Polimorfismo S19W (Ser19Ter) de la APOA5 y su relación con la hipertrigliceridemia en una población de Colombia / S19W polymorphism (Ser19Ter) of APOA5 and its relationship with hypertriglyceridemia in a Colombian population

RESUMEN Introducción: Las enfermedades cardiovasculares (ECV) son responsables del 29,69% de las muertes en Colombia. Se ha encontrado la hipertrigliceridemia, en diversos estudios como factor de riesgo independiente para la ECV. El polimorfismo S19W (Ser19Ter) de la ApoA5 se ha asociado en algunas poblaciones con la hipertrigliceridemia. Sin embargo, en Colombia esto ha sido poco estudiado. Objetivo: Estimar la asociación entre el polimorfismo S19W y la hipertrigliceridemia en población colombiana. Metodología: Estudio tipo Corte Transversal, con 400 individuos provenientes de Bucaramanga, Colombia. Se cuantificó los TAG y se genotipificaron mediante la técnica de SNaPshot y mini secuenciación. Los resultados fueron analizados utilizando el software de análisis genético Arlequín 3.5.1.2. Resultados: El polimorfismo S19W (Ser19Ter) mostró tres perfiles, CC, GG y CG. El polimorfismo S19W se caracterizó tanto en afectados como en no afectados, mostrando que no existen diferencias significativas en esta distribución cuando se comparan los dos grupos. Discusión: Diversos mecanismos se han propuesto para sustentar la hipertrigliceridemia como un factor de riesgo para ECV, entre los que se cuenta la APOA5. El estudio comprobó que la población estudiada se encuentra en equilibrio de Hardy Weinberg y al genotipo CC como el más frecuente. Los genotipos GG y el GC presentaron valores significativos en el grupo de sujetos afectados, (p<0,01 y p=0,03; respectivamente). Se demostró la existencia de una estrecha relación entre el polimorfismo Ser19Trp y la hipertrigliceridemia (p<0,01). Conclusión: Se pudo demostrar la existencia de una relación entre el polimorfismo Ser19Trp de la Apo A5 con los niveles elevados de TAG (p<0,01).

ABSTRACT Introduction: Cardiovascular diseases (CVD) are responsible for 29.69% of the deaths in Colombia. Several studies have shown that hypertriglyceridemia is an independent risk factor for CVD. ApoA5 gene S19W (Ser19Ter) polymorphism has been associated with hypertriglyceridemia in some populations; however, their influence in Colombia is unknown. Objective: To determine the relationship between S19W polymorphism and hypertriglyceridemia in Colombian population. Methodology: Transversal crossover Studio, included a total of 400 individuals. TAG was quantified and genotyped using the technique SnapShot and mini sequencing. The results were analyzed using genetic analysis software Arlequin 3.5.1.2. Results: S19W (Ser19Ter) polymorphism showed three profiles, CC, GG and CG. The S19W polymorphism was characterized both affected and not affected. There wasn´t significant differences in the distribution when the two groups are compared. Discussion: Various mechanisms have been proposed to support hypertriglyceridemia as a risk factor for CVD, including the APOA5 counted. The study found that the study population is in Hardy Weinberg and CC genotype as the most frequent. The GG and GC genotypes showed significant values in the group of affected subjects (p = 0.002 and 0.03). It demonstrated the existence of a close relationship between the Ser19Trp polymorphism and hypertriglyceridemia (p<0,01). Conclusion: It was possible to demonstrate the existence of a relationship between polymorphism Ser19Trp of ApoA5 with elevated levels of TAG (p<0,01).

Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients.

We hypothesized that IV busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and that this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation. To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine 40 mg/m2 once daily x4, each dose followed by IV Bu, randomized to 130 mg/m2 (N=107) or PK-guided to average daily SE, AUC of 6000 µM min (N=111), stratified for remission status and allo-grafting from HLA-matched donors. Toxicity and GvHD rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK-guidance yielded safer disease control, leading to improved overall and PFS, most prominently in MDS patients and in AML patients not in remission at allogeneic stem cell transplantation. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu dosing. This could be considered an alternative to fixed-dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD.

Symptomatic BK Virus Infection Is Associated With Kidney Function Decline and Poor Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients.

Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT.

Comparison of outcomes at two institutions of patients with ALL receiving ex vivo T-cell-depleted or unmodified allografts.

We compared outcomes of adult patients receiving T-cell-depleted (TCD) hematopoietic SCT (HCT) without additional GVHD prophylaxis at Memorial Sloan Kettering Cancer Center (MSKCC, N=52), with those of patients receiving conventional grafts at MD Anderson Cancer Center (MDACC, N=115) for ALL in CR1 or CR2. Patients received myeloablative conditioning. Thirty-nine patients received anti-thymocyte globulin at MSKCC and 29 at MDACC. Cumulative incidence of grades 2-4 acute (P=0.001, 17.3% vs 42.6% at 100 days) and chronic GVHD (P=0.006, 13.5% vs 33.4% at 3 years) were significantly lower in the TCD group. The non-relapse mortality at day 100, 1 and 3 years was 15.4, 25.0 and 35.9% in the TCD group and 9.6, 23.6 and 28.6% in the unmodified group (P=0.368). There was no difference in relapse (P=0.107, 21.3% vs 35.5% at 3 years), OS (P=0.854, 42.6% vs 43.0% at 3 years) or RFS (P=0.653, 42.8% vs 35.9% at 3 years). In an adjusted model, age >50, cytogenetics and CR status were associated with inferior RFS (hazard ratio (HR)=2.16, P=0.003, HR=1.77, P=0.022, HR=2.47, P<0.001), whereas graft type was NS (HR=0.90, P=0.635). OS and RFS rates are similar in patients undergoing TCD or conventional HCT, but TCD effectively reduces the rate of GVHD.

Low-, medium- and high-dose steroids with or without aminocaproic acid in adult hematopoietic SCT patients with diffuse alveolar hemorrhage.

Diffuse alveolar hemorrhage (DAH) is a poorly understood complication of transplantation carrying a high mortality. Patients commonly deteriorate and require intensive care unit (ICU) admission. Treatment with high-dose steroids and aminocaproic acid (ACA) has been suggested. The current study examined 119 critically ill adult hematopoietic transplant patients treated for DAH. Patients were subdivided into low-, medium- and high-dose steroid groups with or without ACA. All groups had similar baseline characteristics and severity of illness scores. Primary objectives were 30, 60, 100 day, ICU and hospital mortality. Overall mortality (n=119) on day 100 was high at 85%. In the steroids and ACA cohort (n=82), there were no significant differences in 30, 60, 100, day, ICU and hospital mortality between the dosing groups. In the steroids only cohort (n=37), the low-dose steroid group had a lower ICU and hospital mortality (P=0.02). Adjunctive treatment with ACA did not produce differences in outcomes. In the multivariate analysis, medium- and high-dose steroids were associated with a higher ICU mortality (P=0.01) as compared with the low-dose group. Our data suggest that treatment strategies may need to be reanalyzed to avoid potentially unnecessary and potentially harmful therapies.

Outcomes of second allogeneic hematopoietic stem cell transplantation for patients with acute lymphoblastic leukemia.

For patients with ALL who relapse following allo-SCT, only a second SCT provides a realistic chance for long-term disease remission. We retrospectively analyzed the outcomes of 31 patients with relapsed ALL after a prior allo-SCT, who received a second SCT (SCT2) at our center. With a median follow-up of 3 years, 1- and 3-year PFS was 23 and 11% and 1- and 3 year OS rates were 23 and 11%. Twelve patients (39%) were transplanted with active disease, of whom 75% attained a CR. We found a significant relationship between the time to treatment failure following first allograft (SCT1) and PFS following SCT2 (P=0.02, hazard ratio=0.93/month). In summary, a second transplant remains a potential treatment option for achieving response in a highly refractory patient population. While long-term survival is limited, a significant proportion of patients remains disease-free for up to 1 year following SCT2, providing a window of time to administer preventive interventions. Notably, our four long-term survivors received novel therapies with their second transplant underscoring the need for a fundamental change in the methods for SCT2 to improve outcome.

Prognostic value of response after upfront therapy for acute GVHD.

One challenge in designing clinical trials for treatment of acute GVHD (aGVHD) is the lack of an established standardized end point to measure the success of therapies. To facilitate assessment of end points in clinical trials for treatment of aGVHD in the current allo-SCT era, a national workshop was recently organized. In this study, which was presented at the workshop, we evaluated the prognostic value of response to upfront therapy in a cohort of 83 patients who had been enrolled on two clinical trials testing novel therapies for aGVHD at our institution. Our results indicate that patients whose aGVHD has a CR or PR by day 28 after initiation of systemic therapy have a significantly lower 6-month cumulative incidence of non-relapse mortality (NRM) (16%) than patients whose aGVHD did not respond to therapy by day 28 (48%, P=0.005). Multivariate analysis based on the Cox proportional hazards regression analysis showed that the impact of response on NRM is independent of patient and aGVHD characteristics. Our data confirm the validity of using day-28 response as a primary end point in clinical trials for upfront therapy for aGVHD.

Reduced-intensity conditioning using fludarabine, melphalan and thiotepa for adult patients undergoing haploidentical SCT.

Haploidentical SCT (HaploSCT) has been most commonly performed using a myeloablative, TBI-based preparative regimen; however, the toxicity with this approach remains very high. We studied the feasibility of a reduced-intensity conditioning regimen in a phase II clinical trial using fludarabine, melphalan and thiotepa and antithymocyte globulin (ATG) for patients with advanced hematological malignancies undergoing T-cell depleted HaploSCT. Twenty-eight patients were entered in the study. Engraftment with donor-derived hematopoiesis was achieved in 78% of patients after a median of 13 days. Six patients experienced primary graft failure, three out of four tested patients had donor-specific anti-HLA antibodies (DSA) (P=0.001). Toxicity included mostly infections. A total of 21 out of 22 patients with AML/myelodysplastic syndrome (MDS) achieved remission after transplant (16 with relapsed/refractory AML). Five out of the 12 patients (42%) with AML/MDS with <15% BM blasts survived long term as compared with none with more advanced disease (P=0.03). HaploSCT with this fludarabine, melphalan and thiotepa and ATG RIC is an effective, well-tolerated conditioning regimen for patients with AML/MDS with low disease burden at the time of transplant and allowed a high rate of engraftment in patients without DSA. Patients with overt relapse fared poorly and require novel treatment strategies.

Prolonged disease control by nonmyeloablative allogeneic transplantation for metastatic breast cancer.

We found earlier that high-dose chemotherapy with Allo-SCT produced a tumor response in patients with chemorefractory metastatic breast cancer. In this study, we examined the efficacy and toxicity of nonmyeloablative allogeneic PBSC transplantation in patients with chemosensitive metastatic breast cancer. Twelve patients with metastatic breast carcinoma who had stable disease after standard-dose chemotherapy and six who had a partial response underwent allogeneic transplantation. The conditioning regimen consisted of reduced-intensity fludarabine and melphalan. All patients achieved engraftment and hematopoietic recovery. Nine patients developed grade II or higher acute GVHD; seven of these nine responded to immunosuppressive therapy. Fourteen patients developed chronic GVHD. The treatment-related mortality rate was 11%. With a median follow-up of 565 days, the median survival duration was 643 days and the median progression-free survival duration was 202 days. Two patients are alive with a complete response 1555 and 2526 days after SCT, and one patient is alive with progressive bone disease at day 1118. We conclude that among patients with chemotherapy-sensitive metastatic breast cancer, a fraction will achieve a durable complete response after SCT with a reduced-intensity conditioning regimen. The question remains how to improve the overall efficacy and reduce the mortality rate for this approach.

Leukemia burden delays lymphocyte and platelet recovery after allo-SCT for AML.

Lymphocyte and platelet recovery may influence outcomes of allo-SCT for treatment of AML. It is not clear, however, if this impact is independent of patient and transplant characteristics. To investigate this question, we evaluated the influence of pre- or post transplant factors on day +30 absolute lymphocyte count (ALC) and the speed of platelet engraftment. We studied 106 AML patients treated with fludarabine and melphalan reduced-intensity conditioning and allo-SCT. Twenty nine percent of patients were in CR at the initiation of the conditioning, 39% had active disease with circulating blasts and 32% had active disease without circulating blasts. The graft source was peripheral blood from a matched sibling donor in 55% and BM from a matched unrelated donor in 45%. Our data showed that the presence of circulating blasts before transplantation is significantly correlated with low post-SCT day +30 ALC and slow platelet engraftment. This finding suggests that the impact of early ALC and platelet recovery on transplant outcome may not be independent of disease status at transplantation.

[Mycoplasma genitalium detection and correlation with clinical manifestations in population of the Zulia State, Venezuela]. / Detección de Mycoplasma genitalium y correlación con manifestaciones clínicas en una población del estado Zulia, Venezuela.

Diverse studies demonstrate an association between Mycoplasma genitalium and urogenital pathologies. The aim of this study was to investigate the prevalence of M. genitalium in patients attending gynecological evaluation in private clinics (n = 172). DNA amplification assays of the genes 16S rRNA and MgPa were utilized. The prevalence of M. genitalium in the study population was 7.5%. M. genitalium was detected in 12.1% and 4.1% of the symptomatic and asymptomatic patients, respectively (p = 0.047). The infection was diagnosed in patients with cervicitis (17.2%) and mucopurulent secretion (16.6%) and the highest prevalence of infections was registered in the 31-40 years age group. No significant association between the presence of M.genitalium and individual clinical manifestations or the patients age was showed (p > 0.05). The high prevalence of M. genitalium infections, mostly in patients with clinical manifestations showed in this study, warrants the application of diagnostic strategies in the population to investigate the clinical meaning of these microorganisms and to reevaluate therapeutic schemes against non-gonococcal and non-chlamydial infections.

Detección de Mycoplasma genitalium y correlación con manifestaciones clínicas en una población del estado Zulia, Venezuela / Mycoplasma genitalium detection and correlation with clinical manifestations in population of the Zulia State, Venezuela

Diverse studies demonstrate an association between Mycoplasma genitalium and urogenital pathologies. The aim of this study was to investigate the prevalence of M. genitalium in patients attending gynecological evaluation in private clinics (n = 172). DNA amplification assays of the genes 16S rRNA and MgPa were utilized. The prevalence of M. genitalium in the study population was 7.5 percent. M. genitalium was detected in 12.1 percent and 4.1 percent of the symptomatic and asymptomatic patients, respectively (p = 0.047). The infection was diagnosed in patients with cervicitis (17.2 percent) and mucopurulent secretion (16.6 percent) and the highest prevalence of infections was registered in the 31-40 years age group. No significant association between the presence of M.genitalium and individual clinical manifestations or the patients age was showed (p > 0.05). The high prevalence of M. genitalium infections, mostly in patients with clinical manifestations showed in this study, warrants the application of diagnostic strategies in the population to investigate the clinical meaning of these microorganisms and to reevaluate therapeutic schemes against non-gonococcal and non-chlamydial infections.

Diversos estudios demuestran una asociación entre Mycoplasma genitalium y patologías urogenitales. El objetivo de este trabajo fue investigar la prevalencia de infecciones por M. genitalium en pacientes atendidas en clínicas privadas (n = 172). Se utilizaron ensayos de amplificación de genes 16S rARN y MgPa. La prevalencia de M. genitalium en esta población fue 7,5 por ciento. Mycoplasma genitalium fue detectado en 12,1 y 4,1 por ciento) de las pacientes sintomáticas y asintomáticas, respectivamente (p = 0,047). La infección se diagnosticó en pacientes con cervicitis (17,2 por ciento) y con secreción mucopurulenta (16,6 por ciento) y la mayor prevalencia de infecciones se registró en el grupo etario de 31 a 40 años. No se encontró asociación significativa entre la presencia de M. genitalium y manifestaciones clínicas individuales o edad de las pacientes (p > 0,05). La alta prevalencia de infecciones por M. genitalium, principalmente en pacientes con manifestaciones clínicas demostrada en este estudio, demanda la aplicación de estrategias diagnósticas en la población para investigar el significado clínico de estos microorganismos y reevaluar esquemas terapéuticos contra infecciones no gonocóccicas y no clamidiales.

Treatment of donor graft failure with nonmyeloablative conditioning of fludarabine, antithymocyte globulin and a second allogeneic hematopoietic transplantation.

Graft failure is a life-threatening complication of allogeneic stem cell transplantation (SCT). We assessed the feasibility of performing a second SCT after such failure when fludarabine and antithymocyte globulin (ATG) are used for non-myeloablative conditioning and tacrolimus for graft-versus-host disease (GVHD) prophylaxis. Nine patients with SCTs for various hematologic malignancies were enrolled, eight with primary and one with secondary graft failure. The median time between the first and second SCT was 53 days. Eight patients had the same donor for their second SCT, and one had a cord blood transplant. Three patients were not evaluable because of early death; the other six had evidence of donor cell engraftment. Six of the nine patients developed acute grade II-IV GVHD, the main cause of death. Overall, we found that fludarabine and ATG conditioning before a second SCT allows engraftment of donor hematopoiesis. Future studies should include more intense GVHD prophylaxis.

Microbial contamination of hematopoietic progenitor cell products: clinical outcome.

We reviewed the results of routine microbiological assays of 3078 infused hematopoietic progenitor cell (HPC) products for autologous and allogeneic transplantation between January 2001 and December 2005. Thirty-seven (1.2%) contaminated products were found. All patients receiving contaminated infusions received empirical antibiotic prophylaxis according to the assay result. None of these patients developed a positive blood culture with the same agent, developed infections that could be attributable to the contaminated product or experienced any clinical sequelae. Coagulase-negative Staphylococcus was found in 32 (86.5%) products. Admission lengths and time to engraftment were within the expected time frame for autologous and allogeneic transplants. Microbial contamination of HPC products occurs at a low frequency; prophylactic use of antibiotics based on the microbiological assay appears to be effective in preventing clinical complications.

High-dose chemotherapy and autologous peripheral blood stem cell transplantation for primary breast cancer refractory to neoadjuvant chemotherapy.

The role of high-dose chemotherapy (HDCT) in patients with refractory breast cancer is not well established. Forty-two female patients (median age of 46 years) with breast cancer refractory to neoadjuvant chemotherapy received HDCT (cyclophosphamide, carmustine and thiotepa) supported by an autologous peripheral blood stem cells transplant. Their disease had been refractory (defined as less than partial response) to one (18 patients) or two (24 patients) regimens of neoadjuvant chemotherapy. Twenty-nine patients had surgery before HDCT. The best response after surgery, HDCT, and radiation therapy was assessed 60 days after transplantation. Thirty patients had complete remission, eight had a PR, one had a minor response, and three had progressive disease. In seven of 13 patients whose disease was inoperable before HDCT, it became operable. After a median follow-up of 42 months, 21 patients were alive, and 15 remained disease free. Five-year overall survival (OS) was 57% (CI, 50-64%), and the estimated 5-year progression-free survival was 40% (CI, 32-48%). Both OS and PFS were better in patients whose disease became operable after chemotherapy than in those whose disease remained inoperable. A randomized study is warranted in this patient population.