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1.  Expectant and medical management of placenta increta in a primiparous woman presenting with postpartum haemorrhage: The role of Imaging 
We report a case of postpartum hemorrhage due to adherent placenta. A 28 year old primiparous woman who underwent manual removal of placenta for primary postpartum haemorrhage soon after delivery was referred to our Institute on her third postnatal day because of persistent tachycardia and low grade fever. Placenta accreta was suspected on initial ultrasonographic examination. MRI examination confirmed the diagnosis of placenta accreta in few areas and revealed increta in other areas. On expectant management she developed genital tract sepsis and hence she was treated with intravenous Methotrexate after controlling infection with appropriate antibiotics. Doppler Imaging showed decreased blood flow to the placental mass and increased echogenecity on gray scale USG after Methotrexate administration. She expelled the whole placental mass on 35th postnatal day and MRI performed the next day showed empty uterine cavity. Morbid adhesion of placenta should be suspected even in primiparous women without any risk factors when there is history of post-partum hemorrhage. MRI is the best modality for evaluation of adherent placenta.
doi:10.3941/jrcr.v4i5.343
PMCID: PMC3303403  PMID: 22470732
Manual removal of placenta; Placenta accreta & increta; MRI; Methotrexate
2.  Prophylactic Hypogastric Artery Ballooning in a Patient with Complete Placenta Previa and Increta 
Journal of Korean Medical Science  2010;25(4):651-655.
Abnormal attachment of the placenta (Placenta accreta, increta, and percreta) is an uncommon but potentially lethal cause of maternal mortality from massive postpartum hemorrhage. A 33-yr-old woman, who had been diagnosed with a placenta previa, was referred at 30 weeks gestation. On ultrasound, a complete type of placenta previa and multiple intraplacental lacunae, suggestive of placenta accreta, were noted. For further evaluation of the placenta, pelvis MRI was performed and revealed findings suspicious of a placenta increta. An elective cesarean delivery and subsequent hysterectomy were planned for the patient at 38 weeks gestation. On the day of delivery, endovascular catheters for balloon occlusion were placed within the hypogastric arteries, prior to the cesarean section. In the operating room, immediately after the delivery of the baby, bilateral hypogastric arteries were occluded by inflation of the balloons in the catheters previously placed within. With the placenta retained within the uterus, a total hysterectomy was performed in the usual fashion. The occluding balloons were deflated after closure of the vaginal cuff with hemostasis. The patient had stable vital signs and normal laboratory findings during the recovery period; she was discharged six days after delivery without complications. The final pathology confirmed a placenta increta.
doi:10.3346/jkms.2010.25.4.651
PMCID: PMC2844598  PMID: 20358016
Placenta Increta; Hypogastric Artery; Balloon Occlusion
3.  Placenta increta as an important cause of uterine mass after first-trimester Curettage (case report) 
Placenta increta during the first trimester of pregnancy is very rare. This report describes two cases of placenta increta that caused prolonged vaginal bleeding after a first-trimester abortion. We were encountered two cases of placenta increta in October 2012 and May 2013. Case I: A 35-year-old patient with continues vaginal bleeding from 2 months after curettage due to missed abortion in the first trimester. The uterus was large, the human chorionic gonadotropin (BHCG) level was 112 mUI/mL and ultrasound showed an echogenic mass in the lower segment of the uterine cavity. She was a candidate for curettage but received hysterectomy because of massive vaginal bleeding. Pathology reported placenta increta. Case II: A 32-year-old patient in the 12th week of gestation with missed abortion. After 6 weeks from curettage, she returned with continues vaginal bleeding, BHCG = 55 mUI/mL and sonography showing mixed echo lesion in the uterine cavity like hydatiform mole. Total abdominal hysterectomy was performed. Pathology reported placenta increta. In patients with a history of recent first-trimester abortion presenting with prolonged vaginal bleeding, uterine mass and low-level BHCG, a diagnosis of abnormal placentaion should be kept in mind.
doi:10.4103/2277-9175.145745
PMCID: PMC4260288  PMID: 25538926
Placenta increta; uterine mass; vaginal bleeding
4.  Incidence and Risk Factors for Placenta Accreta/Increta/Percreta in the UK: A National Case-Control Study 
PLoS ONE  2012;7(12):e52893.
Background
Placenta accreta/increta/percreta is associated with major pregnancy complications and is thought to be becoming more common. The aims of this study were to estimate the incidence of placenta accreta/increta/percreta in the UK and to investigate and quantify the associated risk factors.
Methods
A national case-control study using the UK Obstetric Surveillance System was undertaken, including 134 women diagnosed with placenta accreta/increta/percreta between May 2010 and April 2011 and 256 control women.
Results
The estimated incidence of placenta accreta/increta/percreta was 1.7 per 10,000 maternities overall; 577 per 10,000 in women with both a previous caesarean delivery and placenta praevia. Women who had a previous caesarean delivery (adjusted odds ratio (aOR) 14.41, 95%CI 5.63–36.85), other previous uterine surgery (aOR 3.40, 95%CI 1.30–8.91), an IVF pregnancy (aOR 32.13, 95%CI 2.03–509.23) and placenta praevia diagnosed antepartum (aOR 65.02, 95%CI 16.58–254.96) had raised odds of having placenta accreta/increta/percreta. There was also a raised odds of placenta accreta/increta/percreta associated with older maternal age in women without a previous caesarean delivery (aOR 1.30, 95%CI 1.13–1.50 for every one year increase in age).
Conclusions
Women with both a prior caesarean delivery and placenta praevia have a high incidence of placenta accreta/increta/percreta. There is a need to maintain a high index of suspicion of abnormal placental invasion in such women and preparations for delivery should be made accordingly.
doi:10.1371/journal.pone.0052893
PMCID: PMC3531337  PMID: 23300807
5.  A Case of Placenta Increta Presenting as Delayed Postabortal Intraperitoneal Bleeding in the First Trimester 
Journal of Korean Medical Science  2007;22(5):932-935.
Placenta increta is an uncommon and life-threatening complication of pregnancy characterized by complete or partial absence of the decidua basalis. Placenta increta usually presents with vaginal bleeding during difficult placental removal in the third-trimester. Although placenta increta may complicate first and early second-trimester pregnancy loss, the diagnosis can be very difficult during early pregnancy and thus the lesion is difficult to identify. We encountered with a woman who was diagnosed with placenta increta after receiving emergency hysterectomy due to intraperitoneal bleeding 2 months after an uncomplicated dilatation and curettage in the first trimester. Therefore, we report this case with a brief review of the literature.
doi:10.3346/jkms.2007.22.5.932
PMCID: PMC2693868  PMID: 17982250
Placenta Increta; First Trimester; Intraperitoneal Bleeding
6.  The METEX study: Methotrexate versus expectant management in women with ectopic pregnancy: A randomised controlled trial 
BMC Women's Health  2008;8:10.
Background
Patients with ectopic pregnancy (EP) and low serum hCG concentrations and women with a pregnancy of unknown location (PUL) and plateauing serum hCG levels are commonly treated with systemic methotrexate (MTX). However, there is no evidence that treatment in these particular subgroups of women is necessary as many of these early EPs may resolve spontaneously. The aim of this study is whether expectant management in women with EP or PUL and with low but plateauing serum hCG concentrations is an alternative to MTX treatment in terms of treatment success, future pregnancy, health related quality of life and costs.
Methods/Design
A multicentre randomised controlled trial in The Netherlands. Hemodynamically stable patients with an EP visible on transvaginal ultrasound and a plateauing serum hCG concentration < 1,500 IU/L or with a persisting PUL with plateauing serum hCG concentrations < 2,000 IU/L are eligible for the trial. Patients with a viable EP, signs of tubal rupture/abdominal bleeding, or a contra-indication for MTX will not be included. Expectant management is compared with systemic MTX in a single dose intramuscular regimen (1 mg/kg) in an outpatient setting. Serum hCG levels are monitored weekly; in case of inadequately declining, systemic MTX is installed or continued. In case of hemodynamic instability and/or signs of tubal rupture, surgery is performed. The primary outcome measure is an uneventful decline of serum hCG to an undetectable level by the initial intervention. Secondary outcomes are (re)interventions (additional systemic MTX injections and/or surgery), treatment complications, health related quality of life, financial costs, and future fertility. Analysis is performed according to the intention to treat principle. Quality of life is assessed by questionnaires before and at three time points after randomisation. Costs are expressed as direct costs with data on costs and used resources in the participating centres. Fertility is assessed by questionnaires after 6, 12, 18 and 24 months. Patients' preferences will be assessed using a discrete choice experiment.
Discussion
This trial will provide guidance on the present management dilemmas in women with EPs and PULs with low and plateauing serum hCG concentrations.
Trial registration
Current Controlled Trials ISRCTN 48210491
doi:10.1186/1472-6874-8-10
PMCID: PMC2453103  PMID: 18565217
7.  A Case of Placenta Increta Mimicking Submucous Leiomyoma 
In recent years with the increase in cesarean section rates, the frequency of placenta accreta cases rises. It causes 33–50% of all emergency peripartum hysterectomies. We present a 42-year-old case who was caught with early postpartum hemorrhage due to retained placental products. The ultrasonography showed a 65 × 84 mm mass in the uterine cavity after the delivery. Due to presence of early postpartum hemorrhage which needs transfusion, an intervention decision was made. The patient underwent curettage but the mass could not be removed so that placental retention was ruled out. Submucous leiomyoma was made as first-prediagnosis. Hysterectomy operation was performed as a curative treatment. Placenta increta diagnosis was made as a final diagnosis with pathological examination. As a result, placental attachment disorders may be overlooked if it is not a placenta previa case.
doi:10.1155/2014/429406
PMCID: PMC4273549  PMID: 25544918
8.  Laparoscopic Management or Laparoscopy Combined with Transvaginal Management of Type II Cesarean Scar Pregnancy 
Laparoscopy combined with transvaginal management appeared to result in less bleeding, shorter operative times, and a lower rate of complication in patients with uterine wound rupture and dense adhesions.
Objective:
To evaluate the clinical effectiveness of laparoscopic management of cesarean scar pregnancy (CSP) by deep implantation.
Background:
A pregnancy implanting within the scar from a previous cesarean delivery is a rare condition of ectopic pregnancy. There are two different types of CSPs. Type I is caused by implantation of the amniotic sac on the scar with progression toward either the cervicoisthmic space or the uterine cavity. Type II (CSP-II) is caused by deep implantation into a previous CS defect with infiltrating growth into the uterine myometrium and bulging from the uterine serosal surface, which may result in uterine rupture and severe bleeding during the first trimester of pregnancy. Thus, timely management with an early and accurate diagnosis of CSP-II is important. However, laparoscopic management in CSP-II has not yet been evaluated.
Methods:
Eleven patients with CSP-II underwent conservative laparoscopic surgery or laparoscopy combined with transvaginal bilateral uterine artery ligation and resection of the scar with gestational tissue and wound repair to preserve the uterus from March 2008 to November 2011. Patients with CSP-II were diagnosed using color Doppler sonography, and the diagnosis was confirmed by laparoscopy. The operation time, the blood loss during surgery, the levels of β-human chorionic gonadotropin (β-hCG) before surgery, the time taken for serum β-hCG levels to return to <100 mIU/mL postoperatively, and the time for the uterine body to revert to its original state were retrospectively analyzed.
Results:
All 11 operations were successfully performed using laparoscopy with preservation of the uterus. One patient underwent a dilation and curettage after laparoscopic bilateral uterine artery ligation. Eight patients were treated solely by laparoscopic bilateral uterine artery ligation and resection of the scar with gestational tissue and wound repair. The remaining two patients underwent laparoscopic bilateral uterine artery ligation and transvaginal resection of the CS with gestational tissue and wound repair because of dense adhesions and heavy bleeding. The average operation time was 85.5 (±17.5) minutes, and the blood loss was 250.0 (±221.4) mL. The blood serum level of β-hCG returned to <100 mIU/mL in 16.4 (±5.3) days postoperatively. Among the 10 patients who underwent resection of CS and wound repair, the time for the uterus to revert to its original state (judged by ultrasonography) was 10.8 (±3.0) days postoperatively.
Conclusions:
Laparoscopy can remove ectopic gestational tissue and allow subsequent wound repair, as well as provide diagnostic confirmation. Being a minimally invasive procedure, laparoscopic or laparoscopy combined with transvaginal bilateral uterine artery ligation and resection of the scar with gestational tissue and wound repair can become an effective alternative for the treatment of CSP-II.
doi:10.4293/108680813X13654754535197
PMCID: PMC3771793  PMID: 23925020
Laparoscopy. Cesarean scar pregnancy; Ectopic pregnancy; Uterine artery ligation
9.  Placenta increta causing hemoperitoneum in the 26th week of pregnancy: a case report 
Introduction
Placenta increta is a serious complication of pregnancy. We describe a case leading to uterine rupture associated with massive intra-abdominal hemorrhage.
Case presentation
A 34-year-old Caucasian Albanian woman, gravida 2, para 1, was admitted to the emergency department of our hospital for acute abdominal pain associated with profound secondary anemia. An anatomopathological diagnosis of placenta increta destruens was made. An urgent hysterectomy was performed after resuscitation procedures, applied due to the severe anemia and the abdominal drama accompanying the case. Intra-operatively, a uterus-saving procedure was found to be impossible, and hysterectomy remained the only surgical option. The uterine structures were sent for further microscopic evaluation. On histological examination, deep trophoblastic infiltration of the uterine wall was observed, justifying the surgeon's decision. Our patient received blood transfusions and antibiotics. Her sutures were removed on the eighth postoperative day and she was discharged the following day in a stable condition.
Conclusion
This case, describing a patient with uterine rupture and massive hemorrhage, illustrates a serious and potentially fatal complication of placenta previa. In such cases, surgery is essential, and hysterectomy may be the only viable option.
doi:10.1186/1752-1947-4-412
PMCID: PMC3017074  PMID: 21176187
10.  Magnetic resonance imaging of placenta accreta 
Placenta accreta (PA) is a severe pregnancy complication which occurs when the chorionic villi (CV) invade the myometrium abnormally. Optimal management requires accurate prenatal diagnosis. Ultrasonography (USG) and magnetic resonance imaging (MRI) are the modalities for prenatal diagnosis of PA, although USG remains the primary investigation of choice. MRI is a complementary technique and reserved for further characterization when USG is inconclusive or incomplete. Breath-hold T2-weighted half-Fourier rapid acquisition with relaxation enhancement (RARE) and balanced steady-state free precession imaging in the three orthogonal planes is the key MRI technique. Markedly heterogeneous placenta, thick intraplacental dark bands on half-Fourier acquisition single-shot turbo spin-echo (HASTE), and disorganized abnormal intraplacental vascularity are the cardinal MRI features of PA. MRI is less reliable in differentiating between different degrees of placental invasion, especially between accreta vera and increta.
doi:10.4103/0971-3026.125592
PMCID: PMC3932583  PMID: 24604945
Abnormal placental vascularity; dark intraplacental bands; magnetic resonance imaging; placenta accreta
11.  In Vivo Response to Methotrexate Forecasts Outcome of Acute Lymphoblastic Leukemia and Has a Distinct Gene Expression Profile 
PLoS Medicine  2008;5(4):e83.
Background
Childhood acute lymphoblastic leukemia (ALL) is the most common cancer in children, and can now be cured in approximately 80% of patients. Nevertheless, drug resistance is the major cause of treatment failure in children with ALL. The drug methotrexate (MTX), which is widely used to treat many human cancers, is used in essentially all treatment protocols worldwide for newly diagnosed ALL. Although MTX has been extensively studied for many years, relatively little is known about mechanisms of de novo resistance in primary cancer cells, including leukemia cells. This lack of knowledge is due in part to the fact that existing in vitro methods are not sufficiently reliable to permit assessment of MTX resistance in primary ALL cells. Therefore, we measured the in vivo antileukemic effects of MTX and identified genes whose expression differed significantly in patients with a good versus poor response to MTX.
Methods and Findings
We utilized measures of decreased circulating leukemia cells of 293 newly diagnosed children after initial “up-front” in vivo MTX treatment (1 g/m2) to elucidate interpatient differences in the antileukemic effects of MTX. To identify genomic determinants of these effects, we performed a genome-wide assessment of gene expression in primary ALL cells from 161 of these newly diagnosed children (1–18 y). We identified 48 genes and two cDNA clones whose expression was significantly related to the reduction of circulating leukemia cells after initial in vivo treatment with MTX. This finding was validated in an independent cohort of children with ALL. Furthermore, this measure of initial MTX in vivo response and the associated gene expression pattern were predictive of long-term disease-free survival (p < 0.001, p = 0.02).
Conclusions
Together, these data provide new insights into the genomic basis of MTX resistance and interpatient differences in MTX response, pointing to new strategies to overcome MTX resistance in childhood ALL.
Trial registrations: Total XV, Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia, http://www.ClinicalTrials.gov (NCT00137111); Total XIIIBH, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Intermediate or High Risk of Treatment Failure (NCI-T93-0101D); Total XIIIBL, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Lower Risk of Treatment Failure (NCI-T93-0103D).
William Evans and colleagues investigate the genomic determinants of methotrexate resistance and interpatient differences in methotrexate response in patients newly diagnosed with childhood acute lymphoblastic leukemia.
Editors' Summary
Background.
Every year about 10,000 children develop cancer in the US. Acute lymphoblastic leukemia (ALL), a rapidly progressing blood cancer, accounts for a quarter of these childhood cancers. Normally, cells in the bone marrow (the spongy material inside bones) develop into lymphocytes (white blood cells that fight infections), red blood cells (which carry oxygen round the body), platelets (which prevent excessive bleeding), and granulocytes (another type of white blood cell). However, in ALL, genetic changes in immature lymphocytes (lymphoblasts) mean that these cells divide uncontrollably and fail to mature. Eventually, the bone marrow fills up with these abnormal cells and can no longer make healthy blood cells. As a result, children with ALL cannot fight infections. They also bruise and bleed easily and, because they do not have enough red blood cells, they often complain of tiredness and weakness. With modern chemotherapy protocols (combinations of drugs that kill the fast-dividing cancer cells but leave the normal, nondividing cells in the body largely unscathed), more than 80% of children with ALL live for at least 5 years.
Why Was This Study Done?
Although this survival rate is good, some patients still die because their cancer cells are resistant to one or more chemotherapy drugs. For some drugs, the genetic characteristics of the ALL cells that make them resistant are known. Unfortunately, little is known about why some ALL cells are resistant to methotrexate, a component of most treatment protocols for newly diagnosed ALL. Methotrexate kills dividing cells by interfering with DNA synthesis and repair. Cancer cells can be resistant to methotrexate for many reasons—they may have acquired genetic changes that stop the drug from entering them, for example. These resistance mechanisms need to be understood better before new strategies can be developed for the treatment of methotrexate-resistant ALL. In this study, the researchers have determined the response of newly diagnosed patients to methotrexate and have investigated the gene expression patterns in ALL cells that correlate with good and bad responses to methotrexate.
What Did the Researchers Do and Find?
The researchers measured the reduction in circulating leukemia cells that followed the first treatment with methotrexate of nearly 300 patients with newly diagnosed ALL. They also used “microarray” analysis to investigate the gene expression patterns in lymphoblast samples taken from the bone marrow of 161 patients before treatment. They found that the expression of 50 genes was significantly related to the reduction in circulating leukemia cells after methotrexate treatment (a result confirmed in an independent group of patients). Of these genes, the expression of 29 was higher in patients who responded poorly to methotrexate than in patients who responded well. A “global analysis test,” which examined the gene expression profile of different cellular pathways in relation to the methotrexate response, found a significant association between the nucleotide biosynthesis pathway (which is needed for DNA synthesis and cellular proliferation) and the methotrexate response. Finally, patients with the best methotrexate response and the 50-gene expression profile indicative of a good response were more likely to be alive after 5 years than patients with the worst methotrexate response and the poor-response gene expression profile.
What Do These Findings Mean?
These findings provide important new insights into the genetic basis of methotrexate resistance in newly diagnosed childhood ALL and begin to explain why some patients fail to respond to this drug. They also show that the reduction in circulating leukemic cells shortly after the first methotrexate dose and a specific gene expression profile both predict the long-term survival of patients. These findings also suggest new ways to modulate sensitivity to methotrexate. Down-regulation of the expression of the genes that are expressed more highly in poor responders than in good responders might improve patient responses to methotrexate. Alternatively, it might be possible to find ways to increase the expression of the genes that are underexpressed in methotrexate poor responders and so improve the outlook for at least some of the children with ALL who fail to respond to current chemotherapy protocols.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050083.
• The US National Cancer Institute provides a fact sheet for patients and caregivers about ALL in children and information about its treatment(in English and Spanish)
• The UK charity Cancerbackup provides information for patients and caregivers on ALL in children and on methotrexate
• The US Leukemia and Lymphoma Society also provides information for patients and caregivers about ALL
• The Children's Cancer and Leukaemia Group (a UK charity) provides information for children with cancer and their families
• MedlinePlus provides additional information about methotrexate (in English and Spanish)
doi:10.1371/journal.pmed.0050083
PMCID: PMC2292747  PMID: 18416598
12.  Relationship of serum methotrexate concentration in high-dose methotrexate chemotherapy to prognosis and tolerability: A prospective cohort study in chinese adults with osteosarcoma 
Background: Cancer that originates in the bone, termed primary bone cancer, is rare. Osteosarcoma (OS) occurs primarily in growing bone tissue and is more prevalent in children and adolescents. OS in adults is rare, with 3 to 5 cases per million population per year worldwide. There are limited data on treatment-related prognosis and adverse reactions in adults reported in the literature.
Objectives: The aims of this study were to investigate factors that influence serum methotrexate (MTX) concentrations used in chemotherapy in Chinese adult patients with OS, and to determine the correlations (based on age, sex, and dosage), if any, between MTX and prognosis, in terms of disease-free survival (DFS) and overall survival (OAS), and tolerability.
Methods: Adult patients aged ≥30 years with OS received ≥3 courses (2 courses before surgery and 3–4 courses postsurgery) of high-dose MTX (6 or 8 g/m2) combined chemotherapy. The regimen consisted of day 1: MTX + folinic acid (herein referred to as citrovorum factor rescue); day 8: cisplatin; days 21 to 25: ifosfamide + mesna; and day 21: doxorubicin. Serum MTX concentrations were assessed immediately after the end of infusion (baseline) and at 24 and 48 hours using high-performance liquid chromatography. Changes in serum MTX concentrations, factors that influence serum MTX concentrations, and the relationship between serum MTX concentrations and prognosis and tolerability (determined by adverse reactions) were analyzed. Patients received a second course of treatment after a 3-week period.
Results: Ninety patients (58 men, 32 women; age range, 30–67 years) with OS were included in the study. A total of 532 courses of combined chemotherapy were administered. The serum MTX concentrations ranged widely at baseline (244.31–929.68 mol/L, Cmin and Cmax, respectively) and at 24 hours (0.73–28.24 mol/L, respectively), suggesting that the serum MTX concentrations varied significantly between different individuals and within the same individual at different time points. The serum MTX concentrations in ~23% of cases (122/532) determined at 24 and/or 48 hours were numerically higher than the safety values (according to Nirenberg's reference: irreversible damage if MTX concentration was >10 umol/L and > 1 umol/L at 24 and 48 hours, respectively). No correlation was found between high serum MTX concentration at baseline and high serum MTX concentration at 24 hours (r = 0.401). The prevalences of the 3 most common adverse reactions in these patients were depressed white blood cell count (44.03%), dental ulcer (23.0%), and rash (18.0%). However, in the remaining 410 courses in which serum MTX concentrations were lower than the safety values, these prevalences were 14.6%, 3–9%, and 2.4%, respectively. Neither age nor sex was significantly associated with MTX Cmax, but dosage was (P < 0.05). Patients with a serum MTX Cmax concentration >500 μmol/L at baseline had a significantly longer DFS rate than those with ≤500 umol/L (P = 0.040). There were no significant between-group differences in the OAS rates.
conclusions: In these Chinese patients with OS, serum MTX concentrations measured at different time points were varied. The findings suggest that adverse reactions occurred in patients whose serum MTX concentrations at 24 and/or 48 hours were higher than the safety values. The dosage appeared to have influenced MTX Cmax, while sex and age did not, and the Cmax was significantly related to DFS but not OAS.
doi:10.1016/j.curtheres.2009.04.005
PMCID: PMC3967322  PMID: 24683226
osteosarcoma; MTX; serum concentration; prognosis; side effect
13.  Lack of nephrotoxicity of gadopentetate dimeglumine-enhanced non-vascular MRI and MRI without contrast agent in patients at high-risk for acute kidney injury 
Background
Gadolinium chelates (GCs) have been traditionally considered as non-nephrotoxic magnetic resonance imaging (MRI) contrast materials. However, it has been suggested in some recent articles that GCs may have a nephrotoxic potential, but most of these reports are retrospective. However, the evaluated contrast agents, their doses, and the tests used to determine the kidney function were not consistent across studies. We aimed to investigate the effect of magnetic field and an MRI contrast agent, gadopentetate dimeglumine (GD), on renal functions in patients at high risk for acute kidney injury (AKI).
Material/Methods
We designed a prospective case-control study with 2 age- and sex-matched groups of patients at high-risk for AKI (n=72 for each group). Patients in Group 1 received a fixed dose of (0.2 mmol/kg) GD-enhanced non-vascular MRI and patients in Group 2 received MRI without GD. Before the MRI and at 6, 24, 72, and 168 hours after the MRI, biochemical tests, estimated glomerular filtration rate (eGFR), albumin/creatinine ratio in spot urine, and early AKI biomarkers (cystatin C, N-Acetyl-Glucosaminidase [NAG], Neutrophil gelatinase-associated lipocalin [NGAL]) were measured.
Results
Serum creatinine, albumin/creatinine ratio, and eGFR were not different between Group 1 and 2 (p>0.05). There were no significant changes in renal function tests and AKI biomarkers (Δserum creatinine, Δalbumin/creatinine ratio, ΔGFR, Δcystatin C, ΔNAG, and ΔNGAL) for either groups 6, 24, 72, and 168 hours after the procedures (p>0.05).
Conclusions
MRI without contrast agent and non-vascular contrast-enhanced (GD, 0.2 mmol/kg) MRI are not nephrotoxic procedures for patients at high risk for AKI.
doi:10.12659/MSM.889579
PMCID: PMC3829701  PMID: 24193150
MRI; gadopentetate dimeglumine; contrast nephropathy; acute kidney injury; NAG; NGAL
14.  Human umbilical cord mesenchymal stem cells as treatment of adjuvant rheumatoid arthritis in a rat model 
World Journal of Stem Cells  2012;4(10):101-109.
AIM: To investigate the effect of human umbilical cord stem cells, both mesenchymal and hematopoietic (CD34+), in the treatment of arthritis.
METHODS: Mesenchymal stem cells (MSCs) and hematopoietic (CD34+) stem cells (HSC) were isolated from human umbilical cord blood obtained from the umbilical cord of healthy pregnant donors undergoing full-term normal vaginal delivery. MSC, HSC, methotrexate (MTX) and sterile saline were injected intra-articularly into the rat hindpaw with complete freunds adjuvant (CFA) induced arthritis after the onset of disease (day 34), when arthritis had become well established (arthritis score ≥ 2). Arthritic indices were evaluated and the levels of interleukin (IL)-1, tumor necrosis factor (TNF)-α and interferon (IFN)-γ and anti-inflammatory cytokine IL-10 in serum were determined using enzyme-linked immunosorbent assay. Animals of all groups were sacrificed 34 d after beginning treatment, except positive control (PC) which was sacrificed at 10, 21 and 34 d for microscopic observation of disease progression. We used hematoxylin, eosin and Masson’s trichrome stains for histopathological examination of cartilage and synovium.
RESULTS: The mean arthritis scores were similar in all groups at 12 and 34 d post immunization, with no statistical significant difference. Upon the injection of stem cells (hematopoietic and mesenchymal), the overall arthritis signs were significantly improved around 21 d after receiving the injection and totally disappeared at day 34 post treatment in MSC group. Mean hindpaw diameter (mm) in the MSC rats was about half that of the PC and MTX groups (P = 0.007 and P = 0.021, respectively) and 0.6 mm less than the HSC group (P = 0.047), as indicated by paw swelling. Associated with these findings, serum levels of TNF-α, IFN-γ and IL-1 decreased significantly in HSC and MSC groups compared to PC and MTX groups (P < 0.05), while the expression of IL-10 was increased. Histopathological examination with H and E stain revealed that the MTX treated group showed significant reduction of leucocytic infiltrate and hypertrophy of the synovial tissue with moderate obliteration of the joint cavity. Stem cells treated groups (both hematopoietic CD34+ and mesenchymal), showed significant reduction in leucocytic infiltrate and hypertrophy of the synovial tissue with mild obliteration of the joint cavity. With Masson’s trichrome, stain sections from the PC group showed evidence of vascular edema of almost all vessels within the synovium in nearly all arthritic rats. Vacuoles were also visible in the outer vessel wall. The vessel became hemorrhagic and finally necrotic. In addition, there was extensive fibrosis completely obliterating the joint cavity. The mean color area percentage of collagen in this group was 0.324 ± 0.096, which was significantly increased when compared to the negative control group. The mean color area percentage of collagen in hematopoietic CD34+ and mesenchymal groups was 0.176 ± 0.0137 and 0.174 ± 0.0197 respectively, which showed a marked decrement compared to the PC group, denoting a mild increase in synovial tissue collagen fibers.
CONCLUSION: MSC enhance the efficacy of CFA-induced arthritis treatment, most likely through the modulation of the expression of cytokines and amelioration of pathological changes in joints.
doi:10.4252/wjsc.v4.i10.101
PMCID: PMC3506964  PMID: 23189211
Complete freunds adjuvant-induced arthritis; Human umbilical mesenchymal stem cell; Hematopoietic stem cell; CD34+
15.  Multicenter, Double-Blind, Randomized, Intra-individual Crossover Comparison of Gadobenate Dimeglumine and Gadopentetate Dimeglumine in MRI of Brain Tumors at 3 Tesla 
Purpose
To prospectively compare 0.1 mmol/kg doses of gadobenate dimeglumine and gadopentetate dimeglumine for contrast-enhanced MRI of brain lesions at 3 Tesla (T).
Materials and Methods
Forty-six randomized patients underwent a first examination with gadobenate dimeglumine (n = 23) or gadopentetate dimeglumine (n = 23) and then, after 2–7 days, a second examination with the other agent. Contrast administration (volume, rate), sequence parameters (T1wSE; T1wGRE), and interval between injection and image acquisition were identical for examinations in each patient. Three blinded neuroradiologists evaluated images qualitatively (lesion delineation, lesion enhancement, global preference) and quantitatively (lesion-to-brain ratio [LBR], contrast-to-noise ratio [CNR],%lesion enhancement). Differences were assessed using Wilcoxon’s signed-rank test. Reader agreement was determined using kappa (κ) statistics.
Results
There were no demographic differences between groups. The three readers preferred gadobenate dimeglumine globally in 22 (53.7%), 21 (51.2%), and 27 (65.9%) patients, respectively, compared with 0, 1, and 0 patients for gadopentetate dimeglumine. Similar significant (P < 0.001) preference was expressed for lesion border delineation and enhancement. Reader agreement was consistently good (κ = 0.48–0.64). Significantly (P < 0.05) higher LBR (+43.5–61.2%), CNR (+51.3–147.6%), and % lesion enhancement (+45.9–49.5%) was noted with gadobenate dimeglumine.
Conclusion
Brain lesion depiction at 3T is significantly improved with 0.1 mmol/kg gadobenate dimeglumine.
doi:10.1002/jmri.21695
PMCID: PMC2730487  PMID: 19306364
brain tumor imaging; gadobenate dimeglumine; comparative studies; high field MRI
16.  Monitoring Therapy with MEK Inhibitor U0126 in a Novel Wilms Tumor Model in Wt1 Knockout Igf2 Transgenic Mice Using 18F-FDG PET with Dual-Contrast Enhanced CT and MRI: Early Metabolic Response Without Inhibition of Tumor Growth 
Molecular Imaging and Biology  2012;15(2):175-185.
Purpose
The understanding of the role of genetic alterations in Wilms tumor development could be greatly advanced using a genetically engineered mouse models that can replicate the development and progression of this disease in human patients and can be monitored using non-invasive structural and molecular imaging optimized for renal tumors.
Procedures
Repetitive dual-contrast computed tomography (CT; intravenous and intraperitoneal contrast), T2-weighted magnetic resonance imaging (MRI), and delayed 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) positron emission tomography (PET) were utilized for characterization of Igf2 biallelic expression/Wt1 knockout mouse model of Wilms tumor. For CT imaging, Ioversol 678 mg/ml in 200 μl was administered i.p. followed by 100 μl injected intravenously at 20 and 15 min prior to imaging, respectively. Static PET imaging studies were acquired at 1, 2, and 3 h after i.v. administration of 18F-FDG (400 μCi). Coronal and sagittal T1-weighted images (TE/TR 8.5/620 ms) were acquired before and immediately after i.v. injection of 0.4 ml/kg gadopentetate dimeglumine followed by T2-weighted images (TE/TR 60/300 ms). Tumor tissue samples were characterized by histopathology and immunohistochemistry for Glut1, FASN, Ki67, and CD34. In addition, six Wt1-Igf2 mice were treated with a mitogen-activated protein kinase (MEK) inhibitor U0126 (50 μmol/kg i.p.) every 4 days for 6 weeks. 18F-FDG PET/CT imaging was repeated at different days after initiation of therapy with U0126. The percent change of initial tumor volume and SUV was compared to non-treated historic control animals.
Results
Overall, the best tumor-to-adjacent kidney contrast as well as soft tissue contrast for other abdominal organs was achieved using T2-weighted MRI. Delayed 18F-FDG PET (3-h post 18F-FDG administration) and dual-contrast CT (intravenous and intraperitoneal contrast) provided a more accurate anatomic and metabolic characterization of Wilms tumors in Wt1-Igf2 mice during early development and progression of renal tumors. Over the 8-month period, 46 Wt1-Igf2 mice and 8 littermate control mice were studied. Renal tumors were identified in 54.3 % of Wt1-Igf2 mice between post-natal 50–100 days. In 35.6 % of Wt1-Igf2 mice, tumors were localized in the right kidney; in 24 %, in the left kidney, while 40.4 % of Wt1-Igf2 mice had bilateral kidney tumors. Metastatic lesions were identified in 15.4 % of Wt1-Igf2 mice. Increased levels of Glut1 and IGF1R expression, high Ki67 labeling index, and a dense network of CD34+ microvessels in renal tumors was consistent with increased 18F-FDG accumulation. Treatment with a MEK 1/2 inhibitor U0126 did not cause the inhibition of tumor growth as compared to untreated animals. However, after the first three to four doses (~2 weeks of treatment), a decrease in 18F-FDG SUV was observed, as compared to pre-treatment levels (p < 0.05, paired Student t test), which constitutes a metabolic response. Six weeks later, despite continuing therapy, the 18F-FDG SUV increased again to previous levels.
Conclusions
The optimized dual contrast PET/CT imaging with early post i.v. and i.p. contrast CT and 3 h delayed PET imaging after 18F-FDG administration provides a sensitive and reliable method for detecting early tumor lesions in this endogenous mouse model of Wilms tumor and for monitoring their growth in response to targeted therapies. Therapy with MEK inhibitor U0126 produces only a transient inhibition of tumor glycolytic activity but does not inhibit tumor growth, which is due to continuing IGF2-induced signaling from IGF1R through the PI3K-AKT-mTOR pathway.
doi:10.1007/s11307-012-0588-5
PMCID: PMC3591528  PMID: 22875335
Transgenic mice; Wilms tumor; 18F-FDG; PET/CT; CT; MRI
17.  Early prediction of treatment resistance in low-risk gestational trophoblastic neoplasia using population kinetic modelling of hCG measurements 
British Journal of Cancer  2013;108(9):1810-1816.
Background:
In low-risk gestational trophoblastic neoplasia (GTN) patients, a predictive marker for early identification of methotrexate (MTX) resistance would be useful. We previously demonstrated that kinetic modelling of human chorionic gonadotrophin (hCG) measurements could provide such a marker. Here we validate this approach in a large independent patient cohort.
Methods:
Serum hCG measurements of 800 low-risk GTN patients treated with MTX were analysed. The cohort was divided into Model and Test data sets. hCG kinetics were described from initial treatment day to day 50 using: ‘(hCG(time))=hCG0*exp(–k*time)+hCGres', where hCGres is the modelled residual production, hCG0 is the baseline hCG level, and k is the rate constant. HCGres-predictive value was investigated against previously reported predictors of MTX resistance.
Results:
Declining hCG measurements were well fitted by the model. The best discriminator of MTX resistance in the Model data set was hCGres, categorised by an optimal cut-off value of >20.44 IU l−1: receiver-operating characteristic (ROC) area under the curve (AUC)=0.87; Se=0.91; Sp=0.83. The predictive value of hCGres was reproducible using the Test data set: ROC AUC=0.87; Se=0.88; Sp=0.86. Multivariate analyses revealed hCGres as a better predictor of MTX resistance (HR=1.01, P<0.0001) and MTX failure-free survival (HR=13.25, P<0.0001) than other reported predictive factors.
Conclusion:
hCGres, a modelled kinetic parameter calculated after fully dosed three MTX cycles, has a reproducible value for identifying patients with MTX resistance.
doi:10.1038/bjc.2013.123
PMCID: PMC3664307  PMID: 23591194
gestational trophoblastic neoplasia; methotrexate; drug resistance; neoplasm; prognosis; decision support techniques; chorionic gonadotropin
18.  Electroporation-Mediated Transcatheter Arterial Chemoembolization (E-TACE) in the Rabbit VX2 Liver Tumor Model 
Investigative Radiology  2012;47(2):116-120.
Rationale and Objectives
Electropermeabilization involves the application of electrical pulses to increase cell membrane permeability. The purpose of our study was to demonstrate the potential to use electroporation-mediated transcatheter arterial chemoembolization (E-TACE) approaches to increase liver tumor drug uptake while using magnetic resonance imaging (MRI) for intra-procedural optimization of these procedures.
Methods
14 VX2 tumors were grown in the left hepatic lobes of 8 rabbits. Two tumors were grown in each of 6 rabbits (one tumor serving as E-TACE treated tumor and other as non-electroporated control) and solitary larger tumors were grown in 2 rabbits (half of the tumor treated with E-TACE, remaining half serving as control). Each rabbit was selectively catheterized under digital subtraction angiography (DSA) guidance. Baseline MRI was performed to generate tumor contrast enhancement curves following catheter-directed infusion of gadopentetate dimeglumine to estimate the proper time delay between subsequent bolus infusion of cisplatin and application of electrical pulses (electrodes were used to deliver 8 100μs 1300V pulses at the selected delay interval post-infusion). 3 hours after E-TACE, rabbits were euthanized and tumors sectioned for inductively coupled plasma mass spectroscopy (ICP-MS) measurements of platinum concentration (serving as reference standard of cisplatin uptake levels).
Results
ICP-MS results demonstrated significantly increased cisplatin uptake in E-TACE treated tumor tissues, increases of 6.0 ± 3.3 fold compared to transcatheter infusion alone (p=0.017).
Conclusions
Our findings suggest that our E-TACE approach may significantly increase liver tumor drug uptake following targeted transcatheter infusion. MRI measurements permitted intra-procedural guidance during these catheter-directed E-TACE procedures.
doi:10.1097/RLI.0b013e31822e57cc
PMCID: PMC3257408  PMID: 21934518
Liver Cancer; Transcatheter Arterial Chemoembolization (TACE); Electroporaiton; MRI; Inductively Coupled Plasma Mass Spectroscopy (ICP-MS)
19.  Injection of MTX for the treatment of cesarean scar pregnancy: comparison between different methods 
The aim of this study was to analyze clinical treatment and outcome of injection MTX for Cesarean scar pregnancy (CSP). We use retrospective study to compare the time in CSP of blood chorionic gonadotropin (β-HCG) and progesterone drooped to the normal, blood flow resistance and hospitalization days. 34 patients diagnosed with CSP were reviewed in our department from 2000 to 2013, including clinical characteristics, early diagnosis, treatment methods and treatment outcome. All patients were divided into B ultrasound-guided gestational MTX inject group (Group one), local intramuscular treatment group (Group two) and uterine artery perfusion MTX group (Group three). All cases had responded well to treatment. Except three cases of local intramuscular serum β-HCG decreased slowly MTX 10 mg intramuscular again, the average serum β-HCG decline of 65% the 4th day after treatment. In intramuscular group, the average length of stay is 19 ± 2.1 days. Serum β-HCG, progesterone recovery time were 20 to 89 days, an average of 54.5 days. B ultrasound-guided group hospital stay were 15 ± 3.1 days, serum β-HCG, progesterone recovery time were 18 to 71 days, an average of 44.5 days. In Uterine artery embolization group, the average length of stay is 16 ± 2.4 days, serum β-HCG, progesterone recovery time were 20 to 70 days, an average of 45 days. Statistical data results using T-test and chi-square test analysis. Three groups of β-HCG, progesterone decreased to normal days the difference was statistically significant (P < 0.05), but uterine artery embolization group and ultrasound-guided group B showed no significant difference (P > 0.05). B ultrasound-guided gestational injection of MTX and uterine artery embolization perfusion MTX are the better ways to treat uterine scar pregnancy.
PMCID: PMC4132156  PMID: 25126192
Cesarean scar pregnancy; B ultrasound-guided; methotrexate; uterine artery embolization
20.  “Post partum hemorrhage: causes and management” 
BMC Research Notes  2013;6:236.
Background
Post partum hemorrhage is defined as blood loss of 500 ml or above. It is the most common cause of pre-mature mortality of women world wide. Our objective was to evaluate the most common etiology and method of management of Post partum Hemorrhage in a tertiary care hospital of Karachi.
Findings
It was a cross sectional study conducted at Liaquat National Hospital Karachi, during the period of July 2011 to May 2012. Review include mode of delivery, possible cause of postpartum hemorrhage, supportive, medical and surgical interventions. All the women admitted with post partum hemorrhage or develop PPH in hospital after delivery were included in our study. Bleeding disorder and use of anticoagulants were set as exclusion criteria. Diagnosis was made on the basis of blood loss assessment which was made via subjective and objective evaluation.
During the targeted months, out of total 1493 deliveries (26/1493 = 1.741%) 26 cases of post partum hemorrhage were reported with a mean age of 26.153 ± 7.37. No deaths were reported and all cases were referred and unbooked cases. All Patients were conscious, tachycardiac and hypotensive. Most of the women were suffering from hemorrhage during or after the birth of their 1st child. Primary post partum hemorrhage emerge as the most common type of post partum hemorrhage and uterine atony was detected as the most common cause of primary post partum hemorrhage. Retained products of conception was the most common cause of secondary post partum hemorrhage and hysterectomy was found to be the most frequent method of management of post partum hemorrhage.
Conclusion
This study highlights the existing variable practices for the management of postpartum hemorrhage. Hemorrhage associated morbidity and mortality can be prevented by critical judgment, early referral and resuscitation by attendants. Introduction of an evidence-based management model can potentially reduce the practice variability and improve the quality of care.
doi:10.1186/1756-0500-6-236
PMCID: PMC3688110  PMID: 23773785
Postpartum hemorrhage; Uterine atony; Hysterectomy
21.  The ectopic pregnancy, a diagnostic and therapeutic challenge 
Journal of Medicine and Life  2008;1(1):40-48.
The classic symptoms of ectopic pregnancy are secondary amenorrhoea, abdominal pain and vaginal haemorrhage, with a clinical picture of varying acuteness.
It is among the commonest causes of maternal mortality during the first three months of pregnancy
In the majority of cases (95%) the pregnancy is tubal, but other sites are possible (cervical, corneal, ovarian, peritoneal).
In the treatment of sterility or medically assisted reproduction, the risk of ectopic pregnancy should be borne in mind.
The individual risk factors may be cumulative, particularly with a previous history of extrauterine pregnancy or tubal surgery (including sterilisations), pelvic post–inflammatory status (adhesions proved by coelioscopy) or presence of an intrauterine device.
Diagnosis is based on serum beta–hCG concentration and transvaginal ultrasound
Laparoscopy is the treatment of choice for tubal pregnancies.
The decision to perform salpingotomy depends on the presence/status of a contra lateral tube.
In carefully selected cases local or intra–muscular administration of methotrexate allows conservative treatment, provided the patient does not present acute bleeding.
It is also indicated where trophoblastic tissue persists after surgery, notably salpingostomy, and in non–tubal ectopic pregnancies.
The latter are rare, however, and it is important to recognise them in view of the more serious complications.
PMCID: PMC3018959  PMID: 20108478
22.  Uterine Healing after Therapeutic Intrauterine Administration of TachoSil (Hemostatic Fleece) in Cesarean Section with Postpartum Hemorrhage Caused by Placenta Previa 
Journal of Pregnancy  2012;2012:635683.
Background. Application of hemostatic fleece (TachoSil) directly onto the bleeding surfaces of the lower uterine segment has been used to obtain hemostasis during cesarean section caused by placenta previa. Methods. Eleven of 15 patients treated with TachoSil for excessive postpartum haemorrhage due to placenta previa were enrolled. An evaluation of the cesarean section scar by transvaginal ultrasound, the uterine cavity and endometrium by hysteroscopy, and the endometrium by biopsy were made. The main outcome measures were intrauterine adhesions, recovery of endometrium at the site of TachoSil application, visible remnants of TachoSil, and scar healing. Results. Eight patients had small remnants of TachoSil in the uterine cavity together with signs of resorption. All had a normal endometrial mucosa, and none had adhesions in the uterine cavity. All cesarean section scars were healed without defects. Conclusion. TachoSil did not seem to impair healing of the endometrium or scar formation in the uterus after intrauterine application. Resorption of TachoSil seems to progress individually. Intrauterine treatment with TachoSil is a valuable supplement to the traditional treatment of post partum haemorrhage and may help retain reproductive capability. This is a small study, and it will require more studies to confirm the reproducibility.
doi:10.1155/2012/635683
PMCID: PMC3348634  PMID: 22619722
23.  Comparative efficacy and safety of local and systemic methotrexate injection in cesarean scar pregnancy 
Objective
To investigate the efficacy of methotrexate (MTX) injection in treatment of cesarean scar pregnancy (CSP).
Method
A randomized controlled study was performed in 104 CSP patients receiving either local or systemic MTX injection at the Peking Union Medical College Hospital from the year 2008 to 2013.
Results
Complete cure was defined as regression of ultrasonographic findings and normalization of serum β-hCG within 60 days. It was regarded as delayed cure if additional dilation and curettage (D&C) was needed. The overall cure rate (complete cure plus delayed cure) was 69.2% versus 67.3% for local injection versus systemic administration (P>0.05). The median time for serum β-hCG remission and uterine mass disappearance after systemic administration (42 [21–69] days and 40 [20–67] days) were significantly lower than those receiving local injection (56 [24–92] days and 53 [23–88] days), with P=0.029 and 0.046, respectively. The mean pretreatment serum β-hCG (human chorionic gonadotropin) level and lesion size in cured group (21,941±18,351 mIU/mL and 2.9±1.3 cm, respectively) were significantly lower than those in the failed group (37,047±30,864 mIU/mL and 3.6±1.3) with P=0.038 and 0.044, respectively.
Conclusion
MTX injection is effective in CSP treatment. Systemic administration shows similar overall cure rate compared to local injection, but requires shorter time for serum β-hCG remission and uterine mass disappearance.
doi:10.2147/TCRM.S76050
PMCID: PMC4315462
cesarean scar pregnancy; methotrexate injection; local; systemic
24.  Use of biotin targeted methotrexate–human serum albumin conjugated nanoparticles to enhance methotrexate antitumor efficacy 
Biotin molecules could be used as suitable targeting moieties in targeted drug delivery systems against tumors. To develop a biotin targeted drug delivery system, we employed human serum albumin (HSA) as a carrier. Methotrexate (MTX) molecules were conjugated to HSA. MTX-HSA nanoparticles (MTX-HSA NPs) were prepared from these conjugates by cross-linking the HSA molecules. Biotin molecules were then conjugated on the surface of MTX-HSA NPs. The anticancer efficacy of biotin targeted MTX-HSA NPs was evaluated in mice bearing 4T1 breast carcinoma. A single dose of biotin targeted MTX-HSA NPs showed stronger in vivo antitumor activity than non-targeted MTX-HSA NPs and free MTX. By 7 days after treatment, average tumor volume in the biotin targeted MTX-HSA NPs-treated group decreased to 17.6% of the initial tumor volume when the number of attached biotin molecules on MTX-HSA-NPs was the highest. Average tumor volume in non-targeted MTX-HSA NPs-treated mice grew rapidly and reached 250.7% of the initial tumor volume. Biotin targeted MTX-HSA NPs increased the survival of tumor-bearing mice to 47.5 ± 0.71 days and increased their life span up to 216.7%. Mice treated with biotin targeted MTX-HSA NPs showed slight body weight loss (8%) 21 days after treatment, whereas non-targeted MTX-HSA NPs treatment at the same dose caused a body weight loss of 27.05% ± 3.1%.
doi:10.2147/IJN.S23949
PMCID: PMC3173049  PMID: 21931482
biotin; targeted drug delivery; in vivo anticancer delivery; human serum albumin; methotrexate; conjugates
25.  Tumorigenic Factor CRIPTO-1 Is Immunolocalized in Extravillous Cytotrophoblast in Placenta Creta 
BioMed Research International  2014;2014:892856.
CRIPTO-(CR)1 is a protein associated with tumorigenesis and metastasis. Here we demonstrate that CR-1 expression in normal and creta placentas is associated with various degrees of uterine invasion. Cytokeratin (CK) and CR-1 protein expression was visualized by immunohistochemical staining of formalin-fixed, paraffin-embedded placental specimens (control placentas, n = 9; accreta, n = 6; increta, n = 10; percreta, n = 15). The pattern of extravillous trophoblast (EVT) cell morphology was distinctive in creta placentas: densely-compacted cell columns and large star-shaped cells with a typically migratory phenotype, not common among third trimester control placentas. Quantification revealed higher CR-1 immunoreactivities in accreta (P = 0.001), increta (P = 0.0002), and percreta placentas (P = 0.001) than in controls. In contrast to controls, there was a significant positive relationship between CR-1 and CK reactivity in all creta placentas (accreta, P = 0.02; increta, P = 0.0001, and percreta, P = 0.025). This study demonstrated CR-1 expression in the placental bed, its increased expression in creta placentas, and EVT cells as the main CR-1-producing cell type. Morphological examination revealed an immature and invasive trophoblast profile in creta placentas, suggesting impairment of the trophoblast differentiation pathway. These findings provide important new insights into the pathophysiology of abnormal creta placentation and its gestational consequences.
doi:10.1155/2014/892856
PMCID: PMC4140153  PMID: 25165718

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