IS2aR, a computational tool to transform voxelized reference phantoms into patient-specific whole-body virtual CTs for peripheral dose estimation.

BACKGROUND: The risk of radiogenic cancer induction due to radiotherapy depends on the dose received by the patient's organs. Knowing the position of all organs is needed to assess this dose in a personalized way. However, radiotherapy planning computed tomography (pCT) scans contain truncated patient anatomy, limiting personalized dose evaluation. PURPOSE: To develop a simple and freely available computational tool that adapts an ICRP reference computational phantom to generate a patient-specific whole-body CT for peripheral dose computations. METHODS: Various bone-segmentation methods were explored onto fifteen pCTs, and the one with the highest Sørensen-Dice coefficient was implemented. The reference phantom is registered to the pCT, obtaining a registration transform matrix, which is then applied to create the whole-body virtual CT. Additional validation involved a comparison of absorbed doses to organs delineated on both the pCT and the virtual CT. RESULTS: A dedicated graphical user interface was designed and implemented to house the developed functions for i) selecting a registration region on which automatic bone segmentation and rigid registration will occur, ii) displaying the results of these processes under selectable views, and iii) exporting the final patient-specific whole-body CT. This software was termed IS2aR. The tested whole-body virtual CT generated by IS2aR fulfilled our requirements. CONCLUSIONS: IS2aR is a user-friendly computational software to create a personalized whole-body CT containing the original structures in the reference phantom. The personalized dose deposited in peripheral organs can be estimated further to assess second cancer induction risk in epidemiological studies.

A simple analytical model for a fast 3D assessment of peripheral photon dose during coplanar isocentric photon radiotherapy.

Considering that cancer survival rates have been growing and that nearly two-thirds of those survivors were exposed to clinical radiation during its treatment, the study of long-term radiation effects, especially secondary cancer induction, has become increasingly important. To correctly assess this risk, knowing the dose to out-of-field organs is essential. As it has been reported, commercial treatment planning systems do not accurately calculate the dose far away from the border of the field; analytical dose estimation models may help this purpose. In this work, the development and validation of a new three-dimensional (3D) analytical model to assess the photon peripheral dose during radiotherapy is presented. It needs only two treatment-specific input parameter values, plus information about the linac-specific leakage, when available. It is easy to use and generates 3D whole-body dose distributions and, particularly, the dose to out-of-field organs (as dose-volume histograms) outside the 5% isodose for any isocentric treatment using coplanar beams [including intensity modulated radiotherapy and volumetric modulated arc therapy (VMAT)]. The model was configured with the corresponding Monte Carlo simulation of the peripheral absorbed dose for a 6 MV abdomen treatment on the International Comission on Radiological Protection (ICRP) 110 computational phantom. It was then validated with experimental measurements using thermoluminescent dosimeters in the male ATOM anthropomorphic phantom irradiated with a VMAT treatment for prostate cancer. Additionally, its performance was challenged by applying it to a lung radiotherapy treatment very different from the one used for training. The model agreed well with measurements and simulated dose values. A graphical user interface was developed as a first step to making this work more approachable to a daily clinical application.

Malformaciones cavernosas cerebrales, presentación de 14 casos y revisión de literatura / Brain cavernous malformations, presentation of 14 cases and literature review

Objetivo: Presentar los resultados de tratamiento quirúrgico obtenidos en una serie de 14 casos de malformación cavernosa, situadas en diferentes localizaciones encefálicas, además de realizar una revisión bibliográfica sobre el tema. Material y métodos: En el periodo de los años 2014-2019, se diagnosticaron y protocolizaron 14 pacientes por medio de la consulta externa de neurocirugía del Hospital Juárez de México. Todos menos 2, fueron intervenidos quirúrgicamente. Resultados: En 12 de los 14 casos que recibieron tratamiento quirúrgico, se documentó mejoría neurológica posterior a la resección total en 10 pacientes, 1 paciente de cavernoma gigante temporal se hizo resección subtotal, en 1 paciente con lesión de localización protuberancial se le realizó únicamente drenaje de hematoma. El déficit preoperatorio tendió a mejorar progresivamente en las lesiones de mayor tamaño y en ningún caso se documentaron complicaciones, las crisis convulsivas se controlaron disminuyendo progresivamente la dosis de fármacos anticonvulsivantes en el periodo postquirúrgico de este grupo de pacientes. Y dos pacientes, uno con lesión mesencefálica y el otro con cavernomatosis solo se sometieron a observación. Conclusiones: La cirugía es el método de elección hoy en día para el tratamiento de las malformaciones cavernosas, siendo los mejores resultados a menor tamaño de la lesión y con localizaciones más superficiales. Los resultados quirúrgicos de nuestros pacientes son similares a lo reportado en la literatura mundial.

Objectives: To present the surgical outcomes obtained in a series of 14 cases of cavernous malformation, located in different brain locations, in addition to conducting a literature review on the subject. Method: Between the years, 2014 and 2019, 14 cases were diagnosed and protocolized in neurosurgery department of Hospital Juárez of México. All patients except two, were surgically treated. Results: In 12 of the 14 cases received surgical treatment, neurological improvement was documented after the total resection in ten patients, one patient with giant temporal cavernoma performed a subtotal resection, other case with a lesion in the pontine location a hematoma drainage was performed. All surgical patients the preoperative clinical deficit tended to improve progressively in larger lesions and no complications were documented. Seizures were controlled by gradually decreasing the dose of anticonvulsant drugs in the post-surgical period of this group of patients. And two patients, one with mesencephalic lesion and another with cavernomatosis, were only observe. Conclusion: Surgery is the method of choice today for the treatment of cavernous malformations, with the best outcome being the smallest size of the lesion and with more superficial locations. The surgical outcomes in our patients are similar to those reported in the world literature

Simulation of hypoxia PET-tracer uptake in tumours: Dependence of clinical uptake-values on transport parameters and arterial input function.

Poor radiotherapy outcome is in many cases related to hypoxia, due to the increased radioresistance of hypoxic tumour cells. Positron emission tomography may be used to non-invasively assess the oxygenation status of the tumour using hypoxia-specific radiotracers. Quantification and interpretation of these images remains challenging, since radiotracer binding and oxygen tension are not uniquely related. Computer simulation is a useful tool to improve the understanding of tracer dynamics and its relation to clinical uptake parameters currently used to quantify hypoxia. In this study, a model for simulating oxygen and radiotracer distribution in tumours was implemented to analyse the impact of physiological transport parameters and of the arterial input function (AIF) on: oxygenation histograms, time-activity curves, tracer binding and clinical uptake-values (tissue-to-blood ratio, TBR, and a composed hypoxia-perfusion metric, FHP). Results were obtained for parallel and orthogonal vessel architectures and for vascular fractions (VFs) of 1% and 3%. The most sensitive parameters were the AIF and the maximum binding rate (Kmax). TBR allowed discriminating VF for different AIF, and FHP for different Kmax, but neither TBR nor FHP were unbiased in all cases. Biases may especially occur in the comparison of TBR- or FHP-values between different tumours, where the relation between measured and actual AIF may vary. Thus, these parameters represent only surrogates rather than absolute measurements of hypoxia in tumours.

Impact of different biologically-adapted radiotherapy strategies on tumor control evaluated with a tumor response model.

Motivated by the capabilities of modern radiotherapy techniques and by the recent developments of functional imaging techniques, dose painting by numbers (DPBN) was proposed to treat tumors with heterogeneous biological characteristics. This work studies different DPBN optimization techniques for virtual head and neck tumors assessing tumor response in terms of cell survival and tumor control probability with a previously published tumor response model (TRM). Uniform doses of 2 Gy are redistributed according to the microscopic oxygen distribution and the density distribution of tumor cells in four virtual tumors with different biological characteristics. In addition, two different optimization objective functions are investigated, which: i) minimize tumor cell survival (OFsurv) or; ii) maximize the homogeneity of the density of surviving tumor cells (OFstd). Several adaptive schemes, ranging from single to daily dose optimization, are studied and the treatment response is compared to that of the uniform dose. The results show that the benefit of DPBN treatments depends on the tumor reoxygenation capability, which strongly differed among the set of virtual tumors investigated. The difference between daily (fraction by fraction) and three weekly optimizations (at the beginning of weeks 1, 3 and 4) was found to be small, and higher benefit was observed for the treatments optimized using OFsurv. This in silico study corroborates the hypothesis that DPBN may be beneficial for treatments of tumors which show reoxygenation during treatment, and that a few optimizations may be sufficient to achieve this therapeutic benefit.

Structural and functional identification of vasculogenic mimicry in vitro.

Vasculogenic mimicry (VM) describes a process by which cancer cells establish an alternative perfusion pathway in an endothelial cell-free manner. Despite its strong correlation with reduced patient survival, controversy still surrounds the existence of an in vitro model of VM. Furthermore, many studies that claim to demonstrate VM fail to provide solid evidence of true hollow channels, raising concerns as to whether actual VM is actually being examined. Herein, we provide a standardized in vitro assay that recreates the formation of functional hollow channels using ovarian cancer cell lines, cancer spheres and primary cultures derived from ovarian cancer ascites. X-ray microtomography 3D-reconstruction, fluorescence confocal microscopy and dye microinjection conclusively confirm the existence of functional glycoprotein-rich lined tubular structures in vitro and demonstrate that many of structures reported in the literature may not represent VM. This assay may be useful to design and test future VM-blocking anticancer therapies.

Modelling radiation-induced cell death and tumour re-oxygenation: local versus global and instant versus delayed cell death.

The resistance of hypoxic cells to radiation, due to the oxygen dependence of radiosensitivity, is well known and must be taken into account to accurately calculate the radiation induced cell death. A proper modelling of the response of tumours to radiation requires deriving the distribution of oxygen at a microscopic scale. This usually involves solving the reaction-diffusion equation in tumour voxels using a vascularization distribution model. Moreover, re-oxygenation arises during the course of radiotherapy, one reason being the increase of available oxygen caused by cell killing, which can turn hypoxic tumours into oxic. In this work we study the effect of cell death kinetics in tumour oxygenation modelling, analysing how it affects the timing of re-oxygenation, surviving fraction and tumour control. Two models of cell death are compared, an instantaneous cell killing, mimicking early apoptosis, and a delayed cell death scenario in which cells can die shortly after being damaged, as well as long after irradiation. For each of these scenarios, the decrease in oxygen consumption due to cell death can be computed globally (macroscopic voxel average) or locally (microscopic). A re-oxygenation model already used in the literature, the so called full re-oxygenation, is also considered. The impact of cell death kinetics and re-oxygenation on tumour responses is illustrated for two radiotherapy fractionation schemes: a conventional schedule, and a hypofractionated treatment. The results show large differences in the doses needed to achieve 50% tumour control for the investigated cell death models. Moreover, the models affect the tumour responses differently depending on the treatment schedule. This corroborates the complex nature of re-oxygenation, showing the need to take into account the kinetics of cell death in radiation response models.

[Analysis of maternal deaths in Mexico occurred during 2009]. / Análisis de las muertes maternas en México ocurridas durante 2009.

BACKGROUND: Mexico reported 955 maternal deaths in 2011, with a ratio of 49 deaths per 100,000 live births. For 2015, the WHO commitment is to reduce the ratio to 22, equivalent to 415 maternal deaths. METHODS: it is a descriptive and retrospective study. In 1257 maternal deaths in 2009, we reviewed a sample of 173 records. Simple frequencies and percentages were calculated. RESULTS: direct causes of maternal death were preeclampsia-eclampsia, infection and obstetrical hemorrhage secondary to uterine atony, placental accreta and placenta previa. Fifteen patients died from abortion complications. Four patients died from extra-uterine pregnancy, because of delayed diagnosis and treatment. Indirect causes of maternal death were neoplasms, abdominal sepsis, vascular events, metabolic problems and heart disease; twenty-five patients died of atypical pneumonia and 11 more of influenza A H1N1. CONCLUSIONS: it is feasible to reduce maternal mortality by means of an adequate prenatal care, in quantity and quality of consultations, and avoiding high risk pregnancies caused by a history of obstetric factors and associated severe diseases. Influenza A H1N1 interrupted the downward trend in maternal mortality.

Introducción: en 2011 ocurrieron 955 defunciones maternas en México, 49.9 por 100 000 nacidos vivos. La meta de la Organización Mundial de la Salud para 2015 es reducir la tasa a 22.5: 560 defunciones anuales. Métodos: estudio descriptivo y retrospectivo de 1257 muertes maternas ocurridas en México durante 2009, con una muestra representativa de 173 expedientes. Se calcularon frecuencias simples y porcentajes. Resultados: las muertes maternas ocurrieron por causas directas como preeclampsia-eclampsia, infección y hemorragia obstétrica secundaria a atonía uterina, acretismo placentario y placenta previa. Quince mujeres tuvieron complicaciones por abortos. Cuatro murieron por embarazo extrauterino debido a diagnóstico y tratamiento tardíos. Las causas indirectas de la muerte materna fueron neoplasias, sepsis abdominal, eventos vasculares, problemas metabólicos y cardiopatías. Veinticinco pacientes fallecieron por neumonía atípica y 11 por influenza A H1N1. Conclusiones: es factible disminuir la mortalidad materna mediante suficientes consultas prenatales de calidad y evitar embarazos con riesgo alto por los antecedentes obstétricos y los padecimientos asociados. La influenza A H1N1 interrumpió la tendencia descendente de la mortalidad materna.

A model to simulate the oxygen distribution in hypoxic tumors for different vascular architectures.

PURPOSE: As hypoxic cells are more resistant to photon radiation, it is desirable to obtain information about the oxygen distribution in tumors prior to the radiation treatment. Noninvasive techniques are currently not able to provide reliable oxygenation maps with sufficient spatial resolution; therefore mathematical models may help to simulate microvascular architectures and the resulting oxygen distributions in the surrounding tissue. Here, the authors present a new computer model, which uses the vascular fraction of tumor voxels, in principle measurable noninvasively in vivo, as input parameter for simulating realistic PO2 histograms in tumors, assuming certain 3D vascular architectures. METHODS: Oxygen distributions were calculated by solving a reaction-diffusion equation in a reference volume using the particle strength exchange method. Different types of vessel architectures as well as different degrees of vascular heterogeneities are considered. Two types of acute hypoxia (ischemic and hypoxemic) occurring additionally to diffusion-limited (chronic) hypoxia were implemented as well. RESULTS: No statistically significant differences were observed when comparing 2D- and 3D-vessel architectures (p>0.79 in all cases) and highly heterogeneously distributed linear vessels show good agreement, when comparing with published experimental intervessel distance distributions and PO2 histograms. It could be shown that, if information about additional acute hypoxia is available, its contribution to the hypoxic fraction (HF) can be simulated as well. Increases of 128% and 168% in the HF were obtained when representative cases of ischemic and hypoxemic acute hypoxia, respectively, were considered in the simulations. CONCLUSIONS: The presented model is able to simulate realistic microscopic oxygen distributions in tumors assuming reasonable vessel architectures and using the vascular fraction as macroscopic input parameter. The model may be used to generate PO2 histograms, which are needed as input in models predicting the radiation response of hypoxic tumors.

Diabetic myonecrosis: an atypical presentation.

Diabetic myonecrosis is a frequently unrecognized complication of longstanding and poorly controlled diabetes mellitus. The clinical presentation is swelling, pain, and tenderness of the involved muscle, most commonly the thigh muscles. Management consists of conservative measures including analgesia and rest. Short-term prognosis is good, but long-term prognosis is poor with most patients dying within 5 years. Failure to properly identify this condition will expose the patient to aggressive measures that could result in increased morbidity. To our knowledge this is the first case reported in which there was involvement of multiple muscle groups including upper and lower limbs.

[Analysis of dengue fever deaths in Mexico: 2009]. / Defunciones por dengue en México. Análisis del año 2009.

OBJECTIVE: to describe the dengue fever mortality. METHODS: a descriptive and retrospective study including 104 files reported deaths caused by dengue fever during 2009 to march 2010, was done. RESULTS: sixty (58 %) were women and 44 (42 %) men. An increased mortality between the ages of 11 and 40 years old (47 %) was observed. Colima was a state with high incidence of cases and Jalisco had the highest mortality. Thrombocytopenia was the rule (90.4 %) and in one third of the cases platelets were below 50,000/mm(3). A quarter of cases were associated with comorbility. The initial clinical manifestations included: bleeding, hypovolemia by depletion or hemorrhage, tachycardia, paleness, depressed level of consciousness and circulatory failure. The main cause of death was hypovolemic shock or sepsis. In 42 cases, severe dengue was considered. CONCLUSIONS: an association between the severity of dengue fever and mortality was observed. The main cause of mortality was a shock state.

[Primary central nervous system lymphoma in immunocompetent patients]. / Linfoma primario del sistema nervioso central en pacientes inmunocompetentes.

Primary central nervous system lymphoma has been traditionally described in patients with immunodeficiency syndromes; however, there is an increasing number of immunocompetent patients with this type of tumor that have been reported recently. In this paper we have retrospectively analyzed 22 immunocompetent patients with a confirmed diagnosis of primary lymphoma of the brain. The mean age in this group was 65 years with a similar male/female ratio. The time of evolution of the clinical course was 80.4 days and it was mainly characterized by headache and focal neurological deficit. In four patients multiple lesions were observed, while the remaining presented single lesions mainly located in the periventricular area of the cerebral hemispheres. All patients were initially administered steroids and a stereotactic biopsy was performed. The majority of tumors were histologically classified as diffuse large cells and all of them showed a positive reaction to B-cells antigens on immunohistochemistry. All patients were treated with radiotherapy and in 10 of them, chemotherapy with methotrexate was also indicated. The mean survival rate was II months among patients treated with radiotherapy alone and increased to 36 months when chemotherapy was added.

Linfoma primario del sistema nervioso central en pacientes inmunocompetentes / Primary central nervous system lymphoma in immunocompetent patients

El linfoma primario del sistema nervioso central ha sido informado con frecuencia en pacientes que padecen síndromes de inmuno deficiencia. Sin embargo ésta no es una condición necesaria para su presentación, dado que existen informes de la enfermedad en sujetos inmunológicamente competentes. En el presente trabajo se analizaron en forma retrospectiva, los expedientes de 22 pacientes inmunocompetentes con diagnóstico confirmado de linfoma primario encefálico, se revisó la literatura mundial, con el fin de analizar objetivamente las manifestaciones clínicas, comportamiento radiológico, aspecto histopatológico, dificul tades diagnósticas y terapéuticas, así como las consideraciones pro nósticas. El promedio de edad fue de 65 años y con una relación equitativa hombre/mujer. El tiempo de evolución del cuadro clínico fue de 80.4 días y estuvo dominado por cefalea y déficit neurológico focal. En cuatro pacientes se encontraron lesiones múltiples, mientras que en el resto se trataba de lesiones únicas con localización predominante en la región periventricular de los hemisferios cerebrales. Todos los pacientes fueron manejados inicialmente con esteroides y sometidos a toma de biopsia por estereotaxia. La variedad histológica más frecuente fue la de células grandes difusas y la totalidad de los casos reaccionaron positivamente a antígenos de células B en la inmunohistoquímica. Los 22 pacientes fueron tratados con radio terapia y 10 de ellos además con quimioterapia con metotrexato. La supervivencia promedio fue de 11 meses en los pacientes radiados y de 36 meses en los que se agregó quimioterapia.

Primary central nervous system lymphoma has been traditionally described in patients with immunodeficiency syndromes; however, there is an increasing number of immunocompetent patients with this type of tumor that have been reported recently. In this paper we have retrospectively analyzed 22 immunocompetent patients with a confirmed diagnosis of primary lymphoma of the brain. The mean age in this group was 65 years with a similar male/female ratio. The time of evolution of the clinical course was 80.4 days and it was mainly characterized by headache and focal neurological deficit. In four patients multiple lesions were observed, while the remaining presented single lesions mainly located in the periventricular area of the cerebral hemispheres. All patients were initially administered steroids and a stereotactic biopsy was performed. The majority of tumors were histologically classified as diffuse large cells and all of them showed a positive reaction to B cells antigens on immunohistochemistry. All patients were treated with radiotherapy and in 10 of them, chemotherapy with methotrexate was also indicated. The mean survival rate was 11 months among patients treated with radiotherapy alone and increased to 36 months when chemotherapy was added.

A Plurihormonal TSH-Secreting Pituitary Microadenoma: Report of a Case with an Atypical Clinical Presentation and Transient Response to Bromocriptine Therapy.

Inappropriate secretion of thyrotropin (TSH) is a rare cause of hyperthyroidism, and it is caused by either a TSH-producing pituitary adenoma (usually a macroadenoma) or to selective pituitary resistance to thyroid hormone. The case of a 31-yr-old male who presented with clinical features of thyrotoxicosis, including episodes of thyrotoxic paralysis, and a thyroid profile characterized by free hyperthyroxinemia and hypertriiodothyronemia with a nonsuppressed, inadequately normal TSH is reported. Dynamic testing showed both, lack of TSH stimulation by thyroid-releasing hormone (TRH), and lack of suppression by T3, consistent with autonomous TSH secretion. Pituitary MRI revealed a microadenoma. Seventy five percent of the patients serum TSH immunoreactivity eluted as u-subunit in Sephadex G-100 chromatography. A diagnosis of TSH-secreting microadenoma was established, and the patient was treated successfully with bromocriptine, which resulted in both clinical and biochemical resolution of his hyperthyroidism. Two months later, he became hyperthyroid again during bromocriptine therapy. Octreotide was started with adequate control of his symptoms and normalization of his free T4 level. He eventually underwent transsphenoidal surgery with successful resection of a chromophobic microadenoma which immunostained for TSH, growth hormone (GH), luteinizing hormone (LN), and follicle-stimulating hormone (FSH). One month postoperatively he is clinically and biochemically euthyroid on no medications.