End-to-end dosimetric audit: A novel procedure developed for Irish HDR brachytherapy centres.

PURPOSE: A dosimetric audit of Ir-192 high dose rate (HDR) brachytherapy remote after-loading units was carried out in 2019. All six brachytherapy departments on the island of Ireland participated in an end-to-end test and in a review of local HDR dosimetry procedures. MATERIALS AND METHODS: A 3D-printed customised phantom was created to position the following detectors at known distances from the HDR source: a Farmer ionization chamber, GafChromic film and thermoluminescent dosimeters (TLDs). Dedicated HDR applicator needles were used to position an Ir-192 source at 2 cm distance from these detectors. The end-to-end dosimetry audit pathway was performed at each host site and included the stages of imaging, applicator reconstruction, treatment planning and delivery. Deviations between planned and measured dose distributions were quantified using gamma analysis methods. Local procedures were also discussed between auditors and hosts. RESULTS: The mean difference between Reference Air Kerma Rate (RAKR) measured during the audit and RAKR specified by the vendor source certificate was 1.3%. The results of end-to-end tests showed a mean difference between calculated and measured dose of 2.5% with TLDs and less than 0.5% with Farmer chamber measurements. GafChromic films showed a mean gamma passing rates of >95% for plastic and metal applicators with 2%/1 mm global tolerance criteria. CONCLUSIONS: The results of this audit indicate dosimetric consistency between centres. The 'end to end' dosimetry audit methodology for HDR brachytherapy has been successfully implemented in a multicentre environment, which included different models of Ir-192 sources and different treatment planning systems. The ability to create a 3D-printed water-equivalent phantom customised to accurately position all three detector types simultaneously at controlled distances from the Ir-192 source under evaluation gives good reproducibility for end-to-end methodology.

Interleukin-8 is not a predictive biomarker for the development of the acute promyelocytic leukemia differentiation syndrome.

BACKGROUND: Differentiation syndrome (DS) is the main life-threatening adverse event that occurs in acute promyelocytic leukemia (APL) patients treated with all-trans retinoic acid (ATRA). Cytokine imbalances have been reported to play role during the developing of acute promyelocytic leukemia differentiation syndrome (APL-DS). However, the relationship between the plasma cytokine levels and their prognostic value for the prediction of DS developing in patients with APL during the treatment with ATRA and anthracyclines has not been previously reported. METHODS: In this study, we followed an APL cohort (n = 17) over 7 days of ATRA therapy in DS (n = 6) and non-DS groups (n = 11). Interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12p70 and TNF-α were measured in the peripheral blood plasma from 17 patients with APL and 11 healthy adult controls by using the cytometric bead array method. RESULTS: In non-DS patients, IL-8 plasma levels were significantly reduced in the seventh day of ATRA treatment (34.16; 6.99 to 147.11 pg mL- 1 in D0 vs. 10.9; 0 to 26.81 pg mL- 1 in D7; p = 0.02) whereas their levels did not discriminate between DS and non-DS development during the entire induction period (all p > 0.05 in D0, D3, and D7). No significant differences were found in IL-6 levels between groups (p > 0.05 in D0-D7). Other cytokines tested were all undetectable in patients with APL or healthy controls. CONCLUSIONS: We demonstrated that the modulation of IL-8 following ATRA treatment may occur regardless of the development of DS and, therefore, does not appear to be a predictive biomarker to monitor the APL-DS.

6X acuros algorithm validation in the presence of inhomogeneities for VMAT treatment planning.

AIM: To validate the Acuros®XB (AXB) dose calculation algorithm for a 6 MV beam from the Varian TrueBeam treatment units. BACKGROUND: Currently Anisotropic Analytic Algorithm (AAA) is clinically used on authors' department but AXB could replace it for VMAT treatments in regions where inhomogeneities and free air are present. MATERIALS AND METHODS: Two steps are followed in the validation process of a new dose calculation algorithm. The first is to check the accuracy of algorithm for a homogenous phantom and regular fields. Multiple fields of increasing complexity have been acquired using a Mapcheck diode array. The accuracy of the algorithm was evaluated using the gamma analysis method. The second is to validate the algorithm in the presence of heterogeneous media. Planar absolute dose was measured with GafChromic®EBT2 film and was compared with the dose calculated by AXB. Gamma analysis was performed between Mapcheck measurements and AXB dose calculations, at a range of clinical source-surface distance. RESULTS: For SSDs ranging from 80 to 100 cm, the results show a minimum pass rate of 95% between AXB and Mapcheck acquisition. For open 6 MV photon beam interacting with a phantom with an air gap, the agreement after the air gap between AXB and GafChromic®EBT2 is less than 1% in the 3 × 3cm2 field and less than 2% in the 10 × 10 cm2 field. CONCLUSIONS: AXB has advanced modelling of lateral electron transport that enables a more accurate dose calculation in heterogeneous regions and, compared with AAA, improves accuracy between different density interfaces. This will be of particular benefit for head/neck treatments.

Energy and dose dependence of GafChromic EBT3-V3 film across a wide energy range.

AIM: To determine the energy and dose dependence of GafChromic EBT3-V3 film over an energy range 0.2 mm Al HVL to 6 MV. BACKGROUND: The decay scheme of a brachytherapy source may be complex and the spectrum of energy can be wide. LiF TLDs are the golden standard recommended for dosimetric measures in brachytherapy, for their energy independence, but TLDs could be not available in some centres. An alternative way to perform dose measurements is to use GafChromic films, but they show energy dependence. METHODS AND MATERIALS: Films have been irradiated at increasing dose with three different beams: 6 MV beam, TPR20, 10 = (0.684 ±â€¯0.01), HVL = (2.00 ±â€¯0.01)mmAl and HVL = (0.20 ±â€¯0.01)mmAl. Calibration curves were generated using the same dose range (0cGy to 850cGy) for the three energies. Using the 6 MV calibration curve as reference, the film response in terms of net optical density (OD) was evaluated. RESULTS: The difference in the calibration curve obtained by irradiating the film with 6 MV and 2 mm Al HVL energy beams is less than 3 %, within the calibration uncertainty, in the dose range 500-850cGy. The OD of EBT3-V3 film is significantly lower at 0.2 mmAl HVL compared to 6 MV, showing differences up to 25 %. CONCLUSION: Within the range 6 MV-2 mm Al HVL and dose higher than 500cGy, GafChromic EBT3-V3 films are energy independent. In this dose range, films can be calibrated in a simple geometry, using a 6 MV Linac beam, and can be used for brachytherapy sources dose measures. The use of EBT3 films can be extended to reference dosimetry in Ir-192 clinical brachytherapy.

Dosimetry assessment of patient-specific 3D printable materials for HDR surface brachytherapy.

PURPOSE: 3D printable material water equivalence was investigated within the range of Iridium-192 source energies. The aim is to compare the dose calculated by our treatment planning system (TPS) with the dose measured in the presence of printed materials. The purpose of this investigation is to assess the feasibility of using 3D materials for brachytherapy surface applicators. METHODS AND MATERIALS: Cheetah was examined both in a water tank and with the CIRS anthropomorphic phantom. Calibrated Gafchromic EBT3-V3 film was used and the measurements compared with TG-43 calculations on Oncentra®Brachy. A 3D-printed slab 5 mm thick was created to position the source and two films were irradiated at 5 mm and 15 mm of distance. A curved mould with 7 trajectories was created and coupled with CIRS phantom. A set of CT images of phantom and mould was acquired and imported on TPS, where a target was defined and a dose plan was created. Plan was delivered with two films positioned between two different slabs of phantom, at reciprocal distance of 2 cm, orientated perpendicularly to the source axis. RESULTS: All PDDs show a maximum difference of 4.7% (average 2.2%). At 5 mm and at 15 mm, the gamma pass rate is 100% with tolerance 2%/1 mm DTA. Results of films placed intra-slabs show a high pass rate (>99%) with tolerances of 2% dose and 1 mm DTA. CONCLUSION: 3D material investigated is water equivalent at Ir-192 energies and agreed with Oncentra®Brachy dose calculations which suggest that it is a suitable material for superficial brachytherapy.

Clinical and hematological effects of hydroxyurea therapy in sickle cell patients: a single-center experience in Brazil.

CONTEXT AND OBJECTIVES Sickle cell disease (SCD) is the most common genetic disorder among people of African descent, affecting approximately 3,500 newborns each year in Brazil. Hydroxyurea (HU) is the only effective drug to treating patients with SCD, thereby reducing morbidity and mortality. The objective was to analyze the effects of HU on SCD patients at our institution. DESIGN AND SETTING Retrospective study conducted at a sickle cell centre in Ribeirão Preto, São Paulo, Brazil. METHODS We analyzed clinical and laboratory data on 37 patients. The hematological parameters and clinical events that occurred during the year before and the first year of treatment with HU were analyzed. The mean dose of HU was 24.5 ± 5.5 mg/kg/day. RESULTS There were rises in three parameters: hemoglobin (8.3 g/dl to 9.0 g/dl, P = 0.0003), fetal hemoglobin (HbF) (2.6% to 19.8%, P < 0.0001) and mean cell volume MCV (89 to 105 fl, P = 0.001); and reductions in the numbers of leukocytes (10,050/µl to 5,700/µl, P < 0.0001), neutrophils (6,200/µl to 3,400/µl, P = 0.001), platelets (459,000/µl to 373,000/µl, P = 0.0002), painful crises (1.86 to 0.81, P = 0.0014), acute chest syndromes (0.35 to 0.08, P = 0.0045), infections (1.03 to 0.5, P = 0.047), hospitalizations (1.63 to 0.53, P = 0.0013) and transfusions (1.23 to 0.1, P = 0.0051). CONCLUSION The patients presented clinical and hematological improvements, with an increase in HbF and a reduction in the infection rate, which had not been addressed in most previous studies.

First test on three stitching methods with digital detectors used in radiography.

In medical radiography, a large area of the human body sometimes needs to be investigated by means of X-ray examinations, for example, the lower spine. With computed radiography (CR) cassettes, due to their large surface area, it is possible to make this type of investigation with a single exposure and use of a single cassette. With flat-panel digital detectors (DR detectors), due to their smaller size and their large cost, it is not possible to make the investigation with a single exposure, but multiple exposures are required according to the extent of the surface to be irradiated, with merging of two or more radiographic images. This operation is called "stitching" because several images are stitched together. We have tested three different modes of performing stitching examinations: linear, rotational and wide. Our purpose was to highlight the differences and issues, taking into account the quality of the images and the simplicity of use, with the goal of choosing the best technique. We evaluated the methods by three different parameters: the image quality, the ease of use (taking into account the time for performing an examination), and the simplicity of development. Each method has good qualities, but also its own problems: choosing the best technique is not easy, because each has advantages and disadvantages. Nowadays, rotational stitching is the most used because the quality of the images is very good and we are confident that the images have no parallax errors. However, this is not an easy system to develop because there are two different mechanical movements to be managed. For this reason, we are improving linear stitching, which is easier, but has a worse image quality. Wide stitching is the system closer to the CR system and has very good image quality, but the difficulty of developing a collimator that allows one to perform the technique presents a big hurdle. We conclude that, even though rotational stitching is complex and expensive, it is the best technique among those investigated.

Clinical and hematological effects of hydroxyurea therapy in sickle cell patients: a single-center experience in Brazil / Efeitos clinicos e hematologicos do tratamento com hidroxiureia em pacientes falciformes: experiencia de um centro no Brasil

CONTEXT AND OBJECTIVES Sickle cell disease (SCD) is the most common genetic disorder among people of African descent, affecting approximately 3,500 newborns each year in Brazil. Hydroxyurea (HU) is the only effective drug to treating patients with SCD, thereby reducing morbidity and mortality. The objective was to analyze the effects of HU on SCD patients at our institution. DESIGN AND SETTING Retrospective study conducted at a sickle cell centre in Ribeirão Preto, São Paulo, Brazil. METHODS We analyzed clinical and laboratory data on 37 patients. The hematological parameters and clinical events that occurred during the year before and the first year of treatment with HU were analyzed. The mean dose of HU was 24.5 ± 5.5 mg/kg/day. RESULTS There were rises in three parameters: hemoglobin (8.3 g/dl to 9.0 g/dl, P = 0.0003), fetal hemoglobin (HbF) (2.6% to 19.8%, P < 0.0001) and mean cell volume MCV (89 to 105 fl, P = 0.001); and reductions in the numbers of leukocytes (10,050/µl to 5,700/µl, P < 0.0001), neutrophils (6,200/µl to 3,400/µl, P = 0.001), platelets (459,000/µl to 373,000/µl, P = 0.0002), painful crises (1.86 to 0.81, P = 0.0014), acute chest syndromes (0.35 to 0.08, P = 0.0045), infections (1.03 to 0.5, P = 0.047), hospitalizations (1.63 to 0.53, P = 0.0013) and transfusions (1.23 to 0.1, P = 0.0051). CONCLUSION The patients presented clinical and hematological improvements, with an increase in HbF and a reduction in the infection rate, which had not been addressed in most previous studies. .

CONTEXTO E OBJETIVO A doença falciforme (SCD) é o distúrbio genético mais comum entre afrodes-cendentes, afetando aproximadamente 3.500 recém-nascidos a cada ano no Brasil. A hidroxiureia (HU) é a única droga efetiva para o tratamento dos pacientes com SCD, reduzindo a morbidade e a mortalidade da doença. O objetivo do estudo foi analisar os efeitos da HU em pacientes com SCD em nossa instituição. TIPO DE ESTUDO E LOCAL Estudo retrospectivo realizado em um centro de anemia falciforme em Ribeirão Preto, São Paulo, Brasil. MÉTODOS Nós analisamos os dados clínicos e laboratoriais de 37 pacientes. Os parâmetros hematológicos e eventos clínicos que ocorreram no ano anterior e durante o primeiro ano de tratamento com HU foram analisados. A dose média de HU foi 24.5 ± 5.5 mg/kg/dia. RESULTADOS Houve aumento em três parâmetros estudados: hemoglobina (8,3 g/dl para 9,0 g/dl, P = 0,0003), hemoglobina fetal (HbF) (2,6% para 19,8%, P < 0,0001) e volume corpuscular médio (VCM) (89 para 105 fl, P = 0,001); e redução do número de leucócitos (10.050/µl para 5.700/µl, P < 0,0001), neutrófilos (6.200/µl para 3.400/µl, P = 0,001), plaquetas (459.000/µl para 373.000/µl, P = 0,0002), crises dolorosas (1,86 para 0,81, P = 0,0014), síndrome torácica aguda (0,35 para 0,08, P = 0,0045), infecções (1,03 para 0,5, P = 0,047), hospitalizações (1,63 para 0,53, P = 0,0013) e número de transfusões (1,23 para 0,1, P = 0,0051). CONCLUSÃO Os pacientes apresentaram melhora clínica e hematológica, com aumento da HbF e redução da taxa de infecção, dado este não explorado na maioria dos estudos clínicos já publicados. .

Molecular basis for the diagnosis and treatment of acute promyelocytic leukemia.

Acute promyelocytic leukemia is characterized by gene rearrangements that always involve the retinoic acid receptor alpha on chromosome 15. In the majority of patients t(15;17) is detected, which generates the promyelocytic leukemia gene/retinoic acid receptor alpha rearrangement. This rearrangement interacts with several proteins, including the native promyelocytic leukemia gene, thus causing its delocalization from the nuclear bodies, impairing its function. The immunofluorescence staining technique using the anti-PML antibody may be used to provide a rapid diagnosis and to immediately start therapy using all-trans retinoic acid. The experience of the International Consortium on Acute Promyelocytic Leukemia has demonstrated that early mortality was significantly reduced by adopting the immunofluorescence technique. All-trans retinoic acid combined with chemotherapy is the standard therapy; this promotes complete remission rates greater than 90% and cure rates of nearly 80%. However, early mortality is still an important limitation and hematologists must be aware of the importance of treating newly diagnosed acute promyelocytic leukemia as a medical emergency.

Methionine-induced hyperhomocysteinemia reverts fibrinolytic pathway activation in a murine model of acute promyelocytic leukemia.

Increased fibrinolysis is an important component of acute promyelocytic leukemia (APL) bleeding diathesis. APL blasts overexpress annexin II (ANXII), a receptor for tissue plasminogen activator (tPA), and plasminogen, thereby increasing plasmin generation. Previous studies suggested that ANXII plays a pivotal role in APL coagulopathy. ANXII binding to tPA can be inhibited by homocysteine and hyperhomocysteinemia can be induced by L-methionine supplementation. In the present study, we used an APL mouse model to study ANXII function and the effects of hyperhomocysteinemia in vivo. Leukemic cells expressed higher ANXII and tPA plasma levels (11.95 ng/mL in leukemic vs 10.74 ng/mL in wild-type; P = .004). In leukemic mice, administration of L-methionine significantly increased homocysteine levels (49.0 µmol/mL and < 6.0 µmol/mL in the treated and nontreated groups, respectively) and reduced tPA levels to baseline concentrations. The latter were also decreased after infusion of the LCKLSL peptide, a competitor for the ANXII tPA-binding site (11.07 ng/mL; P = .001). We also expressed and purified the p36 component of ANXII in Pichia methanolica. The infusion of p36 in wild-type mice increased tPA and thrombin-antithrombin levels, and the latter was reversed by L-methionine administration. The results of the present study demonstrate the relevance of ANXII in vivo and suggest that methionine-induced hyperhomocysteinemia may reverse hyperfibrinolysis in APL.

Co-existence of t(6;13)(p21;q14.1) and trisomy 12 in chronic lymphocytic leukemia.

We report a case of a 57-year-old man diagnosed with chronic lymphocytic leukemia (CLL) and presence of a rare t(6;13)(p21;q14.1) in association with an extra copy of chromosome 12. Classical cytogenetic analysis using the immunostimulatory combination of DSP30 and IL-2 showed the karyotype 47,XY,t(6;13)(p21;q14.1), +12 in 75% of the metaphase cells. Spectral karyotype analysis (SKY) confirmed the abnormality previously seen by G-banding. Additionally, interphase fluorescence in situ hybridization using an LSI CEP 12 probe performed on peripheral blood cells without any stimulant agent showed trisomy of chromosome 12 in 67% of analyzed cells (134/200). To the best of our knowledge, the association of t(6;13)(p21;q14.1) and +12 in CLL has never been described. The prognostic significance of these new findings in CLL remains to be elucidated. However, the patient has been followed up since 2009 without any therapeutic intervention and has so far remained stable.

Hematological differences between patients with different subtypes of sickle cell disease on hydroxyurea treatment.

OBJECTIVE: Sickle cell anemia and the interaction S/Beta thalassemia differ in hematological values due to microcytosis and hypochromia caused by the thalassemic mutation. The clinical benefit of long-term hydroxyurea treatment is undeniable in sickle cell disease with monitoring of the biological action of the drug being by the complete blood count. The objective of this work is to compare changes in some of the erythrocytic indexes between S/Beta thalassemia and sickle cell anemia patients on long-term hydroxyurea treatment. METHODS: The values of erythrocyte indexes (mean corpuscular volume and mean corpuscular hemoglobin) were compared in a retrospective study of two groups of patients (Sickle cell anemia and S/Beta thalassemia) on hydroxyurea treatment over a mean of six years. RESULTS: The quantitative values of the two parameters differed between the groups. Increases in mean corpuscular volume and reductions in mean corpuscular hemoglobin delay longer in S/Beta thalassemia patients (p-value = 0.018). CONCLUSION: Hematological changes are some of the beneficial effects of hydroxyurea in sickle cell disease as cellular hydration increases and the hemoglobin S concentration is reduced. The complete blood count is the best test to monitor changes, but the interpretation of the results in S/Beta thalassemia should be different.

Molecular basis for the diagnosis and treatment of acute promyelocytic leukemia

Acute promyelocytic leukemia is characterized by gene rearrangements that always involve the retinoic acid receptor alpha on chromosome 15. In the majority of patients t(15;17) is detected, which generates the promyelocytic leukemia gene/retinoic acid receptor alpha rearrangement. This rearrangement interacts with several proteins, including the native promyelocytic leukemia gene, thus causing its delocalization from the nuclear bodies, impairing its function. The immunofluorescence staining technique using the anti-PML antibody may be used to provide a rapid diagnosis and to immediately start therapy using all-trans retinoic acid. The experience of the International Consortium on Acute Promyelocytic Leukemia has demonstrated that early mortality was significantly reduced by adopting the immunofluorescence technique. All-trans retinoic acid combined with chemotherapy is the standard therapy; this promotes complete remission rates greater than 90% and cure rates of nearly 80%. However, early mortality is still an important limitation and hematologists must be aware of the importance of treating newly diagnosed acute promyelocytic leukemia as a medical emergency.

Hematological differences between patients with different subtypes of sickle cell disease on hydroxyurea treatment

OBJECTIVE: Sickle cell anemia and the interaction S/Beta thalassemia differ in hematological values due to microcytosis and hypochromia caused by the thalassemic mutation. The clinical benefit of long-term hydroxyurea treatment is undeniable in sickle cell disease with monitoring of the biological action of the drug being by the complete blood count. The objective of this work is to compare changes in some of the erythrocytic indexes between S/Beta thalassemia and sickle cell anemia patients on long-term hydroxyurea treatment. METHODS: The values of erythrocyte indexes (mean corpuscular volume and mean corpuscular hemoglobin) were compared in a retrospective study of two groups of patients (Sickle cell anemia and S/Beta thalassemia) on hydroxyurea treatment over a mean of six years. RESULTS: The quantitative values of the two parameters differed between the groups. Increases in mean corpuscular volume and reductions in mean corpuscular hemoglobin delay longer in S/Beta thalassemia patients (p-value = 0.018). CONCLUSION: Hematological changes are some of the beneficial effects of hydroxyurea in sickle cell disease as cellular hydration increases and the hemoglobin S concentration is reduced. The complete blood count is the best test to monitor changes, but the interpretation of the results in S/Beta thalassemia should be different.

Intrahepatic cholestasis in sickle cell disease: a case report.

Intrahepatic cholestasis (SCIC) is an uncommon but potentially fatal complication of sickle cell disease (SCD), with a high death rate, observed mainly in patients with homozygous sickle cell anemia. Herein, we describe a case of severe SCIC treated successfully with aggressive manual exchange transfusion (ET). The patient was admitted with enlarged liver and signs of hepatic failure, such as hyperbilirubinemia and coagulopathy. There was no evidence of viral hepatitis or biliary obstruction. We performed several sessions of ET in order to reduce the percentage of HbS to levels inferior to 30%, which was successfully accomplished. The patient had a complete recovery of hepatic function. This case has shown that ET is an effective treatment of SCIC and should be introduced early on the onset of this severe complication.