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1.
Cells ; 9(4)2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32290286

RESUMO

Diseases of the kidney contribute a significant morbidity and mortality burden on society. Localized delivery of therapeutics directly into the kidney, via its arterial blood supply, has the potential to enhance their therapeutic efficacy while limiting side effects associated with conventional systemic delivery. Targeted delivery in humans is feasible given that we can access the renal arterial blood supply using minimally invasive endovascular techniques and imaging guidance. However, there is currently no described way to reproduce or mimic this approach in a small animal model. Here, we develop in mice a reproducible microsurgical technique for the delivery of therapeutics directly into each kidney, via its arterial blood supply. Using our technique, intra-arterially (IA) injected tattoo dye homogenously stained both kidneys, without staining any other organ. Survival studies showed no resulting mortality or iatrogenic kidney injury. We demonstrate the therapeutic potential of our technique in a mouse model of cisplatin-induced acute kidney injury (AKI). IA injection of mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) successfully reversed AKI, with reduced physiological and molecular markers of kidney injury, attenuated inflammation, and restoration of proliferation and regeneration markers. This reproducible delivery technique will allow for further pre-clinical translational studies investigating other therapies for the treatment of renal pathologies.

2.
Biomedicines ; 8(3)2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32143316

RESUMO

The antigen-specific apoptotic DNA immunotherapeutic, ADi-100, is designed to suppress type 1 diabetes and consists of two DNA plasmids encoding genetic sequences of the apoptosis-inducing molecule, BAX, and the secreted form of the autoantigen, glutamic acid decarboxylase 65, that is CpG hyper-methylated to avoid inflammatory signaling (msGAD55). Upon a four-day treatment with ADi-100 of young female non-obese diabetic (NOD) mice, the frequency of various tolerogenic dendritic cell populations increased in draining lymph nodes; these cells lost the capacity to stimulate glutamic acid decarboxylase (GAD)-specific CD4+ T lymphocytes and were associated with the previously demonstrated enhancement of GAD-specific regulatory T cells. The efficacy of two ADi-100 formulations containing different proportions of BAX and msGAD55, 1:4 (10/40 µg) and 1:2 (17/33 µg), was evaluated in mildly hyperglycemic pre-diabetic NOD female mice. Both formulations suppressed the incidence of diabetes by 80% in an antigen-specific manner, while all untreated mice developed diabetes. However, treatment of pre-diabetic mice with significantly higher hyperglycemia, denoting progressive disease, showed that ADi-100 1:2 strongly suppressed diabetes incidence by 80% whereas the ADi-100 1:4 was less effective (50%). As an antigen-specific monotherapy, ADi-100 is highly efficacious in reversing elevated hyperglycemia to prevent diabetes, in which increasing apoptosis-inducing BAX content is a promising immune tolerance feature.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32157802

RESUMO

Mesenchymal stromal cells (MSCs) have been a popular platform for cell-based therapy in regenerative medicine due to their propensity to home to damaged tissue and act as a repository of regenerative molecules that can promote tissue repair and exert immunomodulatory effects. Accordingly, a great deal of research has gone into optimizing MSC homing and increasing their secretion of therapeutic molecules. A variety of methods have been used to these ends, but one emerging technique gaining significant interest is the use of ultrasound. Sound waves exert mechanical pressure on cells, activating mechano-transduction pathways and altering gene expression. Ultrasound has been applied both to cultured MSCs to modulate self-renewal and differentiation, and to tissues-of-interest to make them a more attractive target for MSC homing. Here, we review the various applications of ultrasound to MSC-based therapies, including low-intensity pulsed ultrasound, pulsed focused ultrasound, and extracorporeal shockwave therapy, as well as the use of adjunctive therapies such as microbubbles. At a molecular level, it seems that ultrasound transiently generates a local gradient of cytokines, growth factors, and adhesion molecules that facilitate MSC homing. However, the molecular mechanisms underlying these methods are far from fully elucidated and may differ depending on the ultrasound parameters. We thus put forth minimal criteria for ultrasound parameter reporting, in order to ensure reproducibility of studies in the field. A deeper understanding of these mechanisms will enhance our ability to optimize this promising therapy to assist MSC-based approaches in regenerative medicine.

4.
Mol Genet Metab ; 130(1): 58-64, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32173240

RESUMO

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal disorder characterized by progressive gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, skeletal myopathy, ophthalmoparesis, and ptosis. MNGIE stems from deficient thymidine phosphorylase activity (TP) leading to toxic elevations of plasma thymidine. Hematopoietic stem cell transplant (HSCT) restores TP activity and halts disease progression but has high transplant-related morbidity and mortality. Liver transplant (LT) was reported to restore TP activity in two adult MNGIE patients. We report successful LT in four additional MNGIE patients, including a pediatric patient. Our patients were diagnosed between ages 14 months and 36 years with elevated thymidine levels and biallelic pathogenic variants in TYMP. Two patients presented with progressive gastrointestinal dysmotility, and three demonstrated progressive peripheral neuropathy with two suffering limitations in ambulation. Two patients, including the child, had liver dysfunction and cirrhosis. Following LT, thymidine levels nearly normalized in all four patients and remained low for the duration of follow-up. Disease symptoms stabilized in all patients, with some manifesting improvements, including intestinal function. No patient died, and LT appeared to have a more favorable safety profile than HSCT, especially when liver disease is present. Follow-up studies will need to document the long-term impact of this new approach on disease outcome. Take Home Message: Liver transplantation is effective in stabilizing symptoms and nearly normalizing thymidine levels in patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and may have an improved safety profile over hematopoietic stem cell transplant.

5.
Clin Transplant ; 34(2): e13777, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31904131

RESUMO

INTRODUCTION: Urinary diversion in pediatric renal transplant candidates with bladders not amenable to primary reconstruction can be achieved by pre-transplant ileal conduit creation. We performed cutaneous ureterostomies to limit pre-transplant surgery, protect the peritoneum for dialysis, transplant patients sooner, and preserve ureter length for future surgical reconstruction. METHODS: We compared four pediatric transplant recipients with ureterostomies to four recipients with ileal conduits from 2009 to 2017. RESULTS: All patients with ileal conduits developed at least one urinary tract infection (UTI) within 1 year of transplant and three of four patients had recurrent UTIs within the first year. Two patients required ileal conduit revisions for redundant conduits and recurrent UTIs. Of the four ureterostomy patients, two patients had UTIs within one year of transplant. Two patients developed ureterostomy strictures requiring revision at the fascial level; one was associated with a UTI. CONCLUSION: In our small case series, ureterostomy allowed for a single operative intervention with preservation of ureter length for later reconstruction. Ureterostomy is safe and recurrent UTI may be lower in the ureterostomy group. Long-term evaluation of ureterostomy for urinary diversion in pediatric kidney transplant is warranted.

6.
Ageing Res Rev ; 57: 100979, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704472

RESUMO

Organismal aging involves the progressive decline in organ function and increased susceptibility to age-associated diseases. This has been associated with the aging of stem cell populations within the body that decreases the capacity of stem cells to self-renew, differentiate, and regenerate damaged tissues and organs. This review aims to explore how aging is associated with the dysregulation of stem cell-derived extracellular vesicles (SCEVs) and their corresponding miRNA cargo (SCEV-miRNAs), which are short non-coding RNAs involved in post-transcriptional regulation of target genes. Recent evidence has suggested that in aging stem cells, SCEV-miRNAs may play a vital role regulating various processes that contribute to aging: cellular senescence, stem cell exhaustion, telomere length, and circadian rhythm. Hence, further clarifying the age-dependent molecular mechanisms through which SCEV-miRNAs exert their downstream effects may inform a greater understanding of the biology of aging, elucidate their role in stem cell function, and identify important targets for future regenerative therapies. Additionally, current studies evaluating therapeutic role of SCEVs and SCEV-miRNAs in treating several age-associated diseases are also discussed.

7.
Front Psychol ; 10: 2388, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31749733

RESUMO

Background: Diverse wellness-promoting mobile health technologies, including mobile apps and wearable trackers, became increasingly popular due to their ability to support patients' self-management of health conditions. However, the patient's acceptance and use depend on the perceived experience and the app appropriateness to the patient's context and needs. We have some understating of the experience and factors influencing the use of these technologies in the general public, but we have a limited understanding of these issues in patients. Objective: By presenting results from an explorative study, this paper aims to identify implications for the design of mobile apps and wearables to effectively support patients' efforts in self-management of health with a special emphasis on support for self-efficacy of activities contributing to health. Methods: An explorative mixed-method study involving 200 chronically ill patients of Stanford Medical Center (Stanford, CA, United States) was conducted between mid-2016 and end of 2018. Amongst these, 20 patients were involved in a 4-weeks study, in which we collected the underlying wearable device use logs (e.g., Fitbit) and subjective use experience [via an Ecological Momentary Assessment (EMA)], as well as patients' momentary perception of general self-efficacy in their natural environments and different daily contexts. Results: The results indicate that mobile apps for health and wearables have the potential to enable better self-management and improve patients' wellbeing but must be further refined to address different human aspects of their use. Specifically, the apps/wearables should be easier to use, more personalized and context-aware for the patient's overall routine and lifestyle choices, as well as with respect to the momentary patient state (e.g., location, type of people around) and health(care) needs. Additionally, apps and devices should be more battery efficient and accurate; providing timely, non-judgmental feedback and personalized advice to the patients anywhere-anytime-anyhow. These results are mapped on major sources of the individuals' self-efficacy. Conclusion: Our results show how the apps/wearables that are aimed at supporting the patients' self-management should be designed to leverage and further improve the patients' general self-efficacy and self-efficacy of activities contributing to chronic disease management.

8.
Stem Cell Res Ther ; 10(1): 347, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771657

RESUMO

Extracellular vesicles (EVs) are cellular-derived versatile transporters with a specialized property for trafficking a variety of cargo, including metabolites, growth factors, cytokines, proteins, lipids, and nucleic acids, throughout the microenvironment. EVs can act in a paracrine manner to facilitate communication between cells as well as modulate immune, inflammatory, regenerative, and remodeling processes. Of particular interest is the emerging association between EVs and stem cells, given their ability to integrate complex inputs for facilitating cellular migration to the sites of tissue injury. Additionally, stem cell-derived EVs can also act in an autocrine manner to influence stem cell proliferation, mobilization, differentiation, and self-renewal. Hence, it has been postulated that stem cells and EVs may work synergistically in the process of tissue repair and that dysregulation of EVs may cause a loss of homeostasis in the microenvironment leading to disease. By harnessing the property of EVs for delivery of small molecules, stem cell-derived EVs possess significant potential as a platform for developing bioengineering approaches for next-generation cancer therapies and targeted drug delivery methods. Although one of the main challenges of clinical cancer treatment remains a lack of specificity for the delivery of effective treatment options, EVs can be modified via genetic, biochemical, or synthetic methods for enhanced targeting ability of chemotherapeutic agents in promoting tumor regression. Here, we summarize recent research on the bioengineering potential of EV-based cancer therapies. A comprehensive understanding of EV modification may provide a novel strategy for cancer therapy and for the utilization of EVs in the targeting of oncogenic processes. Furthermore, innovative and emerging new technologies are shifting the paradigm and playing pivotal roles by continually expanding novel methods and materials for synthetic processes involved in the bioengineering of EVs for enhanced precision therapeutics.

9.
Dig Dis Sci ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31372912

RESUMO

BACKGROUND/AIMS: Alcoholic hepatitis (AH) can lead to sudden and severe hepatic decompensation necessitating recurrent hospitalizations. We evaluated the trends, predictors, and healthcare cost burden of AH-related readmissions in the USA. METHODS: Utilizing the National Readmissions Database 2010-2014, we performed a retrospective longitudinal analysis to identify the index readmission with AH for up to 90 days after discharge. Annual trends of 30- and 90-day AH-related readmissions were calculated. Predictors of 30- and 90-day readmission were determined by multivariate logistic regression. Annual healthcare cost burden associated with AH-linked readmissions was estimated. RESULTS: Of the 21,572 (unweighted: 50,769) AH-related hospitalizations, 4917 (22.8%) and 7890 (36.6%) were readmitted in 30 and 90 day, respectively, with rates that were statistically unchanged from 2010 to 2014. Predictors of 30-day readmissions included female gender, hepatitis C virus infection, cirrhosis, ascites, acute kidney injury, urinary tract infection, history of bariatric surgery, chronic pancreatitis, and high medical comorbidity index. Acute pancreatitis and palliative care consultation were associated with a lower risk of 30-day readmission. Predictors of 90-day readmission were similar to risk factors for 30-day readmission. From 2010 to 2014, the annual cost (and total hospitalization days) burden increased in 2014 to $164 million (22,244 days) and $321 million (42,772 days) for 30- and 90-day AH-related readmissions, respectively. CONCLUSION: Despite relatively stable trends in AH-related readmission, the total LOS and cost has been rising. A target-directed approach with a focus on high-risk subpopulations may help understand the unique challenges associated with the rising cost of AH-related readmissions.

10.
Pediatr Transplant ; 23(6): e13532, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31259459

RESUMO

Bilateral renal agenesis is associated with severe oligohydramnios and was considered incompatible with postnatal life due to severe pulmonary hypoplasia. The use of renal replacement therapy was limited by significant morbidity and mortality associated with dialysis in very young infants with major pulmonary pathology. In the United States, there is a tremendous controversy about whether or not the use of prenatal amniotic fluid infusions provides a benefit to fetuses with bilateral renal agenesis. One of the critical issues identified is that there are, as yet, no children reported who had achieved long-term survival. Previous reports all indicated these children died shortly after birth or after unsuccessful peritoneal dialysis. We present two infants with a prenatal diagnosis of bilateral renal agenesis whose mothers elected to undergo prenatal amnioinfusions. One was born at 28 weeks with a birthweight of 1230 g and the other born at 34 weeks with a birthweight of 1940 g. We present the details of both cases, with initial management on chronic peritoneal dialysis, which started shortly after birth, as a bridge to living related kidney transplants.

11.
Oncotarget ; 10(37): 3435-3450, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31191817

RESUMO

The development of chemotherapy drug resistance remains a significant barrier for effective therapy in several cancers including breast cancer. Bone marrow-derived mesenchymal stem cells (BMMSCs) have previously been shown to influence tumor progression and the development of chemoresistance. In the present study, we showed that when GFP labelled BMMSCs and RFP labelled HCC1806 cells are injected together in vivo, they create tumors which contain a new hybrid cell that has characteristics of both BMMSCs and HCC1806 cells. By labelling these cells prior to their injection, we were then able to isolate new hybrid cell from harvested tumors using FACS (DP-HCC1806:BMMSCs). Interestingly, when DP-HCC1806:BMMSCs were then injected into the mammary fat pad of NOD/SCID mice, they produced xenograft tumors which were smaller in size, and exhibited resistance to chemotherapy drugs (i.e. doxorubicin and 5-fluorouracil), when compared tumors from HCC1806 cells alone. This chemoresistance was shown to associated with an increased expression of tetraspanins (CD9, CD81) and drug resistance proteins (BCRP, MDR1). Subsequent siRNA-mediated knockdown of BMMSC-CD9 in DP-HCC1806:BMMSCs resulted in an attenuation of doxorubicin and 5-fluorouracil chemoresistance associated with decreased BCRP and serum cytokine expression (CCL5, CCR5, CXCR12). Our findings suggest that within the tumor microenvironment, CD9 is responsible for the crosstalk between BMMSCs and HCC1806 breast cancer cells (via CCL5, CCR5, and CXCR12) which contributes to chemoresistance. Hence, BMMSC-CD9 may serve as an important therapeutic target for the treatment of breast cancer.

12.
Clin Transplant ; 33(6): e13540, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30891780

RESUMO

Patients with failing Fontan physiology and liver cirrhosis are being considered for combined heart and liver transplantation. We performed a retrospective review of our experience with en bloc combined heart and liver transplantation in Fontan patients > 10 years old from 2006 to 18 per Institutional Review Board approval. Six females and 3 males (median age 20.7, range 14.2-41.3 years) underwent en bloc combined heart and liver transplantation. Indications for heart transplant included ventricular dysfunction, atrioventricular valve regurgitation, arrhythmia, and/or lymphatic abnormalities. Indication for liver transplant included portal hypertension and cirrhosis. Median Fontan/single ventricular end-diastolic pressure was 18/12 mm Hg, respectively. Median Model for End-Stage Liver Disease excluding International Normalized Ratio score was 10 (7-26), eight patients had a varices, ascites, splenomegaly, thrombocytopenia score of ≥ 2, and all patients had cirrhosis. Median cardiopulmonary bypass and donor ischemic times were 262 (178-307) and 287 (227-396) minutes, respectively. Median intensive care and hospital stay were 19 (5-96) and 29 (13-197) days, respectively. Survival was 100%, and rejection was 0% at 30 days and 1 year post-transplant. En bloc combined heart and liver transplantation is an acceptable treatment in the failing Fontan patient with liver cirrhosis.

13.
J Infect Dis ; 220(3): 370-376, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-30869132

RESUMO

BACKGROUND: BK virus (BKV) is a significant cause of nephropathy in kidney transplantation. The goal of this study was to characterize the course and source of BKV in kidney transplant recipients. METHODS: We prospectively collected pretransplant plasma and urine samples from living and deceased kidney donors and performed BKV polymerase chain reaction (PCR) and immunoglobulin G (IgG) testing on pretransplant and serially collected posttransplant samples in kidney transplant recipients. RESULTS: Among deceased donors, 8.1% (17/208) had detectable BKV DNA in urine prior to organ procurement. BK viruria was observed in 15.4% (6/39) of living donors and 8.5% (4/47) of deceased donors of recipients at our institution (P = .50). BKV VP1 sequencing revealed identical virus between donor-recipient pairs to suggest donor transmission of virus. Recipients of BK viruric donors were more likely to develop BK viruria (66.6% vs 7.8%; P < .001) and viremia (66.6% vs 8.9%; P < .001) with a shorter time to onset (log-rank test, P < .001). Though donor BKV IgG titers were higher in recipients who developed BK viremia, pretransplant donor, recipient, and combined donor/recipient serology status was not associated with BK viremia (P = .31, P = .75, and P = .51, respectively). CONCLUSIONS: Donor BK viruria is associated with early BK viruria and viremia in kidney transplant recipients. BKV PCR testing of donor urine may be useful in identifying recipients at risk for BKV complications.


Assuntos
Vírus BK/isolamento & purificação , Nefropatias/virologia , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/virologia , Infecções Tumorais por Vírus/virologia , Adulto , Feminino , Humanos , Imunoglobulina G/sangue , Rim/virologia , Nefropatias/sangue , Nefropatias/urina , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/sangue , Infecções por Polyomavirus/urina , Estudos Prospectivos , Transplantados , Infecções Tumorais por Vírus/sangue , Infecções Tumorais por Vírus/urina , Viremia/sangue , Viremia/urina , Viremia/virologia
14.
Pediatr Transplant ; 22(8): e13299, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30324753

RESUMO

PURPOSE: The treatment of VUR in children with UTI has changed significantly, due to studies showing that antibiotic prophylaxis does not decrease renal scarring. As children with kidney transplants are at higher risk for UTI, we investigated if select patients with renal transplant VUR could be managed without surgery. MATERIALS AND METHODS: A total of 18 patients with VUR into their renal grafts were identified, and 319 patients underwent transplantation from 2006 to 2016. The cause for the detection of the VUR, treatment, and graft function was reviewed. RESULTS: Six boys and 12 girls were identified, 13 of whom had grade 3 or 4 VUR into the renal graft. Nine patients presented with hydronephrosis or abnormal renal biopsy: eight were successfully managed with antibiotic prophylaxis and bladder training, one developed UTI and underwent Dx/HA subureteric injection. Nine patients presented with recurrent febrile UTI, only one was successfully managed without surgery. Only 2 of 9 (22%) patients who underwent Dx/HA injection had resolution of their reflux. Of the remaining seven, five required open ureteral reimplantation (two for obstruction), one lost the graft due to rejection, and one had significant hydronephrosis. eGFR was similar between the hydronephrosis, UTI, and abnormal renal biopsy groups at all times. CONCLUSION: Patients with transplant VUR and recurrent febrile UTI are more likely to require surgical therapy, but the complication and failure rate for Dx/HA injection is significant. Patients with transplant VUR without febrile UTI can be successfully managed with bladder training and temporary antibiotic prophylaxis.


Assuntos
Transplante de Rim/efeitos adversos , Infecções Urinárias/terapia , Refluxo Vesicoureteral/terapia , Adolescente , Antibioticoprofilaxia , Biópsia , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Humanos , Ácido Hialurônico/administração & dosagem , Hidronefrose/complicações , Lactente , Rim/patologia , Masculino , Risco , Resultado do Tratamento , Ureter , Infecções Urinárias/etiologia , Refluxo Vesicoureteral/complicações
15.
Transplantation ; 102(7): 1172-1178, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29953422

RESUMO

BACKGROUND: Native nephrectomy in pediatric kidney transplant recipients is performed for multiple indications. Posttransplant hypertension requiring medical management is common, and the effect of native nephrectomy on posttransplant hypertension is poorly studied. Our aim is to evaluate the impact of native nephrectomy on posttransplant hypertension. METHODS: One hundred thirty-six consecutive pediatric kidney transplant recipients from 2007 to 2012 were studied at a single institution and divided into 2 groups: no nephrectomy and native nephrectomy (unilateral and bilateral nephrectomy). Antihypertensive medication use was evaluated before nephrectomy/transplant, at discharge from transplant and at 1, 3, and 5 years posttransplant. RESULTS: In a bivariate analysis, nephrectomy was associated with a significant reduction in the percentage of patients requiring antihypertensive medication at the time of discharge (27.3%) and 1 year posttransplant (10.7%) as compared with patients without nephrectomy (71.7%, and 50%, respectively, P < 0.05). This trend toward reduction in antihypertensive medication in the nephrectomy group as compared with the no nephrectomy group persisted at 3 (18.6% versus 43.2%) and 5 years (19.7% versus 37.5%) posttransplant. Multivariable logistic regression demonstrated that patients without native nephrectomy had higher odds of requiring antihypertensive medication at the time of discharge (3.3) and 1 year (5.2) as compared with patients who underwent native nephrectomy (P = 0.036 and P = 0.013, respectively). CONCLUSIONS: Native nephrectomy reduces the odds of needing antihypertensive medication after transplant. The impact of native nephrectomy is crucial to the comprehensive management of pediatric transplant recipients where medication compliance is challenging and lifelong hypertension is known to negatively impact cardiovascular health.


Assuntos
Hipertensão/epidemiologia , Nefropatias/cirurgia , Transplante de Rim/efeitos adversos , Nefrectomia/métodos , Complicações Pós-Operatórias/epidemiologia , Adolescente , Anti-Hipertensivos/uso terapêutico , Criança , Pré-Escolar , Feminino , Rejeição de Enxerto/epidemiologia , Humanos , Hipertensão/etiologia , Hipertensão/prevenção & controle , Lactente , Masculino , Nefrectomia/estatística & dados numéricos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Transplantados/estatística & dados numéricos , Resultado do Tratamento
16.
Pediatr Transplant ; 22(4): e13187, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29707868

RESUMO

Children with unresectable HCC have a dismal prognosis and few approved treatment options. TACE is an effective treatment option for adults with HCC, but experience in children is very limited. Retrospective analysis was performed of 8 patients aged 4-17 years (4 male, mean 12.5 years) who underwent TACE for unresectable HCC. Response to TACE was evaluated by change in AFP, RECIST and tumor volume, PRETEXT, and transplantation eligibility by UCSF and Milan criteria. Post-procedure mean follow-up was 8.2 years. Mean overall change in tumor volume for the 8 patients was 51%. Percent change in AFP ranged from a decrease of 100% to an increase of 89.3%, with a mean change of -49.6%. Two patients did not undergo resection or transplantation and died of progressive disease. Six patients underwent orthotopic liver transplantation with mean first TACE-to-transplant interval of 141 days (range 11-514). Following transplantation, 5 patients were alive at the end of the follow-up period and one died of recurrent disease. Based on our initial experience, TACE for children with unresectable HCC appears to be a safe and effective method for managing hepatic tumor burden and for downstaging and bridging to liver transplantation.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Neoplasias Hepáticas/terapia , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Transplante de Fígado , Masculino , Estudos Retrospectivos , Resultado do Tratamento
17.
Mol Genet Metab ; 123(3): 297-300, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29396029

RESUMO

PURPOSE OF STUDY: Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor. METHODS USED: Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery. SUMMARY OF RESULTS: Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years. CONCLUSION: Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.


Assuntos
Hiperamonemia/tratamento farmacológico , Doença da Deficiência de Ornitina Carbomoiltransferase/tratamento farmacológico , Fenilacetatos/uso terapêutico , Cuidado Pré-Natal/métodos , Benzoato de Sódio/uso terapêutico , Amônia/sangue , Amônia/toxicidade , Combinação de Medicamentos , Feminino , Glutamina/sangue , Humanos , Hiperamonemia/sangue , Hiperamonemia/diagnóstico , Hiperamonemia/genética , Recém-Nascido , Masculino , Mutação , Ornitina Carbamoiltransferase/genética , Doença da Deficiência de Ornitina Carbomoiltransferase/sangue , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Gravidez , Diagnóstico Pré-Natal , Resultado do Tratamento , Ureia/metabolismo
18.
AJR Am J Roentgenol ; 210(4): 766-774, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29470153

RESUMO

OBJECTIVE: The purpose of this study is to evaluate whether use of a standardized radiology report template would improve the ability of liver transplant surgeons to diagnose stage T2 hepatocellular carcinoma (HCC) and determine patient suitability to undergo orthotopic liver transplant (OLT). MATERIALS AND METHODS: In this retrospective study, a standardized template was devised, and its use was mandated for reporting of liver CT findings for patients with cirrhosis and HCC. Two surgeons analyzed 200 reports (100 before and 100 after template implementation) for descriptions of cirrhosis, portal hypertension, lesion enhancement characteristics, tumor thrombus, portal and superior mesenteric vein patency, and Organ Procurement Transplantation Network (OPTN) class. Ability to determine Milan criteria and surgeon satisfaction were also assessed. Data obtained before and after template implementation were statistically analyzed using the Cochran-Mantel-Haenszel test. RESULTS: Template implementation increased the percentage of reports documenting the presence or absence of portal hypertension (74% to 88% for surgeon 1 and 86% to 87% for surgeon 2; p = 0.042); lesion number (76% to 88% for surgeon 2 [no change for surgeon 1]; p = 0.038), size (95% to 96% for surgeon 1 and 82% to 93% for surgeon 2; p = 0.03), and enhancement (93% to 94% for surgeon 1 and 80% to 91% for surgeon 2; p = 0.049); presence of tumor thrombus (10% to 57% for surgeon 1 and 31% to 63% for surgeon 2; p < 0.001); and OPTN class (8% to 82% for surgeon 1 and 2% to 81% for surgeon 2; p < 0.001). The surgeons were significantly more able to determine the presence of T2 disease and qualification for exception points after implementation of the template (increasing from 80% to 94%; p = 0.025). Satisfaction with reports also improved (p < 0.0001). CONCLUSION: The reporting template improved determination of patient suitability to undergo transplant according to the Milan criteria.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Seleção de Pacientes , Sistemas de Informação em Radiologia/normas , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Obtenção de Tecidos e Órgãos/normas
19.
Cureus ; 10(10): e3499, 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30648040

RESUMO

Here we describe the case of a 10-year-old boy with a history of chronic hepatitis B who was diagnosed with hepatocellular carcinoma (HCC) with a large central hepatic mass and metastatic disease in a celiac lymph node. His tumor was unresectable, due to location and lack of clear margins, and he could not receive chemotherapy due to elevated bilirubin. He was treated with stereotactic body radiotherapy (SBRT) to the primary site and involved nodal region. After completing radiotherapy, his total bilirubin level fell below 1.0 mg/dL, allowing him to begin systemic therapy with cisplatin and doxorubicin. At three months after SBRT, his bilirubin was 0.1 mg/dL, alpha-fetoprotein (AFP) was 88 ng/mL, and imaging demonstrated a decrease in tumor size (total volume 28.7 cc), with no evidence of local or distant disease progression. He then developed distant disease within the liver, but his disease remained controlled at the primary site and nodes that had been treated with SBRT. He underwent orthotopic liver transplantation (OLT) with an uneventful operative course and remains with no evidence of disease at seven months after OLT. This is one of the first reported cases of successful downstaging of pediatric HCC with nodal involvement to allow for OLT, and it argues for consideration of similar patients for OLT.

20.
Mol Imaging Biol ; 20(1): 139-149, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28411307

RESUMO

PURPOSE: To evaluate whether ultrasmall superparamagnetic iron oxide nanoparticle (USPIO)-enhanced magnetic resonance imaging (MRI) can detect allograft rejection in pediatric kidney transplant patients. PROCEDURES: The USPIO ferumoxytol has a long blood half-life and is phagocytosed by macrophages. In an IRB-approved single-center prospective clinical trial, 26 pediatric patients and adolescents (age 10-26 years) with acute allograft rejection (n = 5), non-rejecting allografts (n = 13), and normal native kidneys (n = 8) underwent multi-echo T2* fast spoiled gradient-echo (FSPGR) MRI after intravenous injection (p.i.) of 5 mg Fe/kg ferumoxytol. T2* relaxation times at 4 h p.i. (perfusion phase) and more than 20 h p.i. (macrophage phase) were compared with biopsy results. The presence of rejection was assessed using the Banff criteria, and the prevalence of macrophages on CD163 immunostains was determined based on a semi-quantitative scoring system. MRI and histology data were compared among patient groups using t tests, analysis of variance, and regression analyses with a significance threshold of p < 0.05. RESULTS: At 4 h p.i., mean T2* values were 6.6 ± 1.5 ms for native kidneys and 3.9 ms for one allograft undergoing acute immune rejection. Surprisingly, at 20-24 h p.i., one rejecting allograft showed significantly prolonged T2* relaxation times (37.0 ms) compared to native kidneys (6.3 ± 1.7 ms) and non-rejecting allografts (7.6 ± 0.1 ms). Likewise, three additional rejecting allografts showed significantly prolonged T2* relaxation times compared to non-rejecting allografts at later post-contrast time points, 25-97 h p.i. (p = 0.008). Histological analysis revealed edema and compressed microvessels in biopsies of rejecting allografts. Allografts with and without rejection showed insignificant differences in macrophage content on histopathology (p = 0.44). CONCLUSION: After ferumoxytol administration, renal allografts undergoing acute rejection show prolonged T2* values compared to non-rejecting allografts. Since histology revealed no significant differences in macrophage content, the increasing T2* value is likely due to the combined effect of reduced perfusion and increased edema in rejecting allografts.


Assuntos
Aloenxertos/imunologia , Óxido Ferroso-Férrico/metabolismo , Rejeição de Enxerto/imunologia , Transplante de Rim , Adolescente , Aloenxertos/patologia , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Criança , Rejeição de Enxerto/diagnóstico , Humanos , Cinética , Imagem por Ressonância Magnética , Receptores de Superfície Celular/metabolismo , Adulto Jovem
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