Detection of minimal residual disease in acute myeloid leukemia: evaluating utility and challenges.

This study discusses the importance of minimal residual disease (MRD) detection in acute myeloid leukemia (AML) patients using liquid biopsy and next-generation sequencing (NGS). AML prognosis is based on various factors, including genetic alterations. NGS has revealed the molecular complexity of AML and helped refine risk stratification and personalized therapies. The long-term survival rates for AML patients are low, and MRD assessment is crucial in predicting prognosis. Currently, the most common methods for MRD detection are flow cytometry and quantitative PCR, but NGS is being incorporated into clinical practice due to its ability to detect genomic aberrations in the majority of AML patients. Typically, bone marrow samples are used for MRD assessment, but using peripheral blood samples or liquid biopsies would be less invasive. Leukemia originates in the bone marrow, along with the cfDNA obtained from peripheral blood. This study aimed to assess the utility of cell-free DNA (cfDNA) from peripheral blood samples for MRD detection in AML patients. A cohort of 20 AML patients was analyzed using NGS, and a correlation between MRD assessment by cfDNA and circulating tumor cells (CTCs) in paired samples was observed. Furthermore, a higher tumor signal was detected in cfDNA compared to CTCs, indicating greater sensitivity. Challenges for the application of liquid biopsy in MRD assessment were discussed, including the selection of appropriate markers and the sensitivity of certain markers. This study emphasizes the potential of liquid biopsy using cfDNA for MRD detection in AML patients and highlights the need for further research in this area.

Electron Scattering from 1-Methyl-5-Nitroimidazole: Cross-Sections for Modeling Electron Transport through Potential Radiosensitizers.

In this study, we present a complete set of electron scattering cross-sections from 1-Methyl-5-Nitroimidazole (1M5NI) molecules for impact energies ranging from 0.1 to 1000 eV. This information is relevant to evaluate the potential role of 1M5NI as a molecular radiosensitizers. The total electron scattering cross-sections (TCS) that we previously measured with a magnetically confined electron transmission apparatus were considered as the reference values for the present analysis. Elastic scattering cross-sections were calculated by means of two different schemes: The Schwinger multichannel (SMC) method for the lower energies (below 15 eV) and the independent atom model-based screening-corrected additivity rule with interferences (IAM-SCARI) for higher energies (above 15 eV). The latter was also applied to calculate the total ionization cross-sections, which were complemented with experimental values of the induced cationic fragmentation by electron impact. Double differential ionization cross-sections were measured with a reaction microscope multi-particle coincidence spectrometer. Using a momentum imaging spectrometer, direct measurements of the anion fragment yields and kinetic energies by the dissociative electron attachment are also presented. Cross-sections for the other inelastic channels were derived with a self-consistent procedure by sampling their values at a given energy to ensure that the sum of the cross-sections of all the scattering processes available at that energy coincides with the corresponding TCS. This cross-section data set is ready to be used for modelling electron-induced radiation damage at the molecular level to biologically relevant media containing 1M5NI as a potential radiosensitizer. Nonetheless, a proper evaluation of its radiosensitizing effects would require further radiobiological experiments.

Dependence of Induced Biological Damage on the Energy Distribution and Intensity of Clinical Intra-Operative Radiotherapy Electron Beams.

The survival fraction of epithelial HaCaT cells was analysed to assess the biological damage caused by intraoperative radiotherapy electron beams with varying energy spectra and intensities. These conditions were achieved by irradiating the cells at different depths in water using nominal 6 MeV electron beams while consistently delivering a dose of 5 Gy to the cell layer. Furthermore, a Monte Carlo simulation of the entire irradiation procedure was performed to evaluate the molecular damage in terms of molecular dissociations induced by the radiation. A significant agreement was found between the molecular damage predicted by the simulation and the damage derived from the analysis of the survival fraction. In both cases, a linear relationship was evident, indicating a clear tendency for increased damage as the averaged incident electron energy and intensity decreased for a constant absorbed dose, lowering the dose rate. This trend suggests that the radiation may have a more pronounced impact on surrounding healthy tissues than initially anticipated. However, it is crucial to conduct additional experiments with different target geometries to confirm this tendency and quantify the extent of this effect.

Interobserver Variability in Contouring Hepatocellular Carcinoma at a Tertiary Center.

BACKGROUND/AIM: The optimal imaging test for delineation of the gross tumor volume (GTV) in hepatocellular carcinoma has not been defined. The hypothesis is that magnetic resonance imaging (MRI) allows for better visualization of the extent of tumor and will optimize the accuracy of tumor delineation for liver stereotactic radiotherapy compared with computed tomography (CT) only. We evaluated the interobserver agreement in GTV of hepatocellular carcinoma in a multicenter panel and compared MRI and CT in GTV delineation. MATERIALS AND METHODS: After the institutional review boards approved the study, we analyzed anonymous CT and MRI obtained from five patients with hepatocellular carcinoma. Eight radiation oncologists at our center used CT and MRI to delineate five GTVs of liver tumors. In both CT and MRI, the GTV volumes were compared. RESULTS: The median GTV volume on MRI was 2.4 cm3 (range=0.59-15.6 cm3) compared to 3.5 cm3 (range=0.52-24.9 cm3) on CT (p=0.36). The GTV volume as defined on MRI was larger or at least as large as the GTV volume on CT in two cases. Variance and standard deviation between observers in CT and MRI were minor (6 vs. 7.87 cm3, and 2.5 vs. 2.8 cm3 respectively). CONCLUSION: In cases with well-defined tumors, CT is easier and reproducible. In cases with no defined tumor in CT, other tools are needed and MRI can be complementary. The interobserver variability in target delineation of hepatocellular carcinoma in this study is noteworthy.

Evaluation of a high resolution diode array for CyberKnife quality assurance.

PURPOSE: The CyberKnife quality assurance (QA) program relies mainly on the use of radiochromic film (RCF). We aimed at evaluating high-resolution arrays of detectors as an alternative to films for CyberKnife machine QA. METHODS: This study will test the SRS Mapcheck (Sun Nuclear, Melbourne, Florida, USA) diode array and its own software, which allows three tests of the CyberKnife QA program to be performed. The first one is a geometrical accuracy test based on the delivery of two orthogonal beams (Automated Quality Assurance, AQA). Besides comparing the constancy and repeatability of both methods, known errors will be introduced to check their sensitivity. The second checks the constancy of the iris collimator field sizes (Iris QA). Changes in the field sizes will be introduced to study the array sensitivity. The last test checks the correct positioning of the multileaf collimator (MLC). It will be tested introducing known systematic displacements to whole banks and to single leaves. RESULTS: The results of the RCF and diode array were equivalent (maximum differences of 0.18 ± 0.14 mm) for the AQA test, showing the array a higher reproducibility. When known errors were introduced, both methods behaved linearly with similar slopes. Regarding Iris QA, the array measurements are highly linear when changes in the field sizes are introduced. Linear regressions show slopes of 0.96-1.17 with r2 above 0.99 in all field sizes. Diode array seems to detect changes of 0.1 mm. In MLC QA, systematic errors of the whole bank of leaves were not detected by the array, while single leaf errors were detected. CONCLUSIONS: The diode array is sensitive and accurate in the AQA and Iris QA tests, which give us the possibility of substituting RCF with a diode array. QA would be performed faster than using the film procedure, obtaining reliable results. Regarding the MLC QA, the inability to detect systematic displacements make it difficult to confidently use the detector.

The use of a thin guide-wire for urethral definition in prostate SBRT treatments with Cyberknife.

PURPOSE: To study and analyze the effect of the use of a thin guide-wire instead of a Foley catheter for urethral definition in prostate stereotactic body radiation therapy (SBRT) treatments and to compare treatment parameters in both situations. MATERIAL AND METHODS: Thirty-seven prostate SBRT patients were employed in this study. A Foley catheter was employed in nine of them, and a guide-wire was employed in the other 28 patients. For each of the 28 patients in which the guide-wire was employed, a comparison between urethral positions in both situations was performed, allowing for a margin definition of the urethra when a Foley catheter was employed. Displacements of the prostate during treatment were obtained, allowing for an analysis of prostate positions in both situations. Also, different treatment parameters such as the number of treatment interruptions, couch movements performed, and x-rays needed were gathered. RESULTS: Large differences between urethral positions can be found in the anterior-posterior (AP) directions compared to those in the lateral (LAT) direction. Differences are also larger in areas closer to the base of the prostate, where margins applied in the case of using a Foley catheter are 16 mm with a mean displacement of 6 mm in the posterior direction. No differences in the treatment parameters were found during treatment in both situations. The difference found in absolute prostate pitch rotations suggests that the Foley catheter provokes a shift of the prostate position, which does not occur when employing the guide-wire. CONCLUSIONS: Foley catheters shift the urethral position, making them a wrong surrogate of the urethra when no catheters are present. The margins needed to assess uncertainties introduced by the use of a Foley catheter are larger than those usually applied. The use of a Foley catheter did not present any additional difficulty during treatment delivery in terms of images employed or interruptions produced.

Genetic Alterations in Members of the Proteasome 26S Subunit, AAA-ATPase (PSMC) Gene Family in the Light of Proteasome Inhibitor Resistance in Multiple Myeloma.

For the treatment of Multiple Myeloma, proteasome inhibitors are highly efficient and widely used, but resistance is a major obstacle to successful therapy. Several underlying mechanisms have been proposed but were only reported for a minority of resistant patients. The proteasome is a large and complex machinery. Here, we focus on the AAA ATPases of the 19S proteasome regulator (PSMC1-6) and their implication in PI resistance. As an example of cancer evolution and the acquisition of resistance, we conducted an in-depth analysis of an index patient by applying FISH, WES, and immunoglobulin-rearrangement sequencing in serial samples, starting from MGUS to newly diagnosed Multiple Myeloma to a PI-resistant relapse. The WES analysis uncovered an acquired PSMC2 Y429S mutation at the relapse after intensive bortezomib-containing therapy, which was functionally confirmed to mediate PI resistance. A meta-analysis comprising 1499 newly diagnosed and 447 progressed patients revealed a total of 36 SNVs over all six PSMC genes that were structurally accumulated in regulatory sites for activity such as the ADP/ATP binding pocket. Other alterations impact the interaction between different PSMC subunits or the intrinsic conformation of an individual subunit, consequently affecting the folding and function of the complex. Interestingly, several mutations were clustered in the central channel of the ATPase ring, where the unfolded substrates enter the 20S core. Our results indicate that PSMC SNVs play a role in PI resistance in MM.

The Minimal Residual Disease Using Liquid Biopsies in Hematological Malignancies.

The study of cell-free DNA (cfDNA) and other peripheral blood components (known as "liquid biopsies") is promising, and has been investigated especially in solid tumors. Nevertheless, it is increasingly showing a greater utility in the diagnosis, prognosis, and response to treatment of hematological malignancies; in the future, it could prevent invasive techniques, such as bone marrow (BM) biopsies. Most of the studies about this topic have focused on B-cell lymphoid malignancies; some of them have shown that cfDNA can be used as a novel way for the diagnosis and minimal residual monitoring of B-cell lymphomas, using techniques such as next-generation sequencing (NGS). In myelodysplastic syndromes, multiple myeloma, or chronic lymphocytic leukemia, liquid biopsies may allow for an interesting genomic representation of the tumor clones affecting different lesions (spatial heterogeneity). In acute leukemias, it can be helpful in the monitoring of the early treatment response and the prediction of treatment failure. In chronic lymphocytic leukemia, the evaluation of cfDNA permits the definition of clonal evolution and drug resistance in real time. However, there are limitations, such as the difficulty in obtaining sufficient circulating tumor DNA for achieving a high sensitivity to assess the minimal residual disease, or the lack of standardization of the method, and clinical studies, to confirm its prognostic impact. This review focuses on the clinical applications of cfDNA on the minimal residual disease in hematological malignancies.

Clinical course and risk factors for mortality from COVID-19 in patients with haematological malignancies.

BACKGROUND: The impact of coronavirus disease 2019 (COVID-19) in haematological patients (HP) has not been comprehensively reported. METHODS: We analysed 39 patients with SARS-CoV-2 infection and haematological malignancies. Clinical characteristics and outcomes were compared to a matched control group of 53 non-cancer patients with COVID-19. Univariate and multivariate analyses were carried out to assess the risk factors associated with poor outcome. RESULTS: The most frequent haematological diseases were lymphoma (30%) and multiple myeloma (30%). Eighty-seven % HP developed moderate or severe disease. Patients with haematological malignancies had a significantly higher mortality rate compared to non-cancer patients (35.9% vs 13.2%; P = .003 (odds ratio 6.652). The worst outcome was observed in chronic lymphocytic leukaemia patients. Only age >70 years and C reactive protein >10 mg/dl at admission were associated with higher risk of death (odds ratio 34.86, P = .003 and 13.56,P = .03). Persistent viral sheddind was detected in 5 HP. Active chemotherapy, viral load at diagnosis and COVID-19 therapy were not predictors of outcome. CONCLUSION: Mortality of COVID-19 is significantly higher in patients with haematological malignancies compared to non-cancer patients. The impact of persistent viral shedding must be considered in order to re-start therapies and maintain infectious control measures.

Dosimetric and Contrast Noise Ratio Comparison of Three Different Digital Imaging Technologies in Mammography.

PURPOSE: The purpose of the study was to compare the three most common technologies available in digital mammography based in the evaluation of average glandular dose and contrast noise ratio (CNR). METHOD: The average glandular dose was estimated with a direct digital detector (aSe) with a pixel size of 0.85 µm, a photon counter with a pixel size of 50 µm and a computerized radiography (CR) system. A semiconductor detector was used to measure the input kerma to the detector, and the average glandular dose was calculated from the conversion factors dependent on the anode filter combination, half value layer and breast glandularity. RESULTS: The average glandular dose obtained with polymethyl methacrylate and CNR of mean thickness 4.5 cm using direct digital equipment was 1.02 mGy and CNR = 7.4; using the photon counter it was 0.43 mGy and CNR = 4.7 in C100 mode, and 0.64 mGy and CNR = 5.7 in C120 mode; and using the photostimulable CR, the estimated value was 1.65 mGy and CNR = 5.1. CONCLUSIONS: The photon counter offers a lower average glandular dose than the other two devices with adequate image quality (CNR). The CR equipment offers a similar CNR value but delivers a higher dose than the new generations of available mammograms.

SaO2 as a predictor of exercise-induced hypoxemia in chronic obstructive pulmonary disease at moderate altitude.

Background: Given the high prevalence of chronic obstructive pulmonary disease (COPD) in Bogota (2630 m above the sea), screening methods are required for COPD patients who develop exercise-induced hypoxemia (EIH). Objective: The objective was to measure the productive capacity of basal oxygen saturation for the detection of EIH during the 6-min walking test (6MWT) in patients diagnosed with COPD in a hospital in Bogotá. Design: This was a cross-sectional, retrospective study. Population: Patients diagnosed with COPD with SaO2≥88% who attended the Pneumology Section of the FSFB for a 6MWT between 2013 and 2017 were included in the study. Measurements: Age, sex, anthropometric data, SaO2, SaO2 during 6MWT, and spirometry were evaluated. Results: Ninety-two patients with EIH and 32 patients without EIH were studied. Statistically significant differences were found in SaO2, minimum SaO2 during 6MWT, and BMI (90.8% vs 93%, 80.3% vs 88.9%, and 26.7 kg/m2 vs 23.8 kg/m2, respectively). FEV1 was without statistically significant differences (74.1% vs 78.6%). The ROC curve showed a better cut-off point for detecting EIH with basal SaO2≤92% (sensitivity 76.1%, specificity 62.5%, NPV 47.6%, and PPV 85.4%) and SaO2≤94% as the best sensitivity point (sensitivity 94.6%, specificity 15.6%, NPV 76.3%, and PPV 50%). Conclusion: SaO2 is not a good screening test for EIH in COPD patients at moderate altitude.

On the use of Bayesian statistics in the application of adaptive setup protocols in radiotherapy.

PURPOSE: To propose adaptive setup protocols using Bayesian statistics that facilitate, based on a prediction of coverage probability, making a decision on which patients should follow daily imaging prior to treatment delivery. MATERIALS AND METHODS: The suitability of the treatment margins was assessed combining interfraction variability measurements of the first days of treatment with previous data gathered from our patient population. From this information, we decided if a patient needs an online imaging protocol to perform daily isocenter correction before each treatment fraction. We applied our method to five different datasets. Protocol parameters were selected from each dataset based on coverage probability, the expected imaging workload of the treatment unit, and the accuracy of patient classification. Time trends were assessed and included in the proposed protocols. To validate the accuracy of the protocols, they were applied to a validation dataset of prostate cancer patients. RESULTS: Adaptive setup protocols lead expected population coverage >97% in all datasets analyzed when time trends were considered. The reduction in imaging workload ranged from 40% in lung treatments to 28.5% in prostate treatments. Results of the protocol on the validation dataset were very similar to those previously predicted. CONCLUSIONS: The adaptive setup protocols based on Bayesian statistics presented in this study enable the optimization of imaging workload in the treatment unit ensuring that appropriate dose coverage remains unchanged.

Hydatid cyst of the gallbaldder: A systematic review of the literature.

AIM: To evaluate all the references about primary gallbladder hidatidosis looking for best treatment evidence. METHODS: Search: 1966-2015 in MEDLINE, Cochrane Library, SciELO, and Tripdatabase. KEY WORDS: "gallabladder hydatid disease" and "gallbladder hydatid cyst". We found 124 papers in our searches but only 14 papers including 16 cases were about hydatid cyst of the gallbladder (GBHC). RESULTS: Eight cases of GBHC were women and seven men. One not mentioned. Median age was 48.3 years. The most frequent clinical symptom was abdominal pain (94%) usually in the right upper quadrant. Ultrasound was performed in ten patients (62.5%) but in most cases a combination of several techniques was performed. The location of the cysts was intravesicular in five patients. Five patients presented GBHC and liver hydatid cysts. Two patients presented cholelithiasis and one choledocholithiasis. The most frequent surgical technique was cholecystectomy by laparotomy (81.25%). Simultaneous surgery of liver cysts was carried out in five cases. Eleven patients did not present postoperative complications, but one died. The mean hospital stay was seven days. No recurrence of GBHC was recorded. CONCLUSION: In GBHC, the most frequent symptom is right hypocondrium pain (evidence level V). Best diagnostic methods are ultrasound and computed tomography (level V, grade D). Suggested treatment is open cholecystectomy and postoperative albendazole (level V, grade D) obtaining good clinical results and none relapses.

Electron collisions with phenol: Total, integral, differential, and momentum transfer cross sections and the role of multichannel coupling effects on the elastic channel.

We report theoretical and experimental total cross sections for electron scattering by phenol (C6H5OH). The experimental data were obtained with an apparatus based in Madrid and the calculated cross sections with two different methodologies, the independent atom method with screening corrected additivity rule (IAM-SCAR), and the Schwinger multichannel method with pseudopotentials (SMCPP). The SMCPP method in the Nopen-channel coupling scheme, at the static-exchange-plus-polarization approximation, is employed to calculate the scattering amplitudes at impact energies ranging from 5.0 eV to 50 eV. We discuss the multichannel coupling effects in the calculated cross sections, in particular how the number of excited states included in the open-channel space impacts upon the convergence of the elastic cross sections at higher collision energies. The IAM-SCAR approach was also used to obtain the elastic differential cross sections (DCSs) and for correcting the experimental total cross sections for the so-called forward angle scattering effect. We found a very good agreement between our SMCPP theoretical differential, integral, and momentum transfer cross sections and experimental data for benzene (a molecule differing from phenol by replacing a hydrogen atom in benzene with a hydroxyl group). Although some discrepancies were found for lower energies, the agreement between the SMCPP data and the DCSs obtained with the IAM-SCAR method improves, as expected, as the impact energy increases. We also have a good agreement among the present SMCPP calculated total cross section (which includes elastic, 32 inelastic electronic excitation processes and ionization contributions, the latter estimated with the binary-encounter-Bethe model), the IAM-SCAR total cross section, and the experimental data when the latter is corrected for the forward angle scattering effect [Fuss et al., Phys. Rev. A 88, 042702 (2013)].

High-dose-rate (HDR) plesiotherapy with custom-made moulds for the treatment of non-melanoma skin cancer.

BACKGROUND: Non-melanoma skin tumours (NMSC) are one of the most frequent types of cancer, accounting for nearly one third of newly diagnosed tumours. NMSC are frequently diagnosed in elderly patients and while mortality rates are low, NMSC can be associated with significant morbidity in terms of cosmetic and functional impairment. OBJECTIVE: Surgical excision is nowadays considered the standard treatment for NMSC, although this approach might not be suitable for all the patients. Good rates of local control and cosmetic outcome are achieved by using high-dose-rate (HDR) plesiotherapy. METHODS: Nine consecutive patients with 11 NMSC were treated with custom-made moulds and HDR plesiotherapy reaching a fi nal dose of 44-48 Gy in 11-12 fractions of 4 Gy over 4 weeks. RESULTS: No local or distant relapses have been observed after a mean follow-up of 15 months (range 4-36 months). Acute toxicity was acceptable and cosmetic result was considered as excellent/good in 7 patients. CONCLUSIONS: This modality of treatment offers an alternative for those patients not candidates for surgical procedures because of medical contraindications or risk of disfigurement or functional impairment.

Concordancia entre el diagnóstico clínico y un cuestionario basado en síntomas para establecer la posibilidad diagnóstica de EPOC en pacientes colombianos / Concordance between clinical diagnosis and a questionnaire based on symptoms to assess the diagnostic possibility of COPD in colombian patients

Introducción: los cuestionarios basados en síntomas pueden ser de utilidad para el rastreo de pacientes con EPOC en la población general o como herramienta para el diagnostico diferencial, facilitando el inicio temprano de la terapia en aquellos lugares donde no se encuentra disponible la espirometría. Metodología: en un estudio piloto 105 médicos especialistas y generales colombianos aplicaron un cuestionario de 8 preguntas a 778 de sus pacientes a quienes previamente les habían hecho el diagnóstico de EPOC. No se tuvo en cuenta si los pacientes recibían o no terapia farmacológica para el tratamiento de la EPOC en el momento de contestar el cuestionario. Resultados: los puntajes obtenidos permitieron clasificar a los pacientes en una de tres categorías de riesgo: 1. Bajo riesgo (117 pacientes) 2. Riesgo moderado (125 pacientes) y 3. Alto riesgo (536 pacientes). El puntaje promedio alcanzado por los pacientes fue de 22,5 (DE: 5,57). Estos resultados sugieren que la sensibilidad del instrumento es de 68,9% y que 31,1% de los pacientes no fue detectado por el cuestionario como enfermo de EPOC. Todos los cuestionarios fueron diligenciados correctamente sin requerir de condiciones diferentes a la de una consulta médica habitual. Conclusiones: el cuestionario empleado en el presente estudio mostró una escasa correlación diagnóstica frente el criterio clínico del médico tratante, se requiere la utilización de la espirometría como estándar de oro para establecer el diagnóstico de EPOC y así poder evaluar todas las propiedades diagnósticas de este cuestionario o de sus modificaciones. El uso de cuestionarios diagnósticos breves, en el marco de una consulta médica habitual, resulta logísticamente posible y no requiere de recursos ni tiempo adicional.

Neumonía eosinofílica / Eosinophilic pneumonia

Dada la variabilidad en el tiempo de resolución radiológica y clínica de las neumonías, resulta controversial decidir cuando iniciar estudios invasivos para la neumonía de lenta resolución o que no resuelve. En paciente inmunocompetentes que ingresan con características clásicas de neumonía adquirida en la comunidad, la respuesta tórpida al tratamiento instaurado es el principal determinante para estudios adicionales. Se recomiendan como estudios adicionales la tomografía de tórax y el lavado broncoalveolar con cultivos apropiados para bacterias, legionella, hongos y micobacterias; con el fin de ampliar el diagnóstico diferencial. En el caso de las neumonías eosinofílicas el diagnóstico se realiza frecuentemente por exclusión, aunque se debe sospechar en pacientes que presenten infiltrados característicos, con eosinofilia asociados a una lenta resolución clínica y radiológica. Se confirma el diagnóstico mediante lavado broncoalveolar , biopsia transbronquial y la excelente respuesta terapéutica a los esteroida.

Hipoventilación alveolar primaria: ¿Enfermedad de monge en Bogotá?

Se presentan dos casos de hipoventilación alveolar sin enfermedad pulmonar ni apneas de sueño, secundarias a trastornos no anatómicos del sistema de control de la respiración. Se discuten los diagnósticos diferenciales y se plantea la hipótesis que su etiología es la hipoventilación crónica de la altura o enfermedad de Monge