Cytogenetic characterisation of childhood acute lymphoblastic leukemia in Nicaragua

BACKGROUND: Within the frame of a twinning programme with Nicaragua, The La Mascota project, we evaluated in our study the contribution of cytogenetic characterization of acute lymphoblastic leukemia (ALL) as prognostic factor compared to clinical, morphological, and immunohistochemical parameters. METHODS: All patients with ALL treated at the only cancer pediatric hospital in Nicaragua during 2006 were studied prospectively. Diagnostic immunophenotyping was performed locally and bone marrow or blood samples were sent to the cytogenetic laboratory of Zurich for fluorescence in situ hybridization (FISH) analysis and G-banding. RESULTS: Sixty-six patients with ALL were evaluated. Their mean age at diagnosis was 7.3 years, 31.8% were >or=10 years. Thirty-four patients (51.5%) presented with hyperleucocytosis >or=50 x 10(9)/L, 45 (68.2%) had hepatosplenomegaly. Immunophenotypically 63/66 patients (95%) had a B-precursor, 2 (3%) a T- and 1 (1.5%) a B-mature ALL. FISH analysis demonstrated a TEL/AML1 fusion in 9/66 (14%), BCR/ABL fusion in 1 (1.5%), MLL rearrangement in 2 (3.1%), iAMP21 in 2 (3.1%), MYC rearrangement in 1 (1.5%), and high-hyperdiploidy in 16 (24%). All patients but two with TEL/AML1 fusion and high-hyperdiploidy were clinically and hematologically in the standard risk group whereas those with poor cytogenetic factors had clinical high-risk features and were treated intensively. CONCLUSIONS: Compared to Europe, the ALL population in Nicaragua is older, has a higher proportion of poor prognostic clinical and hematological features and receives more intensive treatment, while patients with TEL/AML1 translocations and high-hyperdiploidy are clinically in the standard risk group. Cytogenetics did not contribute as an additional prognostic factor in this setting

GIS and statistical analysis for landslide susceptibility mapping in the Daunia area, Italy

This study focuses on landslide susceptibility mapping in the Daunia area (Apulian Apennines, Italy) and achieves this by using a multivariate statistical method and data processing in a Geographical Information System (GIS). The Logistic Regression (hereafter LR) method was chosen to produce a susceptibility map over an area of 130 000 ha where small settlements are historically threatened by landslide phenomena. By means of LR analysis, the tendency to landslide occurrences was, therefore, assessed by relating a landslide inventory (dependent variable) to a series of causal factors (independent variables) which were managed in the GIS, while the statistical analyses were performed by means of the SPSS (Statistical Package for the Social Sciences) software. The LR analysis produced a reliable susceptibility map of the investigated area and the probability level of landslide occurrence was ranked in four classes. The overall performance achieved by the LR analysis was assessed by local comparison between the expected susceptibility and an independent dataset extrapolated from the landslide inventory. Of the samples classified as susceptible to landslide occurrences, 85% correspond to areas where landslide phenomena have actually occurred. In addition, the consideration of the regression coefficients provided by the analysis demonstrated that a major role is played by the "land cover" and "lithology" causal factors in determining the occurrence and distribution of landslide phenomena in the Apulian Apennines

Cloud feedback mechanisms and their representation in global climate models

Cloud feedback—the change in top‐of‐atmosphere radiative flux resulting from the cloud response to warming—constitutes by far the largest source of uncertainty in the climate response to CO2 forcing simulated by global climate models (GCMs). We review the main mechanisms for cloud feedbacks, and discuss their representation in climate models and the sources of intermodel spread. Global‐mean cloud feedback in GCMs results from three main effects: (1) rising free‐tropospheric clouds (a positive longwave effect); (2) decreasing tropical low cloud amount (a positive shortwave [SW] effect); (3) increasing high‐latitude low cloud optical depth (a negative SW effect). These cloud responses simulated by GCMs are qualitatively supported by theory, high‐resolution modeling, and observations. Rising high clouds are consistent with the fixed anvil temperature (FAT) hypothesis, whereby enhanced upper‐tropospheric radiative cooling causes anvil cloud tops to remain at a nearly fixed temperature as the atmosphere warms. Tropical low cloud amount decreases are driven by a delicate balance between the effects of vertical turbulent fluxes, radiative cooling, large‐scale subsidence, and lower‐tropospheric stability on the boundary‐layer moisture budget. High‐latitude low cloud optical depth increases are dominated by phase changes in mixed‐phase clouds. The causes of intermodel spread in cloud feedback are discussed, focusing particularly on the role of unresolved parameterized processes such as cloud microphysics, turbulence, and convection

Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis

Background: The role of platinum-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients is highly controversial and it is not endorsed by current guidelines. Our meta-analysis aimed to better elucidate its activity, efficacy and safety. Material and methods: A systematic search of Medline, Web of Science and conferences proceedings up to 30 October 2017 was carried out to identify randomized controlled trials (RCTs) investigating platinum-based versus platinum-free neoadjuvant chemotherapy in TNBC patients. Using the fixed and random effects models, pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CI) were calculated for pathological complete response (pCR, defined as ypT0/is pN0), event-free survival (EFS), overall survival (OS) and grade 3 and 4 adverse events (AEs: neutropenia, anemia, thrombocytopenia and neuropathy). Results: Nine RCTs (N \ubc 2109) were included. Overall, platinum-based neoadjuvant chemotherapy significantly increased pCR rate from 37.0% to 52.1% (OR 1.96, 95% CI 1.46\u20132.62, P < 0.001). Platinum-based neoadjuvant chemotherapy remained significantly associated with increased pCR rate also after restricting the analysis to the three RCTs (N \ubc 611) that used the same standard regimen in both groups of weekly paclitaxel (with or without carboplatin) followed by anthracycline and cyclophosphamide (OR 2.53, 95% CI 1.37\u20134.66, P \ubc 0.003). Conversely, among the 96 BRCA-mutated patients included in two RCTs, the addition of carboplatin was not associated with significantly increased pCR rate (OR 1.17, 95% CI 0.51\u20132.67, P \ubc 0.711). Two RCTs (N \ubc 748) reported survival outcomes: no significant difference in EFS (HR 0.72, 95% CI 0.49\u20131.06, P \ubc 0.094) and OS (HR 0.86, 95% CI 0.46\u20131.63, P \ubc 0.651) was observed. A significant higher risk of grade 3 and 4 hematological AEs, with no increased risk of grade 3 and 4 neuropathy was observed with platinum-based neoadjuvant chemotherapy. Conclusion: In TNBC patients, platinum-based neoadjuvant chemotherapy is associated with significantly increased pCR rates at the cost of worse hematological toxicities. Platinum-based neoadjuvant chemotherapy may be considered an option in TNBC patients

Composite index of risk shows that benefit from adjuvant dose dense chemotherapy is not confined to triple negative breast cancer

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Composite risk and benefit from adjuvant dose-dense chemotherapy in hormone receptor-positive breast cancer

The GIM2 phase III trial demonstrated the benefit of dose-dense chemotherapy in node-positive early breast cancer (eBC). To better define the dose-dense effect in the hormone receptor-positive subgroup, we evaluated its benefit through a composite measure of recurrence risk. We conducted an ancillary analysis of the GIM2 trial evaluating the absolute treatment effect through a composite measure of recurrence risk (CPRS) in patients with hormone receptor-positive HER2-negative eBC. CPRS was estimated through Cox proportional hazards models applied to the different clinicopathological features. The treatment effect was compared to the values of CPRS by using the Sub-population Treatment Effect Pattern Plot (STEPP) process. The Disease-Free Survival (DFS)-oriented STEPP analysis showed distinct patterns of relative treatment effect with respect to CPRS. Overall, 5-year DFS differed across CPRS quartiles ranging from 95.2 to 66.4%. Each CPRS quartile was characterized by a different patients\u2019 composition, especially for age, lymph node involvement, tumor size, estrogen and progesterone receptor expression, and Ki-67. A number needed to treat of 154 and 6 was associated with the lowest and the highest CPRS quartile, respectively. Dose-dense adjuvant chemotherapy showed a consistent benefit in node-positive eBC patients with hormone receptor-positive HER2-negative disease, but its effect varied according to CPRS

Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting

Background!#!The identification of novel targets is of paramount importance to develop more effective drugs and improve the treatment of non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths worldwide. Since cells alter their metabolic rewiring during tumorigenesis and along cancer progression, targeting key metabolic players and metabolism-associated proteins represents a valuable approach with a high therapeutic potential. Metabolic fitness relies on the functionality of heat shock proteins (HSPs), molecular chaperones that facilitate the correct folding of metabolism enzymes and their assembly in macromolecular structures.!##!Methods!#!Gene fitness was determined by bioinformatics analysis from available datasets from genetic screenings. HSPD1 expression was evaluated by immunohistochemistry from formalin-fixed paraffin-embedded tissues from NSCLC patients. Real-time proliferation assays with and without cytotoxicity reagents, colony formation assays and cell cycle analyses were used to monitor growth and drug sensitivity of different NSCLC cells in vitro. In vivo growth was monitored with subcutaneous injections in immune-deficient mice. Cell metabolic activity was analyzed through extracellular metabolic flux analysis. Specific knockouts were introduced by CRISPR/Cas9.!##!Results!#!We show heat shock protein family D member 1 (HSPD1 or HSP60) as a survival gene ubiquitously expressed in NSCLC and associated with poor patients' prognosis. HSPD1 knockdown or its chemical disruption by the small molecule KHS101 induces a drastic breakdown of oxidative phosphorylation, and suppresses cell proliferation both in vitro and in vivo. By combining drug profiling with transcriptomics and through a whole-genome CRISPR/Cas9 screen, we demonstrate that HSPD1-targeted anti-cancer effects are dependent on oxidative phosphorylation and validated molecular determinants of KHS101 sensitivity, in particular, the creatine-transporter SLC6A8 and the subunit of the cytochrome c oxidase complex COX5B.!##!Conclusions!#!These results highlight mitochondrial metabolism as an attractive target and HSPD1 as a potential theranostic marker for developing therapies to combat NSCLC