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During ancient times, human interest in naturally-occurring gases was religious, while it was scientific in the historical age and industrial in modern times. Gases were also utilized for practical purposes and more than 3 000 years before present day, Chinese populations made use of methane for salt extraction while in the 17th century it was observed that native Americans ignited methane seepages. The development of human thinking on gases followed the fundamental steps that characterized the natural sciences during the 18th century scientific revolution that was based on significant improvements in analytical methods. These improvements are still ongoing while present-day scientific publications evidence the spread of the field of interest and more cooperation with geophysical sciences to solve common interest problems. The existence of proper meetings and dedicated scientific journals confirms that gas geochemistry has ended this pioneering phase to enter a more mature condition. [ABSTRACT FROM AUTHOR]

Disease classification of complex and heterogenous diseases, such as acute myeloid leukaemia (AML), is continuously updated to define diagnoses, appropriate treatments, and assist research and education. Recent availability of molecular profiling techniques further benefits the classification of AML. The World Health Organization (WHO) classification of haematolymphoid tumours and the International Consensus Classification of myeloid neoplasms and acute leukaemia from 2022 are two updated versions of the WHO 2016 classification. As a consequence, the European LeukemiaNet 2022 recommendations on the diagnosis and management of AML in adults have been also updated. The current review provides a practical interpretation of these guidelines to facilitate the diagnosis of AML and discusses genetic testing, disease genetic heterogeneity, and FLT3 mutations. We propose a practical algorithm for the speedy diagnosis of AML. Future classifications may need to incorporate gene mutation combinations to enable personalised treatment regimens in the management of patients with AML. [Display omitted] • Two versions of acute myeloid leukaemia (AML) classification were updated in 2022. • Main differences include subtype genetic basis, secondary AML and blast cut-offs. • This review provides a practical interpretation of these guidelines to diagnose AML. • We propose a practical algorithm for the timely clinical diagnosis of AML. • Updated classifications may support personalised treatment options for AML patients. [ABSTRACT FROM AUTHOR]

To evaluate long-term durability of blinatumomab, a BiTE® (bispecific T-cell engager) molecule, in adults with relapsed/refractory (R/R) Philadelphia chromosome–positive (Ph+) B-cell precursor acute lymphoblastic leukaemia (ALL). In this final analysis of an open-label, single-arm, phase 2, multicentre ALCANTARA study (NCT02000427), adults (age ≥18 years) with Ph+ ALL who had relapsed or were refractory to at least one TKI were included. The primary endpoint was the proportion of patients who achieved complete remission (CR)/CR with partial haematologic recovery (CRh) during the first two cycles of blinatumomab treatment. The final analysis included 45 patients who completed the study between 3rd January 2014 and 6th January 2017, of which 16 (35.6%; 95% CI, 21.9%–51.2%) achieved CR/CRh within the first two blinatumomab cycles. After a median follow-up of 16.1 months, median relapse-free survival (RFS) was 6.8 (95% CI, 4.4–not estimable [NE]) months. Median overall survival (OS) was 9.0 (95% CI, 5.7–13.5) months with a median follow-up of 25.1 months. Median OS in patients with CR (19.8 [95% CI, 12.1–NE] months) was greater than in those without CR (6.0 [95% CI, 2.9–7.1] months). Of 16 patients with CR/CRh, 14 achieved complete minimal residual disease (MRD) response; the median duration of complete MRD response was 9.7 (95% CI, 5.2–NE) months. Treatment-related adverse events were consistent with those previously reported. Long-term durability of responses to blinatumomab was demonstrated in patients with R/R Ph+ ALL. • Alternatives for treating relapsed/refractory (R/R) Philadelphia (Ph+) ALL needed. • Blinatumomab simultaneously engages CD19+ B cells and CD3+ T cells. • Efficacy and safety results of the final analysis consistent with the primary analysis. • Blinatumomab treatment in R/R Ph + ALL results in a durable complete MRD response. [ABSTRACT FROM AUTHOR]

Background: Patients with relapsed/refractory (R/R) Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) have a poor prognosis and limited treatment options. Methods: The efficacy of inotuzumab ozogamicin (InO), a humanized anti‐CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, was evaluated in R/R ALL patients in the phase 1/2 study 1010 (NCT01363297) and open‐label, randomized, phase 3 study 1022 (INO‐VATE; NCT01564784). This analysis focused specifically on Ph+ R/R ALL patients. In study 1022, Ph+ patients were randomly assigned 1:1 to InO (n = 22) or standard intensive chemotherapy (SC) (n = 27) and 16 Ph+ patients in study 1010 received InO. Results: In study 1022, rates of complete remission/complete remission with incomplete hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity (patients achieving CR/CRi) were higher with InO (CR/CRi = 73%; MRD = 81%) versus SC (CR/CRi = 56%; MRD = 33%). The corresponding rates in study 1010 were 56% (CR/CRi) and 100% (MRD). The hematopoietic stem cell transplantation (HSCT) rate in study 1022 was 41% versus 19% for InO versus SC; however, there was no benefit in overall survival (median OS: 8.7 vs 8.4 months; hazard ratio, 1.17 [95% CI, 0.64‐2.14]). The probability of being event‐free (progression‐free survival) at 12 months was greater with InO versus SC (20.1% vs 4.8%). Conclusion: Given the substantial improvement in responses and rates of HSCT, InO is an important treatment option for patients with R/R Ph+ ALL. Future studies need to consider better characterization of disease characteristics, more sensitive MRD measurements, MRD‐directed therapy before HSCT, and potentially combination therapies, including tyrosine kinase inhibitors. An analysis of 65 patients with relapsed/refractory Philadelphia chromosome‐positive acute lymphoblastic leukemia shows that patients receiving inotuzumab ozogamicin (InO) have higher rates of complete remission/complete remission with incomplete hematologic recovery, minimal residual disease negativity, and subsequent hematopoietic stem cell transplantation than those receiving standard intensive chemotherapy (SC). Although this does not result in prolonged progression‐free survival or overall survival compared with SC, InO remains an important treatment option for patients with resistant and difficult‐to–treat disease. [ABSTRACT FROM AUTHOR]

Background: Deregulated Notch signaling is implicated in T‐cell acute lymphoblastic leukemia (T‐ALL)/T‐cell lymphoblastic lymphoma (T‐LBL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed/refractory T‐ALL/T‐LBL. Methods: JJCB was a multicenter, nonrandomized, open‐label, dose‐escalation, phase 1 study in adult patients with relapsed/refractory T‐ALL/T‐LBL. Eligible patients received Crenigacestat orally 3 times per week plus dexamethasone at 24 mg twice daily on days 1 to 5 every other week in a 28‐day cycle. The starting level of Crenigacestat was 50 mg, and dose escalation was performed with a modified 3+3 scheme for the estimation of dose‐limiting toxicity (DLT) at the recommended dose level. Results: In total, 36 patients with T‐ALL (n = 31 [86.1%]) or T‐LBL (n = 5 [13.9%]) were treated with Crenigacestat and dexamethasone. Six patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75‐mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100‐mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125‐mg cohort (grade 3 diarrhea, nausea, and vomiting). The maximum tolerated dosewas 75 mg plus 24 mg of dexamethasone daily on days 1 to 5. Twenty‐eight patients (77.8%) experienced 1 or more treatment‐emergent adverse events related to the study treatment. The best overall response was a confirmed response, with 1 patient (2.8%) having a duration of response of 10.51 months. Six patients (16.7%) achieved stable disease, and 12 patients (33.3%) experienced progressive disease. The remaining 17 patients (47.2%) were not evaluable. The median event‐free survival was 1.18 months (95% confidence interval, 0.76‐2.14 months) among all groups. A pharmacodynamic analysis showed decreased plasma amyloid β levels. Conclusions: Crenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T‐ALL/T‐LBL. This report describes the clinical activity of a highly potent and selective Notch inhibitor, Crenigacestat, in combination with dexamethasone in adult patients with relapsed/refractory T‐cell acute lymphoblastic leukemia (T‐ALL)/T‐cell lymphoblastic lymphoma (‐LBL). In this study, the recommended phase 2 dose of 75 mg of Crenigacestat 3 times per week is established for patients with T‐ALL/T‐LBL in combination with dexamethasone. [ABSTRACT FROM AUTHOR]

Motivation Microscopy images of stained cells and tissues play a central role in most biomedical experiments and routine histopathology. Storing colour histological images digitally opens the possibility to process numerically colour distribution and intensity to extract quantitative data. Among those numerical procedures are colour deconvolution, which enable decomposing an RGB image into channels representing the optical absorbance and transmittance of the dyes when their RGB representation is known. Consequently, a range of new applications become possible for morphological and histochemical segmentation, automated marker localization and image enhancement. Availability and implementation Colour deconvolution is presented here in two open-source forms: a MATLAB program/function and an ImageJ plugin written in Java. Both versions run in Windows, Macintosh and UNIX-based systems under the respective platforms. Source code and further documentation are available at: https://blog.bham.ac.uk/intellimic/g-landini-software/colour-deconvolution-2/. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Earthquake precursors are elusive, and this elusiveness has hampered earthquake prediction. In this paper, the available catalogues of historical and contemporary geochemical and fluid-related precursors of earthquakes are considered. The locations of recording sites are mapped and compared with data concerning volcanic locations, heat flows, crustal velocities and the depth of seismic events. Possible relations among the considered geophysical parameters and the occurrence of fluid-related earthquake precursors are discussed. Only some geological and geophysical conditions may allow for the occurrence of fluid-related earthquake precursory phenomena. As a consequence, the geophysical models utilized to explain the occurrence of earthquake precursors should be updated. Furthermore, only some areas of the world are deemed suitable for earthquake fluid-related precursor monitoring. [ABSTRACT FROM AUTHOR]

Automatic monitoring techniques were utilized in the area of the Nirano mud volcanoes. Research activities included measurements of temperature and the level of muddy water. Automatic monitoring confirmed the suitability of the technologies used in unfavourable environmental locations. Preliminary data show possible dependence of the parameters monitored on atmospheric parameters and the lack of dependence with tidal parameters. Further research developments should consider possible variations of gas flow rate with time. [ABSTRACT FROM AUTHOR]

This paper describes the configuration of a permanent magnet linear actuator for biometric applications and explains the basics of the methodology used to evaluate the actuator thrust. The methodology, based on analytical expressions of the magnet flux linkage, enables a fast and accurate evaluation of the axial force and can apply to any set of coaxial coils. The formulations are used to optimize the actuator configuration, in order to improve the thrust uniformity along the mover stroke, some technological design fulfilling some technological design constraints. Introducing an auxiliary set of coaxial coils, the optimization procedure enables a remarkable uniformity improvement. The results are verified by finite-element analyses, and the measurements performed on a prototype confirm the effectiveness of the design procedure. [ABSTRACT FROM AUTHOR]

Surface latent heat flux (SLHF) is proportional to the heat released by phase changes during solidification, evaporation or melting. Effects of SLHF on the earth’s surface could be measured by satellite techniques capable of measuring thermal infrared radiation (TIR). Recent studies have found a possible correlation between SLHF and earthquakes, hence satellite techniques are widely used in research into the possible link between SLHF and earthquakes. Possible fluctuations in SLHF values during seismic periods have been attributed to different causes, such as the expulsion from the ground of greenhouse gases or because of radon. In particular, ionization processes due to radon decay could lead to changes in air temperature. Laboratory experiments have been carried out to highlight the possible role of radon in the thermal environmental conditions of a laboratory-controlled atmospheric volume. [ABSTRACT FROM AUTHOR]

Uncontrolled proliferative signals and cell cycle dysregulation due to genomic or functional alterations are important drivers of the expansion of undifferentiated blast cells in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. Therefore, they are largely studied as potential therapeutic targets in the field. We here present the most recent advancements in the evaluation of novel compounds targeting cell cycle proteins or oncogenic mechanisms, including those showing an antiproliferative effect in acute leukemia, independently of the identification of a specific target. Several new kinase inhibitors have been synthesized that showed effectiveness in a nanomolar to micromolar concentration range as inhibitors of FLT3 and its mutant forms, a highly attractive therapeutic target due to its driver role in a significant fraction of AML cases. Moreover, we introduce novel molecules functioning as microtubule-depolymerizing or P53-restoring agents, G-quadruplex-stabilizing molecules and CDK2, CHK1, PI3Kδ, STAT5, BRD4 and BRPF1 inhibitors. We here discuss their mechanisms of action, including the downstream intracellular changes induced by in vitro treatment, hematopoietic toxicity, in vivo bio-availability and efficacy in murine xenograft models. The promising activity profile demonstrated by some of these candidates deserves further development towards clinical investigation. [ABSTRACT FROM AUTHOR]

Abstract: The efficacy of high-dose chemotherapy (HDC) and autologous hemopoietic progenitor cell transplantation (AHPCT) for breast cancer (BC) patients has been an area of intense controversy among the medical oncology community. The aim of this study was to assess toxicity and efficacy of this procedure in a large cohort of high-risk primary BC patients who underwent AHPCT in Italy. A total of 1183 patients receiving HDC for high-risk BC (HRBC) (>3 positive nodes) were identified in the Italian registry. The median age was 46 years, 62% of patients were premenopausal at treatment, 60.1% had endocrine-responsive tumors, and 20.7% had a human epidermal growth factor receptor 2 (HER2)–positive tumor. The median number of positive lymph nodes (LN) at surgery was 15, with 71.5% of patients having ≥ 10 positive nodes. Seventy-three percent received an alkylating agent-based HDC as a single procedure, whereas 27% received epirubicin or mitoxantrone-containing HDC, usually within a multitransplantation program. The source of stem cells was peripheral blood in the vast majority of patients. Transplantation-related mortality was .8%, whereas late cardiac and secondary tumor-related mortality were around 1%, overall. With a median follow-up of 79 months, median disease-free and overall survival (OS) in the entire population were 101 and 134 months, respectively. Subgroup analysis demonstrated that OS was significantly better in patients with endocrine-responsive tumors and in patients receiving multiple transplantation procedures. HER2 status did not affect survival probability. The size of the primary tumor and number of involved LN negatively affected OS. Adjuvant HDC with AHPCT has a low mortality rate and provides impressive long-term survival rates in patients with high-risk primary BC. Our results suggest that this treatment modality should be proposed in selected HRBC patients and further investigated in clinical trials. [Copyright &y& Elsevier]

BACKGROUND In this phase 2 study, the authors evaluated the efficacy, safety, and tolerability of the Aurora B kinase inhibitor barasertib compared with low-dose cytosine arabinoside (LDAC) in patients aged ≥60 years with acute myeloid leukemia (AML). METHODS Patients were randomized 2:1 to receive either open-label barasertib 1200 mg (as a 7-day intravenous infusion) or LDAC 20 mg (subcutaneously twice daily for 10 days) in 28-day cycles. The primary endpoint was the objective complete response rate (OCRR) (complete responses [CR] plus confirmed CRs with incomplete recovery of neutrophils or platelets [CRi] according to Cheson criteria [also requiring reconfirmation of CRi ≥21 days after the first appearance and associated with partial recovery of platelets and neutrophils]). Secondary endpoints included overall survival (OS) and safety. RESULTS In total, 74 patients (barasertib, n = 48; LDAC, n = 26) completed ≥1 cycle of treatment. A significant improvement in the OCRR was observed with barasertib (35.4% vs 11.5%; difference, 23.9%; 95% confidence interval, 2.7%-39.9%; P < .05). Although the study was not formally sized to compare OS data, the median OS with barasertib was 8.2 months versus 4.5 months with LDAC (hazard ratio, 0.88; 95% confidence interval, 0.49-1.58; P = .663). Stomatitis and febrile neutropenia were the most common adverse events with barasertib versus LDAC (71% vs 15% and 67% vs 19%, respectively). CONCLUSIONS Barasertib produced a significant improvement in the OCRR versus LDAC and had a more toxic but manageable safety profile, consistent with previous studies. Cancer 2013;119:2611-2619. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

We report a study of an alternative treatment schedule of imatinib (IM) in chronic myeloid leukemia (CML). Seventy-six Philadelphia-positive (Ph +), BCR-ABL-positive patients aged 65 years or older who had been treated with IM for more than 2 years and who were in stable complete cytogenetic response (CC9R) and major molecular response (MMR) were enrolled in a single-arm study to test the effects of a policy of intermittent lM (INTERIM) therapy for 1 month on and 1 month off. With a minimum follow-up of 4 years, 13 patients (17%) lost CCgR and MMR and 14 (18%) lost MMR only. All these patients resumed continuous IM and all but one (lost to follow-up) regained CC9R and MMR. No patients progressed to accelerated or blastic phase or developed clonal chromosomal abnormalities in Ph+ cells or BCR-ABL mutations. In elderly Ph+ CML patients carefully selected for a stable CCgR (lasting >2 years), the policy of INTERIM treatment affected the markers of residual disease, but not the clinical outcomes (overall and progression-free survival). This trial was registered at www.clinicaltrials.gov as NCT 00858806. [ABSTRACT FROM AUTHOR]

Background: We evaluated BCR-ABL1 kinetics in patients treated with nilotinib and analyzed whether a dynamic model of changes in BCR-ABL1 levels over time could be used to predict long-term responses. Methods: Patients from the nilotinib registration trial (CAMN107A2101; registered at www.clinicaltrials.gov as NCT00109707) who had imatinib-resistant or -intolerant Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) or accelerated phase with BCR-ABL1 > 10% (on the international scale [IS]) at baseline and, in the first 6 months, had at least three BCR-ABL1 transcript measurements and an average daily dose of at least 720 mg were included in this analysis (N = 123). Results: More than half of patients (65/123; 53%) had a slow monophasic response and the remainder (58/123; 47%) had a biphasic response, in which patients had a rapid initial decrease in BCR-ABL1 transcripts followed by a more gradual response. The biphasic response type strongly correlated with improved event-free survival (EFS). Data in the first 6 months of follow-up were sufficient to predict EFS at 24 months. Conclusions: Unlike newly diagnosed patients with Ph+ CML-CP-in whom the majority had a biphasic response-approximately half of patients with imatinib-resistant or -intolerant CML had a slower, monophasic response. Second-line patients who did have a biphasic response had an EFS outlook similar to that of newly diagnosed patients treated with imatinib. Our model was comparable to using BCR-ABL1 (IS) ⩽ 10% at 6 months as a threshold for predicting EFS. [ABSTRACT FROM AUTHOR]

Here, we present the results of a randomised clinical trial carried out between 1998 and 2004, evaluating the possible role of radiotherapy (RT) as consolidation treatment after induction chemotherapy (CT) in diffuse large B-cell (DLBC) gastric lymphoma. Fifty-four patients were enrolled and all received anthracycline containing regimens as induction CT. Patients were evaluated after four to six cycles and those in complete remission (CR) were randomised to receive gastric involved field (IF) RT or two addition cycles of the same CT. Forty-five patients (83%) were randomised after the induction CT. Clinical results of patients allocated to the RT arm showed a significant reduction in incidence of local relapse versus patients who received CT alone. However, overall survival was not different between the two arms. Our results confirm that CT could be considered as first line therapy for newly diagnosed gastric DLBC lymphoma; IF RT delivered in those patients achieving CR after induction CT is able to prevent local relapse. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The addition of gemtuzumab-ozogamicin (GO) to an induction regimen including synergistic drugs, such as intermediate dose of cytarabine (Ara-C), idarubicin and fludarabine (FLAI), could reduce treatment failure in acute myeloid leukemia (AML) patients. Nevertheless, the role and safety of this antibody target-therapy in first-line chemotherapy in patients younger than 65 years has not yet been defined. Patients and methods: The primary goal of this prospective phase II pilot study was to evaluate the efficacy and the safety profile of FLAI plus GO as induction regimen. Thirty consecutive AML patients were included. All patients were younger than 65 with a median age of 53 years and CD33 expression exceeded 20% in all cases. The M/F ratio was 16/14 and 21/30 (70%) of patients were poor-risk at diagnosis. The induction regimen (FLAI-GO) included fludarabine (30mg/m2) and Ara-C (2g/m2) on days 1–5, idarubicin (10mg/m2) on days 1, 3, and 5 and GO (3mg/m2) on day 6. Hematopoietic stem cell transplant (HSCT) was planned for all high risk AML patients in first complete remission (CR) after consolidation with intermediate doses of Ara-C and idarubicin (IDAC-IDA). Cytogenetic, multidrug-resistance phenotype, FLT3 mutation status, and WT1 quantitative expression analyses were performed at diagnosis in all patients. WT1 expression and cytogenetic (in positive cases) analyses were performed after induction to detect and follow minimal residual disease. Results: Patients were evaluated for response rate, treatment-related adverse events, overall survival and relapse free survival. After induction with FLAI-GO, CR rate was 90% (26 of 29 evaluable pts); one patient achieved partial remission and two were resistant. There was only one case of death during induction (DDI). After FLAI-GO, the mean value of WT1 dropped from 4200±2777copies/104ABL to 192±399copies/104ABL. The toxicity of FLAI-GO was acceptable; 57% of patients experienced transient and reversible GO infusion-related adverse events (especially fever and chills), but no cases of veno-occlusive disease occurred during CHT or after HSCT. After a median follow-up of 16 months (range 2–25), 24/30 (80%) patients are alive (24/24 in CR). The probability of 1-year OS and RFS was 90 and 85%, respectively. Allogeneic and autologus HSCT was performed in 19 (63%) and 4 (13%) patients, respectively. Conclusions: These preliminary results suggest that FLAI-GO is an effective and well tolerated induction regimen for CD33 positive AML patients younger than 65 years, with a high complete response rate, favourable safety profile, low DDI. These results encourage the testing of this regimen in a multicenter prospective trial. [Copyright &y& Elsevier]

Chronic myeloid leukemia is a clonal myeloproliferative disorder characterized by the presence of the fusion gene BCR/ABL. We had previously demonstrated an increased proapoptotic effect of imatinib (STI571) in combination with amifostine (AMI) in K562 cell line. In this study, we used genomic scale gene expression profiling to monitor changes at transcriptional level in K562 cells during the treatment with AMI + STI571. cRNA from Control and treated K562 cells were mixed in equal amounts and incubated with a microarray slide for hybridization. RNA from six independent paired experiments was subjected to transcriptional profiling. With the aim to automate the process of biological theme determination, selected genes were further analyzed by EASE. Validation of the expression was carried out by quantitative real-time PCR and western blotting. As expected, a small percentage of genes accounts for the effects of the combined drug treatment. We identified 61 sequences corresponding to known genes; 17 of the 61 genes were up regulated, such as RHO6, PPP2R5E, PPM1E and BTF that appear to reflect favorable events for apoptosis induction. Between down regulated genes, API5, TUBB2 and TLK1 are also of considerable interest. We identified a transcriptional repressor of survival genes, known as BTF, which triggers a proapoptotic signal, potentially helpful to overcome the resistance to STI571. This finding could be particularly useful to design novel therapeutic strategies for leukemia patients. This study demonstrates the importance of in vitro testing of a novel drug combination most likely to predict its potential usefulness for in vivo application. [ABSTRACT FROM AUTHOR]

Background. Gram-positive pathogens can cause serious infections in neutropenic patients with cancer, and vancomycin therapy is often initiated empirically. Linezolid may offer an option for these patients. Methods. To compare the safety and efficacy of linezolid and vancomycin in febrile, neutropenic patients with cancer, we conducted a double-blind, multicenter equivalence study. Eligible patients with proven or suspected infection due to a gram-positive pathogen were randomized to receive linezolid or vancomycin. Results. Clinical success rates 7 days after completion of therapy (primary end point) were equivalent between groups in the intent-to-treat (ITT) analysis (linezolid, 219 [87.3%] of 251 patients; vancomycin, 202 [85.2%] of 237 patients; 95% CI, -4.1 to 8.1; P = 52), modified ITT analysis, clinically evaluable analysis, and microbiologically evaluable analysis, as well as between subsets analyzed by malignancy and infection type. Mean time to defervescence was shorter for linezolid than vancomycin in the modified ITT (6.6 vs. 8.5 days; P = .04) and microbiologically evaluable subsets (5.9 vs. 9.1 days; P = .01), although post hoc analyses revealed delayed recovery of absolute neutrophil counts for linezolid in these subsets (P<.05). There were no between-group differences in microbiologic success rates in the modified ITT subset (41 [57.7%] of 71 patients vs. 29 [50.0%] of 58 patients; P = .38) and microbiologically evaluable subsets, as well as in mortality rates in the ITT subset (17 [5.6%] of 304 patients vs. 23 [7.6%] of 301 patients; P = .31) and all subsets. Distribution of adverse events, including reported hematologic events, was similar between groups, except that linezolid was associated with fewer drug-related adverse events (52 [17.2%] of 303 patients vs. 72 [24.0%] of 300 patients; P = .04) and fewer cases of drug-related renal failure (1 [0.3%] of 303 patients vs. 7 [2.3%] of patients; P = .04). Conclusions. Linezolid demonstrated efficacy and similar safety outcomes equivalent to those for vancomycin in febrile neutropenic patients with cancer. [ABSTRACT FROM AUTHOR]

Antibody-targeted chemotherapy is a promising approach in patients with hematological malignancies. In particular, gemtuzumab ozogamicin (GO, formerly CMA-676), an anti-CD33 antibody linked to calicheamicin, has been approved for the treatment of elderly patients with acute myeloid leukemia (AML) in relapse. Nevertheless, no data are until now available concerning the possible efficacy of GO for myeloid sarcomas (MS). We treated with GO 24 AML patients, in 5 cases presenting with myeloid sarcomas of the skin or bones. The overall complete response rate was 21%. The median duration of response was 6 months. Four out of the 5 patients with myeloid sarcoma showed a regression of the masses, in two cases also obtaining a clearance of marrow blasts. The most common adverse events included thrombocytopenia, neutropenia, infections, elevation of bilirubin and hepatic transaminases. Notably, severe bleeding occurred in 5 cases (21%). VOD was documented in 1 case. We conclude that GO is effective as a single agent in AML and myeloid sarcomas. Further data are required to clarify the possible correlation between GO administration and occurrence of bleeding. [ABSTRACT FROM AUTHOR]

Gemtuzumab ozogamicin (GO), an anti-CD33 monoclonal antibody conjugated to calicheamicin, is effective as single agent in the treatment of poor risk acute myeloid leukaemia (AML) patients. We treated with GO in combination with cytarabine as continuous perfusion nine elderly AML patients, either untreated (five cases), or with relapsed/refractory disease (four cases). Five patients achieved a complete remission (CR), four were resistant. One patient died while in CR due to CNS haemorrhage, two relapsed and two are still in CR. The median CR duration was 10 months. The median overall survival was 6 months (1–19 months). The most common adverse event was myelosuppression, as expected. No hepatic veno-occlusive disease was recorded. Notably, in four cases we observed a grade III/IV bleeding, including gasto-intestinal bleeding, epistaxis, CNS haemorrhage, and ocular bleeding. Larger prospective studies are now warranted in order to better define the possible role of this regimen in the treatment of elderly AML patients. [Copyright &y& Elsevier]

This paper investigates the possible role of mechanochemical CO2 production due to stimulation from the action of friction on calcite. This experimentation has two objectives: firstly, to obtain information on the effect of the mechanical disassociation of carbon dioxide from the carbonates and, secondly, to simulate the conditions that may arise during a tectonic action.The action of disassociation has been observed on pure calcium carbonate from analyses ground at different times in a ring-roller mill. The ring-roller mill is a grinding system that mainly works through friction and, to a lesser extent, by non-hydrostatic compression.It has been observed that the grinding action determines an abundant release of carbon dioxide, with a non-linear trend that emulates the trend in the decrease in crystallinity. This indicates a close connection between crystallinity and the dissociation of carbonate. The Authors hypothesize a carbon dioxide release mechanism linked to the factures induced by the friction and the increase in the structural disorder induced in the lattice by the plastic sliding. This mechanism could play an important role in the natural release of CO2, along with the other carbon dioxide sources that are already known of. [Copyright &y& Elsevier]

We investigated the toxicity and efficacy of the chimaeric anti-CD20 antibody rituximab in combination with standard-dose chlorambucil in newly diagnosed and relapsed/refractory indolent B-cell lymphoma patients. A total of 29 patients (15 newly diagnosed and 14 relapsed/refractory) with low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) were included in this phase II study. Therapy consisted of chlorambucil 6 mg/m2/d for 6 consecutive weeks in combination with a standard 4-weekly rituximab administration schedule in the induction phase. Patients responding to the induction therapy received four additional cycles with chlorambucil (6 mg/m2/d for 2 weeks/month) plus rituximab (once a month). Twenty-six patients (89%) completed the treatment; only one patient discontinued treatment because of haematological toxicity. At the end of the study, the dose of chlorambucil had to be reduced in seven patients (27%) and six patients (23%) required a delay in further treatment, as a result of toxicity during consolidation therapy. Only one patient was withdrawn from the study because of progressive disease; the 27 patients evaluable for response at the end of consolidation achieved a clinical response (63% complete response and 26% partial response). A significant CD4+ and CD56+ depletion was observed after induction and during consolidation therapy; two herpes zoster virus infections and one perianal abscess represented major infectious morbidities registered during the study. Based on our preliminary data, the combination of chlorambucil with rituximab seemed to be well tolerated and active. Its definitive role in the treatment of low-grade NHL should be further evaluated in randomized trials. [ABSTRACT FROM AUTHOR]

Evaluates the cytogenetic response of patients with chronic myeloid leukemia treated with alpha-interferon. Feasibility of peripheral blood stem cell mobilization induced by granulocyte-colony stimulating factor (G-CSF); Patient tolerance for G-CSF; Number of patients who achieved karyotypic remission before mobilization.

During the COVID-19 pandemic, there has been a significant increase in the use of non-contact infrared devices for screening the body temperatures of people at the entrances of hospitals, airports, train stations, churches, schools, shops, sports centres, offices, and public places in general. The strong correlation between a high body temperature and SARS-CoV-2 infection has motivated the governments of several countries to restrict access to public indoor places simply based on a person's body temperature. Negating/allowing entrance to a public place can have a strong impact on people. For example, a cancer patient could be refused access to a cancer centre because of an incorrect high temperature measurement. On the other hand, underestimating an individual's body temperature may allow infected patients to enter indoor public places where it is much easier for the virus to spread to other people. Accordingly, during the COVID-19 pandemic, the reliability of body temperature measurements has become fundamental. In particular, a debated issue is the reliability of remote temperature measurements, especially when these are aimed at identifying in a quick and reliable way infected subjects. Working distance, body–device angle, and light conditions and many other metrological and subjective issues significantly affect the data acquired via common contactless infrared point thermometers, making the acquisition of reliable measurements at the entrance to public places a challenging task. The main objective of this work is to sensitize the community to the typical incorrect uses of infrared point thermometers, as well as the resulting drifts in measurements of body temperature. Using several commercial contactless infrared point thermometers, we performed four different experiments to simulate common scenarios in a triage emergency room. In the first experiment, we acquired several measurements for each thermometer without measuring the working distance or angle of inclination to show that, for some instruments, the values obtained can differ by 1 °C. In the second and third experiments, we analysed the impacts of the working distance and angle of inclination of the thermometers, respectively, to prove that only a few cm/degrees can cause drifts higher than 1 °C. Finally, in the fourth experiment, we showed that the light in the environment can also cause changes in temperature up to 0.5 °C. Ultimately, in this study, we quantitatively demonstrated that the working distance, angle of inclination, and light conditions can strongly impact temperature measurements, which could invalidate the screening results. [ABSTRACT FROM AUTHOR]

The treatment landscape of chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults, is constantly changing. CLL patients can be divided into three risk categories, based on their IGHV mutational status and the occurrence of TP53 disruption and/or complex karyotype. For the first-line treatment of low- and intermediate-risk CLL, both the BCL2 inhibitor venetoclax plus obinutuzumab and the second generation BTK inhibitors (BTKi), namely acalabrutinib and zanubrutinib, are valuable and effective options. Conversely, venetoclax-based fixed duration therapies have not shown remarkable results in high-risk CLL patients, while continuous treatment with acalabrutinib and zanubrutinib displayed favorable outcomes, similar to those obtained in TP53 wild-type patients. The development of acquired resistance to pathway inhibitors is still a clinical challenge, and the optimal treatment sequencing of relapsed/refractory CLL is not completely established. Covalent BTKi-refractory patients should be treated with venetoclax plus rituximab, whereas venetoclax-refractory CLL may be treated with second generation BTKi in the case of early relapse, while venetoclax plus rituximab might be used if late relapse has occurred. On these grounds, here we provide an overview of the current state-of-the-art therapeutic algorithms for treatment-naïve patients, as well as for relapsed/refractory disease. [ABSTRACT FROM AUTHOR]

Seismic hazard reduction policies usually utilize earthquake catalogues and probability evaluations of occurrence. Further geophysical and geochemical parameters could contribute to hazard reduction policies as is currently the case in some countries, such as Iceland, Taiwan, China and Russian Federation. In the past four decades, intense research activity carried out by many different institutions in Italy has allowed us to recognize the most relevant sensitive sites for detecting acceleration in crustal deformation processes by means of geofluids monitoring. All scientific papers published in the period 1976–2020 concerning tectonic-related signals in geofluids have been considered. An in-depth review of previous and present-day research activities, as well as an update of two unpublished time series recorded in Central and Southern Italy, has contributed to identifying areas where an instrumental array is still lacking and the most relevant priority areas for monitoring activities in geofluids. An atlas of all experimental sites utilized in recent decades has been obtained with the purpose of contributing to identifying the most suitable monitoring areas. [ABSTRACT FROM AUTHOR]

The feasibility of sequential positive and negative selection of mobilized CD34+ B-lineage negative cells to achieve tumour-free autografts in multiple myeloma (MM) patients was evaluated. Peripheral blood stem cells (PBSC) of 14 patients with advanced disease were mobilized. CD34+ cells were enriched in 12 of the patients by the avidin–biotin immunoabsorption technique. Subsequently, CD10+, CD19+, CD20+ and CD56+ cells (B-lin cells) were removed by immunomagnetic depletion. Minimal residual disease (MRD) was detected by flow cytometry and PCR-based molecular analysis of the patient specific IgH complementary-determining region III (CDRIII). Positive selection of stem cells produced a median recovery of 54.7% of the initial content of CD34+ cells (median purity 71.9%). Negative depletion of B-lineage cells reduced the number of CD34+ cells to 33.3% of the baseline value (median purity 72.7%). However, long-term culture assays showed the recovery of >60% of primitive haemopoietic progenitor cells after depletion of the B-lineage-positive cells. All evaluable patients had detectable disease in PBSC collections. The first step of positive selection of CD34+ cells resulted in >2 logs of tumour cell purging. However, molecular assessment showed the persistence of the disease in 6/7 cases. Immunofluorescence analysis demonstrated 1 additional log of B-cell purging by negative depletion. More importantly, molecular evaluation of IgH CDRIII region showed the disappearance of myeloma cells in 6/7 patients. 12 patients received a median of 3.9 × 106 CD34+ B-lin- cells/kg after conditioning with high-dose melphalan and showed a rapid reconstitution of haemopoiesis. These results were similar to two similar cohorts of patients who received either unmanipulated PBSC or positively selected CD34+ cells after the same... [ABSTRACT FROM AUTHOR]

Fitness sensors and health systems are paving the way toward improving the quality of medical care by exploiting the benefits of new technology. For example, the great amount of patient-generated health data available today gives new opportunities to measure life parameters in real time and create a revolution in communication for professionals and patients. In this work, we concentrated on the basic parameter typically measured by fitness applications and devices—the number of steps taken daily. In particular, the main goal of this study was to compare the accuracy and precision of smartphone applications versus those of wearable devices to give users an idea about what can be expected regarding the relative difference in measurements achieved using different system typologies. In particular, the data obtained showed a difference of approximately 30%, proving that smartphone applications provide inaccurate measurements in long-term analysis, while wearable devices are precise and accurate. Accordingly, we challenge the reliability of previous studies reporting data collected with phone-based applications, and besides discussing the current limitations, we support the use of wearable devices for mHealth. [ABSTRACT FROM AUTHOR]

This study assesses the correlations between the intensity of stress undergone by crystals and the morphological characteristics of particles and fracturing products. The effects of the fractures on the microstructure of quartz are also studied. Alpha quartz, subjected to shear stress, is quickly crushed according to a fracturing sequence, with a total fracture length that is correlated to the stress rate. The shear stress generates a sequence of macro and microstructural events, in particular localized melting phenomena, never highlighted before on quartz and the formation of different polymorphs, such as cristobalite and tridymite together with amorphous silica. [ABSTRACT FROM AUTHOR]

The huge volume of data gathered from wearable fitness devices and wellness appliances, if effectively analysed and integrated, can be exploited to improve clinical decision making and to stimulate promising applications, as they can provide good measures of everyday patient behaviour and lifestyle. However, several obstacles currently limit the true exploitation of these opportunities. In particular, the healthcare landscape is characterised by a pervasive presence of data silos which prevent users and healthcare professionals from obtaining an overall view of the knowledge, mainly due to the lack of device interoperability and data representation format heterogeneity. This work focuses on current, important needs in self-tracked health data modelling, and summarises challenges and opportunities that will characterise the community in the upcoming years. The paper describes a virtually integrated approach using standard Web Semantic technologies and Linked Open Data to cope with heterogeneous health data integration. The proposed approach is verified using data collected from several IoT fitness vendors to form a standard context-aware resource graph, and linking other health ontologies and open projects. We developed a web portal for integrating, sharing and analysing through a customisable dashboard heterogeneous IoT health and fitness data. In this way, we are able to map information onto an integrated domain model by providing support for logical reasoning. [ABSTRACT FROM AUTHOR]

In adult patients, acute lymphoblastic leukemia (ALL) is a rare hematological cancer with a cure rate below 50% and frequent relapses. With traditional therapies, patients with relapsed or refractory (R/R) ALL have a survival that may be measured in months; in these patients, inotuzumab ozogamicin (IO) is an effective therapy. IO was linked to increased risk of veno‐occlusive disease/sinusoid obstruction syndrome (VOD/SOS), liver injury, and various grade of liver‐related complications during clinical trials and real‐life settings; however, hepatologic monitoring protocol is not established in this population. In our institution, 21 patients who received IO (median of 6 doses of IO administered) for R/R ALL were prospectively followed for hepatologic surveillance, including clinical evaluation, ultrasonography, and liver stiffness measurement (LSM) biochemistry. After a median follow‐up of 17.2 months, two SOS events were reported (both after allogeneic transplant) as IO potentially related clinically relevant adverse event. Mild alterations were reported in almost the totality of patients and moderate‐severe liver biochemical alterations in a quarter of patients. Within biochemicals value, AST and ALP showed an augment related to IO administration. LSM linearly augmented for each IO course administered. Baseline LSM was related to liver‐related changes, especially with the severity of portal hypertension (PH)‐related complications. Pre‐transplant LSM was higher in patients receiving IO when compared with a control cohort. PH‐related complications were discovered in nearly 77% of patients, with clinically significant PH occurrence and development of ascites in 38% and 14%, respectively. This prospective experience constitutes the rationale to design a hepatologic monitoring program in patients receiving IO. LSM may be of pivotal importance in this program, constituting a rapid and effective screening that quantitatively correlates with liver alterations. [ABSTRACT FROM AUTHOR]

For advanced therapy medicinal products, the development and validation of potency assays are required, in accordance with international guidelines, to characterise the product and obtain reliable and consistent data. Our purpose was to validate the killing assay for the evaluation of autologous anti-CD19 chimeric antigen receptor (CAR) T potency. We used CD4 + and CD8 + lymphocytes or anti-CD19 CAR-T cells as effector cells and REH (CD19 +) or MOLM-13 (CD19 −) cell lines as target cells. After co-culturing target and effector cells (1:1 ratio) for 24 h, samples were labelled with 7-AAD, anti-CD3 and anti-CD19 antibodies and the frequency of CD19 + dead cells was evaluated by flow cytometry. In order to verify the CAR-T specificity for the CD19 + target, the co-culture between CAR-T and REH or MOLM-13 at different effector-to-target ratios was scheduled. Moreover, not transduced CD4 + and CD8 + lymphocytes were tested in comparison with CAR-T from the same donor to demonstrate the assay specificity. Linearity and accuracy were evaluated, and established acceptance criteria were compiled for both parameters (r2 ≥ 0.97 for linearity and average relative error ≤ 10% for accuracy). Furthermore, the method was considered robust when performed between 23 and 25 h of co-culture, and the intra-assay, inter-assay and inter-day precision was obtained. Finally, in order to verify the inter-analyst precision, the test was executed by three different operators and the intra-class correlation coefficient was > 0.4 in both cases. In conclusion, we consider this CAR-T potency assay as validated and usable in all steps of product development and quality control. [ABSTRACT FROM AUTHOR]

Hazard reduction policies include seismic hazard maps based on probabilistic evaluations and the evaluation of geophysical parameters continuously recorded by instrumental networks. Over the past 25 centuries, a large amount of information about earthquake precursory phenomena has been recorded by scholars, scientific institutions, and civil defense agencies. In particular, hydrogeologic measurements and geochemical analyses have been performed in geofluids in search of possible and reliable earthquake precursors. Controlled experimental areas have been set up to investigate physical and chemical mechanisms originating possible preseismic precursory signals. The main test sites for such research are located in China, Iceland, Japan, the Russian Federation, Taiwan, and the USA. The present state of the art about the most relevant scientific achievements has been described. Future research trends and possible development paths have been identified and allow for possible improvements in policies oriented to seismic hazard reduction by geofluid monitoring. [ABSTRACT FROM AUTHOR]

This paper presents the results of measurements performed on α-quartz subjected to shear stress in dry conditions, to understand the relationship between the shear intensity and the resulting physical and chemical effects. If a shear stress of intensity higher than 100 MPa is applied continuously to alpha quartz crystals, they will tend to lose their crystallinity, progressively reduce their friction coefficient (Cof) and change into a low-order material, apparently amorphous under X-ray diffraction, but with a structure different from silica glass. Raman and Pair Distribution Function analyses suggested a structure like cristobalite, a silica polymorph well-known for its auxetic behavior, i.e., having a negative Poisson ratio. This elastic parameter pre-eminently controls the friction coefficient of the material and, if it is negative, the Cof lowering. As a result, the increase in low crystallinity cristobalite is sufficientto explain the lowering of the quartz friction coefficient up to values able to contribute, in principle, to the triggering processes of active faults. This allows hypothesizing a slip induction mechanism that does not include the need to have the interposition of layers of hydrated silica, as invoked by many authors, to justify the low friction coefficients that are achieved in shear stress tests on rocks abundant in quartz. [ABSTRACT FROM AUTHOR]

Shear tests on quartz rocks and single quartz crystals have been conducted to understand the possible relationship between the intensity of detectable stress in fault areas and the energy released in the form of electromagnetic waves in the range 30 KHz-1 MHz (LF–MF). For these tests, a new type of piston-cylinder has been developed, instrumented to collect the electromagnetic signals generated by the quartz during shear stress tests and that allows energy measurements on electromagnetic emissions (EMR) to be performed. The data obtained indicate that shear-stressed quartz crystals can generate electromagnetic emissions in the LF–MF range. These emissions represent a tiny fraction of the total energy dissipated in the fracturing process. The spectrum of radio emissions consists of continuous radiation and overlapping peaks. For the first time, a characteristic migration of peak frequencies was observed, proportional to the evolution of the fracturing process. In particular, the continuous recording of the radio emission spectra shows a migration of the peaks toward higher frequencies, as stress continues over time and smaller and larger fractures form. This migration could be used to distinguish possible natural signals emitted by quartz in tectonically active environments from possible signals of other geophysical and possibly anthropogenic origin. [ABSTRACT FROM AUTHOR]

Bone marrow aspiration and biopsy (BMAB) is a painful procedure, and the routinely used local infiltration anesthesia (LIA) with lidocaine is unable to provide pain relief during the most uncomfortable phases. The primary endpoint of the present randomized, patient-blinded trial was to evaluate the efficacy of an opioid and benzodiazepine combination plus LIA (sedoanalgesia) in patients undergoing BMAB for hematological malignancies. The secondary endpoint was the safety of the procedure in an outpatient setting. Ancillary assessments were anticipatory anxiety related to pain recall in the event of re-biopsy, and adequacy of bone tissue harvested. Patients were randomly assigned to one of 2 arms to receive either sedoanalgesic placebo plus LIA (standard group) or oral fentanyl citrate 200 μg plus oral midazolam 5 mg plus LIA (combo group) during BMAB. Pre-procedural anxiety and procedural pain were assessed according to the Numerical Rating Scale (NRS: 0–10), dividing the time of the procedure into five intervals (T0, T1, T2a, T2b and T3) and evaluating the degree of discomfort at each time (T) in both groups. One hundred and sixteen patients were eligible for the study. At T2b (time of biopsy) and T3 (time after biopsy), a significantly lower perception of pain was registered in the combo group. Moreover, there were no significant sedoanalgesia-related side-effects. Finally, histological specimens were higher in quality in the combo group. Sedoanalgesia was highly effective in reducing pain during biopsy, diminished anticipatory anxiety in patients undergoing re-biopsy and led to fewer non-diagnostic specimens being harvested. [ABSTRACT FROM AUTHOR]

Mitosis is the process whereby an eukaryotic cell divides into two identical copies. Different multiprotein complexes are involved in the fine regulation of cell division, including the mitotic promoting factor and the anaphase promoting complex. Prolonged mitosis can result in cellular division, cell death, or mitotic slippage, the latter leading to a new interphase without cellular division. Mitotic slippage is one of the causes of genomic instability and has an important therapeutic and clinical impact. It has been widely studied in solid tumors but not in hematological malignancies, in particular, in acute leukemia. We review the literature data available on mitotic regulation, alterations in mitotic proteins occurring in acute leukemia, induction of prolonged mitosis and its consequences, focusing in particular on the balance between cell death and mitotic slippage and on its therapeutic potentials. We also present the most recent preclinical and clinical data on the efficacy of second-generation mitotic drugs (CDK1-Cyclin B1, APC/CCDC20, PLK, Aurora kinase inhibitors). Despite the poor clinical activity showed by these drugs as single agents, they offer a potential therapeutic window for synthetic lethal combinations aimed to selectively target leukemic cells at the right time, thus decreasing the risk of mitotic slippage events. [ABSTRACT FROM AUTHOR]

Despite aggressive approaches, including second transplant, donor lymphocyte infusion and several new agents, the prognosis of acute lymphoid leukemia (ALL) patients relapsing after stem-cell transplantation (SCT) remains poor. Monoclonal-antibodies (moAb) could provide a useful tool in this setting. In particular, anti-CD52 moAb is useful in lymphoid malignancies. We thus treated as compassionate with campath-1H 3 ALL patients relapsed after SCT. In 2 cases we observed a reduction of peripheral blood and/or bone marrow blasts. In 1 case a GVHD grade reduction was observed. Larger trials are required in order to define the role of campath-1H in ALL. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) survival rates have been substantially increased thanks to novel agents that have improved survival outcomes and shown better tolerability than treatments of earlier years. These new agents include immunomodulating imide drugs (IMiD) thalidomide and lenalidomide, the proteasome inhibitor bortezomib (PI), recently followed by new generation IMID pomalidomide, monoclonal antibodies daratumumab and elotuzumab, and next generation PI carfilzomib and ixazomib. However, even in this more promising scenario, febrile neutropenia remains a severe side effect of antineoplastic therapies and can lead to a delay and/or dose reduction in subsequent cycles. Supportive care has thus become key in helping patients to obtain the maximum benefit from novel agents. Filgrastim is a human recombinant subcutaneous preparation of G-CSF, largely adopted in hematological supportive care as "on demand" (or secondary) prophylaxis to recovery from neutropenia and its infectious consequences during anti-myeloma treatment. On the contrary, pegfilgrastim is a pegylated long-acting recombinant form of granulocyte colony-stimulating factor (G-CSF) that, given its extended half-life, can be particularly useful when adopted as "primary prophylaxis," therefore before the onset of neutropenia, along chemotherapy treatment in multiple myeloma patients. There is no direct comparison between the two G-CSF delivery modalities. In this review, we compare data on the two administrations' modality, highlighting the efficacy of the secondary prophylaxis over multiple myeloma treatment. Advantage of pegfilgrastim could be as follows: the fixed administration rather than multiple injections, reduction in neutropenia and febrile neutropenia rates, and, finally, a cost-effectiveness advantage. [ABSTRACT FROM AUTHOR]

Most of the time, the deep analysis of a biological sample requires the acquisition of images at different time points, using different modalities and/or different stainings. This information gives morphological, functional, and physiological insights, but the acquired images must be aligned to be able to proceed with the co-localisation analysis. Practically speaking, according to Aristotle's principle, "The whole is greater than the sum of its parts", multi-modal image registration is a challenging task that involves fusing complementary signals. In the past few years, several methods for image registration have been described in the literature, but unfortunately, there is not one method that works for all applications. In addition, there is currently no user-friendly solution for aligning images that does not require any computer skills. In this work, DS4H Image Alignment (DS4H-IA), an open-source ImageJ/Fiji plugin for aligning multimodality, immunohistochemistry (IHC), and/or immunofluorescence (IF) 2D microscopy images, designed with the goal of being extremely easy to use, is described. All of the available solutions for aligning 2D microscopy images have also been revised. The DS4H-IA source code; standalone applications for MAC, Linux, and Windows; video tutorials; manual documentation; and sample datasets are publicly available. [ABSTRACT FROM AUTHOR]

ETV6::ABL1 rearranged neoplasms are rare hematological diseases. To date, about 80 cases have been reported, including myeloid and lymphoid leukemias. The ETV6 gene codes for an ETS family transcription factor and several fusion partners have been described. When translocated, ETV6 causes the constitutive activation of the partner genes. Here, we report the case of a 54-year-old woman with a cryptic insertion of the 3′ region of ABL1 in the ETV6 gene. The patient was first diagnosed with idiopathic hypereosinophilic syndrome, according to the clinical history, conventional cytogenetics, standard molecular analyses and pathologist description. Next generation sequencing of diagnosis samples unexpectedly detected both ETV6::ABL1 type A and B fusion transcripts, which were then confirmed by FISH. The diagnosis was Myeloid/Lymphoid neoplasm with ETV6::ABL1 fusion, and the patient received imatinib mesylate treatment. In a follow-up after more than one year, the patient still maintained the molecular and complete hematological responses. This case highlights the importance of timely and proper diagnostics and prompt tyrosine kinase inhibitor treatment. [ABSTRACT FROM AUTHOR]

Glasdegib is an inhibitor of the Hedgehog pathway recently approved in the United States for the treatment of acute myeloid leukemia. A population pharmacokinetic analysis was conducted to characterize the kinetic behavior of glasdegib and its sources of variability (covariates) by utilizing data from 269 patients with cancer treated with oral glasdegib doses ranging from 5 to 640 mg/d. Nonlinear mixed-effects modeling was conducted using NONMEM (v.7.3) and Perl-speaks NONMEM (v.4.2.0). The estimated apparent total clearance, apparent central volume of distribution, and apparent peripheral volume of distribution were 6.27 L/h, 3.32 L, and 279.2 L, respectively. Age, sex, race, and hepatic function were not significant covariates on glasdegib pharmacokinetic parameters. Baseline body weight, percentage bone marrow blasts, creatinine clearance, and use of moderate or strong cytochrome P450 3A inhibitors were statistically significant covariates on apparent total clearance; however, the magnitude of the effects was not considered clinically meaningful. [ABSTRACT FROM AUTHOR]

Circulating tumor DNA predicts prognosis of mCRC patients receiving first-line bevacizumab based-chemotherapy PURPOSE: Plasma circulating tumor DNA (ctDNA) is a valuable resource for tumor characterization and for monitoring of residual disease during treatment; however, it is not yet introduced in metastatic colorectal cancer (mCRC) routine clinical practice. In this retrospective exploratory study, we evaluated the role of ctDNA in patients with mCRC treated with chemotherapy plus bevacizumab. MATERIALS AND METHODS: Fifty-three patients were characterized for RAS and BRAF status on tumor tissue before the start of treatment. Plasma was collected at baseline, at first clinical evaluation, and at disease progression. ctDNA analysis was performed using Oncomine Colon cfDNA Assay on the Ion S5 XL instrument. RESULTS: At baseline, from a plasma sample, RAS , BRAF , or PIK3CA mutations were detected in 44 patients. A high correspondence was observed between ctDNA and tumor tissue mutations (KRAS 100%, NRAS 97.9%, BRAF 97.9%, PIK3CA 90%). Low baseline variant allele frequency (VAF) was found to be associated with longer median progression-free survival (PFS) compared with those with high VAF (15.9 v 12.2 months, P =.02). A higher PFS {12.29 months (95% CI, 9.03 to 17.9) v 8.15 months (95% CI, 2.76 to not available [NA]), P =.04} and overall survival (34.1 months [95% CI, 21.68 to NA] v 11.1 months [95% CI, 3.71 to NA], P =.003) were observed in patients with large decline in VAF at first evaluation. CONCLUSION: ctDNA analysis is useful for molecular characterization and tumor response monitoring in patients with mCRC. Quantitative variations of released ctDNA are associated with clinical outcomes. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL), is a hematologic malignancy characterized by the uncontrolled proliferation of mature B lymphocytes. CLL is the most prevalent leukemia in Western countries. Its presentation can range from asymptomatic with the incidental finding of absolute lymphocytosis on a routine blood test, to symptomatic disease requiring immediate intervention. Prognosis of the disease is defined by the presence or absence of specific mutations such as TP53, chromosomal abnormalities such as del(17p), a type of IGHV mutational status, and elevation of B2M and LDH. Treatment of CLL in the United States and Europe has evolved over the recent years thanks to the development of targeted therapies. The standard of care has shifted from traditional chemoimmunotherapy approaches to targeted therapies including Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors, administered either as monotherapy or in combination with CD20 monoclonal antibodies. Several clinical trials have also recently evaluated combinations of BTKi and venetoclax and showed the combination to be well tolerated and able to induce deep remissions. Targeted therapies have a good safety profile overall; however, they also have unique toxicities that are important to recognize. Diarrhea, fatigue, arthralgia, infections, cytopenias, bleeding, and cardiovascular toxicities (including atrial fibrillation, ventricular arrhythmias, and hypertension) are the adverse events (AEs) commonly associated with BTKis. Initiation of therapy with venetoclax requires close monitoring because of the risk for tumor lysis syndrome associated with this agent, particularly in patients with a high disease burden. Development of newer target therapies is ongoing and the therapeutic landscape in CLL is expanding rapidly. [ABSTRACT FROM AUTHOR]

Introduction: Three-dimensional (3D) multicellular spheroids are fundamental in vitro tools for studying in vivo tissues. Volume is the main feature used for evaluating the drug/treatment effects, but several other features can be estimated even from a simple 2D image. For high-content screening analysis, the bottleneck is the segmentation stage, which is essential for detecting the spheroids in the images and then proceeding to the feature extraction stage for performing morphotypic analysis. Problem: Today, several tools are available for extracting morphological features from spheroid images, but all of them have pros and cons and there is no general validated solution. Thanks to new deep learning models, it is possible to standardize the process and adapt the analysis to big data. Novelty: Starting from the first version of AnaSP, an open-source software suitable for estimating several morphological features of 3D spheroids, we implemented a new module for automatically segmenting 2D brightfield images of spheroids by exploiting convolutional neural networks. Results: Several deep learning segmentation models (i.e., VVG16, VGG19, ResNet18, ResNet50) have been trained and compared. All of them obtained very interesting results and ResNet18 ranked as the best-performing. Conclusions: A network based on an 18-layer deep residual architecture (ResNet-18) has been integrated into AnaSP, releasing AnaSP 2.0, a version of the tool optimized for high-content screening analysis. The source code, standalone versions, user manual, sample images, video tutorial, and further documentation are freely available at: https://sourceforge.net/p/anasp. [ABSTRACT FROM AUTHOR]

Background: Patients with relapsed or refractory FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia have a poor prognosis, including high frequency of relapse, poorer response to salvage therapy, and shorter overall survival than those with FLT3 wild-type disease. We aimed to assess whether single-agent quizartinib, an oral, highly potent and selective type II FLT3 inhibitor, improves overall survival versus salvage chemotherapy.Methods: QuANTUM-R is a randomised, controlled, phase 3 trial done at 152 hospitals and cancer centres in 19 countries. Eligible patients aged 18 years or older with ECOG performance status 0-2 with relapsed or refractory (duration of first composite complete remission ≤6 months) FLT3-ITD acute myeloid leukaemia after standard therapy with or without allogeneic haemopoietic stem-cell transplantation were randomly assigned (2:1; permuted block size of 6; stratified by response to previous therapy and choice of chemotherapy via a phone-based and web-based interactive response system) to quizartinib (60 mg [30 mg lead-in] orally once daily) or investigator's choice of preselected chemotherapy: subcutaneous low-dose cytarabine (subcutaneous injection of cytarabine 20 mg twice daily on days 1-10 of 28-day cycles); intravenous infusions of mitoxantrone (8 mg/m2 per day), etoposide (100 mg/m2 per day), and cytarabine (1000 mg/m2 per day on days 1-5 of up to two 28-day cycles); or intravenous granulocyte colony-stimulating factor (300 μg/m2 per day or 5 μg/kg per day subcutaneously on days 1-5), fludarabine (intravenous infusion 30 mg/m2 per day on days 2-6), cytarabine (intravenous infusion 2000 mg/m2 per day on days 2-6), and idarubicin (intravenous infusion 10 mg/m2 per day on days 2-4 in up to two 28-day cycles). Patients proceeding to haemopoietic stem-cell transplantation after quizartinib could resume quizartinib after haemopoietic stem-cell transplantation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02039726, and follow-up is ongoing.Findings: Between May 7, 2014, and Sept 13, 2017, 367 patients were enrolled, of whom 245 were randomly allocated to quizartinib and 122 to chemotherapy. Four patients in the quizartinib group and 28 in the chemotherapy group were not treated. Median follow-up was 23·5 months (IQR 15·4-32·3). Overall survival was longer for quizartinib than for chemotherapy (hazard ratio 0·76 [95% CI 0·58-0·98; p=0·02]). Median overall survival was 6·2 months (5·3-7·2) in the quizartinib group and 4·7 months (4·0-5·5) in the chemotherapy group. The most common non-haematological grade 3-5 treatment-emergent adverse events (within ≤30 days of last dose or >30 days if suspected to be a treatment-related event) for quizartinib (241 patients) and chemotherapy (94 patients) were sepsis or septic shock (46 patients [19%] for quizartinib vs 18 [19%] for chemotherapy), pneumonia (29 [12%] vs eight [9%]), and hypokalaemia (28 [12%] vs eight [9%]). The most frequent treatment-related serious adverse events were febrile neutropenia (18 patients [7%]), sepsis or septic shock (11 [5%]), QT prolongation (five [2%]), and nausea (five [2%]) in the quizartinib group, and febrile neutropenia (five [5%]), sepsis or septic shock (four [4%]), pneumonia (two [2%]), and pyrexia (two [2%]) in the chemotherapy group. Grade 3 QT prolongation in the quizartinib group was uncommon (eight [3%] by central reading, ten [4%] by investigator report); no grade 4 events occurred. There were 80 (33%) treatment-emergent deaths in the quizartinib group (31 [13%] of which were due to adverse events) and 16 (17%) in the chemotherapy group (nine [10%] of which were due to adverse events).Interpretation: Treatment with quizartinib had a survival benefit versus salvage chemotherapy and had a manageable safety profile in patients with rapidly proliferative disease and very poor prognosis. Quizartinib could be considered a new standard of care. Given that there are only a few available treatment options, this study highlights the value of targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor.Funding: Daiichi Sankyo. [ABSTRACT FROM AUTHOR]