First-line treatment of acute lymphoblastic leukemia with pegasparaginase.

open2noAcute lymphoblastic leukemia (ALL) accounts for almost 4000 cases annually in the United States, approximately two thirds of which are in children and adolescents. Treatment results of ALL have improved considerably in the past decade, due to an optimal stratification of patients and a rational use of different antileukemic agents among which L-asparaginase (L-ASNase) plays a fundamental role. This drug has been used in pediatric ALL chemotherapy protocols for almost 3 decades. In the 1970s and 1980s a chemically modified form of this enzyme called pegasparaginase (PEG-ASNase) was rationally synthesized to decrease immunogenicity of the enzyme and prolong its half-life. The different advantages of PEG-ASNase have been demonstrated in many clinical studies, the last of which underline the utility of this drug in front-line therapy of ALL. In this review, we discuss the pharmacological advantages and clinical potential of PEG-ASNase and its important use in first-line treatment of ALL.openMasetti R;Pession AMasetti R;Pession

Successes and Challenges for Diagnosis and Therapy of Acute Leukemia

Editoria

Avances en la terapia de la leucemia infantil

En esta revisión se describen las características generales de las formas más frecuentes de leucemia, especialmente de la leucemia infantil, que ha sido el modelo de estudio para la biología de la enfermedad. Además, se presentan nuevos abordajes terapeúticos para el tratamiento de este tipo de leucemia: inhibidores de las proteínas tirosina-quinasas, anticuerpos específicos frente a los antígenos expresados por el clon leucémico e inhibidores del proteosoma y de las enzimas ADN metiltransferasas. El artículo concluye con la revisión de la eficacia de las denominadas células CAR-T (células T con Receptores de Antígenos Quiméricos) frente a las células cancerígenas de leucemia

The Role of Strategic Fundraising in Marketing Plan of Non-profit Companies: The Case of Susan G. Komen Italy

The case is mainly focused on the consequences of the Covid-19 pandemic on Susan G. Komen Italia, on all the initiatives put through by the association and on the role of Strategic Fundraising in NPOs’ marketing plans. The Italian charity sector is populated by small and medium entities competing to “win” donors supporting their cause, and in turn organisations of smaller scale have to confront with larger NPOs, both cancer and non-cancer focused, well-known throughout the National territory , which are favoured by their brand equity and their past reputation, leading to an intense competition in terms of potential “donors wallet”. This framework has undergone several challenges related to the worldwide spread of Covid-19: the pandemic caused dramatic changes in terms of events and initiatives to be rescheduled or rearranged, favouring the shift to online instruments. The “next normality” driven by the lockdown has become a trigger for the creativity of marketers in several different fields, including NPOs’ sector. With this in mind, this paper highlights Komen’s effort in Italy to rethink its marketing and fundraising approach reorganizing activities along the Donor Decision Journey. The case focuses on analysing strategic fundraising as the key element of NPOs’ marketing plans

The Role of HDACs Inhibitors in Childhood and Adolescence Acute Leukemias

Acute leukemia is the most common type of childhood and adolescence cancer, characterized by clonal proliferation of variably differentiated myeloid or lymphoid precursors. Recent insights into the molecular pathogenesis of leukemia have shown that epigenetic modifications, such as deacetylation of histones and DNA methylation, play crucial roles in leukemogenesis, by transcriptional silencing of critical genes. Histone deacetylases (HDACs) are potential targets in the treatment of leukaemia, and, as a consequence, inhibitors of HDACs (HDIs) are being studied for therapeutic purposes. HDIs promote or enhance several different anticancer mechanisms, such as apoptosis, cell cycle arrest, and cellular differentiation and, therefore, are in evidence as promising treatment for children and adolescents with acute leukemia, in monotherapy or in association with other anticancer drugs. Here we review the main preclinical and clinical studies regarding the use of HDIs in treating childhood and adolescence leukemia

update on one stage immediate breast reconstruction with definitive prosthesis after sparing mastectomies

Abstract Immediate breast reconstruction after skin and nipple-sparing mastectomies is commonly performed as a two-stage procedure; to overcome the paradox of traditional two-stage tissue expander/implant reconstruction used to create a tight muscular pocket that needs expansion to produce lower pole fullness, while losing the laxity of the mastectomy skin flaps, the authors conceived a subpectoral-subfascial pocket by elevating the major pectoral muscle in continuity with the superficial pectoralis fascia up to the inframammary fold. This alteration allowed for the immediate insertion of the definitive implant. The authors present their experience in 220 cases of immediate one-stage breast reconstructions with definitive prostheses in sparing mastectomies. Immediate and long-term local complications were evaluated. Immediate breast reconstruction with definitive anatomical silicone-filled implants can produce excellent cosmetic results (78.6%) with a low rate of complications (17.7%); these results allow for agreement between oncologic, aesthetic and economic purposes

Results obtained with level II oncoplastic surgery spanning 20 years of breast cancer treatment: Do we really need further demonstration of reliability?

Oncoplastic surgery (OPS) has demonstrated its superiority above traditional breast conserving surgery, but is still struggling to consolidate its role in breast cancer therapeutic protocols mainly because of contrasting scientific evidences and reduced follow-up results available. The objective of our contribution is to analyze results obtained with 381 patients consecutively treated in our Multidisciplinary Breast Center by means of level II OPS between January 1998 and January 2018 for unilateral, primary breast cancer. Surgical endpoints were mean specimen weight and volume, mean diameter of main lesion (MLD), rates of positive margins (PMR), re-excision (RR), conversion to mastectomy (CMR), complications (CR) and oncological endpoints as overall survival (OS), disease-free survival (DFS), and local recurrence rate (LR). About 29.1% were treated for multifocal/multicentric disease, and 29.1% previously underwent neo-adjuvant chemotherapy (NACT). Regarding surgical techniques, 53.0% of patients received "inverted T" and 30.1% "J" mammoplasties, whereas 13.6% underwent "round block," 2.3% "Grisotti," and 1% "batwing" techniques. Regarding surgical outcomes, mean specimen weight was 215 g (50-2157) and volume 345 mm3 (21-7980). MLD 23 mm, PMR 7.6%, RR 3.6%, CMR 1.6%, and CR 5.8%. With a mean follow-up of 118 months, oncological outcomes were: OS 93.7%, DFS 82.3%, LR 4.4%. In conclusion, our analysis confirmed level II OPS reliability even for longer follow-up timing and in difficult situations as multifocal disease or after NACT

Allogeneic hematopoietic stem cell transplantation for pediatric acute myeloid leukemia in first complete remission: a meta-analysis

Identification of pediatric patients with acute myeloid leukemia (AML) candidates to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) is still a matter of debate. Currently, transplantation is reserved to patients considered at high risk of relapse based on cytogenetics, molecular biology, and minimal residual disease (MRD) assessment. However, no randomized clinical trial exists in the literature comparing transplantation with other types of consolidation therapy. Here, we provide an up-to-date meta-analysis of studies comparing allo-HSCT in CR1 with chemotherapy alone as a post-remission treatment in high-risk pediatric AML. The literature search strategy identified 10 cohorts from 9 studies performing as-treated analysis. The quantitative synthesis showed improved overall survival (OS) (relative risk, 1.15; 95% confidence interval [CI], 1.06-1.24; P = 0.0006) and disease-free survival (relative risk, 1.31; 95% CI, 1.17-1.47; P = 0.0001) in the allo-HSCT group, with increased relapse rate in the chemotherapy group (relative risk, 1.26; 95% CI, 1.07-1.49; P = 0.006). Sensitivity analysis including prospective studies alone and excluding studies that reported the comparison only on intermediate-risk patients confirmed the benefit of allo-HSCT on OS. Further research should focus on individualizing allo-HSCT indications based on molecular stratification and MRD monitoring

Integrated Approach Including Docking, MD Simulations, and Network Analysis Highlights the Action Mechanism of the Cardiac hERG Activator RPR260243

hERG is a voltage-gatedpotassium channel involved inthe heartcontraction whose defections are associated with the cardiac arrhythmiaLong QT Syndrome type 2. The activator RPR260243 (RPR) representsa possible candidate to pharmacologically treat LQTS2 because it enhancesthe opening of the channel. However, the molecular detail of its actionmechanism remains quite elusive. Here, we address the problem usinga combination of docking, molecular dynamics simulations, and networkanalysis. We show that the drug preferably binds at the interfacebetween the voltage sensor and the pore, enhancing the canonical activationpath and determining a whole-structure rearrangement of the channelthat slightly impairs inactivation

Conduction and Gating Properties of the TRAAK Channel from Molecular Dynamics Simulations with Different Force Fields

In recent years, the K2P family of potassium channels has been the subject of intense research activity. Owing to the complex function and regulation of this family of ion channels, it is common practice to complement experimental findings with the atomistic description provided by computational approaches such as molecular dynamics (MD) simulations, especially, in light of the unprecedented timescales accessible at present. However, despite recent substantial improvements, the accuracy of MD simulations is still undermined by the intrinsic limitations of force fields. Here, we systematically assessed the performance of the most popular force fields employed to study ion channels at timescales that are orders of magnitude greater than the ones accessible when these energy functions were first developed. Using 32 μs of trajectories, we investigated the dynamics of a member of the K2P ion channel family, the TRAAK channel, using two established force fields in simulations of biological systems: AMBER and CHARMM. We found that while results are comparable on the nanosecond timescales, significant inconsistencies arise at microsecond timescales.</p