Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) Patients: A Retrospective Analysis of Eligibility Criteria for CAR-T Cell Therapy

Patients (pts) with diffuse large B-cell lymphoma (DLBCL) refractory to second-line therapy or relapsed after an autologous stem cell transplant (ASCT) have a very poor clinical outcome with a median overall survival (OS) of 5 and 8-10 months, respectively. Autologous anti-CD19 chimeric antigen receptor (CD19 CAR) T cells have been associated with sustained complete remissions and long-term survivals in a large proportion of pts with R/R DLBCL by the two pivotal clinical trials Zuma1 and Juliet. This has led to the rapid approval by FDA and then by EMA of CAR-T cells for the third-line treatment of R/R DLBCL. Despite being a potentially revolutionary treatment for pts with advanced disease, the costs are much greater than any previously approved cancer therapy and this may become a substantial economic challenge for the health care system. The definition of inclusion and exclusion criteria capable of identifying more precisely pts who can successfully undergo CAR-T cell therapy, minimizing the severity of the toxicity, still remains a matter of discussion. Moreover, some eligible pts run the risk of becoming ineligible because of poor disease control. Indeed, one of the major obstacles to the successful use of CAR-T cells is the 4-5 week period so far required for the manufacturing and transfer of CAR-T cells. To address this issue, we have examined data of R/R DLBCL pts managed between 2010 and 2018 at our Center in order to: 1) better identify the characteristics and outcome of a cohort of R/R DLBCL pts potentially eligible, according to the approval criteria, for CAR-T cell therapy; 2) define factors influencing CAR-T cell eligibility; 3) make a realistic estimate of pts eligible for CAR-T cells. In this retrospective real-life cohort of R/R DLBCLs, 82/480 pts (17%) were R/R tosecond-line treatment including ASCT. Considering Juliet's inclusion/exclusion criteria for CAR-T cell therapy, only 50 pts (10.4%) would be eligible for CAR-T cells. Our analysis suggests that elevated LDH plus ECOG ≥2 have to be considered the two most significant features of very rapid disease progression. These variables should be taken in account in order to better select DLBCL pts potentially eligible to CAR-T therapy

Low Incidence Rate of Opportunistic and Viral Infections During Imatinib Treatment in Chronic Myeloid Leukemia Patients in Early and Late Chronic Phase.

<!--StartFragment--> <p class="MsoNormal" style="text-align: justify; line-height: 150%;"><span style="font-family: Arial; mso-ansi-language: EN-GB;" lang="EN-GB">Background: Imatinib has become first line therapy in chronic myeloid leukemia patients. Little is known about the infective consequences during the treatment with this drug in large series of chronic phase patients. </span></p> <p class="MsoNormal" style="text-align: justify; line-height: 150%;"><span style="font-family: Arial; mso-ansi-language: EN-GB;" lang="EN-GB">Material and methods: From January 2001 to September 2006 we treated with imatinib 250 patients in first line (early CP) or after interferon failure (late CP), out of clinical trials and recorded all the bacterial and viral infections occurred.</span></p> <p class="MsoNormal" style="text-align: justify; line-height: 150%;"><span style="font-family: Arial; mso-ansi-language: EN-GB;" lang="EN-GB">Results: We recorded a similar incidence of bacterial and viral infections both in first line and late CP patients (respectively, 16% and 13%) during 3.5 years of follow-up. Analysis of presenting features predisposing to infections revealed differences only in late CP patients, with elevated percentage of high Sokal risk patients and a more longer median time from diagnosis to start of imatinib.</span></p> <p class="MsoNormal" style="text-align: justify; line-height: 150%;"><span style="font-family: Arial; mso-ansi-language: EN-GB;" lang="EN-GB">Conclusions: Opportunistic infections and reactivation of Herpes Zoster are observed during imatinib therapy at very low incidence.</span></p> <!--EndFragment--&gt

Management of elderly and unfit patients with chronic lymphocytic leukemia

Introduction: About 75% of patients with chronic lymphocytic leukemia (CLL) are more than 65 years at the time of diagnosis. Treatment of the elderly remains complicated due to multiple factors, such as comorbidities, decline in functional reserve and fitness. Since chronological age by itself cannot properly predict life expectancy and treatment tolerance, an accurate assessment of the fitness status is of crucial importance for an optimal treatment choice. Areas covered: This review will discuss the most relevant aspects concerning the issues experienced in the management of elderly/unfit patients with CLL. The most frequently observed age-related toxicities, fitness assessments, supportive care measures and treatment options for elderly patients and for patients who are deemed unfit will be discussed. Literature search methodology included examination of PubMed index. Expert commentary: During the last decade, different trials focusing on elderly/unfit patients have investigated more tolerable chemoimmunotherapy schedules and, more recently, the activity and safety of chemo-free regimens. Chlorambucil combined with an anti-CD20 monoclonal antibody has shown clinical activity with a relatively good profile of toxicity. The recent introduction of the B-cell receptor antagonists, ibrutinib and idelalisib, and other targeted drugs in development (e.g. venetoclax), is broadening the therapeutic armamentarium of elderly CLL patients

Pathogenetic investigations on the enteric nervous system plexuses of sarda breed sheep with different PrP genotypes following oral experimental scrapie infection

We investigated the ileal myenteric (MPs) and submucosal plexuses (SMPs) of 32 Sarda breed sheep carrying different PrP genotypes (ARQ/ARQ, ARQ/AHQ, ARQ/ARR, ARR/ARR), which had been orally dosed with scrapie at 8 months of age and euthanized at definite time intervals post-infection (p.i.)

Radiotherapy Timing in 4,820 Patients With Breast Cancer: University of Florence Experience

PURPOSE: To analyze the relationship between a delay in radiotherapy (RT) after breast-conserving surgery and ipsilateral breast recurrence (BR). METHODS AND MATERIALS: We included in our analysis 4,820 breast cancer patients who had undergone postoperative RT at the University of Florence. The patients were categorized into four groups according to the interval between surgery and RT (T1, 180 days). RESULTS: On multivariate analysis, the timing of RT did not reach statistical significance in patients who received only postoperative RT (n = 1,935) or RT and hormonal therapy (HT) (n = 1,684) or RT, chemotherapy (CHT), and HT (n = 529). In the postoperative RT-only group, age at presentation, surgical margin status, and a boost to the tumor bed were independent prognostic factors for BR. In the RT plus HT group, age at presentation and boost emerged as independent prognostic factors for BR (p = 0.006 and p = 0.049, respectively). Finally, in the RT, CHT, and HT group, only multifocality was an independent BR predictor (p = 0.01). Only in the group of patients treated with RT and CHT (n = 672) did multivariate analysis with stepwise selection show RT timing as an independent prognostic factor (hazard ratio, 1.59; 95% confidence interval, 1.01-2.52; p = 0.045). Analyzing this group of patients, we found that most patients included had worse prognostic factors and had received CHT consisting of cyclophosphamide, methotrexate, and 5-fluorouracil before undergoing RT. CONCLUSION: The results of our study have shown that the timing of RT itself does not affect local recurrence, which is mainly related to prognostic factors. Thus, the "waiting list" should be thought of as a "programming list," with patients scheduled for RT according to their prognostic factors

Mapping Flood-Related Mortality in the Mediterranean Basin. Results from the MEFF v2.0 DB

Recent events in Western Attica in Greece (24 deaths in November 2017), in the Balearic Islands (13 deaths in October 2018), and in southern France (15 deaths in October 2018) show that flood-related mortality remains a major concern in Mediterranean countries facing flash floods. Over the past several years, many initiatives have arisen to create databases on flood-related mortality. An international initiative started in 2011 pooling regional and national databases on flood mortality from region and/or countries bordering the Mediterranean Sea. The MEditerranean Flood Fatality Database (MEFF DB) brings together, in 2018, six Mediterranean regions/countries: Catalonia (Spain), Balearic Islands (Spain), Southern France, Calabria (Italy), Greece, and Turkey, and covers the period 1980-2018. MEFF DB is on progress and, every year, new data are included, but for this study, we kept only the preliminary data that were geolocated and validated on 31st of December 2018. This research introduces a new step in the analysis of flood-related mortality and follows the statistical description of the MEFF DB already published. The goals of this paper are to draw the spatial distribution of flood mortality through a geographical information system (GIS) at different spatial scales: country, NUTS 3 (Nomenclature of Territorial Units for Statistics. Level 3) regions, catchment areas, and grid. A fatality rate (F: number of deaths/year/million of inhabitants) is created to help this analysis. Then, we try to relate mortality to basic (human or physical) drivers such as population density, rainfall seasonality, or rainfall frequency across the Mediterranean Basin. The mapping of F shows a negative mortality gradient between the western and the eastern parts of the Mediterranean Sea. The south of France appears to be the most affected region. The maps also highlight the seasonality of flood-related deaths with the same west-east gradient. It confirms that flood mortality follows the climatological seasonal patterns across the Mediterranean Basin. Flood-related fatalities mainly occur during the early fall season in the western part of the Mediterranean area, while the Easter Basin is affected later, in November or during the winter season. Eastern Turkey introduces another pattern, as mortality is more severe in summer. Mortality maps are then compared with factors that potentially contribute to the occurrence of flood fatalities, such as precipitation intensity (rainfall hazard), to explain geographical differences in the fatality rate. The density of a fatal event is correlated to the population density and the rainfall frequency. Conversely, the average number of deaths per event depends on other factors such as prevention or crisis managemen

Flood Fatalities in Europe, 1980-2018: Variability, Features, and Lessons to Learn

Floods are still a significant threat to people, despite of the considerable developments in forecasting, management, defensive, and rescue works. In the near future, climate and societal changes as both urbanization of flood prone areas and individual dangerous behaviors could increase flood fatalities. This paper analyzes flood mortality in eight countries using a 39-year database (1980-2018) named EUFF (EUropean Flood Fatalities), which was built using documentary sources. The narratives of fatalities were investigated and standardized in the database reporting the details of the events. The entire dataset shows a stable trend on flood fatalities, despite the existence of individual increasing (Greece, Italy, and South France) and decreasing (Turkey and Catalonia) trends. The 2466 fatalities were mainly males, aged between 30-49 years and the majority of them happened outdoor. Most often people were dragged by water/mud when travelling by motor vehicles. Some cases of hazardous behaviors, such as fording rivers, were also detected. The primary cause of death was drowning, followed by heart attack. This work contributes to understand the human-flood interaction that caused fatalities. The changes in society's vulnerability highlighted throughout this study contribute to manage future risks, to improve people protection actions, and to reduce risk behaviors

XIPE: the X-ray Imaging Polarimetry Explorer

X-ray polarimetry, sometimes alone, and sometimes coupled to spectral and temporal variability measurements and to imaging, allows a wealth of physical phenomena in astrophysics to be studied. X-ray polarimetry investigates the acceleration process, for example, including those typical of magnetic reconnection in solar flares, but also emission in the strong magnetic fields of neutron stars and white dwarfs. It detects scattering in asymmetric structures such as accretion disks and columns, and in the so-called molecular torus and ionization cones. In addition, it allows fundamental physics in regimes of gravity and of magnetic field intensity not accessible to experiments on the Earth to be probed. Finally, models that describe fundamental interactions (e.g. quantum gravity and the extension of the Standard Model) can be tested. We describe in this paper the X-ray Imaging Polarimetry Explorer (XIPE), proposed in June 2012 to the first ESA call for a small mission with a launch in 2017 but not selected. XIPE is composed of two out of the three existing JET-X telescopes with two Gas Pixel Detectors (GPD) filled with a He-DME mixture at their focus and two additional GPDs filled with pressurized Ar-DME facing the sun. The Minimum Detectable Polarization is 14 % at 1 mCrab in 10E5 s (2-10 keV) and 0.6 % for an X10 class flare. The Half Energy Width, measured at PANTER X-ray test facility (MPE, Germany) with JET-X optics is 24 arcsec. XIPE takes advantage of a low-earth equatorial orbit with Malindi as down-link station and of a Mission Operation Center (MOC) at INPE (Brazil).Comment: 49 pages, 14 figures, 6 tables. Paper published in Experimental Astronomy http://link.springer.com/journal/1068

Autologous stem-cell transplantation as consolidation of first-line chemotherapy in patients with peripheral T-cell lymphoma : a multicenter GELTAMO/FIL study

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of rare lymphoid malignancies that mostly have poor prognoses with currently available treatments. Upfront consolidation with autologous stem cell transplantation (ASCT) is frequently carried out, but its efficacy has never been investigated in randomized trials. We designed a multicenter, international, retrospective study with the main objective of comparing progression-free survival and overall survival of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy with a control group who did not undergo ASCT. From the initial population of 286 registered patients, 174 patients with PTCL other than anaplastic large cell lymphoma, ALK-positive, deemed fit for ASCT at the time of diagnosis, and who were in CR or uncertain CR after induction therapy (CR1) were included in our analysis. one hundred and three patients underwent ASCT, whereas 71 did not, in most cases (n=53) because the physician decided against it. With a median follow-up of 65.5 months, progression-free survival was significantly better in the transplanted patients than in the non-transplanted group: 63% versus 48% at 5 years (P =0.042). Overall survival was significantly longer for ASCT patients in the subgroup with advanced stage at diagnosis (5-year overall survival: 70% vs. 50%, P =0.028). In the multivariate analysis, first-line ASCT was associated with significantly prolonged progression-free survival (HR=0.57, 95% CI: 0.35-0.93) and overall survival (HR=0.57, 95% CI: 0.33-0.99). In conclusion, our study supports the use of ASCT as a consolidation strategy for patients with PTCL in CR1. These results should be confirmed in a prospective randomized study

Tumorigenic Potential of Olfactory Bulb-Derived Human Adult Neural Stem Cells Associates with Activation of TERT and NOTCH1

BACKGROUND: Multipotent neural stem cells (NSCs) have been isolated from neurogenic regions of the adult brain. Reportedly, these cells can be expanded in vitro under prolonged mitogen stimulation without propensity to transform. However, the constitutive activation of the cellular machinery required to bypass apoptosis and senescence places these cells at risk for malignant transformation. METHODOLOGY/PRINCIPAL FINDINGS: Using serum-free medium supplemented with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), we established clonally derived NS/progenitor cell (NS/PC) cultures from the olfactory bulb (OB) of five adult patients. The NS/PC cultures obtained from one OB specimen lost growth factor dependence and neuronal differentiation at early passage. These cells developed glioblastoma tumors upon xenografting in immunosuppressed mice. The remaining NS/PC cultures were propagated either as floating neurospheres or as adherent monolayers with maintenance of growth factor dependence and multipotentiality at late passage. These cells were engrafted onto the CNS of immunosuppressed rodents. Overall, the grafted NS/PCs homed in the host parenchyma showing ramified morphology and neuronal marker expression. However, a group of animals transplanted with NS/PCs obtained from an adherent culture developed fast growing tumors histologically resembling neuroesthesioblastoma. Cytogenetic and molecular analyses showed that the NS/PC undergo chromosomal changes with repeated in vitro passages under mitogen stimulation, and that up-regulation of hTERT and NOTCH1 associates with in vivo tumorigenicity. CONCLUSIONS/SIGNIFICANCE: Using culturing techniques described in current literature, NS/PCs arise from the OB of adult patients which in vivo either integrate in the CNS parenchyma showing neuron-like features or initiate tumor formation. Extensive xenografting studies on each human derived NS cell line appear mandatory before any use of these cells in the clinical setting