Willingness to pay for high-quality remote radiation oncology training in Latin America.

Access to high-quality continuing medical education, particularly in Radiation Oncology, can be challenging in some developing countries due to economic barriers. Despite the current offer of free-access self-educational material, end user training faces a backlog still difficult to overcome. The purpose of this investigation is to report the willingness-to-pay profile of practitioners in Latin America, as a surrogate of quality perception of remote educational resources. Related factors include professional experience and baseline practice confidence levels. Most of practitioners would cover their own expenses, while an increased tendency in less-experienced professionals was observed. However, baseline knowledge confidence levels were not influential in decision making. This report contributes to better know the profile of Latin American professionals, in order to design future educational interventions in the region and bridging the current accessibility gap.

Impact of a SBRT/SRS longitudinal telehealth training pilot course in Latin America.

PURPOSE: To assess the impact of longitudinal telehealth training in stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) for clinicians in Latin America. MATERIALS AND METHODS: Professionals from two Peruvian centers received an initial SBRT/SRS on-site training course and subsequently received follow-up telehealth training (interventional group) or not (negative control arm). Twelve live video conference sessions were scheduled. Surveys pre- and post-curriculum measured participants' confidence in seven practical domains of SBRT/SRS, based on Likert scales of 1-5, and post-curriculum surveys assessed educators' experiences. RESULTS: Sixty-one participants were registered, with an average of 24 attendees per session. Pre- and post- surveys were completed by 22 participants. For interventional and negative-control groups, mean changes in Likert scale were satisfactory for the former and remained unmodified for the latter. CONCLUSIONS: Conducting telehealth educational programs via virtual classroom sessions could be a reliable method to augment training for SBRT and SRS.

Updates in the Treatment of Breast Cancer with Radiotherapy.

Breast-conserving therapy is one of the most remarkable achievements of modern cancer care. The authors review the evidence supporting the role of adjuvant radiotherapy as the standard of care for breast cancer after breast-conserving surgery, consensus guidelines for margins in invasive cancer disease and ductal carcinoma in situ, the role of partial-breast irradiation and hypofractionated whole-breast irradiation, and the evolving indications for postmastectomy radiation therapy and extent of nodal coverage. Areas of research include specific methods of partial-breast irradiation, interactions between neoadjuvant chemotherapy and radiotherapy, and integration of molecular profiles with the selection of the best treatment modality and timing.

Radiotherapy for Anal Cancer: Intensity-Modulated Radiotherapy and Future Directions.

The treatment of anal cancer has evolved remarkably in the past 30 years. Definitive chemoradiotherapy is the standard of care, allowing organ preservation and maintenance of continence for most patients. This article reviews recent advances in radiotherapy planning and delivery that have resulted in improvements in treatment-related toxicity. Most notably, the advent and wide adoption of intensity-modulated radiotherapy provides a superior toxicity profile compared with older techniques, while maintaining similar oncologic outcomes. Current areas of active research include optimizing and individualizing treatment intensity and possible integration of biologic agents and immunotherapies in the treatment of anal cancer.

An oral HemokineTM, α-methylhydrocinnamate, enhances myeloid and neutrophil recovery following irradiation in vivo.

An oral therapeutic which reduces duration of cytopenias and is active following accidental radiation exposures is an unmet need in radiation countermeasures. Alpha methylhydrocinnamate (ST7) prolongs STAT-5 phosphorylation, reduces growth-factor dependency of multi-lineage cell lines, and stimulates erythropoiesis. Here, ST7 and its isomers were studied for their effects on myeloid progenitors and hematopoietic stem cells (HSCs) following radiation, in nonhuman primates, and murine irradiation models. Addition of ST7 or ST7-S increased CFU-GM production by 1.7-fold (p<0.001), reduced neutrophil apoptosis comparable to G-CSF, and enhanced HSC survival post-radiation by 2-fold, (p=0.028). ST7 and ST7-S administered in normal baboons increased ANC and platelet counts by 50-400%. In sub-lethally-irradiated mice, ANC nadir remained >200/mm3 and neutropenia recovered in 6days with ST7 treatment and 18days in controls (p<0.05). In lethally-irradiated mice, marrow pathology at 15days was hypocellular (10% cellularity) in controls, but normal (55-75% cellularity) with complete neutrophil maturation with ST7-S treatment. Following lethal irradiation, ST7, given orally for 4days, reduced mortality, with 30% survival in ST7-animals vs 8% in controls, (p<0.05). Collectively, the studies indicate that ST7 and ST7-S enhance myeloid recovery post-radiation and merit further evaluation to accelerate hematologic recovery in conditions of radiation-related and other marrow hypoplasias.

Lack of Association between Recurrent Pregnancy Loss and Inherited Thrombophilia in a Group of Colombian Patients.

Studies have shown an association between recurrent pregnancy loss and inherited thrombophilia in Caucasian populations, but there is insufficient knowledge concerning triethnic populations such as the Colombian. The aim of this study was to evaluate whether inherited thrombophilia is associated with recurrent pregnancy loss. Methods. We conducted a case-control study of 93 patients with recurrent pregnancy loss (cases) and 206 healthy multiparous women (controls) in a Colombian subpopulation. Three single nucleotide polymorphisms (SNPs) markers of the inherited thrombophilias factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T were genotyped by PCR-RFLP. Activated protein C resistance and plasma levels of antithrombin, protein C, and protein S were also measured. Results. The frequency of thrombophilia-associated SNPs, activated protein C resistance, and anticoagulant protein deficiencies, was low overall, except for the methylenetetrahydrofolate reductase C677T SNP. The differences between patients and controls had no statistical significance. Conclusion. Our study confirms the low prevalence of inherited thrombophilias in non-Caucasian populations and it is unlikely that the tested thrombophilias play a role in the pathogenesis of recurrent pregnancy loss in this Colombian population.

Novel therapeutic candidates, identified by molecular modeling, induce γ-globin gene expression in vivo.

The ß-hemoglobinopathies and thalassemias are serious genetic blood disorders affecting the ß-globin chain of hemoglobin A (α(2)ß(Α)(2)). Their clinical severity can be reduced by enhancing expression of fetal hemoglobin (γ-globin), producing HbF (α(2)γ(2,)). In studies reported here, γ-globin induction by 23 novel, structurally-unrelated compounds, which had been predicted through molecular modeling and in silico screening of a 13,000 chemical library, was evaluated in vitro in erythroid progenitors cultured from normal subjects and ß-thalassemia patients, and in vivo in transgenic mice or anemic baboons. Four predicted candidates were found to have high potency, with 4- to 8-fold induction of HbF. Two of these compounds have pharmacokinetic profiles favorable for clinical application. These studies thus effectively identified high potency γ-globin inducing candidate therapeutics and validated the utility of in silico molecular modeling.

A randomized phase II trial of Arginine Butyrate with standard local therapy in refractory sickle cell leg ulcers.

Sickle cell leg ulcers are often debilitating, refractory to healing, and prone to recurrence. Healing of leg ulcers was incidentally observed during dose-ranging trials of Arginine Butyrate in beta haemoglobinopathies. Here, a controlled Phase II trial was performed in sickle cell patients who had lower extremity ulcers refractory to standard care for at least 6 months. Patients were randomized to receive standard local care alone (Control Arm) or standard care with Arginine Butyrate administered 5 d/week (Treatment Arm), for 12 weeks. Ulcers were photographed weekly, traced, and ulcer areas were calculated by computerized planimetry and compared between the two study arms. Twenty-seven study courses were evaluated. Control Arm subjects had 25 ulcers with a mean area of 25·7 cm(2) initially and 23·2 cm(2) after 12 weeks; 2/25 (8%) healed completely. Treatment Arm subjects had 37 ulcers with a mean area of 50·6 cm(2) initially and 28·3 cm(2) at 12 weeks; 11/37 of these (30%) healed completely. After 3 months, proportions of ulcers which healed were 6/25 (24%) and 29/37 (78%), in the Control and Treatment Arms respectively (P < 0·001). These findings strongly suggest that Arginine Butyrate merits further evaluation for the treatment of refractory sickle cell leg ulcers in larger trials.

Fetal globin gene inducers: novel agents and new potential.

Inducing expression of endogenous fetal globin (gamma-globin) gene expression to 60-70% of alpha globin synthesis produces beta-thalassemia trait globin synthetic ratios and can reduce anemia to a mild level. Several classes of therapeutics have induced gamma-globin expression in beta-thalassemia patients and subsequently raised total hemoglobin levels, demonstrating proof-of-concept of the approach. Butyrate treatment eliminated transfusion requirements in formerly transfusion-dependent patients with treatment for as long as seven years. However, prior generation inducers were not readily applicable for widespread use. Currently, a novel oral dual-action therapeutic, sodium 2,2-dimethylbutyrate, is in clinical trials, an oral decitabine formulation is under development, and agents with complementary mechanisms of action can be applied in combined regimens. Identification of three major genetic trait loci which modulate clinical severity provides avenues for developing tailored regimens. These refinements offer renewed potential to apply fetal globin induction as a treatment approach in patient-friendly regimens that can be used worldwide.

The first homozygous family for prothrombin G20210A polymorphism reported in Latin America.

The 20210A allele of the prothrombin gene is associated with increased risk of venous thromboembolism. In this study, we described manifestations of thrombosis in four generations of a Colombian family, with four 20210A homozygous carriers and six 20210G/A heterozygous carriers for polymorphism as well as unrelated participants from the same population. The levels of prothrombin in the 20210A homozygote patients were higher than in the normal 20210G homozygotes (133 + 11% and 92.3 + 12.4%, respectively, P < .01) and the 20210G/A heterozygotes (133 + 11% vs. 114.8 + 24%, P < .05). About 2 out of 4 20210A homozygotes and 5 out of 6 20210G/A heterozygous members of this family did not have venous thromboembolism or any other thrombotic manifestation even though one of them had been exposed to thrombotic risk factors. Thus, we posit the effect of 20210A on the thrombotic phenotype in this family seems to be weak.

Short-chain fatty acids induce gamma-globin gene expression by displacement of a HDAC3-NCoR repressor complex.

High-level induction of fetal (gamma) globin gene expression for therapy of beta-hemoglobinopathies likely requires local chromatin modification and dissociation of repressor complexes for gamma-globin promoter activation. A novel gamma-globin-inducing short-chain fatty acid derivative (SCFAD), RB7, which was identified through computational modeling, produced a 6-fold induction in a reporter assay that detects only strong inducers of the gamma-globin gene promoter and in cultured human erythroid progenitors. To elucidate the molecular mechanisms used by high-potency SCFADs, chromatin immunoprecipitation (ChIP) assays performed at the human gamma- and beta-globin gene promoters in GM979 cells and in erythroid progenitors demonstrate that RB7 and butyrate induce dissociation of HDAC3 (but not HDAC1 or HDAC2) and its adaptor protein NCoR, specifically from the gamma-globin gene promoter. A coincident and proportional recruitment of RNA polymerase II to the gamma-globin gene promoter was observed with exposure to these gamma-globin inducers. Knockdown of HDAC3 by siRNA induced transcription of the gamma-globin gene promoter, demonstrating that displacement of HDAC3 from the gamma-globin gene promoter by the SCFAD is sufficient to induce gamma-globin gene expression. These studies demonstrate new dynamic alterations in transcriptional regulatory complexes associated with SCFAD-induced activation of the gamma-globin gene and provide a specific molecular target for potential therapeutic intervention.

Induction of fetal globin in beta-thalassemia: Cellular obstacles and molecular progress.

Accelerated apoptosis of erythroid progenitors in beta-thalassemia is a significant barrier to definitive therapy because the beneficial effects of fetal globin-inducing agents on globin chain balance may not be inducible in cells in which programmed cell death is established early. Accordingly, our objectives have been to identify methods to decrease cellular apoptosis and to identify orally tolerable fetal globin gene inducers. A pilot clinical trial was conducted to determine whether combined use of a fetal globin gene inducer (butyrate) and rhu-erythropoietin (EPO), the hematopoietic growth factor that prolongs erythroid cell survival and stimulates erythroid proliferation, would produce additive hematologic responses in any thalassemia subjects. Butyrate and EPO were administered in 10 patients. Novel fetal globin gene inducers that also stimulate erythroid proliferation were evaluated for pharmacokinetic profiles. Patients with beta+-thalassemia had relatively low levels of endogenous EPO (<145 mU/mL) and had additive responses to administered EPO and butyrate. Patients with at least one beta 0-globin mutation had higher baseline HbF levels (>60%) and EPO levels (>160 mU/mL), and three-fourths of these subjects responded to the fetal globin gene inducer alone. A few select fetal globin-inducing short-chain fatty acid derivatives that stimulated cell proliferation also had favorable pharmacokinetics. These studies identify a significant subset of thalassemia patients who appear to require exogenous EPO to respond optimally to any HbF inducer, as well as new therapeutic candidates that act on both cellular and molecular pathologies of beta-thalassemia. Both approaches now offer excellent potential for tolerable, definitive treatment of beta-thalassemia.

Enhancement of growth and survival and alterations in Bcl-family proteins in beta-thalassemic erythroid progenitors by novel short-chain fatty acid derivatives.

Accelerated apoptosis of erythroid progenitors is a characteristic of beta-thalassemia which presents a significant barrier to definitive therapeutic approaches utilizing induction of endogenous fetal globin gene expression. gamma-globin gene expression may not be inducible in, or may not be able to rescue, erythroid cells in which programmed cell death is initiated early in erythroblast development. In this report, short-chain fatty acid derivatives (SCFADs) which induce fetal globin gene expression were tested for their ability to promote proliferation and survival of erythroid progenitors cultured from beta-thalassemic subjects, and of cytokine-dependent erythroid cell lines. Certain SCFADs promoted thalassemic Bfu-e growth and cytokine-independent growth and survival of erythroid cell lines. A 40-80% increase in erythroid Bfu-e colony number was observed in cultures established with any of five mitogenic SCFADs, compared to control or butyrate-treated cultures from the same subjects. Immunoblot analysis demonstrated that these same SCFADs also regulated the expression of specific protein inhibitors of apoptosis. Anti-apoptotic ratios of the proteins Bcl-xL/Bcl-xS in thalassemic Bfu-e were increased by 30-120% with exposure to the SCFDs, compared to the ratios in the same cells cultured under control conditions. Similar anti-apoptotic increases in Mcl-1L/Mcl-1S ratios were induced by the SCFADs. These findings suggest that select fetal globin-inducing SCFADs which enhance proliferation of beta-thalassemia progenitors may enhance survival of these progenitors by altering levels of Bcl-family protein members. This combination of effects should enhance erythroid cell survival in the beta-thalassemia syndromes, allowing fetal globin gene expression to be induced more effectively than currently available, growth-suppressing, fetal globin-inducing agents, such as the butyrates or chemotherapeutic agents.

Trombofilias heredadas y pérdida gestacional recurrente / Inherited thrombophilia and recurrent pregnancy loss

Una de las causas de pérdida gestacional recurrente es la trombofilia, que se define como una tendencia a la trombosis o hipercoagulabilidad, con variabilidad en las manifestaciones clínicas dependiente de la región vascular afectada por la ausencia de flujo sanguíneo. Las trombofilias se pueden clasificar como heredadas y adquiridas de acuerdo con la naturaleza de su causa. Entre las trombofilias heredadas están el factor V Leiden, la protrombina G20210A, la metilentetrahidrofolato reductasa C677T, las deficiencias de los anticoagulantes naturales antitrombina III, proteína C y proteína S, las disfibrinogenemias y la homocistinuria. En el grupo de las trombofilias adquiridas se encuentran el síndrome antifosfolípido, la resistencia a la proteína C activada sin alteraciones en el gen del factor V y la hiperhomocisteinemia leve o moderada.Este artículo es una revisión de la literatura de estudios recientes que han buscado la asociación entre las diferentes trombofilias y la pérdida gestacional recurrente. Se incluyen las recomendaciones diagnósticas, profilácticas y terapéuticas para mujeres con trombofilia y pérdida gestacional.

Concentracion plasmatica de homocisteina en ayunas en individuos sanos de la ciudad de Medellin / Plasmatic concentration of homocysteine in fasting in normal persons of Medellin city

El aumento moderado de la concentración de homocisteína (Hcy) en sangre es considerado un factor de riesgo para enfermedades cardiovasculares Objetivo: determinar la concentración de Hcy en individuos sanos de la ciudad de Medellín. Material y métodos: se seleccionaron 57 individuos que decidieron voluntariamente participar. De éstos, se incluyeron 48 (30 mujeres y 18 hombres). Con un promedio de edad de 35±3,5 años, sin antecedentes de alteración metabólica, manifestación clínica de hipertensión arterial o de enfermedades cardiovasculares. Resultados: la concentración promedio de Hcy plasmática en ayuno fue de 8,5 ± 3,7 ymoles/l (intervalo de confianza del 95 por ciento 7,45 - 9,54 ymoles/l para el grupo en general). Por género, el promedio fue de 7.6+2.7 ymoles/l en las mujeres (intervalo de confianza 95 por ciento de 6,6 - 8,6 ymoles/I) y de 10.1 ±4,7 ymoles/l en los hombres (intervalo de confianza 95 por ciento de 7,9 - 12,3 ymoles/l). Esta fue significativamente mayor en los hombres que en las mujeres (p < 0.02). El limite superior normal fue de 13,0 ymoles/l en las mujeres y de 19,5 ymoles/l en los hombres. El 8,3 por ciento presentó hiperhomocisteinemia moderada (dos hombres y dos mujeres). Conclusión: los resultados de esta primera aproximación a la concentración de Hcy en una población colombiana sugieren que ésta difiere de la de otros países y confirma las diferencias entre hombres y mujeres. Estos datos deben ser confirmados por un estudio que involucre un mayor número de individuos y que determine su importancia como factor de riesgo en la población general y en pacientes con enfermedades cardiovasculares.