PURPOSE:Digital Breast Tomosynthesis (DBT) is an advanced mammography technique for which there are currently no internationally agreed methods and reference values for image quality assessment. The aim of this multicentre study was to evaluate a simple method to assess the technical image quality of reconstructed and synthetic 2D (SM) images of different models of DBT systems using commercially available phantoms. METHODS:The signal difference to noise ratio (SDNR) was chosen as an index of technical image quality and was evaluated for three commercial phantoms, Tomophan, Tormam and CIRS model 015, on 55 DBT systems (six vendors, nine models). RESULTS:SDNR was found to depend on several factors: detail size, average glandular dose (AGD), reconstruction algorithm, software version and applied post-processing. In particular, an increase in SDNR was observed with increasing detail size, AGD, as well as with the use of contrast-enhanced post-processing and iterative reconstruction algorithms. Most systems showed higher SDNR values in SM images respect to DBT for the largest details and a decrease for smaller details. CONCLUSIONS:This study proposes a straightforward method to assess the technical image quality of reconstructed DBT and SM images using three different commercial phantoms. The algorithms used to generate SM and DBT images might perform differently when applied to phantoms with homogeneous backgrounds compared to clinical breast structures. However this method could be used to establish reference values for technical image quality during quality control (QC) which could be used to monitor the consistency of the system's performance over time.

Background: Cardiac toxicity resulting from radiation therapy (RT) for left-sided breast cancer (LBC) is recognized as dose-dependent. This prospective analysis aimed to assess the efficacy of RT utilizing the moderate deep inspiration breath-hold (mDIBH) technique assisted by the Active Breathing Coordinator (ABC) in reducing the mean heart dose (MHD) and mean/maximum doses to the left descending coronary artery (LAD). We examined the feasibility of this technique across different doses and treatment volumes.

PURPOSE:The aim of the present study, conducted by a working group of the Italian Association of Medical Physics (AIFM), was to define typical z-resolution values for different digital breast tomosynthesis (DBT) models to be used as a reference for quality control (QC). Currently, there are no typical values published in internationally agreed QC protocols.METHODS:To characterize the z-resolution of the DBT models, the full width at half maximum (FWHM) of the artifact spread function (ASF), a technical parameter that quantifies the signal intensity of a detail along reconstructed planes, was analyzed. Five different commercial phantoms, CIRS Model 011, CIRS Model 015, Modular DBT phantom, Pixmam 3-D, and Tomophan, were evaluated on reconstructed DBT images and 82 DBT systems (6 vendors, 9 models) in use at 39 centers in Italy were involved.RESULTS:The ASF was found to be dependent on the detail size, the DBT angular acquisition range, the reconstruction algorithm and applied image processing. In particular, a progressively greater signal spread was observed as the detail size increased and the acquisition angle decreased. However, a clear correlation between signal spread and angular range width was not observed due to the different signal reconstruction and image processing strategies implemented in the algorithms developed by the vendors studied.CONCLUSIONS:The analysis led to the identification of typical z-resolution values for different DBT model-phantom configurations that could be used as a reference during a QC program.

Background: Persistence of minimal residual disease (MRD) is associated with a high rate of treatment failure, relapse, and death in B-cell acute lymphoblastic leukemia (B-ALL). Particularly, patients who remain MRD positive before an allogeneic hematopoietic stem cell transplant (HSCT) have an expected disease-related death rate due to the disease of about 60%. The T cell-engager CD19-directed therapy blinatumomab demonstrated considerable efficacy in this setting, however resistant or unsuitable patients have no alternative therapy. Inotuzumab Ozogamicin (IO) is a CD22-directed antibody-drug conjugate with remarkable efficacy in B-ALL with overt disease. Furthermore, IO does not need a high effective immune system to exert activity. Methods: In this multicenter phase 2 trial (NCT03610438), we are investigating the efficacy of IO in obtaining MRD negativity in two cohorts of 38 Ph+ and 38 Ph- B-ALL patients. IO was administered at the dose of 0.5 mg/sqm on days 1, 8, and 15 of a 28-days cycle. Patients who did not obtain MRD negativity after the 1st IO cycle had the option to receive the 2nd IO cycle maintaining the same dosage. Responding Ph- patients received short-term maintenance with low-dose chemotherapy (alternating vincristine, cyclophosphamide, prednisone, methotrexate, and 6-mercaptopurine), responding PH+ patients received tyrosine kinase inhibitor (TKI) for up to 12 weeks, allowing proper IO washout before HSCT. HSCT ineligible patients entered into low-dose chemotherapy or TKI maintenance for up to 2 years. For the primary endpoint, MRD was centrally assessed at baseline, after course 1, after course 2, and eventually before transplant with high sensitive molecular methods for BCR-ABL1 or V(d)J fusion transcripts. Here, we present the results of an unplanned interim analysis that was generated to evaluate the continuation of the study considering the slow accrual due to the Sars-COV2 pandemic. Results: To date, 51 patients underwent screening procedures, and 43 were considered eligible. We report data from the first 39 patients treated in the study. Nineteen out of 39 patients had Ph- B-ALL and 20/39 Ph+ B-ALL. Eighteen out of 39 (46%) patients were male. The median age was 55 years (22-84), 15/39 patients (38%) were older than 65 years. Demographics were comparable between Ph+ and Ph- patients. Within Ph+, ALL 39% of patients harbored p190 and 61% p210 fusion transcript. Within Ph- B-ALL, 1 patient harbored ALL1/AF4 and 1 patient harbored ALL1/ENL fusion transcript. Most of the patients received 1 (16/39, 42%) or 2 (19/39, 50%) previous lines of therapy; 5 patients (13%) were resistant to blinatumomab, and all of them had Ph- B-ALL. Twelve out of 19 (63%) Ph- B-ALL patients received only 1 IO cycle, 7/19 (37%) received 2 cycles; 5/20(25%) Ph+ B-ALL received only 1 IO cycle, and 15/20 (75%) received 2 cycles. To date, central MRD monitoring is available for 20 patients (12 Ph- and 8 Ph+ B-ALL, ongoing for the remaining cases). Overall, MRD negativity was obtained in 7/20 patients (35%); Particularly, in Ph- B-ALL cohort 5/12 (42%) patients achieved MRD negativity, 4/12 (38%) achieved disease reduction at low level MRD positivity (<10-4); in Ph+ B-ALL cohort, 2/8 (25%) patients achieved MRD negativity. One out of 5 (20%) blinatumomab pre-treated patients obtained MRD negative response. IO was an effective bridge to HSCT for 10/39 patients (26%; in patients <65 years old, 9/24 patients, 37%); Specifically, all 7 patients who obtained MRD negativity after IO, a patient with low-positive MRD and 2 patients with non yet available MRD data were bridged to HSCT. Accordingly, with the caveat of a short median follow-up (2.8 months, range 0.6-20.0 months), overall survival in the study population seems promising (figure 1, median OS not reached). Overall, adverse events collected during the study were limited in number and grading. Also, myelotoxicity was manageable. Out of 39 patients, we documented 1 veno-occlusive disease (2.5%) that occurred within 20 days from the last IO dose and before any HSCT. Conclusions: IO administration demonstrated activity with a good safety profile in the setting of MRD positive B-ALL, including blinatumomab resistant patients. Importantly, IO was capable to bridge 37% of eligible patients to HSCT, augmenting the chance to achieve a cure. The continuation of the study will deliver mature efficacy and survival data for a proper evaluation of this promising strategy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Objective Autoantibodies against antigens carrying distinct post-translational modifications (PTMs), such as citrulline, homocitrulline or acetyllysine, are hallmarks of rheumatoid arthritis (RA). The relation between these anti-modified protein antibody (AMPA)-classes is poorly understood as is the ability of different PTM-antigens to activate B-cell receptors (BCRs) directed against citrullinated proteins (CP). Insights into the nature of PTMs able to activate such B cells are pivotal to understand the ‘evolution’ of the autoimmune response conceivable underlying the disease. Here, we investigated the cross-reactivity of monoclonal AMPA and the ability of different types of PTM-antigens to activate CP-reactive BCRs. Methods BCR sequences from B cells isolated using citrullinated or acetylated antigens were used to produce monoclonal antibodies (mAb) followed by a detailed analysis of their cross-reactivity towards PTM-antigens. Ramos B-cell transfectants expressing CP-reactive IgG BCRs were generated and their activation on stimulation with PTM-antigens investigated. Results Most mAbs were highly cross-reactive towards multiple PTMs, while no reactivity was observed to the unmodified controls. B cells carrying CP-reactive BCRs showed activation on stimulation with various types of PTM-antigens. Conclusions Our study illustrates that AMPA exhibit a high cross-reactivity towards at least two PTMs indicating that their recognition pattern is not confined to one type of modification. Furthermore, our data show that CP-reactive B cells are not only activated by citrullinated, but also by carbamylated and/or acetylated antigens. These data are vital for the understanding of the breach of B-cell tolerance against PTM-antigens and the possible contribution of these antigens to RA-pathogenesis.

INTRODUCTION. Richter syndrome (RS), the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, is a rare but a life threatening complication. Complex karyotype (CK), defined by the presence of ≥3 chromosomal lesions, is a heterogeneous cytogenetic category associated with a shorter survival in CLL, but its impact on the evolution into a RS has not been investigated. Among CK cases, those with≥5 lesions (highCK) and those with major structural abnormalities [type-2 CK (CK2)] display a more aggressive clinical course. The aim of this study was to assess the impact of CK subtypes on the risk of CLL evolution into a RS. METHODS. We performed a retrospective study in 3 Italian CLL centers. Stimulated cytogenetic with CpG+IL2 was performed in 540 patients within the first year after CLL diagnosis. CK cases with unbalanced translocations, additions, insertions, derivative or marker chromosomes were classified as type-2 CK (CK2). Instead, high-CK cases were those presenting at least 5 chromosome abnormalities. An IGHV gene sequence homology ≥98% was considered as unmutated (U-IGHV), as opposed to mutated (M-IGHV). TP53 disruptions (TP53dis) included deletions and/or mutations. Time to Richter syndrome (TTRS) was calculated from CLL diagnosis to either histologically confirmed diffuse large B-cell lymphoma transformation or last known follow-up visit. Survival curves were compared with the log-rank test and p<0.05 was considered as significant. Hazard ratio (HR) was calculated by multivariate analysis. RESULTS. Among the 540 patients, the median age at diagnosis was 63±12 years, 61% were males, 76% were at Binet stage A, 52% were U-IGHV, 11% had TP53dis, 20% harbored a CK. According to the qualitative classification of CK subtypes, 78/107 (73%) were CK2, whereas, with regards to the number of chromosome lesions, 52/107 (49%) were classified as high-CK. High-CK was present in 63% of CK2 patients. Seventeen % of patients died and 5% developed a RS over a median follow-up of 7 years. Overall, the rate of RS after 5 and 10 years from the diagnosis of CLL was 2.6% and 12%. We observed that patients who developed a RS were more commonly at a more advanced Binet stage at CLL diagnosis (46% vs 23%, p=0.0113) and displayed more frequently an U-IGHV status (79% vs 56%, p=0.0191), TP53 abnormalities (32% vs 10%, p=0.0043), CK2 (46% vs 13%, p<0.0001) and a high-CK (39% vs 8%, p<0.0001) profile, as compared to patients who did not developed RS. By univariate and multivariate analysis, the presence of a CK (overall), of a CK2 and of a high-CK subtypes were all significantly associated with a shorter TTRS, together with U-IGHV status, TP53dis, 11q- by FISH and Binet stage B-C. Patients with a CK2 (HR=5.6 p<0.0001) and/or a high-CK (HR=6.9 p<0.0001) harbored the highest risk of developing a RS, with a 10-year TTRS of 38% and 41%, respectively, vs 8% of patients without a CK. Other variables associated with TTRS at univariate and multivariate analysis were Binet stage B-C, U-IGHV, 11q-, TP53 dis. By integrating the statistically significant variables, we developed a hierarchical model based on HR values (Figure 1): 15% of patients were classified as high-CK and/or CK2, for whom the 10-year TTRS was 31% and the HR 13; 45% were U-IGHV/TP53dis/11q-/Binet B-C and showed a 10-year TTRS of 12% and the HR 3; 40% were M-IGHV without CK and TP53 wild-type, the 10-year TTRS was only 3%. This model was confirmed in multivariate analysis and internally validated (p<0.0001). Moreover, our RS scoring system prove to better forecast the risk to develop RS that the hierarchical FISH score, the CLL-IPI and the Barcelona-Brno score, based both lower prediction error and Akaike index. CONCLUSIONS. We herein identified variables associated with a higher risk of developing a RS and recapitulated them into a RS scoring system. Remarkably, patients harboring a CK subtype at CLL diagnosis have the highest risk of developing a RS and should be carefully monitored during the clinical follow-up. Figure Disclosures Visentin: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rigolin:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mauro:Octopharma: Consultancy; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foà:Roche: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Semenzato:Takeda: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Cuneo:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trentin:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria.

INTRODUCTION. Complex karyotype (CK), defined by the presence of at least 3 chromosomal abnormalities, is a heterogeneous cytogenetic category associated with adverse prognosis in several hematologic malignancies. Recently, Rigolin et al. provided evidence that CK with major structural abnormalities (CK2) at chronic lymphocytic leukemia (CLL) diagnosis negatively impact on the time to first treatment (TTFT) and overall survival (OS) (Rigolin GM, BJH 2018). However, it is unknown whether the prognostic strength of CK could be implemented when combined with stable markers such as the IGHV mutational status. In the present study, we assessed the prognostic and predictive role of the combination of CK subtypes and IGHV status in a large CLL series. METHODS. Stimulated cytogenetics with CpG+IL2 was performed in 736 CLL patients in 3 referenced Italian hematological centers. According to Rigolin et al, CK2 cases included unbalanced translocations, addition, insertion, derivative and marker chromosomes. All other CK were classified as type 1 (CK1). An IGHV gene sequence homology >98% was considered as unmutated (U-IGHV), as opposed to mutated (M-IGHV). Treatment was initiated according to the iwCLL guidelines. TTFT and OS were calculated from diagnosis to first treatment or death, respectively, or last known follow-up. Survival curves were compared with the log-rank test and p<.05 was considered as significant. Harrell concordance index (c-index) was used to compare our prognostic model with Dohner's and FISH-IGHV models. RESULTS. We focused on 520 out of the 736 patients with cytogenetic and IGHV status assessed within 12 months from diagnosis. The median age at diagnosis was 63 years, 322 (62%) were males, 68% at Binet A stage, 45% U-IGHV, 48 harbored TP53 abnormalities, 99 a CK (28 CK1 and 71 CK2), 232 received at least one line of therapy (31% FCR, 16% BR, 8% ibrutinib, 5% chlorambucil-antiCD20, 40% other treatments) and 80 died over a median follow-up of 5.8 years. 71 (14%) harbored CK2, 214 (41%) CK1 or U-IGHV and 235 (45%) M-IGHV without CK2. The former group were characterized by a higher prevalence TP53 (38% vs 8% vs 3%, p<0.0001) and cytogenetics abnormalities but lower cases with low-risk FISH (i.e. 13q or normal; 38% vs 54% vs 91%, p<0.0001) as compared with others two groups. We observed that subjects with CK2 had a shorter TTFT (median years 1.97, 3.40 and 19.1, p<0.0001) and 5 years OS (67%, 85%, 93%, p<0.0001) compared to cases with CK1/U-IGHV, or M-IGHV without CK. These data were confirmed in multivariate analysis. The worse prognosis of CK2 patients was independent of TP53 status (p values 0.0770 and 0.8122 for TTFT and OS, respectively). The c-indexes for our model were 69% and 68% for TTFT and OS, respectively, and were not inferior to those calculated with Dohner's (64% and 61%) and FISH-IGHV (69% and 63%) models. The combination of these two markers also provides predictive information after first-line therapy (p<0.0001 for both TTFT and OS). In particular, among 107 patients treated with FCR or BR just one of the M-IGHV cases relapsed but none died after a median follow-up of 43 months as compared with the other two subgroups (3-year PFS 92%, 69% and 23%, p<0.0001; 3-year OS: 100%, 94%, 62%, p<0.0001). CONCLUSIONS. In this study, we demonstrated that the combination of CK subtypes and IGHV status provides important prognostic and predictive data in CLL. Moreover, our model was not inferior to other commonly used prognostic scores. While patients with M-IGHV without any subtypes of CK showed an excellent outcome with chemoimmunotherapy, new alternative therapies should be explored for patients with CK2. Visentin: janssen: Consultancy, Honoraria. Rigolin:Gilead: Research Funding. Mauro:abbvie: Other: board member; janssen: Other: board member. Foà:JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; NOVARTIS: Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau. Cuneo:Roche: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Trentin:Gilead: Research Funding; Janssen: Research Funding; Abbvie: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees.

We investigated whether karyotype analysis and mutational screening by next generation sequencing could predict outcome in 101 newly diagnosed chronic lymphocytic leukemia patients with high-risk features, as defined by the presence of unmutated IGHV gene and/or 11q22/17p13 deletion by FISH and/or TP53 mutations. Cytogenetic analysis showed favorable findings (normal karyotype and isolated 13q14 deletion) in 30 patients, unfavorable (complex karyotype and/or 17p13/11q22 deletion) in 34 cases and intermediate (all other abnormalities) in 36 cases. A complex karyotype was present in 21 patients. Mutations were detected in 56 cases and were associated with unmutated IGHV status (p = 0.040) and complex karyotype (p = 0.047). TP53 disruption (i.e. TP53 mutations and/or 17p13 deletion by FISH) correlated with the presence of ≥ 2 mutations (p = 0.001) and a complex karyotype (p = 0.012). By multivariate analysis, an advanced Binet stage (p < 0.001) and an unfavorable karyotype (p = 0.001) predicted a shorter time to first treatment. TP53 disruption (p = 0.019) and the unfavorable karyotype (p = 0.028) predicted a worse overall survival. A shorter time to chemorefractoriness was associated with TP53 disruption (p = 0.001) and unfavorable karyotype (p = 0.025). Patients with both unfavorable karyotype and TP53 disruption presented a dismal outcome (median overall survival and time to chemorefractoriness of 28.7 and 15.0 months, respectively). In conclusion, karyotype analysis refines risk stratification in high-risk CLL patients and could identify a subset of patients with highly unfavorable outcome requiring alternative treatments.

A procedure for the projection of structure-borne sound fields is introduced, following the basic idea behind Near-Field Acoustic Holography. It is shown that the bending wave field of an infinite plate subjected to point force excitation can be reconstructed by means of Fourier transform-based wave field extrapolation. All required information on the wave field is obtained by vibrational response measurement in the near-field of the excitation, using a circular geometry with a limited number of positions. The procedure is verified both numerically and experimentally, to very satisfying results. The experiments indicate that the reconstruction at the source becomes erratic when standoff distances greater than half of the minimum wavelength under consideration are used. Reconstruction of the far-field plate response is found to be less restrictive.