ALBERT

Description: Journal of the American Chemical Society DOI: 10.1021/jacs.5b06160

Description: This paper explores the role of immigrants within farms and is framed within constructivist approaches to the analysis of immigrants in rural areas. The aim of the paper is to analyse migrants’ contributions to building up multifunctional agricultural systems. To achieve this purpose, a sound empirical analysis is carried out, built on the profile of farms employing immigrants, with special reference to three indicators: the style of farming, territorial localisation of farming activity and the qualification held by the immigrant employed in the farm. The results of analysis confirm a diversified range of contribution on behalf of migrants, with strong diversification on the basis of workers’ provenance. The results of the study suggest that an adequate policy action targeted to the immigrants may bring about positive effects in terms of multifunctionality building at both the individual and territorial level.

Description: In the Italian agrifood sector, one observes heterogeneity in the types of quality certification processes. This heterogeneity cannot be explained by standard governance theories like transaction costs economics (TCE). We use the governance value analysis (GVA) perspective that synthesizes TCE and a resources-based view (RBV), to suggest that the observed heterogeneity in organizational forms is a result of heterogeneous differentiating strategies that farms have pursued in the face of competitive pricing pressures. To empirically test GVA, data are obtained using a survey methodology on lamb meat produced by local farms in the Abruzzo region of Italy, challenged by price-costs squeeze. Our empirical test evidences the relevance of the adopted approach, enlightening different organizational arrangements, strictly linked to both the strategic positioning and to the farms’ resources and core competencies.

Description: Background. High rates of response and minimal residual disease (MRD) negativity have been reported with the use of novel treatment options in multiple myeloma (MM) patients (pts) eligible for autologous stem-cell transplantation (ASCT). Despite very promising results, there is still a proportion of pts who do not respond to therapy or relapse early. This represents an unmet medical need. Aim. To identify the main factors predictive of early relapse in the context of novel treatment approaches. Methods. Data from newly diagnosed MM (NDMM) pts ≤65 years enrolled in the FORTE trial were analyzed. The evaluated baseline standard clinical and biological features included: age, Hb, creatinine, tumor circulating plasma cells (PCpb) evaluated by flow cytometry, bone marrow plasma cells (PCbm) evaluated as continuous variables, free light chain (L vs K), M-component subtype (IgA vs others), Revised International Staging System (R-ISS II/III vs I), LDH (〉ULN vs ≤ULN), ISS (III vs II vs I), presence vs absence of chromosomal abnormalities detected by FISH [(del17p, t(4;14), t(14;16), t(11;14), amp1q, del1p, del13], and presence vs absence of plasmacytomas. Pts were randomized to receive carfilzomib, lenalidomide, dexamethasone (KRd) induction - ASCT intensification - KRd consolidation (arm A); KRd12 (arm B); and carfilzomib, cyclophosphamide, dexamethasone (KCd) induction - ASCT intensification - KCd consolidation (arm C). Thereafter, patients were randomized to maintenance with lenalidomide alone or lenalidomide plus carfilzomib. Pre-maintenance MRD evaluation was performed by 8-color second generation flow cytometry (sensitivity 10-5) in patients who achieved at least a very good partial response (VGPR). Early relapse was defined as relapse ≤18 months from randomization. Univariate feature selection was performed between both categorical and continuous baseline variables and the achievement of pre-maintenance MRD negativity, according to Chi-square and Kruskal tests. The same baseline features, plus the achievement of MRD negativity, were included in a univariate analysis to select candidate predictors of early relapse. Selected features were then included in a multivariate logistic model. A multivariate analysis was performed to evaluate predictors of MRD negativity and early relapse. The model was adjusted for age and administered therapy. Results. 474 patients were enrolled in the trial. Baseline features were well balanced in the 3 arms. Predictors of MRD negativity (10-5): In univariate analysis, the baseline factors selected basing on the probability of achieving pre-maintenance MRD negativity were creatinine levels, ISS stage, R-ISS stage, del17p, PCbm (P=0.004) and PCpb. In multivariate analysis, including single variables not aggregated in R-ISS, increased creatinine levels (OR 0.48, 95% CI 0.25-0.94, P=0.03), increased PCbm (OR 0.95, 95% CI 0.91-0.99, P=0.01) and presence of del17p (OR 0.44, 95% CI 0.23-0.83, P=0.01) reduced the probability of achieving MRD negativity (Table). Predictors of early relapse: In univariate analysis, the main baseline factors selected basing on the risk of early relapse were LDH, ISS, R-ISS, PCbm, PCpb, del17p and achievement of MRD negativity. In multivariate analysis, R-ISS II/III vs I (OR 3.7, 95% CI 1.24-11, P

Description: Background and aims: Persistence of molecularly detectable minimal residual disease (MRD) is a nearly constant finding in MM following autologous transplantation (ASCT). On the other hand, molecular remission (MR) can be obtained in MM in the allogeneic setting and is a basic requisite for long-term disease control (Corradini et al, Blood 2003). In this study a consolidation treatment, including Bortezomib/Thalidomide/Dexamethasone (VTD), was employed in the post-ASCT setting in patients (pts) undergoing strict molecular monitoring by qualitative and quantitative PCR to induce further cytoreduction and to verify if a proportion of them could enter MR. Patients and methods: Inclusion criteria were: a documented complete or very good partial remission (CR or VGPR) following ASCT delivered as first line treatment; no previous treatment with thalidomide and bortezomib; presence of a molecular marker based on the IgH rearrangment. Primary endpoint of the study was to obtain MR in 〉 20% of pts. Methods: VTD had to be started within 6 months from ASCT. Each cycle consisted of: Bortezomib 1.6 mg/m2 as an IV injection once weekly (on days 1, 8, 15, 22) followed by a 13-day rest period (days 23–35); Thalidomide at the initial dose of 50 mg/day PO once daily, with increments of 50 mg every 7 days up to 200 mg; Dexamethasone 20 mg/day PO once daily, on days 1 to 4, 8 to 11 and 15 to 18 followed by a 17-day rest period (days 19–35). A total of 4 cycles were delivered. MRD was assessed on bone marrow (BM) samples at study entry, after two VTD courses, at the end of treatment and then at six months intervals. Qualitative and quantitative PCR analysis were carried out using IgH-derived patient-specific primers as already described (Voena et al, Leukemia 1997; Ladetto et al, Biol Bone Marrow Transpl 2000). Results: Forty pts were enrolled and are evaluable at study entry. As expected 94% of pts were PCR-positive following ASCT. 18% did not receive the whole planned treatment, including one toxic death. The six pts requiring treatment reduction/discontinuation were nevertheless included in the MRD analysis. 35 PCR-positive pts at study entry are evaluable after 2 VTD courses and 17% converted to PCR negativity. 27 pts are evaluable at the end of the program with a PCR-negativity rate of 22%. Subsequent follow-up samples are available in 22 pts. All PCR-negative pts assessed at 6 months (four cases) and at 6 and 12 months (two cases) persisted in MR. Seven relapses/progressions occurred and were all among PCR-positive pts. Real-time PCR has been so far performed in ten persistently PCR-positive pts with a 〉0.5 log tumor reduction in eight of them (median 1.2 log; range 0.2–2.1). Conclusions: VTD consolidation allows a proportion of CR/VGPR MM pts to enter MR and has a measurable anti-tumor effect also in persistently PCR-positive pts. This study is the first demonstration that new non chemotherapeutic agents have activity on MRD persisting following ASCT and indicate that MR is an achievable goal also outside the allogeneic transplantation setting.

Description: Background. Array-based technology has been showing a great impact on clinical cancer cytogenetic, especially on genetically heterogeneous disease, such as MM, where relevant lesions might be the hallmarks of different patients’ subgroups, thus becoming of clinical relevance as well. We present herein the results of a molecular sub-study of the EMN02 phase III study (EMN02_HOVON95) which was designed to compare consolidation therapy Bortezomib, Melphalan and Prednisone versus upfront autologous stem cell transplantation, both applied after induction therapy with bortezomib-cyclophosphamide-dexamethasone (VCD). The sub-study was aimed at developing a comprehensive, high throughput genomic profile to be used to stratify uniformly treated MM patients according to their genomic background at baseline and to perform correlations with response to induction therapy. Patients and methods. Data obtained from 170 patients who consecutively entered the study and received three 21-day cycles of VCD induction therapy were analyzed. Baseline patients’ characteristics, including cytogenetic abnormalities, were comparable with those of 717 patients enrolled by participating Italian centres. Highly purified CD138+ bone marrow plasma cells were profiled by SNPs array (Affymetrix 6.0 and CytoScanHD® chip). ChAS (Affymetrix) and Nexus Copy NumberTM 7.5 (Biodiscovery) software were used to perform Copy Number Alterations (CNAs) analyses and clinical correlations, respectively. Results. After induction therapy, 66 out of 170 (38.8%) patients achieved a very good partial response (VGPR) or better, including 15 (8,8%) who attained a complete response (CR). On the contrary, 104/170 (61.1%) patients achieved

Description: Multiple myeloma (MM) is a plasma cell (PC) malignancy characterized by a unique ability to evade immunosurveillance through the induction of antigen-presenting cell dysfunction, the release of immunoregulatory cytokines and the expansion of regulatory T cells (Treg). Hepatocyte growth factor (HGF), a mesenchyme-derived cytokine, is greatly elevated in MM and confers an unfavorable prognosis. We have previously shown that HGF induces the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) in human monocyte-derived dendritic cells. This study aimed to determine whether HGF may also promote IDO expression and/or function in MM plasma cells. We first measured IDO-1 expression by a panel of human MM cell lines using real-time PCR, before and after their in vitro treatment with 10 ng/ml IFN-γ. Exposure to IFN-γ translated into a 5-fold induction of IDO-1 mRNA in LP-1 and OPM-2 cells, in parallel with an increased ability to release kynurenines in culture supernatants. Conversely, mRNA signals for IDO-1 were undetectable in MOLP-8 and HUNS-1 cells. Next, the IDO-expressing MM cell lines were evaluated for their ability to release HGF. Whereas OPM-2 cells were incapable of producing HGF, LP-1 cells secreted copious amounts of HGF (8,393 pg/ml on average after 96 hours of culture), and promoted the in vitro conversion of naïve allogeneic CD4+CD25− T cells into bona fide CD4+CD25+FoxP3+ Treg cells, and this was reverted by the IDO inhibitor 1-methyl-tryptophan. In order to provide convincing evidence in favor of HGF effects on IDO expression, we challenged IDO-negative HUNS-1 cells with 100 ng/ml HGF. Under these conditions, an average 6-fold induction of IDO mRNA could be detected starting from 24 hours of culture. Accordingly, the addition of blocking antibodies against HGF to IDO-positive LP-1 cells was associated with an average 6-fold reduction of IDO mRNA. Interestingly, the co-culture of IDO-negative HUNS-1 cells with normal bone marrow (BM)-derived stromal cells promoted the induction of IDO mRNA, suggesting that microenvironmental interactions might also be implicated in IDO expression by the malignant PC. In a final set of ex vivo experiments, we purified CD56+CD138+ malignant PC from 9 patients with either newly diagnosed MM or with MM in partial remission. IDO-1 mRNA could be readily detected in 6 out of 9 cases (median IDO-1 mRNA content equal to 5 [range 2.1–14.1] relative to the HUNS-1 MM cells set arbitrarily at 1). IDO-1 mRNA levels in the malignant PC positively correlated with the frequency of circulating CD4+CD25+FoxP3+ Treg cells (p = 0.04). Furthermore, serum HGF was increased in patients’ peripheral blood (median 1,407 pg/ml, range 370–4940) and BM fluid (median 2,735 pg/ml, range 870–8,620) compared with healthy controls (median 1,000 pg/ml, range 710–1,300 and 1,875 pg/ml, range 1,310–2,430 in peripheral blood and BM, respectively). HGF levels positively correlated with the amount of M-component (p = 0.002), a measure of disease burden, and with the percentage of circulating Treg cells (p = 0.02). Serum kynurenines were increased in 6 patients with MM (median level equal to 3.8 μM, range 2.9–4.43, compared with 2.5 μM in healthy controls; p = 0.03). In line with this, serum tryptophan was significantly decreased in patients with MM (median value equal to 42.34 μM) compared with healthy controls (median value equal to 83.9 μM; p = 0.0012). Collectively, these data suggest that IDO-1 may be expressed by MM PC and that the IDO-mediated generation of immunosuppressive tryptophan metabolites may play a role in the in vivo expansion of the Treg compartment. Whether this will impact on the ability of the immune system to control disease progression remains to be prospectively investigated in larger cohorts of patients.

Description: Background The role of up-front consolidation for newly diagnosed, transplant eligible MM (NDMM) patients (pts) has not yet been prospectively addressed in the novel agents era. Methods The EMN02/HO95 trial was designed to randomly (R) compare (R1) 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), either single or double, as intensification therapy after induction with bortezomib-cyclophosphamide-dexamethasone (VCD) (M Cavo et al, ASCO 2016, abstract #8000). A second randomization to consolidation therapy with 2 cycles of VRD vs no consolidation (R2) was performed after intensification, to be followed by lenalidomide maintenance (lenalidomide 10 mg continuously) until progression or toxicity in both arms. (VRD: bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, 11; lenalidomide 25 mg orally days 1 - 21; dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11, 12 of a 28 days cycle). Primary study end points were progression-free survival (PFS) from R1 and PFS from R2. A first planned interim analysis for R2 was performed in July 2016 when at least 33% (= 172) of the required events for PFS had been observed. Results From February 2011 to April 2014, 1510 pts aged ≤ 65 years with symptomatic MM were enrolled, of whom 1499 were eligible. Of these, 1211 were randomized (stratification by ISS stage) to VMP (505 pts) or HDM (1 or 2 ASCT) (706 pts). For R2 903 eligible patients were randomized to consolidation (459 pts) or no consolidation (444 pts). Median follow up from R2 was 25 months (maximum 53). Response status at time of R2 was ≥ CR (23%), ≥ VGPR (67%), ≥ PR (93%), and will be updated for status at start of maintenance. At the time of analysis, 258 events for PFS after R2 had been reported. 3-year. PFS from R2 was 62% in all patients, i.e., 60% without consolidation and 65% in patients with consolidation, and median PFS had not yet been reached. PFS from R2 with adjustment for R1 was prolonged in pts randomized to VRD (HR=0.78; 95% CI=0.61-1.00; P=0.045), a benefit retained across predefined subgroups with revised ISS stage III (HR=0.67; P=0.26) and in patients randomized in R1 to VMP (HR=0.76; P=0.19) and to HDM (HR=0.79; P=0.13). The benefit of consolidation was observed in patients with low-risk cytogenetics (HR=0.68; P=0.03), but not in patients with high-risk cytogenetics (del(17p) and/or t(4;14) and/or t(14;16); HR=1.03; P=0.91). At 3 years OS from R2 was 86% and 87%, respectively. Toxicity from VRD was limited with 5% CTCAE grade 4, mainly hematological. Conclusions Consolidation treatment with VRD followed by Lenalidomide maintenance until progression or toxicity shows promising results as compared to maintenance alone for younger NDMM pts, but further study follow-up is needed. This trial was registered at www.trialregister.nl as NTR 2528, EudraCT 2009-017903-28 This trial was supported by unrestricted grants from Celgene and Janssen. Disclosures Sonneveld: Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Driessen:janssen: Consultancy; celgene: Consultancy; Mundipharma-EDO: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay:Celgene: Honoraria; Mundipharma: Other: Advisory Board; Amgen: Honoraria; BMS: Honoraria; Janssen-Cilag: Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Mellqvist:Mundipharma: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schjesvold:Janssen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Palumbo:Takeda: Employment, Honoraria; Janssen Cilag: Honoraria. Cavo:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria.

Description: In a recent phase 3 trial, bortezomib-melphalan-prednisone-thalidomide followed by maintenance treatment with bortezomib-thalidomide demonstrated superior efficacy compared with bortezomib-melphalan-prednisone. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions: 372 patients received once-weekly and 139 twice-weekly bortezomib. In this post-hoc analysis we assessed the impact of the schedule change on clinical outcomes and safety. Long-term outcomes appeared similar: 3-year progression-free survival rate was 50% in the once-weekly and 47% in the twice-weekly group (P 〉 .999), and 3-year overall survival rate was 88% and 89%, respectively (P = .54). The complete response rate was 30% in the once-weekly and 35% in the twice-weekly group (P = .27). Nonhematologic grade 3/4 adverse events were reported in 35% of once-weekly patients and 51% of twice-weekly patients (P = .003). The incidence of grade 3/4 peripheral neuropathy was 8% in the once-weekly and 28% in the twice-weekly group (P 〈 .001); 5% of patients in the once-weekly and 15% in the twice-weekly group discontinued therapy because of peripheral neuropathy (P 〈 .001). This improvement in safety did not appear to affect efficacy. This study is registered at http://www.clinicaltrials.gov as NCT01063179.