM) cell lines (HMCLs) were treated with CFZ and a cell-viability profile was assessed categorizing HMCLs as sensitive or resistant to CFZ. The gene expression profiles (GEP) of untreated resistant versus sensitive HMCLs revealed 29 differentially expressed genes. TOP2A, an enzyme involved in cell cycle and proliferation, was overexpressed in carfilzomib-resistant HMCLs. TOP2A protein expression levels, evaluated utilizing trephine biopsy specimens acquired prior to treatment with proteasome inhibitors, were higher in patients failing to achieve a response when compared to responding patients. Logistic-regression analysis confirmed that TOP2A protein expression was a highly significant predictor of response to PIs (AUC 0.738). Further, the combination of CFZ with TOP2A inhibitors, demonstrated synergistic cytotoxic effects , providing a rationale for combining topoisomerase inhibitors with CFZ to overcome resistance in MM.
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http://dx.doi.org/10.1080/10428194.2020.1832659DOI Listing
February 2021

Right Heart Changes Impact on Clinical Phenotype of Amyloid Cardiac Involvement: A Single Centre Study.

Life (Basel) 2020 Oct 18;10(10). Epub 2020 Oct 18.

Unit of Internal Medicine "Guido Baccelli", Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro Medical School, Piazza Giulio Cesare 11, I-70124 Bari, Italy.

Amyloidosis is due to deposition of an excessive amount of protein in many parenchymal tissues, including myocardium. The onset of cardiac Amyloidosis (CA) is an inauspicious prognostic factor, which can lead to sudden death. We retrospectively analyzed 135 patients with systemic amyloidosis, admitted to our ward between 1981 and 2019. Among them, 54 patients (46.30% F/53.70% M, aged 63.95 ± 12.82) presented CA at baseline. In 53 patients, it was associated with a multiorgan involvement, while in one there was a primary myocardial deposition. As a control group, we enrolled 81 patients (49.30% F/50.70% M, aged 58.33 ± 15.65) who did not meet the criteria for CA. In 44/54 of patients CA was associated with AL, 5/54 with AA and 3/54 of patients with ATTR, and in 1/54 AL was related to hemodialysis and in 1/54 to Gel-Amyloidosis. The most common AL type was IgG (28/44); less frequent forms were either IgA (7/44) or IgD (2/44), while seven patients had a λ free light chain form. The 32 AL with complete Ig were 31 λ-chain and just one k-chain. CA patients presented normal BP (SBP 118.0 ± 8.4 mmHg; DBP 73.8 ± 4.9 mmHg), while those with nCA had an increased proteinuria ( = 0.02). TnI and NT-proBNP were significantly increased compared to nCA ( = 0.031 and = 0.047, respectively). In CA patients we found an increased LDH compared to nCA ( = 0.0011). CA patients were also found to have an increased interventricular septum thickness compared to nCA ( = 0.002), a decreased Ejection Fraction % ( = 0.0018) and Doppler velocity E/e' ratio ( = 0.0095). Moreover, CA patients had an enhanced right atrium area ( = 0.0179), right ventricle basal diameter ( = 0.0112) and wall thickness ( = 0.0471) compared to nCA, and an increased inferior cava vein diameter ( = 0.0495) as well. TAPSE was the method chosen to evaluate systolic function of the right heart. In CA subjects very poor TAPSE levels were found compared to nCA patients ( = 0.0495). Additionally, we found a significant positive correlation between TAPSE and lymphocyte count (r = 0.47; = 0.031) as well as Gamma globulins (r = 0.43, = 0.033), Monoclonal components (r = 0.72; = 0.047) and IgG values (r = 0.62, = 0.018). Conversely, a significant negative correlation with LDH (r = -0.57, = 0.005), IVS (r = -0.51, = 0.008) and diastolic function evaluated as E/e' (r = -0.60, = 0.003) were verified. CA patients had very poor survival rates compared to controls (30 vs. 66 months in CA vs. nCA, respectively, = 0.15). Mean survival of CA individuals was worse also when stratified according to NT-proBNP levels, using 2500 pg/mL as class boundary (174 vs. 5.5 months, for patients with lower vs. higher values than the median, respectively = 0.013). In much the same way, a decreased right heart systolic function was correlated with a worse prognosis (18.0 months median survival, not reached in subjects with lower values than 18 mm, = 0.0186). Finally, our data highlight the potential prognostic and predictive value of right heart alterations characterizing amyloidosis, as a novel clinical parameter correlated to increased LDH and immunoglobulins levels. Overall, we confirm the clinical relevance of cardiac involvement suggests that right heart evaluation may be considered as a new marker for clinical risk stratification in patients with amyloidosis.
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http://dx.doi.org/10.3390/life10100247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603245PMC
October 2020

Jagged Ligands Enhance the Pro-Angiogenic Activity of Multiple Myeloma Cells.

Cancers (Basel) 2020 Sep 11;12(9). Epub 2020 Sep 11.

Department of Health Sciences, Università degli Studi di Milano, 20142 Milano, Italy.

Multiple myeloma (MM) is an incurable plasma cell malignancy arising primarily within the bone marrow (BM). During MM progression, different modifications occur in the tumor cells and BM microenvironment, including the angiogenic shift characterized by the increased capability of endothelial cells to organize a network, migrate and express angiogenic factors, including vascular endothelial growth factor (VEGF). Here, we studied the functional outcome of the dysregulation of Notch ligands, Jagged1 and Jagged2, occurring during disease progression, on the angiogenic potential of MM cells and BM stromal cells (BMSCs). Jagged1-2 expression was modulated by RNA interference or soluble peptide administration, and the effects on the MM cell lines' ability to induce human pulmonary artery cells (HPAECs) angiogenesis or to indirectly increase the BMSC angiogenic potential was analyzed in vitro; in vivo validation was performed on a zebrafish model and MM patients' BM biopsies. Overall, our results indicate that the MM-derived Jagged ligands (1) increase the tumor cell angiogenic potential by directly triggering Notch activation in the HPAECs or stimulating the release of angiogenic factors, i.e., VEGF; and (2) stimulate the BMSCs to promote angiogenesis through VEGF secretion. The observed pro-angiogenic effect of Notch activation in the BM during MM progression provides further evidence of the potential of a therapy targeting the Jagged ligands.
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http://dx.doi.org/10.3390/cancers12092600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565520PMC
September 2020

Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients.

J Clin Med 2020 Jun 6;9(6). Epub 2020 Jun 6.

Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari "Aldo Moro" Medical School, 70124 Bari, Italy.

The interaction between the bone marrow microenvironment and plasma cells plays an essential role in multiple myeloma progression and drug resistance. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway in vascular endothelial cells activates and promotes angiogenesis. Moreover, VEGF activates and promotes vasculogenesis and vasculogenic mimicry when it interacts with VEGF receptors expressed in precursor cells and inflammatory cells, respectively. In myeloma bone marrow, VEGF and VEGF receptor expression are upregulated and hyperactive in the stromal and tumor cells. It has been demonstrated that several antiangiogenic agents can effectively target VEGF-related pathways in the preclinical phase. However, they are not successful in treating multiple myeloma, probably due to the vicarious action of other cytokines and signaling pathways. Thus, the simultaneous blocking of multiple cytokine pathways, including the VEGF/VEGFR pathway, may represent a valid strategy to treat multiple myeloma. This review aims to summarize recent advances in understanding the role of the VEGF/VEGFR pathway in multiple myeloma, and mainly focuses on the transcription pathway and on strategies that target this pathway.
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http://dx.doi.org/10.3390/jcm9061765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355441PMC
June 2020

Effect of thyroidectomy on circulating angiogenic cytokines in papillary thyroid carcinoma and benign goiter: Potential for new biomarkers?

Surgery 2021 01 30;169(1):27-33. Epub 2020 May 30.

Academic General Surgery Unit, Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro" Medical School, Bari, (BA), Italy.

Background: Circulating angiogenic factors have been associated with clinical outcomes of papillary thyroid carcinoma, although they may also be released in the context of benign multinodular goiter. We sought to investigate the effect of thyroidectomy on the activity and importance of multiple circulating angiogenic factors in papillary thyroid carcinoma and benign multinodular goiter.

Methods: Between May 2015 and December 2016, patients scheduled for total thyroidectomy for papillary thyroid carcinoma or benign multinodular goiter were offered to enroll in this study. Serum levels of angiopoietin-2, fibroblast growth factor-2, hepatocyte growth factor, platelet-derived growth factor-BB, placenta growth factor, heparin-binding epidermal growth factor, and vascular endothelial growth factor-A and -C were collected preoperatively and 2 weeks postsurgery. These levels were measured by enzyme-linked immunosorbent assay and compared with those of 35 healthy control subjects.

Results: Sixty patients with a median age of 52 years, 37 of whom were females, were included: 36 had papillary thyroid carcinoma, and 24 had benign multinodular goiter. In both benign multinodular goiter and papillary thyroid carcinoma, preoperative, circulating angiogenic factors levels were increased with respect to controls (P < .0001), and a decrease after total thyroidectomy was observed in the levels of angiopoietin-2 (P < .0001), fibroblast growth factor-2 (P < .0001), hepatocyte growth factor (P < .001), and heparin-binding epidermal growth factor (P < .01 each). Only patients with papillary thyroid carcinomas, however, showed decrease in the postoperative levels of platelet-derived growth factor-BB and vascular endothelial growth factor-A (P = .001 each).

Conclusion: Results from this study raise the potential for vascular endothelial growth factor-A and platelet-derived growth factor-BB to be used as biomarkers of the effectiveness of treatment of papillary thyroid carcinoma. These results warrant further investigation and may have potential prognostic implications.
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http://dx.doi.org/10.1016/j.surg.2020.03.031DOI Listing
January 2021

Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores the angiogenic homeostasis and suppresses tumor progression.

Haematologica 2020 04 30. Epub 2020 Apr 30.

1Department of Medicine II, University Hospital of Würzburg, Würzburg, Germany; 7Interdisciplinary Center for Clinical Research Laboratory, University Hospital of Würzburg, Würzburg, Germany;

Interactions of malignant multiple myeloma (MM) plasma cells (MM-cells) with the microenvironment control MM-cell growth, survival, drug-resistance and dissemination. As in MM microvascular density increases in the bone marrow (BM), we investigated whether BM MM endothelial cells (MMECs) control disease progression via the junctional adhesion molecule A (JAM-A). Membrane and cytoplasmic JAM-A levels were upregulated in MMECs in 111 newly diagnosed (NDMM) and 201 relapsed-refractory (RRMM) patients compared to monoclonal gammopathy of undetermined significance (MGUS) and healthy controls. Elevated membrane expression of JAM-A on MMECs predicted poor clinical outcome. Mechanistically, addition of recombinant JAM-A to MMECs increased angiogenesis whereas its inhibition impaired angiogenesis and MM growth in 2D and 3D in vitro cell culture and chorioallantoic membrane-assays. To corroborate these findings, we treated MM bearing mice with JAM-A blocking mAb and demonstrated impaired MM progression corresponding to decreased MM-related vascularity. These findings support JAM-A as an important mediator of MM progression through facilitating MM-associated angiogenesis. Collectively, elevated JAM-A expression on bone marrow endothelial cells is an independent prognostic factor for patient survival in both NDMM and RRMM. Blocking JAM-A restricts angiogenesis in vitro, in embrio and in vivo and represents a suitable druggable molecule to halt neoangiogenesis and MM progression.
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http://dx.doi.org/10.3324/haematol.2019.239913DOI Listing
April 2020

Serum Free Light Chains in Common Variable Immunodeficiency Disorders: Role in Differential Diagnosis and Association With Clinical Phenotype.

Front Immunol 2020 31;11:319. Epub 2020 Mar 31.

Department of Medicine-DIMED, University of Padova, Padova, Italy.

We report on an observational, multicenter study of 345 adult CVID patients, designed to assess the diagnostic value and the clinical association of serum free light chain (sFLC) pattern in Common Variable Immunodeficiency disorders (CVID). Sixty CVID patients were tested twice in order to assess intraindividual variability of sFLC. As control groups we included 138 patients affected by undefined primary antibody defects (UAD), lymphoproliferative diseases (LPDs), and secondary antibody deficiencies not related to hematological malignancies (SID). CVID patients presented lower κ and λ chain concentration compared to controls, showing low intraindividual sFLC variability. On the basis of the sFLC pattern, patients were classified into four groups: κ-λ+, κ+λ-, κ-λ-, κ+λ+. The most common pattern in CVID patients was κ-λ- (51%), followed by κ-λ+, (25%), κ+λ+ (22%), and κ+λ- (3%). In UAD, LPD, and SID groups κ+λ+ was the most common pattern observed. By analyzing the possible association between sFLC patterns and disease-related complications of CVID, we observed that patients belonging to the κ-λ- group presented more commonly unexplained enteropathy compared to the κ+λ+ group and showed higher frequency of bronchiectasis and splenomegaly compared to both the κ-λ+ and κ+λ+ patients. When compared to the other groups, κ-λ- had also lower serum IgG, IgA, and IgM concentrations at diagnosis, lower frequency of CD27+IgD-IgM- switched memory B cells, and higher frequency of CD21 B cells, receiving earlier CVID diagnosis. Thus, lower levels of sFLC might be an epiphenomenon of impairment in B cell differentiation, possibly leading κ-λ- patients to a higher risk for bacterial infections and chronic lung damage. Based on these results, we suggest adding sFLC assay to the diagnostic work-up of hypogammaglobulinemia and during follow-up. The assay may be useful to differentiate CVID from other causes of hypogammaglobulinemia and to early detect monoclonal lymphoproliferation occurring over years. Moreover, since the sFLC pattern seems to be related to disease phenotypes and clinical manifestations of CVID and after confirmation by further studies, sFLC assay might be considered a promising prognostic tool for identifying patients at higher risk of developing enteropathy and chronic lung damage or splenomegaly. This will allow designing a tailored follow-up for CVID patients.
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http://dx.doi.org/10.3389/fimmu.2020.00319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136404PMC
March 2021

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma.

J Clin Med 2020 Feb 18;9(2). Epub 2020 Feb 18.

Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine "Guido Baccelli", University of Bari Medical School, 70124 Bari, Italy.

Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15-20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed.

Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM.

Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation.

Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse.
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http://dx.doi.org/10.3390/jcm9020552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073518PMC
February 2020

Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma.

Int J Mol Sci 2020 Jan 17;21(2). Epub 2020 Jan 17.

Section of Internal Medicine "G. Baccelli", Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro" Medical School, Bari, 70124 Bari, Italy.

Multiple myeloma is a B-cell lineage cancer in which neoplastic plasma cells expand in the bone marrow and pathophysiological interactions with components of microenvironment influence many biological aspects of the malignant phenotype, including apoptosis, survival, proliferation, and invasion. Despite the therapeutic progress achieved in the last two decades with the introduction of a more effective and safe new class of drugs (i.e., immunomodulators, proteasome inhibitors, monoclonal antibodies), there is improvement in patient survival, and multiple myeloma (MM) remains a non-curable disease. The bone marrow microenvironment is a complex structure composed of cells, extracellular matrix (ECM) proteins, and cytokines, in which tumor plasma cells home and expand. The role of the bone marrow (BM) microenvironment is fundamental during MM disease progression because modification induced by tumor plasma cells is crucial for composing a "permissive" environment that supports MM plasma cells proliferation, migration, survival, and drug resistance. The "activated phenotype" of the microenvironment of multiple myeloma is functional to plasma cell proliferation and spreading and to plasma cell drug resistance. Plasma cell drug resistance induced by bone marrow stromal cells is mediated by stress-managing pathways, autophagy, transcriptional rewiring, and non-coding RNAs dysregulation. These processes represent novel targets for the ever-increasing anti-MM therapeutic armamentarium.
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http://dx.doi.org/10.3390/ijms21020613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013615PMC
January 2020

Mechanisms of Resistance to Anti-CD38 Daratumumab in Multiple Myeloma.

Cells 2020 01 9;9(1). Epub 2020 Jan 9.

Department of Biomedical Sciences and Human Oncology, Unit of General Pathology, University of Bari "Aldo Moro", 70124 Bari, Italy.

Daratumumab (Dara) is the first-in-class human-specific anti-CD38 mAb approved for the treatment of multiple myeloma (MM). Although recent data have demonstrated very promising results in clinical practice and trials, some patients do not achieve a partial response, and ultimately all patients undergo progression. Dara exerts anti-MM activity via antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and immunomodulatory effects. Deregulation of these pleiotropic mechanisms may cause development of Dara resistance. Knowledge of this resistance may improve the therapeutic management of MM patients.
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http://dx.doi.org/10.3390/cells9010167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017193PMC
January 2020

High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment.

J Clin Med 2019 Jul 9;8(7). Epub 2019 Jul 9.

Department of Internal Medicine II, University Hospital, 97080 Würzburg, Germany.

Multiple myeloma (MM) is a genetically heterogeneous disease that includes a subgroup of 10-15% of patients facing dismal survival despite the most intensive treatment. Despite improvements in biological knowledge, MM is still an incurable neoplasia, and therapeutic options able to overcome the relapsing/refractory behavior represent an unmet clinical need. The aim of this review is to provide an integrated clinical and biological overview of high-risk MM, discussing novel therapeutic perspectives, targeting the neoplastic clone and its microenvironment. The dissection of the molecular determinants of the aggressive phenotypes and drug-resistance can foster a better tailored clinical management of the high-risk profile and therapy-refractoriness. Among the current clinical difficulties in MM, patients' management by manipulating the tumor niche represents a major challenge. The angiogenesis and the stromal infiltrate constitute pivotal mechanisms of a mutual collaboration between MM and the non-tumoral counterpart. Immuno-modulatory and anti-angiogenic therapy hold great efficacy, but variable and unpredictable responses in high-risk MM. The comprehensive understanding of the genetic heterogeneity and MM high-risk ecosystem enforce a systematic bench-to-bedside approach. Here, we provide a broad outlook of novel druggable targets. We also summarize the existing multi-omics-based risk profiling tools, in order to better select candidates for dual immune/vasculogenesis targeting.
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http://dx.doi.org/10.3390/jcm8070997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678140PMC
July 2019

Functional interplay between NF-κB-inducing kinase and c-Abl kinases limits response to Aurora inhibitors in multiple myeloma.

Haematologica 2019 12 4;104(12):2465-2481. Epub 2019 Apr 4.

Center for Molecular and Translational Oncology, University of Parma, Parma

Considering that Aurora kinase inhibitors are currently under clinical investigation in hematologic cancers, the identification of molecular events that limit the response to such agents is essential for enhancing clinical outcomes. Here, we discover a NF-κB-inducing kinase (NIK)-c-Abl-STAT3 signaling-centered feedback loop that restrains the efficacy of Aurora inhibitors in multiple myeloma. Mechanistically, we demonstrate that Aurora inhibition promotes NIK protein stabilization downregulation of its negative regulator TRAF2. Accumulated NIK converts c-Abl tyrosine kinase from a nuclear proapoptotic into a cytoplasmic antiapoptotic effector by inducing its phosphorylation at Thr735, Tyr245 and Tyr412 residues, and, by entering into a trimeric complex formation with c-Abl and STAT3, increases both the transcriptional activity of STAT3 and expression of the antiapoptotic STAT3 target genes PIM1 and PIM2. This consequently promotes cell survival and limits the response to Aurora inhibition. The functional disruption of any of the components of the trimer NIK-c-Abl-STAT3 or the PIM survival kinases consistently enhances the responsiveness of myeloma cells to Aurora inhibitors. Importantly, concurrent inhibition of NIK or c-Abl disrupts Aurora inhibitor-induced feedback activation of STAT3 and sensitizes myeloma cells to Aurora inhibitors, implicating a combined inhibition of Aurora and NIK or c-Abl kinases as potential therapies for multiple myeloma. Accordingly, pharmacological inhibition of c-Abl together with Aurora resulted in substantial cell death and tumor regression The findings reveal an important functional interaction between NIK, Abl and Aurora kinases, and identify the NIK, c-Abl and PIM survival kinases as potential pharmacological targets for improving the efficacy of Aurora inhibitors in myeloma.
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http://dx.doi.org/10.3324/haematol.2018.208280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959191PMC
December 2019

Prognostic or predictive value of circulating cytokines and angiogenic factors for initial treatment of multiple myeloma in the GIMEMA MM0305 randomized controlled trial.

J Hematol Oncol 2019 01 9;12(1). Epub 2019 Jan 9.

Department of Biomedical Science and Human Oncology, University of Bari "Aldo Moro" Medical School, Bari, Italy.

Background: Several new drugs are approved for treatment of patients with multiple myeloma (MM), but no validated biomarkers are available for the prediction of a clinical outcome. We aimed to establish whether pretreatment blood and bone marrow plasma concentrations of major cytokines and angiogenic factors (CAFs) of patients from a phase 3 trial of a MM treatment could have a prognostic and predictive value in terms of response to therapy and progression-free and overall survival and whether these patients could be stratified for their prognosis.

Methods: Blood and bone marrow plasma levels of Ang-2, FGF-2, HGF, VEGF, PDGF-β, IL-8, TNF-α, TIMP-1, and TIMP-2 were determined at diagnosis in MM patients enrolled in the GIMEMA MM0305 randomized controlled trial by an enzyme-linked immunosorbent assay (ELISA). These levels were correlated both reciprocally and with the type of therapy and patients' characteristics and with a group of non-MM patients as controls.

Results: No significant differences were detected between the blood and bone marrow plasma levels of angiogenic cytokines. A cutoff for each CAF was established. The therapeutic response of patients with blood plasma levels of CAFs lower than the cutoff was better than the response of those with higher levels in terms of percentage of responding patients and quality of response.

Conclusion: FGF-2, HGF, VEGF, and PDGF-β plasma levels at diagnosis have predictive significance for response to treatment. The stratification of patients based on the levels of CAFs at diagnosis and their variations after therapy is useful to characterize different risk groups concerning outcome and response to therapy.

Trial Registration: Clinical trial information can be found at the following link: NCT01063179.
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http://dx.doi.org/10.1186/s13045-018-0691-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327520PMC
January 2019

Bone marrow endothelial cells sustain a tumor-specific CD8 T cell subset with suppressive function in myeloma patients.

Oncoimmunology 2019;8(1):e1486949. Epub 2018 Oct 22.

Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine "Guido Baccelli", University of Bari Medical School, Bari, Italy.

Endothelial cells (EC) line the bone marrow microvasculature and are in close contact with CD8 T cells that come and go across the permeable capillaries. Because of these intimate interactions, we investigated the capacity of EC to act as antigen-presenting cells (APC) and modulate CD8 T cell activation and proliferation in bone marrow of patients with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance. We found that EC from MM patients show a phenotype of semi-professional APC given that they express low levels of the co-stimulatory molecules CD40, CD80 and CD86, and of the inducible co-stimulator ligand (ICOSL). In addition, they do not undergo the strong switch from immunoproteasome to standard proteasome subunit expression which is typical of mature professional APC such as dendritic cells. EC can trap and present antigen to CD8 T cells, stimulating a central memory CD8 T cell population that expresses Foxp3 and produces high amounts of IL-10 and TGF-β. Another CD8 T cell population is stimulated by professional APC, produces IFN-γ, and exerts antitumor activity. Thus, two distinct CD8 T cell populations coexist in the bone marrow of MM patients: the first population is sustained by EC, expresses Foxp3, produces IL-10 and TGF-β, and exerts pro-tumor activity by negatively regulating the second population. This study adds new insight into the role that EC play in MM biology and describes an additional immune regulatory mechanism that inhibits the development of antitumor immunity and may impair the success of cancer immunotherapy.
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http://dx.doi.org/10.1080/2162402X.2018.1486949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287798PMC
October 2018

Homotypic and Heterotypic Activation of the Notch Pathway in Multiple Myeloma-Enhanced Angiogenesis: A Novel Therapeutic Target?

Neoplasia 2019 01 5;21(1):93-105. Epub 2018 Dec 5.

Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.

Interactions of multiple myeloma (MM) cells with endothelial cells (ECs) enhance angiogenesis and MM progression. Here, we investigated the role of Notch signaling in the cross talk between ECs and MM cells enabling angiogenesis. MMECs showed higher expression of Jagged1/2 ligands, of activated Notch1/2 receptors, and of Hes1/Hey1 Notch target genes than ECs from monoclonal gammopathy of undetermined significance patients, suggesting that homotypic activation of Notch pathway occurs in MM. MM cells co-cultured with MMECs triggered Notch activation in these cells through a cell-to-cell contact-dependent way via Jagged1/2, resulting in Hes1/Hey1 overexpression. The angiogenic effect of Notch pathway was analyzed through Notch1/2·siRNAs and the γ-secretase inhibitor MK-0752 by in vitro (adhesion, migration, chemotaxis, angiogenesis) and in vivo (Vk12598/C57B/6 J mouse model) studies. Activated Notch1/2 pathway was associated with the overangiogenic MMEC phenotype: Notch1/2 knockdown or MK-0752 treatment reduced Hes1/Hey1 expression, impairing in vitro angiogenesis of both MMECs alone and co-cultured with MM cells. MM cells were unable to restore angiogenic abilities of treated MMECs, proving that MMEC angiogenic activities closely rely on Notch pathway. Furthermore, Notch1/2 knockdown affected VEGF/VEGFR2 axis, indicating that the Notch pathway interferes with VEGF-mediated control on angiogenesis. MK-0752 reduced secretion of proangiogenic/proinflammatory cytokines in conditioned media, thus inhibiting blood vessel formation in the CAM assay. In the Vk12598/C57B/6 J mouse, MK-0752 treatment restrained angiogenesis by reducing microvessel density. Overall, homotypic and heterotypic Jagged1/2-mediated Notch activation enhances MMECs angiogenesis. Notch axis inhibition blocked angiogenesis in vitro and in vivo, suggesting that the Notch pathway may represent a novel therapeutic target in MM.
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http://dx.doi.org/10.1016/j.neo.2018.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282459PMC
January 2019

Continuous therapy in standard- and high-risk newly-diagnosed multiple myeloma: A pooled analysis of 2 phase III trials.

Crit Rev Oncol Hematol 2018 Dec 14;132:9-16. Epub 2018 Sep 14.

Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy. Electronic address:

Background: Risk-adapted therapy is a common strategy in curable hematologic malignancies: standard-risk patients receive less intensive treatment, whereas high-risk patients require a more intensive approach. This model cannot be applied in multiple myeloma (MM), which is still incurable. Continuous treatment (CT) is a key strategy for MM treatment, since it improves duration of remission. However, the role of CT according to standard- or high-risk baseline prognosis remains an open question.

Patients And Methods: We performed a pooled analysis of 2 phase III trials (GIMEMA-MM-03-05 and RV-MM-PI-209) that randomized patients to CT vs fixed-duration therapy (FDT).

Results: In the overall patient population (n = 550), CT improved progression-free survival1 (PFS1) (HR 0.54), PFS2 (HR 0.61) and overall survival (OS) (HR 0.71) vs FDT. CT improved PFS1 both in R-ISS I (HR 0.49) and R-ISS II/III patients (HR 0.55). Four-year PFS1 was 38% in R-ISS II/III patients receiving CT and 25% in R-ISS I patients receiving FDT, with similar trends for PFS2 and OS. High-risk patients benefited more from proteasome-inhibitor plus immunomodulatory-based CT than immunomodulatory alone.

Conclusion: Good prognosis patients receiving FDT lose their prognostic advantage over high-risk patients receiving CT and high-risk patients may benefit from more intensive maintenance including proteasome inhibitors and immunomodulators.
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http://dx.doi.org/10.1016/j.critrevonc.2018.09.008DOI Listing
December 2018

Suspected Pericardial Tuberculosis Revealed as an Amyloid Pericardial Mass.

Case Rep Hematol 2018 17;2018:8606430. Epub 2018 Oct 17.

Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine "G. Baccelli", University of Bari Aldo Moro Medical School, Bari, Italy.

Primary systemic amyloidosis is not easily diagnosed. The immunoglobulin deposits are usually localized in the kidney, heart, and liver. We describe an unusual case of a patient suffering from a pericardial amyloidoma with internal calcifications and air bubbles that compressed the right ventricle and shifted the heart to the left. Since the patient was in shock, urgent pericardiotomy was performed. This site showed PET uptake. A monoclonal component was present. On these findings, differential diagnoses included multiple myeloma and atypical pericardial tuberculosis, whereas a periumbilical fat tissue biopsy demonstrated amyloidosis. A previous species infection had most likely stimulated the production of amyloid. The patient received bortezomib/dexamethasone treatment and achieved a good response.
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http://dx.doi.org/10.1155/2018/8606430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207883PMC
October 2018

Is re-challenge still an option as salvage therapy in multiple myeloma? The case of REal-life BOrtezomib re-Use as secoND treatment for relapsed patients exposed frontline to bortezomib-based therapies (the REBOUND Study).

Ann Hematol 2019 Feb 23;98(2):361-367. Epub 2018 Oct 23.

Haematology Unit, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

Therapeutic re-challenge is currently a debated issue in the field of multiple myeloma (MM), given the recent availability of several new drugs and combinations. However, very few specific evidences are available about bortezomib re-use at first relapse. This multicenter, observational, retrospective study enrolled 134 MM patients with significant response after bortezomib-based frontline regimens and who had received a first salvage treatment containing bortezomib at relapse. The overall response rate was 71%, including 40% partial responses, 24% very good partial responses, and 7% complete responses. Re-treatment was well-tolerated, with no significant new or unexpected toxicities observed. The median duration of second progression-free survival (PFS) was 15 months, while median PFS2 was 55 months. With a median follow-up of 56 months, overall survival was 94 months for the entire series, without significant differences between patients undergoing or not undergoing transplant procedures. This real-life survey indicates that re-treatment including bortezomib as a first salvage therapy could be still considered in MM patients achieving durable response after initial exposure to bortezomib.
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http://dx.doi.org/10.1007/s00277-018-3524-1DOI Listing
February 2019

A multiple myeloma that progressed as type I cryoglobulinemia with skin ulcers and foot necrosis: A case report.

Medicine (Baltimore) 2018 Sep;97(39):e12355

Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari "Aldo Moro" Medical School.

Rationale: Type I cryoglobulinemia is a rare and life-threatening condition. It occurs mainly in B-cell lymphoproliferative disorder. In almost half of the patients, type I cryoglobulinemia is characterized by severe cutaneous involvement.

Patient Concerns: A 71-year-old man comes to our observation because of the onset of persistence of paresthesia and painful acrocyanosis in the fingers and toes. IgG-k multiple myeloma treated with chemotherapy and radiation therapy on the left iliac wing characterized his clinical history. At the evaluation of response after the first-line therapy, the patient achieved a very good partial response. At the time of progression, the same myelomatous disease has taken a typical behavior of cryoglobulinemia.

Diagnoses: Type I multiple myeloma-associated cryoglobulinemia was diagnosed.

Interventions: The patient underwent to an immediate composite therapeutic approach based on prostanoid infusion, plasmapheresis along with second-line chemotherapy.

Outcomes: Despite the rapid biochemical response, the ischemia of the feet worsened. Moreover, a bacterial infection overlapped. The surgical amputation of both feet was necessary. Allowing MM cytoreduction continuation the patient's clinical condition became stabilized.

Lessons: Though rare, type I cryoglobulinemia can be associated with plasma cell dyscrasias. Any delay in diagnosis and the start of therapy can cause worsening of organ damage and endanger the patient's life. Therapeutic strategies in these cases should be directed to the underlying diseases.
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http://dx.doi.org/10.1097/MD.0000000000012355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181604PMC
September 2018

Treatment Intensification With Autologous Stem Cell Transplantation and Lenalidomide Maintenance Improves Survival Outcomes of Patients With Newly Diagnosed Multiple Myeloma in Complete Response.

Clin Lymphoma Myeloma Leuk 2018 08 28;18(8):533-540. Epub 2018 May 28.

Myeloma Unit, Division of Hematology, University of Torino, Azienda-Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy. Electronic address:

Background: High-dose therapy with autologous stem cell transplantation (HDT-ASCT) and maintenance treatment with novel agents are the best options for patients with newly diagnosed multiple myeloma, increasing the rate of complete response (CR) and prolonging progression-free survival (PFS) and overall survival (OS). Indeed, the achievement of a CR is a predictor of long-term survival among transplant-eligible patients. However, it is unclear whether patients reaching a CR after induction treatment could receive less intense consolidation or avoid maintenance therapy.

Patients And Methods: We analyzed CR patients treated in 2 phase III trials, GIMEMA-RV-MM-PI-209 and RV-MM-EMN-441, to compare HDT-ASCT with an R-Alk (lenalidomide, alkylator) regimen as consolidation, and lenalidomide (R) maintenance with no maintenance. The primary endpoints were PFS, second PFS (PFS2), and OS from consolidation and maintenance (_m).

Results: Overall, the data from 166 patients in CR were analyzed, 95 in the HDT-ASCT group and 71 in the R-Alk group. The CR patients who received HDT-ASCT had a better PFS (hazard ratio [HR], 0.55; P = .01), PFS2 (HR, 0.46; P = .02), and OS (HR, 0.42; P = .03) compared with patients randomized to R-Alk. The survival benefit with HDT-ASCT was confirmed among all the subgroups, according to age, International Staging System (ISS stage, cytogenetic profile, and receipt of maintenance therapy. CR patients who received lenalidomide maintenance had a better PFS_m (4 years: 54% vs. 19%; HR, 0.43; P = .02) compared with those who received no maintenance. However, no difference was observed in terms of PFS2_m (4 years: 72% vs. 58%; HR, 0.83; P = .67) and OS_m (4 years: 79% vs. 72%; HR, 0.82; P = .73) with maintenance therapy.

Conclusion: Even in CR patients, outcomes were improved by an intensified approach with HDT-ASCT consolidation and lenalidomide-based maintenance therapy.
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http://dx.doi.org/10.1016/j.clml.2018.05.019DOI Listing
August 2018

Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma.

Oncotarget 2018 Apr 17;9(29):20563-20577. Epub 2018 Apr 17.

Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy.

The mammalian Target of Rapamycin (mTOR) is an intracellular serine/threonine kinase that mediates intracellular metabolism, cell survival and actin rearrangement. mTOR is made of two independent complexes, mTORC1 and mTORC2, activated by the scaffold proteins RAPTOR and RICTOR, respectively. The activation of mTORC1 triggers protein synthesis and autophagy inhibition, while mTORC2 activation promotes progression, survival, actin reorganization, and drug resistance through AKT hyper-phosphorylation on Ser473. Due to the mTOR pivotal role in the survival of tumor cells, we evaluated its activation in endothelial cells (ECs) from 20 patients with monoclonal gammopathy of undetermined significance (MGUS) and 47 patients with multiple myeloma (MM), and its involvement in angiogenesis. MM-ECs showed a significantly higher expression of mTOR and RICTOR than MGUS-ECs. These data were supported by the higher activation of mTORC2 downstream effectors, suggesting a major role of mTORC2 in the angiogenic switch to MM. Specific inhibition of mTOR activity through siRNA targeting RICTOR and dual mTOR inhibitor PP242 reduced the MM-ECs angiogenic functions, including cell migration, chemotaxis, adhesion, invasion, angiogenesis on Matrigel, and cytoskeleton reorganization. In addition, PP242 treatment showed anti-angiogenic effects in the Chick Chorioallantoic Membrane (CAM) and Matrigel plug assays. PP242 exhibited a synergistic effect with lenalidomide and bortezomib, suggesting that mTOR inhibition can enhance the anti-angiogenic effect of these drugs. Data to be shown indicate that mTORC2 is involved in MM angiogenesis, and suggest that the dual mTOR inhibitor PP242 may be useful for the anti-angiogenic management of MM patients.
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http://dx.doi.org/10.18632/oncotarget.25003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945497PMC
April 2018

Maintenance in myeloma patients achieving complete response after upfront therapy: a pooled analysis.

J Cancer Res Clin Oncol 2018 Jul 19;144(7):1357-1366. Epub 2018 Apr 19.

Myeloma Unit, Division of Hematology, University of Torino, Azienda-Ospedaliero Universitaria Città della Salute e della Scienza di Torino, via Genova 3, 10126, Torino, Italy.

Purpose: Maintenance demonstrated to improve survival in newly diagnosed multiple myeloma (NDMM) patients and the achievement of complete response (CR) is a strong predictor of survival. Nevertheless, the role of maintenance according to response after induction/consolidation has not been investigated so far. To evaluate the impact of maintenance according to response, we pooled together and retrospectively analyzed data from 955 NDMM patients enrolled in two trials (GIMEMA-MM-03-05 and RV-MM-PI-209).

Methods: Primary endpoints were progression-free survival (PFS)1, PFS2 and overall survival (OS) of CR patients randomized to maintenance and no maintenance. Secondary endpoints were PFS1, PFS2 and OS in very good partial response/partial response (VGPR/PR) patients.

Results: Overall, 213 patients obtained CR after induction/consolidation, 118 received maintenance and 95 no maintenance. In patients achieving CR, maintenance significantly improved PFS1 (HR 0.50, P < 0.001), PFS2 (HR 0.58, P 0.02) and OS (HR 0.51, P 0.02) compared with no maintenance; the advantage was maintained across all the analyzed subgroups according to age, International Staging System (ISS) stage, cytogenetic profile and treatment. Similar features were seen in VGPR/PR patients.

Conclusion: Maintenance prolonged survival in CR and in VGPR/PR patients. The benefit in CR patients suggests the importance of continuing treatment in patients with chemo-sensitive disease.

Trial Registration: The two source studies are registered at ClinicalTrials.gov: identification numbers NCT01063179 and NCT00551928.
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http://dx.doi.org/10.1007/s00432-018-2641-5DOI Listing
July 2018

Different Adaptive Responses to Hypoxia in Normal and Multiple Myeloma Endothelial Cells.

Cell Physiol Biochem 2018 21;46(1):203-212. Epub 2018 Mar 21.

Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

Background/aims: Hypoxia is a powerful stimulator of angiogenesis under physiological as well as pathological conditions. Normal endothelial cells (EC), such as human umbilical vein EC (HUVEC), are relatively affected by hypoxic insult in terms of cell survival. In contrast, EC from tumors are particularly resistant to hypoxia-induced cell death. Previous reports have shown that EC in bone marrow from multiple myeloma (MM) patients had a hypoxic phenotype, even under normoxic conditions. The aim of this study was to evaluate whether HUVEC and MMEC adapt differently to hypoxia.

Methods: Cell proliferation was assessed by the CyQUANT assay. Cdc25A, p21, Bax, Bcl-xl, BNIP3, glucose transporter (GLUT)-1, monocarboxylate transporter (MCT)-4 and carbonic anhydrase (CA)IX mRNA expression was determined by qRT-PCR. HIF-1α, BNIP3, Beclin-1, LC3B, livin, Bax, Bcl-xl, p21, p62 and β-actin protein expression was analyzed by western blot. Apoptosis was determined by TUNEL assay. Silencing of BNIP3 was achieved by stealth RNA system technology.

Results: While HUVEC survival was reduced after prolonged hypoxic exposure, MMEC were completely unaffected. This difference was also significant in terms of livin, cdc25A and p21 expression. Hypoxia induced apoptosis and inhibited autophagy in HUVEC, but not in MMEC, where hypoxic treatment resulted in a more sustained adaptive response. In fact, MMEC showed a more significant increase in the expression of genes regulated transcriptionally by hypoxia-inducible factor (HIF)-1α. Interestingly, they showed higher expression of BNIP3 than did HUVEC, indicating a more pronounced autophagic (and pro-survival) phenotype. The potential role of BNIP3 in EC survival was confirmed by BNIP3 siRNA experiments in HUVEC, where BNIP3 inhibition resulted in reduced cell survival and increased apoptosis.

Conclusion: These findings provide further information on how hypoxia may affect EC survival and could be important for a better understanding of EC physiology under normal and pathological conditions, such as in multiple myeloma.
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http://dx.doi.org/10.1159/000488423DOI Listing
June 2018

Heavy-Chain Diseases and Myeloma-Associated Fanconi Syndrome: an Update.

Mediterr J Hematol Infect Dis 2018 1;10(1):e2018011. Epub 2018 Jan 1.

Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine, University of Bari "Aldo Moro" Medical School, Bari, Italy.

The heavy chain diseases (HCDs) are rare B-cell malignancies characterized by the production of a monoclonal immunoglobulin heavy chain without an associated light chain. There are three types of HCD, defined by the class of immunoglobulin heavy chain produced: IgA (α-HCD), IgG (γ-HCD), and IgM (μ-HCD). Alpha-HCD is the most common and usually occurs as intestinal malabsorption in a young adult from a country of the Mediterranean area. Gamma- and μ-HCDs are rarer and associated with a B-cell non-Hodgkin lymphoma that produces an abnormal Ig heavy chain. These patients may occasionally be diagnosed with a monoclonal gammopathy of undetermined significance (MGUS). Fanconi syndrome, on the other hand, can be primary (inherited) or secondary (acquired). The only exception to this rule is the idiopathic form. Adult acquired Fanconi syndrome can be a rare complication of a monoclonal gammopathy. At diagnosis, most patients have an MGUS or smoldering multiple myeloma, with renal failure and evidence of osteomalacia. During follow-up, patients can develop an end-stage renal disease. Chemotherapy provides little benefit on renal function.
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http://dx.doi.org/10.4084/MJHID.2018.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760076PMC
January 2018