[The impact of novel drugs on the survival of patients with multiple myeloma in two chilean centers]. / Mieloma múltiple en Chile. Uso de drogas noveles en dos centros nacionales.

BACKGROUND: The incorporation of novel drugs, such as proteasome inhibitors and immunomodulators, improved considerably the survival of patients with multiple myeloma. AIM: To evaluate the effect on survival of proteasome inhibitors and immunomodulators in patients with multiple myeloma in two national hospitals. MATERIAL AND METHODS: Review of clinical records from two hospitals of Santiago. Epidemiological, clinical, laboratory and therapeutic data was obtained from 144 patients with multiple myeloma diagnosed between 2002 and 2016. RESULTS: Information was retrieved from 78 patients at one center and from 66 at the other center. The mean age at diagnosis was 58 and 62 years, the proportion of males was 53% and 52%, and presentation at stage III was 34% and 46%, respectively. The use of novel drugs, mainly bortezomib, was 90% in one of the centers and 3% in the other one. The use of autologous stem-cell transplantation was 47% and 3% respectively. The median overall survival of patients from the centers with and without access to novel drugs was 117 and 71 months respectively (p < 0.05). The five-year overall survival was 93 and 43% respectively (p < 0.05). CONCLUSIONS: The use of novel drugs, especially bortezomib, and autologous stem-cell transplantation significantly improved the survival of multiple myeloma patients treated in national hospitals. It is necessary to include them as a first line treatment.

Mieloma múltiple en Chile. Uso de drogas noveles en dos centros nacionales

Background: The incorporation of novel drugs, such as proteasome inhibitors and immunomodulators, improved considerably the survival of patients with multiple myeloma. Aim: To evaluate the effect on survival of proteasome inhibitors and immunomodulators in patients with multiple myeloma in two national hospitals. Material and Methods: Review of clinical records from two hospitals of Santiago. Epidemiological, clinical, laboratory and therapeutic data was obtained from 144 patients with multiple myeloma diagnosed between 2002 and 2016. Results: Information was retrieved from 78 patients at one center and from 66 at the other center. The mean age at diagnosis was 58 and 62 years, the proportion of males was 53% and 52%, and presentation at stage III was 34% and 46%, respectively. The use of novel drugs, mainly bortezomib, was 90% in one of the centers and 3% in the other one. The use of autologous stem-cell transplantation was 47% and 3% respectively. The median overall survival of patients from the centers with and without access to novel drugs was 117 and 71 months respectively (p < 0.05). The five-year overall survival was 93 and 43% respectively (p < 0.05). Conclusions: The use of novel drugs, especially bortezomib, and autologous stem-cell transplantation significantly improved the survival of multiple myeloma patients treated in national hospitals. It is necessary to include them as a first line treatment.

Infección por SARS-CoV-2. Una nueva enfermedad endotelial trombo-inflamatoria

Coronavirus disease 19 is characterized by an intense inflammatory response and a high incidence of thrombotic events. Autopsy studies show severe endothelial injury associated with thrombosis of the alveolar capillaries of the lungs and other organs. In the pathophysiology of this disease endothelial injury and dysfunction, inflammation and thrombosis are key factors for the development of severe phenotypes. Therefore, we should consider this entity as a systemic endothelial disease in which an obstructive microvascular syndrome secondary to an intense thrombo-inflammatory response leads to acute respiratory insufficiency and multiorgan failure. Heparin is an excellent drug to treat Covid-19 patients due to its anticoagulant, anti-inflammatory, antiviral and endothelial effects. Clinical guidelines agree that the use of heparin thromboprophylaxis is a component of Covid-19 coagulopathy treatment, even though the dose and duration of treatments are not well defined.

[SARS-CoV-2 infection as a thrombo-inflammatory endothelial disease]. / Infección por SARS-CoV-2. Una nueva enfermedad endotelial trombo-inflamatoria.

Coronavirus disease 19 is characterized by an intense inflammatory response and a high incidence of thrombotic events. Autopsy studies show severe endothelial injury associated with thrombosis of the alveolar capillaries of the lungs and other organs. In the pathophysiology of this disease endothelial injury and dysfunction, inflammation and thrombosis are key factors for the development of severe phenotypes. Therefore, we should consider this entity as a systemic endothelial disease in which an obstructive microvascular syndrome secondary to an intense thrombo-inflammatory response leads to acute respiratory insufficiency and multiorgan failure. Heparin is an excellent drug to treat Covid-19 patients due to its anticoagulant, anti-inflammatory, antiviral and endothelial effects. Clinical guidelines agree that the use of heparin thromboprophylaxis is a component of Covid-19 coagulopathy treatment, even though the dose and duration of treatments are not well defined.

Survival differences in multiple myeloma in Latin America and Asia: a comparison involving 3664 patients from regional registries.

In previous observational studies, we have separately characterized patients with multiple myeloma (MM) both from Latin America (LA) and from Asia. Here, we analyze these two datasets jointly, in order to assess the overall survival (OS) in these two world regions. Data were available from 3664 patients (1968 from LA and 1696 from Asia); all of whom diagnosed between 1998 and 2007. Approximately, 26% of patients in both world regions underwent transplantation. OS (from diagnosis of MM) was explored with Kaplan-Meier analyses and Cox proportional hazards models. Patients from LA were significantly younger and had hypercalcemia more often than Asian patients, who in turn had higher proportions of anemia and International Staging System (ISS) stage III disease. The median OS was 56 months in LA, and 47 months in Asia (hazard ratio [HR] = 0.83; 95% confidence interval [CI], 0.76 to 0.91; P < 0.001). In multivariable analysis, age, ISS stage III, anemia, hypercalcemia, and world region remained significantly associated with OS (P < 0.001 for all covariates). These results were largely driven by patients not undergoing transplantation, as no difference in OS emerged between the two world regions in univariable or multivariable analysis for transplanted patients. Despite adverse prognostic features differentially favoring each region, and adjusting for such differences, we found an OS advantage for patients from LA, in comparison with contemporaneous patients from Asia. Whether this is due to different biological features, differences in access to novel agents (especially thalidomide in earlier periods of the study), unmeasured confounders, or the play of chance, remain unknown.

Trombocitopenia hereditaria relacionada a gen MYH-9: primera familia reportada en Chile con diagnóstico molecular: caso clínico / Hereditary thrombocytopenia associated with a mutation in the MYH-9 gene: report of one case

We report a 51-year-old female who had a first episode of thrombocytopenia at 23 years of age during a pregnancy. At the age of fifty, a hysterectomy was indicated due to a metrorrhagia: a platelet count of 21,000/ul was detected. She was treated with eltrombopag with a good response. The family history of the patient revealed the presence of thrombocytopenia in several family members. Suspecting a hereditary thrombocytopenia, a genetic study revealed a mutation in the MYH-9 gene. This mutation can be suspected when there is a family history of thrombocytopenia with autosomal dominant inheritance, macrothrombocytopenia and in this particular case, due to the response to thrombopoietin receptor agonist, eltrombopag.

[Hereditary thrombocytopenia associated with a mutation in the MYH-9 gene. Report of one case]. / Trombocitopenia hereditaria relacionada a gen MYH-9: Primera familia reportada en Chile con diagnóstico molecular. Caso clínico.

We report a 51-year-old female who had a first episode of thrombocytopenia at 23 years of age during a pregnancy. At the age of fifty, a hysterectomy was indicated due to a metrorrhagia: a platelet count of 21,000/ul was detected. She was treated with eltrombopag with a good response. The family history of the patient revealed the presence of thrombocytopenia in several family members. Suspecting a hereditary thrombocytopenia, a genetic study revealed a mutation in the MYH-9 gene. This mutation can be suspected when there is a family history of thrombocytopenia with autosomal dominant inheritance, macrothrombocytopenia and in this particular case, due to the response to thrombopoietin receptor agonist, eltrombopag.

Observational study of multiple myeloma in Latin America.

Relatively little is known about the outcomes of multiple myeloma in Latin America, a world region where incorporation of novel agents is generally slow. In the current retrospective-prospective study, we aimed to describe the patterns of care and treatment results in five Latin American countries. Between April 2007 and October 2009, patients who had been diagnosed from January 2005 to December 2007 were registered at 23 institutions from Argentina, Brazil, Chile, Mexico, and Peru. We divided patients into two cohorts, according to transplantation eligibility, and analyzed them with regard to first-line treatment and overall survival (OS). We analyzed a total of 852 patients, 46.9 % of whom were female. The median follow-up was 62 months. Among transplantation-ineligible patients (N = 461), the mean age was 67.4 years, approximately one third of patients received a thalidomide-based treatment in the first line, and the median OS was 43.0 months. Transplantation-eligible patients (N = 391) had a mean age of 54.7 years and a median OS of 73.6 months. Autologous transplantation was performed in 58.6 % of the patients for whom this procedure was initially planned and in only 26.9 % of the overall patients. Our long-term results reflect the contemporary literature for patients with multiple myeloma treated with autologous transplantation and thalidomide-based regimens in clinical trials and observational studies. However, further efforts are needed to approve and incorporate novel agents in Latin American countries, as well as to increase access to transplantation, in order to achieve the expected improvements in patient outcomes.

Hematoma subcapsular esplénico en paciente portador de rasgo falciforme / Sub capsular splenic hematoma in a sickle cell trait carrier. Case report

Drepanocytic anemia is an uncommon hereditary disease in Chile. The heterozygous state of drepanocytic anemia or "sickle trait" has a frequency of 8 percent among Afro-Americans. A small number of patients carrying hemoglobin S are homozygous, with clinical manifestations of hemolytic anemia and thrombotic disease. Sickle trait is usually asymptomatic. We report a 59-year-old male who presented an acute abdominal pain and dyspnea while staying at high altitude. Six days later, an angio CAT scan showed the presence of a subcapsular splenic hematoma that was managed conservatively. Sickle cell induction with sodium metabisulphite was positive. Hemoglobin electrophoresis confirmed the sickle trait.

[Sub capsular splenic hematoma in a sickle cell trait carrier. Case report]. / Hematoma subcapsular esplénico en paciente portador de rasgo falciforme.

Drepanocytic anemia is an uncommon hereditary disease in Chile. The heterozygous state of drepanocytic anemia or "sickle trait" has a frequency of 8% among Afro-Americans. A small number of patients carrying hemoglobin S are homozygous, with clinical manifestations of hemolytic anemia and thrombotic disease. Sickle trait is usually asymptomatic. We report a 59-year-old male who presented an acute abdominal pain and dyspnea while staying at high altitude. Six days later, an angio CAT scan showed the presence of a subcapsular splenic hematoma that was managed conservatively. Sickle cell induction with sodium metabisulphite was positive. Hemoglobin electrophoresis confirmed the sickle trait.

[Frequency of venous thromboembolism among hospitalized patients with cancer]. / Frecuencia de tromboembolismo venoso en pacientes hospitalizados con cáncer. Factores de riesgo y eficacia de la tromboprofilaxis farmacológica.

BACKGROUND: Hospitalized patients with cancer have a high risk of venous thromboembolism (VTE). AIM: To study the frequency of VTE and its risk factors in hospitalized patients with cancer. MATERIAL AND METHODS: Retrospective analysis of clinical records of patients with cancer, hospitalized at a university hospital between 2002 and 2004. Patients with the diagnosis of VTE at admission or using anticoagulants, were excluded from the analysis. RESULTS: The medical records of 366 patients were reviewed. Fifty three percent had a digestive cancer, 19% lung cancer, 10% breast cancer and 18% had a tumor of other origin. In 77%, the tumor was in an advanced stage. The most common admission diagnoses were pneumonia, vomiting and dehydration, gastrointestinal bleeding and urinary infection. In 125 patients (34%) pharmacological thrombo-prophylaxis was not used and 242 (66%) received regular or low molecular weight heparin. VTE was detected in 11 patients (3%) and was significantly more common among patients not receiving thrombo prophylaxis compared to those receiving heparin (6.4% and 1.2%, respectively p =0.014). Factors associated to VTE were a history of previous VTE with an odds ratio (OR) of 12.9 (p <0.01), obesity with an OR of 13.3 (p <0.01), recent chemotherapy with an OR of 6.9 (p =0.01). The use of pharmacological thromboprophylaxis had an OR of 0.24 (p =0.05). CONCLUSIONS: Three percent of patients in this series had VTE during the hospitalization. Pharmacological thrombo-prophylaxis significantly reduced the risk of VTE.

[Autologous transplant (AT) with peripheral-blood stem-cell rescue for multiple myeloma. A clinical experience]. / Autotrasplante (AT) de progenitores hematopoyéticos en mieloma múltiple. Experiencia clínica.

BACKGROUND: Multiple myeloma is rarely curable. Advances in high dose chemotherapy and stem cell transplantation have improved overall survival and event-free disease periods, but relapses are inevitable. AIM: To report our experience with AT in multiple myeloma, between 1994 and 2003. MATERIAL AND METHODS: Retrospective analysis of 20 patients (12 women), with a mean age of 51.1 years. VAD (vincristine, doxorubicin and dexamethasone) was used as initial therapy in 19 patients. High dose cyclophosphamide (11 patients) and variations of VAD regimen (7) associated with granulocyte colony stimulating factor were used for peripheral-blood stem cell harvest. The conditioning regimen consisted of melphalan 200 mg/m2 followed by the reinfusion of peripheral-blood stem cells 24 hours later. The median number of CD34 cells infused was 3.3x10(6)/kg. Three patients were subjected to a second auto graft and one to a non-myeloablative transplant. Mean follow up was 35.5 months. RESULTS: Mucositis and febrile neutropenia were common complications. The median number of days for neutrophil engraftment was 9 (range 8-11) and for platelets, 10 (range 7-13). No patient died. Complete remission was obtained in 60% (12/20), progression-free survival was 30 months and overall median survival, 47 months. CONCLUSIONS: The AT with high-dose melphalan is a safe procedure in our hospital, without mortality and engraftment in all the patients. Complete remission and progression free survival were similar to those reported abroad but the overall median survival was lower.

[Free protein S (PS) in normal pregnancy: a comparison between two analytical methods]. / Proteína S libre en embarazadas normales: comparación entre dos métodos.

BACKGROUND: Pregnancy is a physiological hypercoagulable state with an increased incidence of thromboembolic phenomena. There is an increase in the concentrations of most clotting factors, a decrease in concentration of some of the natural anticoagulants and reduced fibrinolytic activity. Changes in PS levels have also been reported. AIM: To establish referral range values of functional PS and free PS antigen, during the second (2nd T) and third trimester (3rd T) of normal gestation. PATIENTS AND METHODS: Forty one normal pregnant women were included in our study, 20 during the 2nd T (22-24 weeks) and 21 during the 3rd T (29-38 weeks). Functional PS was measured by a clot based test and free PS antigen by ELISA. RESULTS: Free PS Antigen was 65.8+/-18.3% during the 2nd T and 62.3+/-16.5% during the 3rd T. The figures for normal controls were 106+/-6.5%. Functional PS was 43.8+/-13.3 and 25.9+/-14.6% during the 2nd T and 3rd T, respectively. The figures for normal controls were 97+/-24% (p <0.001 compared with pregnant women). Free PS antigen did not change from the 2nd to the 3rd T (p=NS), however functional PS fell significantly from the 2nd to the 3rd T (p <0.001) and was significantly lower than free PS antigen in both trimesters (p <0.001). CONCLUSIONS: Pregnancy is associated to a decrease in PS. This abnormality is more pronounced for functional PS than free PS antigen and functional PS falls progressively during pregnancy. These assays should not be used to screen for PS deficiency during pregnancy because they could lead to a misdiagnosis.

[Markers of thrombophilia in patients with retinal vein thrombosis]. / Determinación de factores trombofílicos en pacientes con trombosis venosas retinianas.

BACKGROUND: Thrombophilia is an alteration of hemostasis that increases the risk to venous or arterial thrombosis. This condition may be the underlying cause of retinal vein thrombosis. AIM: To study the presence of thrombophilia in patients with retinal vein thrombosis. PATIENTS AND METHODS: Prospective study of 55 patients aged 22 to 86 years, with retinal vein thrombosis (central or branch). Antithrombin III, coagulant protein C, functional protein S, resistance to activated C protein, homocysteine, prothrombin G20210A gene, lupus anticoagulant and anticardiolipin antibodies were measured in all. RESULTS: Seventeen patients had thrombophilic markers (antiphospholipid syndrome in seven, hyperhomocysteinemia in six and resistance to protein C in three). Of these 17 patients, 53% had high blood pressure, 35% an abnormal serum lipid profile and 23% a personal history of thrombosis. The thrombosis was central in 12 (ischemic in four) and of a branch in five (ischemic in two). CONCLUSIONS: Thrombophilic markers must be assessed in patients with retinal vein thrombosis.

La resistencia a aspirina en pacientes cardiovasculares chilenos es frecuente / Aspirin resistance is frecuent in chilean cardiovascular patients

Introducción: La aspirina se usa frecuentemente para la prevención y tratamiento de eventos isquémicos cardiovasculares. Estudios en población anglosajona han mostrado que entre 5-9 por ciento de los pacientes presentan resistencia total a la acción antiplaquetaria de aspirina. Objetivos: Conocer la prevalencia de resistencia a aspirina en enfermos cardiovasculares chilenos. Evaluar factores asociados a la resistencia. Pacientes y Métodos: Se estudian 68 pacientes (21 mujeres, ± 10 años) con enfermedades cardiovasculares estables usuarios de aspirina (100-325 mg/día). Se evalúan variables clínicas y de coagulación básica. Se estudió la agregación plaquetaria con agregómetro óptico en plasma rico en plaquetas con 3 agonista. Se definió Resistencia Total a la aspirina como. 1) agregación (20 por ciento con ácido araquidónico y 2) agregación > 70 por ciento con ADP y/o colágeno. Resultados: Siete pacientes (10,3 por ciento, IC 95 por ciento = 4,2-20,1 por ciento) cumplieron ambos criterios y se consideraron como resistentes totales, 34 (50 por ciento, IC 95 por ciento = 37,6-62,4 por ciento) cumplieron con sólo un criterio y se consideraron como resistentes parciales, y los 27 pacientes restantes (39,7 por ciento, IC 95 por ciento = 28,0-52,3 por ciento) no cumplieron con ninguno de los criterios y se clasificaron como respondedores a AAS. Hubo una mayor frecuencia de fumadores (55,6 vs 23,7 por ciento) en los pacientes con Resistencia Total, pero no alcanzó significación estadística (p = 0,06). Conclusiones: La mayoría de los pacientes cardiovasculares presentan algún grado de resistencia al AAS y un 10,3 por ciento presentan Resistencia Total. No encontramos diferencias significativas entre los los pacientes con y sin resistencia total a aspirina.

Alteración de la estabilización del coágulo de fibrina por la presencia de un inhibidor adquirido del factor XIII. Caso clínico (revisión de la literatura) / Alteration of fibrin clot stabilization due to presence of an acquired factor XIII inhibitor

El factor XIII (FXIII) hace el coágulo de fibrina más estable y más resistente a la fibrinólisis. La deficiencia de FXIII puede ser congénita o adquirida y es causa de hemorragias severas. Se han reportado 24 casos de inhibidores adquiridos de FXIII y existen pocos antecedentes de la evolución y manejo de esta condición. Caso clínico. Mujer 57 años de edad que consulta por presentar en forma espontánea extensos hematomas subcutáneos, sin antecedentes personales ni familiares de tendencia hemorrágica, de ingestión de drogas u otras enfermedades. El examen físico muestra equimosis y hematomas en extremidades y pared abdominal. Radiografia de tórax, función hepática, renal, estudio inmunológico y de coagulación (TTPK, tiempo de protrombina, tiempo de trombina, recuento de plaquetas, fibrinógeno, FDP, dímero D, lisis de euglobulinas, agregación plaquetaria y estudio de von Willebrand) en rangos normales. El test de solubilidad del coágulo con urea fue de 35 min (normal: > 24 h), que no se corrigió con una mezcla 1:1 de plasma normal, demostrando la presencia de un inhibidor. Con mezclas 1:2, 1:4, 1:6 y 1:8 el coágulo se disolvió antes de los 40 min. La terapia con esteroides y ciclofosfamida no fue efectiva. Se encuentra con ácido tranexámico y persiste con hematomas de menor magnitud. Conclusión. Los inhibidores adquiridos de FXIII son una causa poco frecuente de sangrado; deben ser sospechados en pacientes con sangrado grave y test de coagulación de rutina en limites normales. El diagnóstico se confirma con un test de solubilidad del coágulo alterado que no se corrige con una mezcla 1:1 de plasma normal (AU)