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1.  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.
PMCID: PMC4260288  PMID: 25538926
Placenta increta; uterine mass; vaginal bleeding
2.  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.
PMCID: PMC3303403  PMID: 22470732
Manual removal of placenta; Placenta accreta & increta; MRI; Methotrexate
3.  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.
PMCID: PMC2844598  PMID: 20358016
Placenta Increta; Hypogastric Artery; Balloon Occlusion
4.  Incidence and Risk Factors for Placenta Accreta/Increta/Percreta in the UK: A National Case-Control Study 
PLoS ONE  2012;7(12):e52893.
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.
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.
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).
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.
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.
PMCID: PMC2693868  PMID: 17982250
Placenta Increta; First Trimester; Intraperitoneal Bleeding
6.  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.
PMCID: PMC4273549  PMID: 25544918
7.  The METEX study: Methotrexate versus expectant management in women with ectopic pregnancy: A randomised controlled trial 
BMC Women's Health  2008;8:10.
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.
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.
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
PMCID: PMC2453103  PMID: 18565217
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.
To evaluate the clinical effectiveness of laparoscopic management of cesarean scar pregnancy (CSP) by deep implantation.
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.
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.
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.
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.
PMCID: PMC3771793  PMID: 23925020
Laparoscopy. Cesarean scar pregnancy; Ectopic pregnancy; Uterine artery ligation
9.  Comparison of gadoxetic acid and gadopentetate dimeglumine-enhanced MRI for HCC detection: prospective crossover study at 3 T 
Acta Radiologica Open  2015;4(2):2047981614561285.
Gadoxetic acid and gadopentetate dimeglumine are gadolinium-based contrast agents (GBCAs) with an established role in HCC detection and characterization.
To compare gadopentetate dimeglumine and gadoxetic acid-enhanced magnetic resonance imaging (MRI) for image quality and hepatocellular carcinoma (HCC) detection/conspicuity.
Material and Methods
In this IRB approved cross-over pilot prospective study, 12 patients (all men; mean age, 56 years) with chronic liver disease at risk of HCC underwent two repeat MRI examinations using gadopentetate dimeglumine and gadoxetic acid (mean interval between studies, 5 days). Two independent observers analyzed images for image quality and HCC detection/conspicuity. Per-lesion sensitivity, positive predictive value, quantitative enhancement, and lesion-to-liver contrast ratio were calculated for both contrast agents.
There was no significant difference in image quality scores between both GBCAs (P = 0.3). A total of 20 HCCs were identified with reference standard in 12 patients (mean size 2.6 cm, range, 1.0–5.0 cm). Higher sensitivity was seen for observer 1 for gadoxetic acid-set in comparison with gadopentetate dimeglumine-set (sensitivity increased from 85.7% to 92.8%), while no difference was noted for observer 2 (sensitivity of 78.5%). Lesion conspicuity was significantly higher on hepatobiliary phase (HBP) images compared to arterial phase images with both GBCAs for both observers (P < 0.05). Lesion-to-liver contrast ratios were significantly higher for HBP compared to all dynamic phases for both agents (P < 0.05).
Our initial experience suggests that gadoxetic acid-set was superior to gadopentetate dimeglumine-set in terms of HCC detection for one observer, with improved lesion conspicuity and liver-to-lesion contrast on HBP images.
PMCID: PMC4364400  PMID: 25793110
Liver; hepatocarcinoma; magnetic resonance imaging; Gd-EOB-DTPA; Gd-DTPA
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.
PMCID: PMC3932583  PMID: 24604945
Abnormal placental vascularity; dark intraplacental bands; magnetic resonance imaging; placenta accreta
11.  Gestational choriocarcinoma with uterine serosal metastasis mimicking ruptured ectopic pregnancy: A case report 
Oncology Letters  2015;9(5):2185-2188.
Primary gestational choriocarcinoma is commonly present in the uterus in cases of atypical genital bleeding. Symptoms similar to those of an ectopic pregnancy develop when an extra-uterine lesion is present in the abdominal cavity, and lesions have been detected in the ovaries and fallopian tubes in a number of cases. In the present study, we describe a patient with choriocarcinoma that metastasized to the uterine serosa and caused symptoms similar to those of an ectopic pregnancy. The patient was a 30-year-old female who presented to our hospital with atypical genital bleeding and a positive pregnancy test 3 months after missed abortion at 10 weeks of gestation. Transvaginal ultrasonography revealed the absence of a gestational sac in or outside the uterus, and intra-abdominal bleeding was noted. An ectopic pregnancy was suspected based on these findings, and emergency laparotomy was performed. A hemorrhagic mass was present on the uterine serosa, and was subsequently resected. Trophoblastic disease was suspected following histopathological examination, for which intra-uterine curettage was performed and choriocarcinoma was diagnosed. Lung metastasis was detected on computed tomography, and a high serum human chorionic gonadotropin (hCG) level persisted following surgery. The lesion disappeared following five cycles of methotrexate+ etoposide+actinomycin D therapy, which was performed as postoperative chemotherapy, and the patient's serum hCG level decreased to below the detection limit. In this case of choriocarcinoma, the primary lesion was present in the uterus and had metastasized to the uterine serosa, which is a very rare metastatic site. This uterine serosal metastatic lesion bled and caused symptoms similar to those of an ectopic pregnancy. Certain patients who undergo surgery for a suspected peritoneal pregnancy may have gestational choriocarcinoma, similar to this case.
PMCID: PMC4467341  PMID: 26137037
gestational choriocarcinoma; uterine serosal metastasis; ectopic pregnancy
12.  Placenta Percreta in First Trimester Leading to Disseminated Intravascular Coagulopathy (DIC): A Rare Case Report 
Placenta percreta is the most severe form of abnormal placental attachment. It is a variant of placenta accreta in which chorionic villi penetrate the entire thickness of the myometrium through the uterine serosa and may involve the adjacent structures. Literature review shows very few cases encountered during the first trimester of pregnancy. A-20-year-old woman with previous one cesarean section presented with continuous vaginal bleeding beginning after incomplete abortion at seven weeks and six days period of gestation for which she underwent dilatation and curettage. MRI revealed irregular heterogeneous signal intensity mass with large area of hemorrhage in lower anterior wall extending towards the endometrial cavity suggestive of morbid adherent placenta. Following continuous bleeding after repeated curettage for retained, adherent placenta her coagulation profile got deranged and DIC developed. Correction of coagulopathy and emergency hysterectomy as a life saving measure for placenta percreta was done in our case.
PMCID: PMC4437120  PMID: 26023604
Dilatation and curettage; Hysterectomy
13.  MRI of placental adhesive disorder 
The British Journal of Radiology  2014;87(1042):20140294.
Placental adhesive disorder (PAD) is a serious pregnancy complication that occurs when the chorionic villi invade the myometrium. Placenta praevia and prior caesarean section are the two important risk factors. PAD is classified on the basis of the depth of myometrial invasion (placenta accreta, placenta increta and placenta percreta). MRI is the preferred image modality for pre-natal diagnosis of PAD and as complementary technique when ultrasonography is inconclusive. Imaging findings that are helpful for the diagnosis include dark intraplacental bands, direct invasion of adjacent structures by placental tissue, interruption of normal trilayered myometrium and uterine bulging. Clinicians should be aware of imaging features of PAD to facilitate optimal patient management.
PMCID: PMC4148826  PMID: 25060799
14.  Clinical Outcomes of Patients treated for Cervical Pregnancy with or without Methotrexate 
Journal of Korean Medical Science  2004;19(6):848-852.
The objective of this study is to describe the clinical outcomes of patients treated for cervical pregnancy with or without methotrexate (MTX) and to evaluate the effects of MTX in the treatment of cervical pregnancy. Between January 1993 and February 2000, 31 patients were diagnosed with cervical pregnancy. Twenty-two patients were treated with MTX chemotherapy and nine patients were treated with surgical procedures without MTX treatment. In the non-MTX treatment group, three patients underwent total abdominal hysterectomy, five required adjuvant procedures to control the bleeding during dilatation and curettage (D&C) and only one patient was treated with a simple D&C. In the MTX treatment group, fourteen (63.6%) patients were treated with only MTX and eight (36.4%) cases underwent concomitant procedures (simple curettage, curettage and Foley catheter tamponade, cervical cerclage, ligation of the descending branches of uterine arteries, or ligation of hypogastric arteries). The uterus was preserved in all cases and three women delivered healthy babies in their subsequent pregnancy. In conclusion, early diagnosis, appropriate MTX regimen in combination of necessary adjuvant conservative procedures could contribute to successful treatment with preservation of the uterus and future reproductive ability.
PMCID: PMC2816301  PMID: 15608396
Methotrexate; Pregnancy, Ectopic; Cervix Uteri; Dilatation and Curettage; Drug Therapy
15.  Placenta increta causing hemoperitoneum in the 26th week of pregnancy: a case report 
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.
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.
PMCID: PMC3017074  PMID: 21176187
16.  A new case of primary signet-ring cell carcinoma of the cervix with prominent endometrial and myometrial involvement: Immunohistochemical and molecular studies and review of the literature 
As a rule, endocervical tumours with signet-ring cell are classed as metastatic extra-genital neoplasms. In a patient aged 45 years, we describe primary cervical signet-ring cell carcinoma (PCSRCC) characterized by prominent endometrial and myometrial involvement, simulating primary endometrial adenocarcinoma with cervical extension. In addition, a review was made of the literature to identify the clinical and pathological features of this rare malignancy.
Case presentation
A 45-year-old woman was referred to our Gynaecology Department due to persistent abnormal vaginal bleeding. Transvaginal ultrasonography showed slight endometrial irregularities in the whole uterine cavity suggestive of endometrial neoplasms. Pelvic magnetic resonance imaging revealed diffuse enlargement of the cervix, which had been replaced by a mass. Induration extended to the parametria and sigmoid colon fat.
Histological examination of endometrial curettage and a cervical biopsy revealed a neoplasm characterized by neoplastic signet-ring cells and trabecular structures. Immunohistochemical analysis and molecular studies showed certain findings consistent with a cervical neoplasm, such as positivity to CEA, keratin 7, Ca-125 and p16 and the presence of HPV (Human Papilloma Virus) DNA 18.
On examination of the hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy, the lesion replacing the cervix, endometrium and myometrium, revealed the same immunohistochemical findings observed on endometrial curettage and cervical biopsy specimens. Metastases were found in an ovarian cystic lesion and the lymph nodes.
With this report the authors have demonstrated that the spread of cervical adenocarcinoma to the uterine corpus, although rare, may be observed, and that in this instance immunohistochemical and molecular studies can provide sufficient information for accurate diagnosis even on small biopsy specimens.
PMCID: PMC3320546  PMID: 22236794
Signet-ring cell carcinoma; Cervical adenocarcinoma; Human Papilloma Virus (HPV); Polymerase Chain Reaction Amplification (PCR)
17.  Comparative efficacy and safety of local and systemic methotrexate injection in cesarean scar pregnancy 
To investigate the efficacy of methotrexate (MTX) injection in treatment of cesarean scar pregnancy (CSP).
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.
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.
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.
PMCID: PMC4315462  PMID: 25670903
cesarean scar pregnancy; methotrexate injection; local; systemic
18.  A case of placental polyp after normal vaginal delivery 
Placental polyp is retained placental tissue within the endometrial cavity, which forms a nidus for inflammation and bleeding. There are very few reported cases of the clinical placental polyp. Here, we report a case of 34-year-old G4L3Ab1 woman with the chief complaint of intermittent vaginal bleeding since her last normal vaginal delivery 3 months ago. Serum human chorionic gonadotropin (hCG) titer was slightly elevated. A polypoid mass was detected within the endometrial cavity by imaging studies. History of the patient, mass lesion within the endometrial cavity and slightly elevated serum hCG titer raised the suspicion of trophoblastic neoplasms. Endometrial curettage yielded unsatisfactory specimen containing only fibrin deposition and was followed by total hysterectomy. The uterus showed slight global enlargement resulting from the presence of a polypoid mass within the endometrial cavity. The red-colored mass had a smooth outer surface and fragile consistency without any permeation into the myometrium. Pathology reported it as the placental polyp. Although very rare, placental polyp should be kept in mind as one of the reasons of abnormal uterine bleeding in parous women. Definite diagnosis is made by pathology examination.
PMCID: PMC4214030  PMID: 25364371
Normal vaginal delivery; placental polyp; uterine bleeding
19.  In Vivo Response to Methotrexate Forecasts Outcome of Acute Lymphoblastic Leukemia and Has a Distinct Gene Expression Profile 
PLoS Medicine  2008;5(4):e83.
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).
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, (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
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
• 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)
PMCID: PMC2292747  PMID: 18416598
20.  A Case Report and Literature Review of Midtrimester Termination of Pregnancy Complicated by Placenta Previa and Placenta Accreta 
AJP Reports  2014;5(1):e6-e11.
Objective Concurrent placenta previa and placenta accreta increase the risk of massive obstetric hemorrhage. Despite extensive research on the management of placenta previa (including placenta accreta, increta, and percreta), the number and quality of previous studies are limited. We present a case of placenta accreta requiring an induced second-trimester abortion because of premature rupture of the membranes (PROM).
Study Design Case report and review of the literature.
Results A 41-year-old female presented at 20 weeks of gestation with placenta previa and PROM. Ultrasonography revealed placenta accreta with multiple placental lacunae. She then developed massive hemorrhaging just prior to a planned termination of pregnancy. We performed a hysterectomy with the intent of preserving life because of the failure of the placenta to detach and blood loss totaling 4,500 mL.
Conclusion Previous studies suggest that second-trimester pregnancy terminations in cases of placenta previa which are not complicated with placenta accreta do not have a particularly high risk of hemorrhage. However, together with our case, the literature suggests that placenta previa complicated with placenta accreta presents a significant risk of hemorrhage both during delivery and intraoperatively. Further reports are needed to evaluate the most appropriate treatment options.
PMCID: PMC4502619  PMID: 26199801
placenta previa; placenta accreta; midtrimester termination; cesarean hysterectomy
21.  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.
PMCID: PMC4140153  PMID: 25165718
22.  Lack of nephrotoxicity of gadopentetate dimeglumine-enhanced non-vascular MRI and MRI without contrast agent in patients at high-risk for acute kidney injury 
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).
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.
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).
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.
PMCID: PMC3829701  PMID: 24193150
MRI; gadopentetate dimeglumine; contrast nephropathy; acute kidney injury; NAG; NGAL
23.  Cervical ectopic pregnancy 
Cervical pregnancy is a rare type of ectopic pregnancy and it represents <1% of all ectopic pregnancies. Early diagnosis and medical management with systemic or local administration of methotrexate is the treatment of choice. If the pregnancy is disturbed, it may lead to massive hemorrhage, which may require hysterectomy to save the patient. We report three cases of cervical pregnancy managed successfully with different approaches of management. Our first case, 28 years old G3P2L2 with previous two lower segment cesarean sections, presented with bleeding per vaginum following 6 weeks of amenorrhea. Clinical examination followed by transvaginal ultrasound confirmed the diagnosis of cervical pregnancy. Total abdominal hysterectomy was done in view of intractable bleeding to save the patient. The second case, a 26-year-old second gravida with previous normal vaginal delivery presented with pain abdomen and single episode of spotting per vaginum following 7 weeks of amenorrhea. Transvaginal ultrasound revealed empty endometrial cavity, closed internal os with gestational sac containing live fetus of 7 weeks gestational age in cervical canal and she was treated with intra-amniotic potassium chloride followed by systemic methotrexate. Follow up with serum beta human chorionic gonadotropin level revealed successful outcome. Our third case, a 27-year-old primigravida with history of infertility treatment admitted with complaints of bleeding per vaginum for 1 day following 8 weeks amenorrhea. She was diagnosed as cervical pregnancy by clinical examination, confirmed by transvaginal ultrasonography and subsequently managed by dilation and curettage with intracervical Foleys’ ballon tamponade.
PMCID: PMC4367055  PMID: 25810679
Cervical pregnancy; ectopic pregnancy; hysterectomy
24.  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.
PMCID: PMC3506964  PMID: 23189211
Complete freunds adjuvant-induced arthritis; Human umbilical mesenchymal stem cell; Hematopoietic stem cell; CD34+
25.  Methotrexate for the Treatment of Unruptured Tubal Pregnancy: A Prospective Nonrandomized Study 
Background and Objectives:
The aim of this study was to compare in a prospective nonrandomized study, the efficacy of 2 methods of administering methotrexate (MTX) in the treatment of ectopic pregnancy (EP): transvaginal injection under sonographic control or intramuscular injection (IM).
Patients with EP who met specific inclusion criteria for medical treatment were treated with MTX: 63 patients (group 1) were treated by IM and 47 patients (group 2) by transvaginal local injection. In group 1, 50 mg/m2 of MTX was injected intramuscularly; in group 2, transvaginal injection of 1 mg/kg of MTX was injected into the ectopic sac under sonographic control. When an additional dose of MTX was required, it was administrated IM at the dosage of 50 mg/m2 in both groups.
The overall success rate, defined by a posttreatment normal hCG level (<10 mUI/mL) was 71.4% in group 1 versus 91.5% in group 2 (P<0.01); for patients with hCG levels <2000 mUI/mL, 83% and 96%, respectively (not significant); for patients with hCG ≥2000 mUI/mL, 37.5% and 86.4%, respectively (P<0.01).
In the medical treatment of EP, the efficacy of MTX is greater when administered by local transvaginal injection than by IM injection. We propose local treatment every time EP can be punctured, especially when hCG levels are ≥2000 mUI/mL.
PMCID: PMC3113203  PMID: 14558711
Ectopic pregnancy; Local methotrexate; IM methotrexate

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