Search

The upfront treatment of very elderly and frail patients with diffuse large B-cell lymphoma (DLBCL) is still a matter of debate. Herein, we report results of the metronomic all-oral DEVEC [prednisolone/deltacortene®, vinorelbine (VNR), etoposide (ETO), cyclophosphamide] combined with i.v. rituximab (R). This schedule was administered as a first line therapy in 22 elderly/frail DLBCL subjects (median age = 84.5 years). In 17/22 (77%) patients, the Elderly-IPI-score was high. After a median follow-up of 24 months, 15 patients had died: seven (50%) for causes unrelated to DLBCL or its treatment, six (40%) for progression, and two (13%) for multiorgan failure. Six treatment-pertinent serious-adverse-events occurred. At the end of induction, 14/22 (64%) achieved complete remission; overall survival and event-free survival at 24 months were both 54% (95% CI = 32–72%), while the time to progression was 74% (95% CI = 48–88%). Furthermore, antiproliferative and proapoptotic assays were performed on DLBCL/OCI-LY3 cell-line using metronomic VNR and ETO and their combination. Both metronomic VNR and ETO had concentration-dependent antiproliferative (IC50 = 0.036 ± 0.01 nM and 7.9 ± 3.6 nM, respectively), and proapoptotic activities in DLBCL cells. Co-administration of the two drugs showed a strong synergism (combination index < 1 and dose reduction index > 1) against cell proliferation and survival. This low-dose schedule seems to compare favourably with intravenous-CHEMO protocols used in the same subset. Indeed, the high synergism shown by metronomic VRN+ETO in in vitro studies, explains the remarkable clinical responses and it allows significant dose reductions.

Background: In order to evaluate the efficacy of residual site radiation therapy (RSRT) in terms of progression-free survival (PFS) and overall survival (OS) in patients with primary mediastinal lymphoma (PMBCL) with Deauville Score 4 (DS 4) following rituximab and chemotherapy treatment (R-ICHT). Methods: Thirty-one patients with PMBCL were recruited. After completion of R-ICHT, patients were staged with 18F-fluorodeoxyglucose positron-emission tomography, showing DS 4, and were treated with adjuvant RSRT. The chosen techniques for RT delivery were intensity-modulated radiation therapy (IMRT) or three-dimensional conformal RT (3D-CRT). Most patients underwent the first one using cone-beam computed tomography (CBCT). All patients were evaluated every 3 months for the first 2 years and every 6 months afterwards for a period of at least 5 years, with clinical and radiological procedures as required. Results: All patients received RSRT with a dose of 30 Gy in 15 fractions. The median follow-up time of 52.7 months (IQR: 26–64.1 months). The 5-year OS rate was 100%. The 2-year and 5-year PFS rates were 96.7% and 92.5%, respectively. Patients with relapsed disease had been treated with high-dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT). Conclusion: RSRT in patients with PMBCL treated with ICHT and DS 4 did not impact unfavorably on patient survival.

Objectives: Interstitial pneumonia is a severe complication induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Several treatments have been proposed alone or, more often, in combination, depending, also, on the presence of other organ disfunction. The most frequently related, well-described, and associated phenomenon is pan-lymphopenia with circulating, high levels of cytokines. We report, here, on two patients with COVID-19 and lymphoproliferative disorders treated with Tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor) and followed by an [18F]FDG PET/CT to early evaluate the therapy’s efficacy. Methods: One patient with angioimmunoblastic T-lymphoma (A), one with Hodgkin lymphoma (A), and both with positive RT-PCR for SARS-CoV-2 and with similar clinical findings of interstitial pneumonia at the CT scan, were imaged by [18F]FDG PET/CT before and 14 days after a single dose of Tocilizumab. Results: In both patients, the basal [18F]FDG PET/CT showed a diffused lung parenchyma uptake, corresponding to the hyperdense areas at the CT scan. After 2 weeks of a Tocilizumab infusion, patient B had an improvement of symptoms, with normalization of the [18F]FDG uptake. By contrast, patient A, who was still symptomatic, showed a persisting and abnormal distribution of [18F]FDG. Interestingly, both patients showed a low bone marrow uptake of [18F]FDG at the diagnosis and after 15 days, while the spleen uptake was low only in lymphopenic patient A; both are indirect signs of an immune deficiency. Conclusions: In conclusion, in these two patients, interstitial pneumonia was efficiently treated with Tocilizumab, as demonstrated by the [18F]FDG PET/CT. Our results confirm that interleukin-6 (IL6) has a role in the COVID-19 disease and that anti-cytokine treatment can also be performed in patients with lymphoproliferative disorders.

Background There is now great interest in using digital health tools to monitor patients' health status in real-world practice. Such tools often include electronic-patient-reported outcome (ePRO) systems in which symptoms questions are included into online interfaces for patient self-reporting, with real-time alerts triggered to the treating physician if severe symptoms or problems are reported. However, there is little information about the clinical utility and user perceptions of these systems, and this is particularly true in the area of hematology. Objectives This study investigates physicians' perceptions of usability and clinical utility of using remote ePROs in routine practice of patients with hematologic malignancies and explored implications in the delivery of patient care. Patients and Methods Remote ePROs are being gathered since December 2020 by the ALLIANCE Digital Health Platform, whose details of the development process have been previously described (Efficace F. et al., JMIR Res Protoc. 2021 Jun 1;10:e25271). Adult patients diagnosed with any hematologic malignancy are eligible to enter the platform, after having provided written informed consent. Aspects related to health-related quality of life (HRQoL), symptoms and medication adherence are assessed via validated PRO measures. The platform allows for real-time graphical presentation to physicians of individual patient symptoms and HRQoL outcomes. Based on a pre-defined algorithm, which includes the presence of clinically important problems and symptoms, the platform triggers automated alerts to the treating haematologists and medical staff. The definition of clinically important problems and symptoms is based on previously defined evidence-based thresholds (Giesinger J. et al., J Clin Epidemiol. 2020 Feb;118:1-8). We asked treating haematologists a feedback about their experience in using the platform, by an ad hoc web-survey consisting of 27 items covering several domains, including: usability and benefits, current use, evaluation of patient health-status, symptoms and adverse events, as well as physician-patient communication. We summarized characteristics of enrolled patients and treating haematologists by proportions, mean, median and range. We also used logistic regression analysis to check the possible association of characteristics of haematologists with survey results. Results Of the 201 patients invited to participate between December 2020 and June 2021 (cut-off date for current analysis), 180 (90%) accepted to enter the ALLIANCE platform, currently activated in 19 centers. The median age of patients was 57 years (range 21-91) and 58% were males. The majority were diagnosed with chronic myeloid leukemia (n=32, 18%) and multiple myeloma (n=31, 17%) and were in stable disease (n=89, 49%). Twenty-three hematologists (44% males) with a median age of 42 years (range 31-63) and an average 17 years (range 5-34) of experience in clinical practice, completed the survey. The majority of physicians (78%) accessed the platform at least once per month (of whom 39% at least once per week), regardless the alerts sent by the system about patients' clinically relevant problems. The frequency of access on a regular basis was also independent of physician sex (p=0.393) and years of experience in clinical practice (p=0.404). Overall, 57% of hematologists discussed often or very often ePROs with their patients, while 83% and 61% deemed this information helpful to better identify symptomatic adverse events (AEs) of grade 1-2 or of grade 3-4, respectively (see figure). Also, 87% and 91% of hematologists found ePROs useful to improve physician-patient communication and the accuracy of documentation of symptomatic AEs (regardless of severity), respectively. Physicians' responses to selected items of the survey are reported in the figure. Conclusions: Current findings support the clinical utility, from the perspective of the treating physician, of integrating ePROs into routine cancer care of patients with hematologic malignancies. Figure 1 Figure 1. Disclosures Efficace: Takeda: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Other: Grants (to Institution); Amgen: Consultancy, Other: Grants (to Institution). Breccia: Bristol Myers Squibb/Celgene: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Fazio: Janseen: Honoraria. Petrucci: Karyopharm: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Rigacci: Merck: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: 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; Menarini: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tafuri: Roche: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Siragusa: Novartis, CSL, Behring, Amgen, Novonoridsk, SOBI, Bayer: Consultancy, Honoraria, Speakers Bureau. Patriarca: Incyte: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Argenix: Honoraria. Luppi: Abbvie: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; MSD: Honoraria; Gilead Science: Honoraria, Other: Travel grant; Daiichi-Sankyo: Honoraria; Jazz Pharma: Honoraria. Vignetti: Novartis: Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria.

In the online minimum spanning tree problem, a graph is revealed vertex by vertex; together with every vertex, all edges to vertices that are already known are given, and an online algorithm must irrevocably choose a subset of them as a part of its solution. The advice complexity of an online problem is a means to quantify the information that needs to be extracted from the input to achieve good results. For a graph of size [Formula: see text], we show an asymptotically tight bound of [Formula: see text] on the number of advice bits to produce an optimal solution for any given graph. For particular graph classes, e.g., with bounded degree or a restricted edge weight function, we prove that the upper bound can be drastically reduced; e.g., [Formula: see text] advice bits allow to compute an optimal result if the weight function equals the Euclidean distance; if the graph is complete and has two different edge weights, even a logarithmic number suffices. Some of these results make use of the optimality of Kruskal’s algorithm for the offline setting. We also study the trade-off between the number of advice bits and the achievable competitive ratio. To this end, we perform a reduction from another online problem to obtain a linear lower bound on the advice complexity for any near-optimal solution. Using our results finally allows us to give a lower bound on the expected competitive ratio of any randomized online algorithm for the problem, even on graphs with three different edge weights.

We first outline main steps and achievements along Bertoni's research path in quantum finite automata theory from the very basic definitions of the models of quantum finite automata throughout the investigation of their computational and descriptional power. Next, we choose to focus on Bertoni's studies on quantum finite automata descriptional complexity. In particular, we expand on a statistical framework for the synthesis of succinct quantum finite automata, discussing its adaptation to the case of multiperiodic events and languages. We then improve such a framework to obtain even more succinct quantum finite automata for some multiperiodic languages. Finally, we introduce some promise problems for multiperiodic inputs, showing that even on this class of problems the descriptional power of quantum finite automata greatly outperforms that of equivalent classical finite automata. We build small size Monte Carlo quantum finite automata for multiperiodic languages.We analyze the modular architecture of such Monte Carlo quantum finite automata.We solve promise problems on multiperiodic inputs by small quantum finite automata.

The existence of a substantial gap between deterministic and nondeterministic two-way automata is one of the most famous open problems in automata theory. This problem is also related to the fundamental DLOG vs. NLOG question. An exponential gap between the number of states of two-way nondeterministic automata (2NFAS) and their deterministic counterparts (2DFAS) has been proved only for some restrictions of 2DFAS up to now. It seems that the hardness of this problem lies in the fact that, when trying to prove lower bounds, we must consider every possible automaton, without imposing any particular structure or meaning to the states, while when designing a specific automaton, we always assign an unambiguous interpretation to the states. In an attempt to capture the concept of meaning of states, a new model of two-way automata, namely reasonable automaton (RA), was introduced in [6]. In a RA, each state is associated with a logical formula expressing some properties of the input word, and transitions are designed to maintain consistency within this setting. In this paper we extend the study, started in [6], of the descriptional complexity of RAS solving the liveness problem, showing several lower and upper bounds with respect to the logic used for describing the meaning of the individual states. ISSN:0129-0541 ISSN:1793-6373

A large Italian multicenter observational retrospective study was conducted on the use of brentuximab vedotin (BV) for patients with relapsed Hodgkin's lymphoma (HL) to check if clinical trial results are confirmed even in a real life context. 234 CD30+ HL patients were enrolled. Best response was observed after a median of 4 cycles in 140 patients (59.8%): 74 (31.6%) patients obtained a complete response (CR) and 66 (28.2%) achieved a partial response (PR); overall response rate at the end of the treatment was 48.3% (62 CR and 51 PR). The best response rate was higher in the elderly subset: 14 (50%) CR and 5 (17.8%) PR. Disease free survival was 26.3% at 3 years and progression free survival 31.9% at 4.5 years. Duration of response did not differ for who achieved at least PR and then either did or did not undergo consolidative transplant. Overall, the treatment was well tolerated and no death has been linked to BV-induced toxicity. Our report confirms activity in elderly patients, duration of response unrelated to the consolidation with transplant procedure, the relevance of the CR status at first restaging, and the role of BV as a bridge to transplant for chemorefractory patients.

We analyze the descriptional power of Quantum Finite Automata with control language.We show an exponential size cost conversion from QFAs with control language to DFAs.We simulate Latvian QFAs by QFAs with control languages.We obtain size lower bounds for several models of QFAs. We compare the descriptional power of quantum finite automata with control language (qfcs) and deterministic finite automata (dfas). By suitably adapting Rabin's technique, we show how to convert any given qfc to an equivalent dfa, incurring in an at most exponential size increase. This enables us to state a lower bound on the size of qfcs, which is logarithmic in the size of equivalent minimal dfas. In turn, this result yields analogous size lower bounds for several models of quantum finite automata in the literature.

Algorithmica, 70 (1), ISSN:0178-4617, ISSN:1432-0541

We investigate and compare the descriptional power of unary probabilistic and nondeterministic automata (pfa's and nfa's, respectively). We show the existence of a family of languages hard for pfa's in the following sense: For any positive integer d, there exists a unary d-cyclic language such that any pfa accepting it requires d states, as the smallest deterministic automaton. On the other hand, we prove that there exist infinitely many languages having pfa's which from one side do not match a known optimal state lower bound and, on the other side, they are smaller than nfa's which, in turn, are smaller than deterministic automata.

The mammalian target of rapamycin (mTOR) is a central processor of intra- and extracellular signals, regulating many fundamental cellular processes such as metabolism, growth, proliferation, and survival. Strong evidences have indicated that mTOR dysregulation is deeply implicated in leukemogenesis. This has led to growing interest in the development of modulators of its activity for leukemia treatment. This review intends to provide an outline of the principal biological and molecular functions of mTOR. We summarize the current understanding of how mTOR interacts with microRNAs, with components of cell metabolism, and with controllers of apoptotic machinery. Lastly, from a clinical/translational perspective, we recapitulate the therapeutic results in leukemia, obtained by using mTOR inhibitors as single agents and in combination with other compounds.

We study the stochastic events induced by MM-qfa's working on unary alphabets. We give two algorithms for unary MM-qfa's: the first computes the dimension of the ergodic and transient components of the non halting subspace, while the second tests whether the induced event is d-periodic. These algorithms run in polynomial time whenever the MM-qfa given in input has complex amplitudes with rational components. We also characterize the recognition power of unary MM-qfa's, by proving that any unary regular language can be accepted by a MM-qfa with constant cut point and isolation. Yet, the amount of states of the resulting MM-qfa is linear in the size of the corresponding minimal dfa. We also single out families of unary regular languages for which the size of the accepting MM-qfa's can be exponentially decreased.

Examination of the bone marrow biopsy and aspirate allows diagnosis and assessment of various conditions such as primary hematologic and metastatic neoplasms, as well as nonmalignant disorders. Despite being performed for many years, according to many different protocols, the procedure still remains painful for the majority of patients. This paper summarizes the current knowledge of pain reduction measures in the bone marrow biopsy and aspiration.

In an L(2,1)-coloring of a graph, the vertices are colored with colors from an ordered set such that neighboring vertices get colors that have distance at least 2 and vertices at distance 2 in the graph get different colors. We consider the problem of finding an L(2,1)-coloring using a minimum range of colors in an online setting where the vertices arrive in consecutive time steps together with information about their neighbors and vertices at distance two among the previously revealed vertices. For this, we restrict our attention to paths and cycles.

We have demonstrated that selective MEK inhibitors (MEK-I) significantly inhibit in vitro the growth of AML cell lines and primary AML blasts (Ricciardi et al., JMM 2012). However, these effects were mostly related to the inhibition of cell cycle progression, while apoptosis induction requires higher concentrations of the inhibitor and longer times of exposure. Among the many downstream effectors of MAPK pathway, metabolism is one of the key aspects that can be targeted at several levels for therapeutic perspectives (Ricciardi et al., Blood 2015). In this study, we have explored on AML cells the functional effects of combining the MEK1/2 inhibitor, PD0325901 (PD), with a metabolic modulator, dichloroacetate (DCA), which acts as pyruvate dehydrogenase kinase (PDHK) inhibitor. AML cell lines (OCI-AML3, U937, MOLM13, HL60) and AML primary samples were exposed to PD (2.5-1000nM) and DCA (0.5-2mM), alone or in combination. PD dose-dependently inhibited cell growth of OCI-AML3, HL60 and MOLM13, showing a constitutive activation of RAS/RAF/MEK/ERK pathway. This activation was not seen in U937, thus exhibiting resistance to PD. DCA shows a pro-apoptotic activity on AML cells, only at the highest concentration. The combination between PD and DCA synergistically enhanced the antiproliferative effect, with a combination index (CI) ranging between 0.37 and 0.41 in OCI-AML3, as measured by isobologram analysis from MTT data. Conversely, in U937 the combination resulted antagonistic. Co-administration of non- or sub-toxic concentrations of DCA (2mM) and of PD (10nM) resulted in a strong increase of cell death in OCI-AML3 (Annexin V). The PD/DCA combination significantly increased Annexin V+ cells, at 72 hours, (65.7±25.0%), compared to single compounds: 16.4±8.7% with 10nM PD (p=0.03) and 28.0±12.4% with 2mM DCA (p=0.04). Similar results were obtained in HL60 and MOLM13 (data not shown). In the U937 cell line, resistant to PD, the levels of apoptosis observed with DCA alone were not further enhanced by the combination: 6.19±1.7% (1000nM PD), 23.63±6.7% (2mM DCA), 31.28±9.9% (PD/DCA). At a protein level, densitometric analysis of Western blot carried out on OCI-AML3 demonstrated that PD/DCA was able to further increase PD-induced ERK inhibition (from 40% to 54%), while DCA alone, as expected, had no effect. Real time metabolic data, obtained by a Seahorse XF24 on OCI-AML3, showed that the combination of PD and DCA affected mitochondrial metabolism: basal respiration and ATP production were impaired by 37.34±10.4% (p=0.012) and by 56.31±10.0% (p=0.003), respectively, compared to control. On the other hand, both maximal respiration and spare respiratory capacity were increased by 28.80±9.5% (p=0.025) and 68.78±14.2% (p These preliminary results suggest that the combination of a signal transduction and a metabolic inhibitor spares mitochondrial machinery while impairing at the same time its activity, thus resulting in an enhanced antiproliferative and pro-apoptotic effect on AML cells. Disclosures No relevant conflicts of interest to declare.

The neutrophil/lymphocyte ratio (N/L) at diagnosis has been shown to be a prognostic factor for survival in solid tumors. An increase in the neutrophil count is a marker of inflammation which is an essential part of the neoplastic process. Conversely, a decrease of the peripheral lymphocyte count might reflect an impairment of the host defense mechanism associated with advanced and aggressive cancers. Since There are only few reports on the N/L ratio in non-Hodgkin lymphomas. We studied the prognostic role of the N/L ratio at diagnosis in 286 patients with diffuse-large-B-cell lymphoma (DLBCL) enrolled in a multicenter prospective registry of the Lazio region in Italy The median age at diagnosis was 69 years (27-91) and the female/male ratio was:141/145.First, we analyzed for associations between N/L ratio and patient characteristics. The optimal cut-off value for the N/L was obtained using the Receiver Operating Curve (ROC) and according to the published data in solid tumor. N/L ≥ 4 was significantly associated with presence of B-symptoms (p=0.01) and elevated LDH levels (p=0.007) at diagnosis. Most patients were treated with R-CHOP (rituximab, cyclophosphamide, Adriamycin, vincristine, and prednisone) or R-CHOP-like (90%). Complete Remission (CR) + Partial Remission (PR) were obtained in 210/286 (73%). The median follow up period was 15 months (range: 1-33 months): 27 patients died for lymphoma relapse/progression and 16 for other causes. Patients with N/L ≥ 4 experienced a higher rate of relapse, while N/L< 4 was associated to a significantly better Overall (OS, P < 0.05) and Event Free Survival (EFS, P< 0.01). (Figure 1, panel a and b).Furthermore, considering only patients with IPI score ≤ 3, those with N/L Conclusion: The N/L ratio may be a useful and unexpensive prognostic marker in patients with DLBCL. The inferior outcome observed in patients with N/L ≥ 4 might reflect an immune and inflammatory imbalance induced by a more aggressive tumor, releasing directly or indirectly inflammatory cytokines and/or inducing immune suppression or exhaustion. A link with inflammation is suggested by the correlation of N/L ratio ≥ 4 with high LDH levels and the presence of B symptoms. Figure 1. Panel A. Overall Survival (OS) and Panel B. Event Free Survival (EFS) by N/L ratio. Panel C. Overall Survival (OS) by N/L in patients with IPI score ≤ 3. Table 1.Baseline patients characteristics (N = 268) and compared by N/L < 4 or ≥ 4 by using Chi-Square Test for categorical variables. Abbreviations not included in the text: IPI = International Prognostic Index; LDH = lactate dehydrogenase, PD: Progression Disease, NA: Not Applicable. Disclosures Cimino: Celgene: Honoraria; Bristol-Mayer: Honoraria.

In the online version of the well-known graph coloring problem, the vertices appear one after the other together with the edges to the already known vertices and have to be irrevocably colored immediately after their appearance. We consider this problem on bipartite, i.e., two-colorable graphs. We prove that 1.13747·log2 n colors are necessary for any deterministic online algorithm to color any bipartite graph on n vertices, thus improving on the previously known lower bound of log2 n + 1 for sufficiently large n.