"Society of Hematologic Oncology (SOHO) State of the Art Updates and Next Questions"-Treatment of ALL.

The outcome of adult acute lymphoblastic leukemia (ALL) has substantially improved by adopting pediatric-inspired regimens, and approximately half of the patients are nowadays cured. The evaluation of minimal residual disease currently represents the most important prognostic indicator, which drives treatment algorithms, which include allogeneic stem cell transplantation (allo-SCT) allocation. Indeed, for high-risk patients, allo-SCT should be pursued as soon as possible, whereas in standard-risk patients this procedure should be avoided also in light of related toxicity and because there are no significant benefits. Furthermore, better characterization of the molecular genetic events can drive therapeutic decisions: a historical example in this respect is represented by the use of tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome-positive ALL; in the upcoming future, TKIs might be used also in other subgroups, such as breakpoint cluster region/Abelson 1-like cases and others with deregulated tyrosine kinases. Finally, the greatest progress is currently achieved with new immunotherapies targeting frequently expressed surface antigens in ALL. It is also a new chance for elderly ALL patients, so far spared from intensive chemotherapy and allo-SCT. These targeted therapies will substantially change this treatment algorithm and the great challenge is to find optimal sequence of the extended therapy options in an individual patient

Recuperación retrospectiva de un archivo policíaco: el “Casellario Politico Centrale”

The research illustrates utilization strategies of description standards and advanced technologies that are the basis of recovery ("recuperación retrospectiva") methodologies of archival finding aids, experienced in overcoming the problems associated with communicating and sharing resources. Considering interoperability, both technological and semantic, and long-term preservation of information as primary objectives of information systems, it is considered that recovery operations have to always be characterized by the choice of reference to specific standard solutions, technological (XML as data format) and descriptive encoding (Ead and Eac-Cpf in the archival area)

Centella asiatica in the Conservative Treatment of Anal Fissure and Hemorrhoids in Comparison with Flavonoids

Background: In this review, we report about therapeutic effects of Centella asiatica (Ca) in comparison with Flavonoids (Fs) to find out which of them best deals with some items such as bleeding and pain healing time in the treatment of outpatients with chronic Anal Fissure (AF) on one hand. On the other hand, we report about the same parameters in outpatients treated for hemorrhoidal disease (HD). Methodology: Ninety-eight outpatients who complained of AF were randomly assigned to the treated group (either Fs or Ca) and control group [1]. The control group (group C, n = 32) underwent standard treatment. Patients assigned the treated group were divided into subgroups that were treated, additionally, either with Fs (group A, n = 30) or Ca (group B, n = 36) and observed over 8 weeks. In another study on 130 outpatients (who underwent hemorrhoidectomy and operated for hemorrhoidal thrombosis) bleeding and pain were studied [2]. The treated group (both conservative and surgical) was randomized into two subgroups: the one treated with Fs (group A), the other with Ca (group B). Sixty patients (the control group C, both conservative and surgical) received the standard treatment. Time-to-stop bleeding was checked at the start (day 0) up to day 42 (end of the 6th week). Results: Outpatients complained of AF, the median time-to-stop bleeding in group A resulted in 1 week, in 3 weeks group B, and 4 weeks in group C respectively. Among groups, for the time-to-end-bleeding (A vs B: p-value = 0.022; A vs C: p-value < 0.001; B vs C: p-value = 0.070) significant differences were observed. As for the pain score, from day 0 up to the end of the 2nd week, on the one hand among groups A and B, and on the other hand among groups A vs C, and B vs C significant differences respectively were observed (A vs C: p-value = 0.004; B vs C: p-value 0.035). All patients healed within the end of 8th week [1]. The paper about patients with HD showed “time-to-stop bleeding of 2 weeks for groups A and B; 3 weeks for group C” [2]. As for the VAS score (irritation) comparison among groups (A vs C: p = 0.007; B vs C: p = 0.041; and A vs B: p = 0.782) respectively resulted [2]. The patients underwent hemorrhoidectomy, “the time-to-stop bleeding was 3 and 4 weeks in groups A and B and 5 in group C”, respectively [2]. “Histopathology showed a tight association between flavonoids and piles’ fibrosis (p = 0.008)” [2]. Discussion: “The outpatients with AF treated with either Fs or Ca experienced an earlier healing and disappearance of pain in comparison with patients underwent to the traditional treatment” [1]. Fs showed the most efficacy for bleeding. Ca showed the most efficacy for edemas. Fs and Ca did not show side effects. Conclusion: The outpatients with AF as well as those with HD treated either with Fs or Ca (phlebotonics) experienced early pain disappearance in comparison with the standard treatment group respectively. In the treatment of HD as well as after anal surgery, Fs and Ca showed significant beneficial effects. Fs among phlebotonics are the most effective against bleeding and anal irritation in HD. As for the Ca, among phlebotonics, seems the most effective for tissues’ edema

Analysis of the role of liprins protein in breast cancer cell invasion.

The metastatic process requires the ability of cancer cells to break the basement mem¬brane and migrate through a complex three-dimensional environment. The laboratory has recently identified the protein liprin-α1 as an important regulator of integrin me¬diated focal adhesion dynamics and cell motility in non-neuronal cells (Asperti et al., 2009, Asperti et al., 2010). Liprins are a family of cytosolic scaffold proteins including the liprin-α and liprin-β subfamilies based on sequence similarities (Serra Pagés et al., 1998). The human genome encodes four liprin-α (liprin-α1-4) and two liprin-β proteins (liprin-β1 and liprin-β2). Interestingly, the gene PPFIA1 for liprin-α1 is frequently am-plified in tumors. Moreover, the levels of expression of the liprin-α1 protein are often increased in human breast cancers (Astro et al., 2011). Functional analysis has revealed that liprin-α1 is specifically required for migration and invasion in vitro of highly invasi¬ve MDA-MB-231 human breast cancer cells. The analysis of lamellipodia dynamics has revealed a decrease of the stability of these protrusions in cells depleted of endogenous liprin-α1, which are defective in cell motility. Furthermore, liprin-α1 silencing causes a reduction of tumor cell invasion through Matrigel. The examination of the invasive po¬tential has demonstrated that liprin-α1 is important also for the degradation of the extra¬cellular matrix (ECM) (Astro et al., 2011). Starting from these observations, the first aim of my project has been to investigate the function of liprin-α1 in vivo. I have generated MDA-MB-231-derived cell lines with either stable overexpression or stable depletion of liprin-α1, and I have used these cells for injection or transplantation in mice, to determine their invasive potential. The characterization of these cell lines in vitro has confirmed that liprin-α1 overexpression causes an increase of both cell migration on FN and invasion through Matrigel, by promoting the stability of the lamellipodia. On the other hand, li¬prin-α1-depleted cells have reduced ability to both migrate and invade in vitro. However, all the cell lines with altered liprin-α1 levels have shown similar proliferation rates and viability compared to the control MDA-MB-231 cells. To investigate the involvement of liprin-α1 in invasion in vivo, experimental metastasis assays and spontaneous metastasis assays were performed. In both assays, the formation of lung metastases by the modified and control breast cancer cell lines has been evaluated. The results indicated that liprin-α1 overexpression did not affect lung colonization. Considering the high invasive ability of MDA-MB-231 wild type cells, increase in lung colonization by liprin-α1 overexpression may be irrelevant in vivo. On the contrary, injection of liprin-α1-depleted cells resulted in the reduction of the formation of lung metastases compared to control cells. This is the first evidence that liprin-α1 is not involved in primary tumor growth, while it is important for tumor cell invasion. Being a scaffold protein, liprin-α1 is unlikely to act alone as a regulator of tumor cell invasion. Previous studies have described the interaction between liprin-α1 and liprin-β1 (Serra-Pages et al., 1998), and have suggested a possible role of liprin-β2 in migration and invasion (von Thun et al., 2012). However, the available data on the functions of li¬prin-β proteins and their relationship with liprin-α1 are not exhaustive. As the second aim of my PhD, I have addressed the biochemical interaction of liprin-α1 with either liprin-β1 or liprin-β2, and I have tried to elucidate the role of the two proteins in cell motility and invasion. While liprin-α1 interacts with liprin-β1, it does not interact with liprin-β2. This is the first evidence of the different ability of the two liprin-β proteins to interact with liprin−α1. The biochemical analysis has shown that the interaction between liprin-α1 and liprin-β1 occurs via the C-terminus of liprin-α1, and that two of the three SAM domains of liprin-α1 are sufficient to mediate this interaction. The study of the subcellular localization has indicated that liprin-β1 colocalizes with liprin-α1 at the cell edge, whereas liprin-β2 partially colocalizes with cortactin-positive invadopodia. Functional analysis has shown that liprin-β1 silencing did not affect cell invasion through matrigel, whereas liprin-β2 silencing led to an increase of cell invasion, and enhanced ECM degradation, supporting the hypothesis of the different role of this protein in regulating the function of invadopodia with respect to liprin-α1 and liprin-β1. Analysis of the involvement of liprin-β1 and liprin-β2 in cell migration underlined the different effects of the two proteins. As previously observed for liprin-α1 (Astro et al, 2011), silencing of liprin-β1 led to a decrease of the speed of the cells in random migra¬tion assays. On the contrary, liprin-β2 silencing did not significantly affect cell motility. These data support the hypothesis of a cooperation between liprin-α1 and liprin-β1 in regulating cell motility, while they indicate that liprin-β2 does not have a relevant role in this process. Altogether the work presented in my thesis sustains a key role of liprin-α1 as a positive regulator of the invasive apparatus of tumour cells in vivo, and has highlighted for the first time first time distinct roles of liprin-β1 and liprin-β2 in tumor cell motility

New approaches to the management of adult acute lymphoblastic leukemia

Traditional treatment regimens for adult acute lymphoblastic leukemia, including allogeneic hematopoietic cell transplantation, result in an overall survival of about 40%, a figure hardly comparable with the extraordinary 80-90% cure rate currently reported in children. When translated to the adult setting, modern pediatric-type regimens improve the survival to about 60% in young adults. The addition of tyrosine kinase inhibitors for patients with Philadelphia chromosome positive disease and the measurement of minimal residual disease to guide risk stratification and post-remission approaches has led to further improvements in outcomes. Relapsed disease and treatment toxicity - sparing no patient but representing a major concern especially in the elderly - are the most critical current issues awaiting further therapeutic advancement. Recently, there has been considerable progress in understanding the disease biology, specifically the Philadelphia-like signature as well as other high-risk subgroups. In addition, there are several new agents that will undoubtedly contribute to further improvement in the current outcomes. The most promising agents are new the monoclonal antibodies, immunomodulators, and chimeric antigen receptor T cells and, to a lesser extent, several new drugs targeting key molecular pathways involved in leukemic cell growth and proliferation. This review examines the evidence supporting the increasing role of the new therapeutic tools and treatment options in different disease subgroups, including frontline and relapsed/refractory disease. It is now possible to define the best individual approach based on to the emerging concepts of precision medicine

Benefits and biosafety of use of buckypaper for surgical applications. A pilot study in a rabbit clinical trial model

Background: One of the main problems related to prosthetic abdominal surgery is mesh fixation. Suture line tension, mesh separation, displacement, or improper application of stitches are the leading causes of complications, including seroma, postoperative pain, and recurrence. A surface able to adhere firmly to living tissue represents an effective alternative to conventional perforating fixations. As a bio-adhesive tape, we report experimental evidence on the potential applicability of the BuckyPaper (BP), a felt composed of entangled multi-walled carbon nanotubes. Matherial and methods: BP is implanted to assess its biosafety and effectiveness as an adhesive prosthetic device. Results: During 35 days we observed no rabbit behavioral alteration, BP stability in the implantation site, good adhesion, and integration of the device with the surrounding tissue, and no adverse reactions. Conclusions: BP could be used as an adhesive to secure the prostheses to tissues in abdominal wall prosthetic surgery, but large-size animal studies are needed

Comparison of Centella with flavonoids for treatment of symptoms in hemorrhoidal disease and after surgical intervention: A randomized clinical trial

Gli effetti dei flebotonici sono stati valutati per il tempo di arresto del sanguinamento e il tempo di scomparsa dell'irritazione anale in 130 pazienti affetti da malattia emorroidaria, tempo di arresto del sanguinamento e tempo di scomparsa del dolore dopo intervento [emorroidectomia (in 31 pazienti) oppure incisione e drenaggio di trombosi emorroidaria (in 34 pazienti)]. Queste valutazioni sono state fatte nel breve periodo di tempo 0-42 gg. Sessanta pazienti randomizzati hanno ricevuto la procedura di routine (sia conservativa che chirurgica) (gruppo di controllo C). Il gruppo dei pazienti che hanno ricevuto il trattamento con flebotonici (sia conservativo che chirurgico) è stato suddiviso in due sottogruppi: quello trattato con flavonoidi (Gruppo A, n = 73) e quello trattato con Centella (Gruppo B, n = 66). Il tempo di scomparsa del sanguinamento è stato verificato dal Giorno 0 fino al Giorno 42. La guarigione è stata stimata con il metodo Kaplan-Meier, il test Kruskal-Wallis è stato utilizzato per valutare le variazioni del punteggio VAS per studiare il dolore (dopo intervento per emorroidectomia oppure incisione e drenaggio di trombosi emorroidaria), oppure irritazione anale nei pazienti trattati conservativamente. Il tempo medio di emorragia è stato di 2 settimane per i gruppi A e B; 3 settimane per il gruppo C. Il confronto dei punteggi VAS tra i gruppi (irritazione): A vs C, p = 0,007; B vs C, p = 0,041; e A vs B, rispettivamente p = 0,782. Per quanto riguarda gli operati con emorroidectomia, il tempo di arresto del sanguinamento è stato rispettivamente di 3 e 4 settimane nei gruppi A e B, 5 settimane nel gruppo C. L'istopatologia ha mostrato un'associazione tra flavonoidi e fibrosi emorroidaria (p = 0,008). I flebotonici hanno mostrato significativi effetti benefici sia negli operati che nei pazienti trattati conservativamente. Tra i flebotonici, i flavonoidi sono stati più efficaci contro il sanguinamento e l'irritazione anale.Phlebotonics' effects were evaluated to reduce time-to-stop bleeding and anal irritation in 130 patients who complained of hemorrhoidal disease (HD); bleeding and pain after hemorrhoidectomy (31 patients) and hemorrhoidal thrombosis (34 patients) in the short time. Sixty patients were randomized to receive the routine treatment (both conservative and surgical) (control Group C). The treated group (both conservative and surgical) was divided into two subgroups: one treated with flavonoids (Group A, n = 73), the other with Centella (Group B, n = 66). Time-to-stop bleeding was checked at baseline and checkups (0 up to day 42). Healing was estimated with Kaplan-Meier method, the Kruskal-Wallis test estimated changes in the VAS scores. The HD median time-to-stop bleeding was 2 weeks for Groups A and B; 3 weeks for Group C. VAS scores comparison among Groups (irritation): A vs C, p = 0.007; B vs C, p = 0.041; and A vs B, p = 0.782 resulted respectively. As for operated hemorrhoids, the time-to-stop bleeding was 3 and 4 weeks in Groups A and B and 5 in Group C. Histopathology showed an association between flavonoids and piles' fibrosis (p = 0.008). Phlebotonics in HD, as well as after surgery, showed significant beneficial effects. Flavonoids are the most effective phlebotonics against bleeding and anal irritation

Enterocutaneous fistula management and clinical nutrition in sepsis of abdominal wall incisional hernia. Tips, tricks and literature revision

Background: The Enterocutaneous Fistula (ECF) treatment requires a multidisciplinary approach and high costs, and shows critical morbidity and mortality rates. For these reasons, it is one of the most challenging problems in colorectal and incisional hernia surgery. Methods: This article synopsizes the current classification systems’ successful management and provides an in-depth review of septic source surgical control, Clinical Nutrition, Hyper Baric Oxygen Therapy (HBOT) and negative pressure (VAC), output quantity management, wound care, operative timeline, and considerations such as Inflammatory Bowel Disease (IBD), and Enteroatmospheric Fistula (EAF). Result: We report a 71-year-old septic fistulated male with an incisional hernia, and chronic medullary dysplasia. This study compares our results with the literature. This case concerns a very complex and long-lasting clinical scenario because of erythropoietic and immunity systems default that led the patient to death. The use of negative pressure therapy to manage abdominal fistula is still controversial. Patients suffering from enterocutaneous fistula require adequate nutritional support to fight hypercatabolism due to the fistula’s inflammation, fluids, proteins, and salts loss. Conclusions: An aggressive multidisciplinary approach, including prosthesis explantation are needed. Clinical nutrition starts with TPN (Total Parenteral Nutrition) followed by EN (Enteral Nutrition) as soon as possible. Moreover, VAC and HBOT therapies are useful to treat this life-threatening condition

The epigenetic factor BORIS/CTCFL regulates the NOTCH3 gene expression in cancer cells.

Aberrant upregulation of NOTCH3 gene plays a critical role in cancer pathogenesis. However, the underlying mechanisms are still unknown. We tested here the hypothesis that aberrant epigenetic modifications in the NOTCH3 promoter region might account for its upregulation in cancer cells. We compared DNA and histone methylation status of NOTCH3 promoter region in human normal blood cells and T cell acute lymphoblastic leukemia (T-ALL) cell lines, differentially expressing NOTCH3. We found that histone methylation, rather than DNA hypomethylation, contributes towards establishing an active chromatin status of NOTCH3 promoter in NOTCH3 overexpressing cancer cells. We discovered that the chromatin regulator protein BORIS/CTCFL plays an important role in regulating NOTCH3 gene expression. We observed that BORIS is present in T-ALL cell lines as well as in cell lines derived from several solid tumors overexpressing NOTCH3. Moreover, BORIS targets NOTCH3 promoter in cancer cells and it is able to induce and to maintain a permissive/active chromatin conformation. Importantly, the association between NOTCH3 overexpression and BORIS presence was confirmed in primary T-ALL samples from patients at the onset of the disease. Overall, our results provide novel insights into the determinants of NOTCH3 overexpression in cancer cells, by revealing a key role for BORIS as the main mediator of transcriptional deregulation of NOTCH3. Copyright © 2014 Elsevier B.V. All rights reserved