Do NPM1 and FLT3-ITD mutations modify prognosis in patients treated with non-intensive regimens?

FLT3-ITD and NPM1 mutations are key to defining the genetic risk profile of acute myeloid leukemia (AML). We aimed to assess the prognostic features of the FLT3-ITD and NPM1 mutations in old and/or unfit individuals with AML treated with non-intensive therapies in the era before azacitidine-venetoclax approbation. The results of various non-intensive regimens were also compared. We conducted a retrospective analysis that included patients treated with different non-intensive regimens, between 2007 and 2020 from PETHEMA AML registry. We compiled 707 patients with a median age of 74 years and median follow-up time of 37.7 months. FLT3-ITD patients (N = 98) showed a non-significant difference in overall survival (OS) compared to FLT3-ITD negative-patients (N = 608) (P = 0.17, median OS was 5 vs 7.3 months respectively). NPM1-mutated patients (N = 144) also showed a non-significant difference with NPM1 wild type (N = 519) patients (P = 0.25, median OS 7.2 vs 6.8 respectively). In the Cox regression analysis neither NPM1 nor FLT3-ITD nor age were significant prognostic variables for OS prediction. Abnormal karyotype and a high leukocyte count showed a statistically significant deleterious effect. Azacitidine also showed better survival compared to FLUGA (low dose cytarabine plus fludarabine). NPM1 and FLT3-ITD seem to lack prognostic value in older/unfit AML patients treated with non-intensive regimens other than azacitidine-venetoclax combination.

Incidence and prognostic impact of U2AF1 mutations and other gene alterations in myelodysplastic neoplasms with isolated 20q deletion.

BACKGROUND: In myelodysplastic neoplasms (MDS), the 20q deletion [del(20q)] is a recurrent chromosomal abnormality that it has a high co-occurrence with U2AF1 mutations. Nevertheless, the prognostic impact of U2AF1 in these MDS patients is uncertain and the possible clinical and/or prognostic differences between the mutation type and the mutational burden are also unknown. METHODS: Our study analyzes different molecular variables in 100 MDS patients with isolated del(20q). RESULTS & CONCLUSIONS: We describe the high incidence and negative prognostic impact of U2AF1 mutations and other alterations such as in ASXL1 gene to identify prognostic markers that would benefit patients to receive earlier treatment.

Response to azacitidine in patients with chronic myelomonocytic leukemia according to overlap myelodysplastic/myeloproliferative neoplasms criteria.

BACKGROUND: Azacitidine (AZA) is approved for the treatment of high-risk chronic myelomonocytic leukemia (CMML) of myelodysplastic (MD) subtype. Data of response rates using the specific response criteria for this disease are scarce. The aim of this study was to evaluate the response to AZA in patients diagnosed with CMML from the Spanish Registry of Myelodysplastic Syndromes (MDS) applying the overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) response criteria. METHODS: We retrospectively studied 91 patients with CMML treated with at least one cycle of AZA from the Spanish Registry of MDS. As it was a real-world study, the response rate was evaluated between cycle 4 and 6, applying the MDS/MPN response criteria FINDINGS: The overall response rate at cycle 4-6 was 58%. Almost half of the patients achieved transfusion independence and one quarter showed clinical benefit, regardless of the CMML French-American-British (FAB) and World Health Organization (WHO) subtypes and CMML Specific Prognosis Scoring (CPSS) risk groups. Toxicity was higher in the MD-CMML subtype. INTERPRETATION: In our series, most CMML patients achieved an overall response rate with AZA according to the overlap-MDS/MPN response criteria regardless of the CMML FAB and WHO subtypes and CPSS risk groups. Thus, AZA may also be a treatment option for patients with the myeloproliferative CMML subtype and those with a lower-risk CPSS, but symptomatic.

Electrocardiography-gated CT for acute aortic syndrome: quantifying the potential impact of subspecialty national recommendations on emergency general radiology reporting.

AIM: To evaluate the detection of acute aortic syndrome (AAS) and the prevalence of alternative diagnoses that may explain the presentation or require follow-up. MATERIALS AND METHODS: This was a retrospective, blinded re-evaluation of consecutive electrocardiography (ECG)-gated computed tomography (CT) aortic studies by a cardiovascular radiologist performed between September 2019 and May 2020 in a tertiary-referral cardiothoracic centre. RESULTS: There were 118 identified examinations, six examinations were excluded leaving 112 (mean age = 61 ± 17; 56% male). Three cases of AAS were present (prevalence 2.7%); only one was reported on initial review. There were no false-positive diagnoses of AAS. The heart was mentioned in 79 (70.5%) reports and 73 (65.2%) of reviews revealed a total of 114 new observations; 111 (97.4%) of these were cardiovascular with 44/112 (39.3%) patients potentially having a significant previously unsuspected cardiovascular diagnosis. CONCLUSION: The implementation of national clinical guidance to increase testing and improve image quality led to a series of challenges. The real value of ECG-gated CT may lie in detecting other diseases that mimic AAS. With the additional workload, increased subspecialty expertise is required but there needs to be a willingness to learn with an adequate support infrastructure.

Expression of CD47 antigen in Reed-Sternberg cells as a new potential biomarker for classical Hodgkin lymphoma.

INTRODUCTION: CD47 over expression has been reported in several tumor subtypes. CD47 interacts with SIRPalpha on macrophages inhibiting phagocytic signal, providing a survival advantage to tumor. CD47, therefore, represents a valuable target for immunotherapy and is currently under clinical investigation. We aimed to study CD47 expression in Hodgkin Reed Sternberg cells (HRS). METHODS: We tested a polyclonal CD47 antibody (LifeSpan Biosciences, Seattle, WA) expression along with classical HRS cell markers on a tissue array of 16 classical Hodgkin Lymphoma (CHL) tumor biopsies obtained from newly diagnosed, non-selected patients (8 Female, 8 Male patients) in our institution from October 2016 to January 2018. Histologic subtypes were nodular sclerosis in 11 cases, mixed Cellularity in 3 cases and lymphocyte rich in 2 additional cases. Median age was 53 years (Range: 8, 74). Early stage disease was found in three patients without unfavorable prognostic factors according to EORTC and GHSG criteria, one patient with unfavorable prognostic factors and nine patients had advanced disease. Bulk disease was present in one patient. Normal lymphoid tissue and normal prostate epithelium were used as normal controls as recommended by manufacturer. Approval from the Local Ethical committee was obtained before any analysis. RESULTS: CD47 was overexpressed on all HRS cells with a characteristic dot-like pattern in 13/13 cases of CHL. HRS clearly expressed CD47 more intensely than infiltrating T and stromal cells. DISCUSSION: We propose that HRS cells, by up-regulating CD47, might avoid innate immunity check on tumor growth, which could be circumvented using blocking monoclonal antibodies.

Long-term outcome of older patients with newly diagnosed de novo acute promyelocytic leukemia treated with ATRA plus anthracycline-based therapy.

Treatment outcome in older patients with acute promyelocytic leukemia (APL) is lower compared with younger patients, mainly because of a higher induction death rate and postremission non-relapse mortality (NRM). This prompted us to design a risk- and age-adapted protocol (Programa Español de Tratamientos en Hematología (PETHEMA)/HOVON LPA2005), with dose reduction of consolidation chemotherapy. Patients aged ⩾60 years reported to the PETHEMA registry and were treated with all-trans retinoic acid (ATRA) plus anthracycline-based regimens according to three consecutive PETHEMA trials that were included. We compared the long-term outcomes of the LPA2005 trial with the preceding PETHEMA trials using non-age-adapted schedules (LPA96&LPA99). From 1996 to 2012, 389 older patients were registered, of whom 268 patients (69%) were eligible. Causes of ineligibility were secondary APL (19%), and unfit for chemotherapy (11%). Median age was 67 years, without relevant differences between LPA2005 and LPA96&LPA99 cohorts. Overall, 216 patients (81%) achieved complete remission with no differences between trials. The 5-year NRM, cumulative incidence of relapse, disease-free survival and overall survival in the LPA2005 vs the LPA96&99 were 5 vs 18% (P=0.15), 7 vs 12% (P=0.23), 87 vs 69% (P=0.04) and 74 vs 60% (P=0.06). A less intensive front-line regimen with ATRA and anthracycline monochemotherapy resulted in improved outcomes in older APL patients.

Effectiveness of azacitidine in unselected high-risk myelodysplastic syndromes: results from the Spanish registry.

The benefit of azacitidine treatment in survival of high-risk myelodysplastic syndromes (MDS) patients compared with conventional care treatment (CCT) has not been established outside clinical trials. To assess its effectiveness, we compared overall survival (OS) between azacitidine and conventional treatment (CCT) in high-risk MDS patients, excluding those undergoing stem cell transplantation, submitted to the Spanish MDS registry from 2000 to 2013. Several Cox regression and competing risk models, considering azacitidine as a time-dependent covariate, were used to assess survival and acute myeloblastic leukemia (AML) progression. Among 821 patients included, 251 received azacitidine. Median survival was 13.4 (11.8-16) months for azacitidine-treated patients and 12.2 (11-14.1) for patients under CCT (P=0.41). In a multivariate model, age, International prognostic scoring system and lactate dehydrogenase were predictors of OS whereas azacitidine was not (adjusted odds ratio 1.08, 95% confidence interval 0.86-1.35, P=0.49). However, in patients with chromosome 7 abnormalities, a trend toward a better survival was observed in azacitidine-treated patients (median survival 13.3 (11-18) months) compared with CCT (median survival 8.6 (5-10.4) months, P=0.08). In conclusion, our data show that, in spite of a widespread use of azacitidine, there is a lack of improvement in survival over the years. Identification of predicting factors of response and survival is mandatory.

Results of allogeneic stem cell transplantation in the Spanish MDS registry: prognostic factors for low risk patients.

Although new agents have been approved for the treatment of MDS, the only curative approach is allogeneic hematopoietic stem cell transplantation (HSCT) and thus, in particular circumstances this procedure has been proposed as a treatment option for low risk patients. We have retrospectively analyzed the results of HSCT in 291 patients from the Spanish MDS registry with special attention to low risk MDS (LR-MDS) in order to define the variables that could impact their clinical evolution after transplantation. At 2 years OS was 51% and EFS was 50% (95% CI 0.7-4.5 years for OS and 95% CI 0.1-3.9 years for EFS). Among 43 LR-MDS, transplant-related mortality was 28%. At 3 years, OS was 67% (95% CI 264.7-8927.2 days for OS) and EFS was 64% (95% CI 0-9697.2 days for EFS). In the multivariate analysis only cytogenetics retained statistical significant effect on both OS (p=.047) and EFS (p=.046). Conditioning regimen could improve outcome among this subset of patients (OS 86% and RFS 100% for patients receiving RIC regimen). The present study confirms that specific disease characteristic as well as transplant characteristics have a significant impact on transplant outcome. Regarding low risk patients a non-myeloablative conditioning would be preferable especially in cases without high-risk cytogenetics.

"No quiero que usted sea así" Macro y microdiscursos que posicionan a los sujetos laborales que trabajan en las calles de Bogotá / "I don't want you to be so". Macro and micro'discourses that position to the laboral subjects who work on Bogotá streets

Enmarcado en la teoría de posicionamiento, este estudio examina la construcción de subjetividades laborales de trabajadores informales. Se entrevista a 14 hombres y 14 mujeres, trabajadores por cuenta propia que laboran en las calles de la ciudad de Bogotá ofreciendo productos o servicios, y que no están cubiertos por la seguridad social. Se indaga por las experiencias y prácticas en el trabajo, a partir de lo cual se interpretan los discursos como espacios de poder en la construcción de la subjetividad, teniendo en cuenta los macrodiscursos como marcos globales y los microdiscursos como referentes de la cotidianidad. Los resultados se interpretan a partir del análisis del discurso y por comparación y contraste de patrones de posicionamiento de los sujetos. Se encuentran diferentes discursos entre hombres y mujeres que los posicionan como independientes, conformes, excluidos, apreciados y a la vez discriminados y ejemplo de lo que no debe ser un trabajador.

Enclosed in the positioning theory, we examine the construction of labor subjectivities among women and men in their informal jobs in the streets of Bogota. 14 men and 14 women were interviewed. Their experiences and worries at work are investigated. Initially, the macro discourses as construction power spaces are proposed in the construction of subjectivity and its connection with the micro discourses found in the everyday jobs of the workers. Results are analyzed by comparing and contrasting the different positioning patterns in the mentioned discourses. Different discourses among men and women are found different, positioning them as independent, conformists, excluded, appreciated, and discriminated at the same time, and an example of how a worker should not be.

Concrete enclosure for shielding a neutron source.

In the aim to design a shielding for a 0.185 TBq (239)PuBe isotopic neutron source several Monte Carlo calculations were carried out using MCNP5 code. First, a point-like source was modeled in vacuum and the neutron spectrum and ambient dose equivalent were calculated at several distances ranging from 5 cm up to 150 cm, these calculations were repeated modeling a real source, including air, and a 1×1×1 m(3) enclosure with 5, 15, 20, 25, 30, 50 and 80 cm-thick Portland type concrete walls. At all the points located inside the enclosure neutron spectra from 10(-8) up to 0.5 MeV were the same regardless the distance from the source showing the room-return effect in the enclosure, for energies larger than 0.5 MeV neutron spectra are diminished as the distance increases. Outside the enclosure it was noticed that neutron spectra becomes "softer" as the concrete thickness increases due to reduction of mean neutron energy. With the ambient dose values the attenuation curve in terms of concrete thickness was calculated.

The degree of neutropenia has a prognostic impact in low risk myelodysplastic syndrome.

The severity of neutropenia in myelodysplastic syndrome (MDS) has not been completely studied. We analyzed the prognostic significance of severe neutropenia (neutrophils count <0.5×10(9)/L) at diagnosis in 1109 patients with de novo MDS and low/intermediate-1 IPSS included in the Spanish MDS Registry. Severe neutropenia was present at diagnosis in 48 of 1109 (4%). Patients with severe neutropenia were most strongly represented within the groups of refractory cytopenia with multilineage dysplasia (40%) and refractory anemia with excess of blast type 1 (29%). Severe neutropenia had negative effects on the low/intermediate-1 risk group. A significant difference in overall survival was observed between patients with severe neutropenia (28 months) and patients with a neutrophil count higher than 0.5×10(9)/L (66 months) (p<0.0001). Also, severe neutropenia predicted a significantly reduced on leukemia-free survival (p<0.0001). In the multivariate analysis, severe neutropenia retained its independent prognostic influence on overall survival [HR: 2.19, 95% CI (1.41-3.10), p<0.0001] and leukemia free survival [HR: 3.51, 95% CI (1.97-6.26), p<0.0001]. The degree of neutropenia should be considered as additional prognostic factor in low/intermediate-1 IPSS MDS.

Seroincidence of porcine T. solium infection in the Peruvian highlands.

We performed repeated serological sampling of pigs in an endemic area of the Peruvian highlands (eight villages) to assess the feasibility of detecting incident cases of Taenia solium infection as indicators of ongoing transmission of the parasite. A total of 2245 samples corresponding to 1548 pigs were collected in three sampling rounds (n=716, 926, and 603, respectively). Village-period specific seroprevalences of antibodies by enzyme-linked immunoelectrotransfer blot (EITB) assay varied from 39% (95% CI: 34, 44) to 76% (95% CI: 72, 79). The prevalence of cysticercosis increased with the age of the pigs (similarly for both sexes). Around 40% of pigs were re-sampled at the end of each 4-month period. Crude incidence risks were 48% (57/120, 95% CI: 43-52) and 58% (111/192, 95% CI: 54-61) for each period. A proportion of seropositive animals became seronegative at the end of each period (23 and 15%). Incidence varied by the village, and the exposure period, and was higher in males than females (but did not differ by age).

Circulating parasite antigen in patients with hydrocephalus secondary to neurocysticercosis.

End stages of neurocysticercosis include residual intraparenchymal brain calcifications and hydrocephalus. Although brain calcifications alone have a benign prognosis, hydrocephalus is frequently associated with chronic inflammation and intracranial hypertension, together with a protracted clinical evolution, and may lead to patient deaths. By using a monoclonal-based antigen detection enzyme-linked immunosorbent assay, we measured the levels of circulating parasite antigen in the sera of 56 patients with neurocysticercosis: 27 with calcifications only and 29 with hydrocephalus. The assay gave positive results in 14 of 29 patients with hydrocephalus but was consistently negative in patients with calcifications. Circulating parasite antigen in hydrocephalus secondary to neurocysticercosis indicates the presence of live parasites in these patients and thus a potential benefit from antiparasitic therapy.

Protection of pigs with cysticercosis from further infections after treatment with oxfendazole.

Cysticercosis, the infection by the larvae of Taenia solium, is a major cause of acquired epilepsy in the world; it also causes significant economic loss because of contaminated pork. This disease is endemic in most developing countries and no control strategy has yet been proven efficient and sustainable. To further evaluate the full potential of single-dose oxfendazole treatment for pigs as a control measure, 20 pigs with cysticercosis were treated with oxfendazole and later matched with 41 naive pigs and exposed to a natural challenge in a hyperendemic area. New infections were found by serologic testing in 15 of the 32 controls (47%), and by the presence of cysts at necropsy in 12 of them (37%). Only minute residual scars were detected in the carcasses of oxfendazole-treated pigs. Pigs with cysticercosis, once treated with oxfendazole, are protected from new infections for at least three months.