Questions concerning tyrosine kinase-inhibitor therapy and transplants in chronic phase chronic myeloid leukaemia

In this provocative commentary, we consider several questions posed by the late chronic myeloid leukaemia (CML) expert Prof. Michele Baccarani, which he challenged us to address after his death. He noted only a small proportion of people with chronic phase CML receiving tyrosine kinase-inhibitor (TKI)-therapy are likely to achieve sustained therapy-free remission (TFR) and even fewer are likely to be cured. Persons most likely to fail TKItherapy can be identified at diagnosis or soon after starting TKI-therapy. These persons are likely to need lifetime TKI-therapy with attendant risks of adverse events, cost and psychological consequences. Allogeneic transplants achieve much higher rates of leukaemia-free survival compared with TKI-therapy but are associated with transplant-related adverse events including an almost 20 percent risk of transplant-related deaths within 1 year post-transplant and a compromised quality-of-life because of complications such as chronic graft-versus-host disease. Subject-, disease- and transplant-related co-variates associated with transplant outcomes are known with reasonable accuracy. Not everyone likely to fail TKI-therapy is a transplant candidate. However, in those who candidates are physicians and patients need to weigh benefits and risks of TKI-therapy versus a transplant. We suggest transplants should be more often considered in the metric when counseling people with chronic phase CML unlikely to achieve TFR with TKI-therapy. We question whether we are discounting a possible important therapy intervention; we think so

Pemodelan Regresi Nonparametrik Spline Truncated dan Aplikasinya pada Angka Kelahiran Kasar di Surabaya

Surabaya sebagai ibukota Propinsi Jawa Timur menempati urutan kedua setelah Jakarta dalam jumlah penduduk. Pada tahun 2012 terjadi 40.343 jumlah kelahiran, dimana angka ini mencerminkan pertumbuhan penduduk yang sangat tinggi. Pertumbuhan penduduk yang begitu pesat dikhawatirkan akan menyebabkan ledakan pertumbuhan penduduk. Pada penelitian ini memodelkan angka kelahiran kasar (CBR) dengan 5 variabel yang diduga berpengaruh. Pemodelan dilakukan dengan metode regresi nonparametrik Spline truncated. Metode ini dipilih karena Spline merupakan metode yang fleksibel, model ini cenderung mencari sendiri estimasi data. Dalam pemodelan ini terdapat titik knot, yaitu titik yang menunjukkan Perubahan data. Pemilihan titik knot optimum dilakukan dengan cara memilih nilai Generalized Cross Validation (GCV) yang paling minimum. Berdasarkan penelitian yang telah dilakukan, 5 variabel dinyatakan berpengaruh terhadap CBR yaitu persentase kepala keluarga yang berstatus pendidikan tidak sekolah/belum tamat SD, persentase kepala keluarga yang berstatus tidak bekerja, persentase kepala keluarga yang menikah pada umur 15-19 tahun, angka perkawinan kasar, dan angka migrasi masuk. Model regresi nonparametrik Spline truncated yang terbentuk memiliki koefisien determinasi sebesar 94,3%, serta nilai MSE yaitu 0,44

Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (Fludarabine/busulfan=166, Fludarabine/melphalan=327) and 379 using MAC (Fludarabine/busulfan=247, Busulfan/cyclophosphamide=132). In multivariable analysis with RIC, Fludarabine/melphalan was associated with inferior overall survival (HR 1.80, 95% CI 1.15-2.81, p=0.009), higher early non-relapse mortality (HR 1.81, 95% CI 1.12-2.91, p=0.01) and higher acute graft versus host disease (GVHD) (grade II-IV- HR 1.45, 95% CI 1.03-2.03, p=0.03; grade III-IV HR 2.21, 95%CI 1.28-3.83, p=0.004) compared to Fludarabine/busulfan. In the MAC setting, Busulfan/cyclophosphamide was associated with a higher acute GVHD (grade II-IV HR 2.33, 95% CI 1.67-3.25, p\u3c0.001; grade III-IV HR 2.31, 95% CI 1.52-3.52, p\u3c0.001) and inferior GVHD-free relapse-free survival (GRFS) (HR 1.94, 95% CI 1.49-2.53, p\u3c0.001) as compared to Fludarabine/busulfan. Hence, our study suggests that Fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GVHD) and MAC (lower acute GVHD and better GRFS) in myelofibrosis

Haploidentical vs. sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia

The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLAmatched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P <_ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P <_ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (<_18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission

Evaluación geológica - minera del ANAP Colca : Prospectos Colca y Huallpachaca

El Instituto Geológico Minero y Metalúrgico a través de las Dirección de Recursos Mineros Energéticos y la Actividad de Área de No Adminsión de Petitorios (ANAP), desarrolló la evaluación geológico económica de del ANAP Colca. El ANAP Colca está ubicado en la región Apurímac, dentro de la provincia de Cotabambas (hoja topográfica 28-r), en los distritos de Cotabambas y Tambobamba, comprendiendo las comunidades de Colca, Pamparki, Paruro, Huañec y Huamancharpa. Tiene un área de 14100 hectáreas y se encuentra a una altura promedio de 2900 m.s.n.m. Dentro del ANAP Colca se ha reconocido dos prospectos que según su importancia económica son: Colca (6200 has) y Hualpachaca (5600 has). La geología está mayormente conformada por rocas del Grupo Tacaza, de edad Paleógeno – Neógeno, que consisten de lavas andesíticas afaníticas y porfiríticas en menor proporción, moderadamente alteradas, con irregular presencia de minerales de cobre, zinc, plomo y oro; rocas intrusivas conformado por dioritas, tonalitas y granodioritas que corresponden al Plutón Cotabambas y Plutón Colca expuestas en el sector sur del ANAP de edad Paleógeno – Neógeno. Las alteraciones hidrotermales observadas en el ANAP Colca son la alteración propilítica y argílica presentándose de manera moderada a débil. La alteración propilítica (clr- ep- ser- calc) ha sido observada mayormente al norte del poblado de Cutuctuy principalmente en la carretera que desciende de Cutuctuy al río Apurímac. La alteración argílica (ser- Arcs - spe - ep) es la que prevalece en el Prospecto Colca no se evidencia alteración filica por la ausencia de cuarzo y pirita por lo que se presume que el yacimiento mineral podría encontrase en el nivel alto del sistema quizás a mayor profundidad se encuentre las asociaciones mineralógicas típicas de esta alteración. La mineralización en ambos prospectos se manifiestan como vetas epitermales de intermedia sulfuración debido a la presencia de óxidos de Fe como jarosita, goethita, especularita; carbonatos (malaquita) y sulfuros como pirita, calcopirita, pirrotita, arsenopirita en trazas. En particular en las zonas de Ninaraura, Cutuctuy y Callapunco del Prospecto Colca con los datos de prospección geofísica mediante la aplicación de Inducción polarizada (IP) con valores altos en cargabilidad (>20 mV/V) y altos en resistividad de 110 -2200 Ohm*m. conducen a direccionar un posible emplazamiento de un depósito tipo pórfido de Cu-Au tanto en la andesita y en el contacto con el intrusivo diorítico. En un recorrido realizado en las cabeceras del río Aquilano, el contacto del intrusivo diorítico y las calizas de la formación Arcurquina (Ferrobamba) forman un skarn donde actualmente realizan labores de minería informal en las comunidades de Pamparki y Colca. Se recolectaron 445 muestras de esquirlas de roca de las cuales tenemos el resultado geoquímico con los valores de Au, destacando los sectores de: Ninaraura con 04 muestras anómalas cuyos valores oscilan de 859 ppb (Rocol-602) a 3063 ppb (Rocol-417), Marangallay con una muestra anómala de 975 ppb (Rocol-547), faldas del cerro Huayllaje en la margen izquierda del río Aquilano con una muestra anómala de 2200 ppb (Rocol-482) y en la zona de Pamparki (Margen izquierda del río Apurímac) una muestra anómala de 1594 ppb (Rocol-523). Estos valores son interesantes en una etapa de exploración (prospección). Es importante mencionar que el prospecto Huallpachaca se encuentra ubicado en el mismo corredor estructural de orientación NE – SO a una distancia horizontal de ± 3 kilómetros en línea recta del pórfido Cotabambas (Cu-Au) de propiedad de Panoro Minerals Ltd

The Mutational Landscape in Chronic Myelomonocytic Leukemia and Its Impact on Allogeneic Hematopoietic Cell Transplantation Outcomes: A Center for Blood and Marrow Transplantation Research (CIBMTR) Analysis

Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of intermediate-2 (HR=1.46, P=0.049) or high (HR=3.22, P=0.0004) correlated significantly with overall survival. When the molecularly informed CPSS-Mol prognostic model was applied, a high CPSS-Mol score (HR=2 P=0.0079) correlated significantly with overall survival. The most common somatic mutations were in ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%). DNMT3A and TP53 mutations were associated with decreased overall survival (HR=1.70 [95% CI: 1.11-2.60], P=0.0147 and HR=2.72 [95% CI: 1.37-5.39], P=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased disease-free survival (HR=1.66 [95% CI: 1.11-2.49], P=0.0138, HR=1.79 [95% CI: 1.06-3.03], P=0.0293, and HR=2.94 [95% CI: 1.50-5.79], P=0.0018, respectively). The only mutation associated with increased relapse was TP53 (HR=2.94, P=0.0201). Nonetheless, the impact of TP53 mutations specifically should be interpreted cautiously given their rarity in CMML. We calculated the goodness of fit measured by Harrell\u27s C-index for both the CPSS and CPSS-Mol, which were very similar. In summary, via registry data we have determined the mutational landscape in patients with CMML who underwent allogeneic HCT, and demonstrated an association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond that provided by the CPSS

Mobility, turnover and storage of pollutants in soils, sediments and waters : achievements and results of the EU project AquaTerra : a review.

AquaTerra is one of the first environmental projects within the 6th Framework program by the European Commission. It began in June 2004 with a multidisciplinary team of 45 partner organizations from 13 EU countries, Switzerland, Serbia, Romania and Montenegro. Results from sampling and modeling in 4 large river basins (Ebro, Danube, Elbe and Meuse) and one catchment of the Brévilles Spring in France led to new evaluations of diffuse and hotspot input of persistent organic and metal pollutants including dynamics of pesticides and polycyclic aromatic hydrocarbons, as well as metal turnover and accumulation. While degradation of selected organic compounds could be demonstrated under controlled conditions in the laboratory, turnover of most persistent pollutants in the field seems to range from decades to centuries. First investigations of long-term cumulative and degradation effects, particularly in the context of climate change, have shown that it is also necessary to consider the predictions of more than one climate model when trying to assess future impacts. This is largely controlled by uncertainties in climate model responses. It is becoming evident, however, that changes to the climate will have important impacts on the diffusion and degradation of pollutants in space and time that are just at the start of their exploration