Systemic Methotrexate Administration Research Articles

Influence of ADORA2A gene polymorphism on leukoencephalopathy risk in MTX-treated pediatric patients affected by hematological malignancies.

Methotrexate (MTX) can lead to neurotoxicity and asymptomatic leukoencephalopathy. However, the mechanism of MTX-related leukoencephalopathy is obscure. MTX and its metabolites inhibit 5-aminoimidazole-4-carboxamide ribonucleotide formiltransferase (ATIC) and promote adenosine release. Recently, it has been reported that adenosine and its receptor are related to certain central nervous system diseases. We investigated whether adenosine pathway gene polymorphisms and clinical factors were related to MTX-related leukoencephalopathy in pediatric patients affected by hematological malignancies. Fifty-six Japanese childhood acute lymphoblastic leukemia or lymphoma patients were investigated. Patients were evaluated by magnetic resonance imaging of the brain before maintenance therapy or stem cell transplantation. Gene polymorphisms within the adenosine pathway (ATIC, adenosine A2A receptor [ADORA2A]) and the MTX pathway (methylenetetrahydrofolate reductase [MTHFR] and ABCB1) were genotyped using TaqMan assays. Clinical data were collected by accessing the medical records. MTX-related leukoencephalopathy was evaluated by a pediatric neurologist. Twenty-one (37%) of 56 patients developed MTX-related leukoencephalopathy. Four of 21 patients developed clinical neurotoxicity. The minor allele CC genotype of rs2298383 (ADORA2A) was associated with MTX-related leukoencephalopathy (P = 0.010, odds ratio = 5.81, 95% confidence interval 1.50-22.50). High cumulative dose of systemic MTX was associated with MTX-related leukoencephalopathy after adjusting for sex, ADORA2A polymorphism, and prolonged high MTX concentration (P = 0.042, odds ratio = 1.18, 95% confidence interval 1.01-1.37). ADORA2A rs2298383 and high cumulative dose of systemic MTX administration were significantly associated with MTX-related leukoencephalopathy. Our results indicate that pharmacological intervention within the adenosine pathway may be both a treatment and preventative option for MTX-related leukoencephalopathy.

Methotrexate mitgates UHMWPE-induced inflammatory osteolysis in murine calvaria model, more than anti-TNF or anti-IL-1R treatments: Implications for extending implant lifetimes

Event Abstract Back to Event Methotrexate mitgates UHMWPE-induced inflammatory osteolysis in murine calvaria model, more than anti-TNF or anti-IL-1R treatments: Implications for extending implant lifetimes Lauryn A. Samelko1, 2, Kyron Mcallister1, Joshua J. Jacobs1 and Nadim Hallab1, 2 1 Rush University, Dept of Orthopedic Surgery, United States 2 Rush University, Dept of Immunology, United States Wear-debris induced osteolysis has been recognized as the primary cause of long term total joint replacement (TJR) failure[1]-[3]. To date, it remains unclear what the most effective strategy for treatment of debris induced periprosthetic osteolysis, with no drugs currently approved for use. Potent anti-inflammatory drugs such as anti-TNF-α, IL-1Ra (Anakinra), and methotrexate (MTX) are used to treat rheumatoid arthritis (RA) and show promise for use in treatment of periprothestic osteolysis, but have yet to be comparatively analyzed and thoroughly investigated. Basic questions remain, such as which drug is more effective and what is the most effective delivery method (local or systemic)? We hypothesize that local administration of MTX will reduce UHMWPE induced-inflammatory osteolysis more than systemic MTX, local anti-TNFa or anti-IL1R, due the pleiotropic anti-inflammatory effects of MTX. To test this, we used an established in vivo murine model of particle-induced osteolysis using UHMWPE particles and subsequently evaluated the degree of particle-induced osteolysis between the different regimens that either received local administration of: (1) sham surgery (did not receive UHMWPE nor biologic treatment; negative control), (2) PBS (positive control), (3) anti-mTNF-α, (4) anti-mIL-1R and (5) MTX (local) and compared that to weekly systemic administration of (6) MTX (systemic), where this latter method has been previously demonstrated to reduce particle induced osteolysis[4]. The greatest and most significant (p<0.02) amount of quantifiable osteolysis in the murine model was observed in the positive control group that received UHMWPE particles +PBS, with 32.5% of bone resorption (Fig. 1b). In contrast, local daily administration of either MTX (10.12% Osteolysis) or anti-mIL-1R (11.59% Osteolysis) to murine calvaria that also received UHMWPE particles, did not significantly increase osteolysis compared to the sham-negative control group (6.23% Osteolysis) (Fig. 1c,e,g). While local anti-mTNF-α (18.54%) administration did not significantly decrease the percentage of osteolysis to sham group but was significantly less compared to the UHMWPE particle +PBS treatment, as well as MTX and anti-mIL-1R treatment group at p<0.02 (Fig. 1d,g). However, there was no statistical significance between osteolysis of anti-mTNF-α and anti-mIL-1R group. The local MTX treatment group had significantly less bone resorption though in comparison to anti-mTNF-α (p=0.05) but not to anti-mIL-1R group. Moreover, systemic administration of MTX was not effective, for the amount of osteolysis is similar to UHMWPE group that did not receive any drug agent, and had significantly more bone resorption compared to local MTX treatment (p=0.008; Fig. 1c,f,h). Our results support our hypothesis that daily local administration of MTX will mitigate UHMWPE-induced inflammatory osteolysis the greatest compared to both local treatment of anti-mTNF-α and anti-mIL-1R or systemic MTX. Local MTX demonstrated to be the most preventive treatment of osteolysis, with bone resorption at only 10.12% and therefore most comparable to that of sham group at 6.23%. More importantly, MTX was more protective given locally as opposed to systemically (p=0.008). Therefore, based on these results, local MTX demonstrates superior promise for use in countering wear-debris induced osteolysis and aseptic loosening. NIH/NIAMS: AR060782.

Hysteroscopically-guided subchorionic methotrexate administration: A new technique for termination of cesarean scar pregnancy

Introduction: cesarean scar pregnancy (csP) is a rare but life-threatening condition, due to the risk of uterine rupture or for the development of placenta previa/accreta. the mainstay of management to spare fertility is early diagnosis and pregnancy termination. Although several conservative treatments have been experienced, no consensus on the best therapeutic approach is currently shared. the medical therapy for csP termination is based on systemic or local Methotrexate (MtX) administration. Hysteroscopy allows the precise visualization of placental implantation and it can be used to drive MtX injection selectively within the intervillous placental spaces. this procedure increases drug concentration delivered to the target tissue, potentially improving its therapeutic index. case report: A 36-year-old female with a history of cesarean section was admitted to our department with a diagnosis of viable 7th weeks csP. the patient gave her consent to pregnancy termination by a hysteroscopically-guided MtX administration within the cervico-isthmic placental implantation site, followed by its resectoscopic removal. In an office setting, 80 mg of MtX were injected through a needle adaptable to the 5-Fr operative channel of hysteroscope, Giancarlo Garuti1, Stefania Calabrese1, Lorenzo Quirino1, Marco Di Mario1 Affiliations: 1MD, Obstetrics and Gynecology Department, Public Hospital of Lodi, Via Savoia 1, 26900-Lodi, Italy. Corresponding Author: Giancarlo Garuti (MD), Obstetrics and Gynecology Department, Lodi Hospital, via Savoia n° 1, 26900-Lodi, Italy; E-mail: giancarlo.garuti@tiscali.it Received: 03 October 2015 Accepted: 02 December 2015 Published: 27 February 2016 under the chorionic membrane of placental implantation site. the duration of the procedure took three minutes and it resulted easy, painless and uneventful. An early embryo demise was obtained; the human chorionic gonadotropinbeta subunit (beta-hcG) serum trend showed a rapid pregnancy termination and no patient complaints were recorded. After 28 days, a resectoscopic removal of the gestational sac and placenta was safely accomplished. conclusion: selective hysteroscopic administration of MtX within intervillous spaces of the ectopic placental implantation is effective and it can be considered for csP termination.

Magnetic resonance imaging for diagnosis and management of unruptured interstitial pregnancy.

The aim of this study was to evaluate the value of magnetic resonance imaging (MRI) for the diagnosis and management of suspicious unruptured interstitial pregnancy. Only patients with unruptured interstitial pregnancy evaluated by MRI and observed for at least a year after surgery were included. Initial evaluation was performed by measurement of serum β-human chorionic gonadotrophin level and ultrasonography. In suspicious cases, emergency MRI was performed to diagnose interstitial pregnancies with the exclusion of rudimentary horn pregnancy and angular pregnancy. Three-dimensional computed tomographic (CT) angiography was additionally performed if the uteroplacental neovascularization needed to be evaluated. Then, management procedures were individually determined along with the need for preoperative transcatheter arterial chemoembolization for immediate devascularization, and for the local or systemic administration of methotrexate. Either laparoscopic cornuostomy or cornual resection was chosen to excise the gestational mass. Five consecutive women with unruptured interstitial pregnancy were enrolled. One case each of rudimentary horn pregnancy and angular pregnancy was excluded. Three-dimensional CT angiography was performed in three cases due to increased vascular flow on color Doppler ultrasonography. Preoperative devascularization by transcatheter arterial chemoembolization was performed in two cases, in which a prominent neovascularized gestational mass was identified. Uterine preservation was achieved by cornuostomy or cornual resection in all cases. Two patients with a desire to become pregnant conceived spontaneously thereafter, followed by successful cesarean birth. This small case series emphasizes that precise localization of gestational products in the interstitial portion of the fallopian tube by MRI can facilitate the minimally invasive management of unruptured interstitial pregnancy for uterine preservation.

Cesarean scar ectopic pregnancy: imaging features, current treatment options, and clinical outcomes.

Cesarean scar ectopic pregnancy (CSEP) is considered to be quite rare, but the frequency is increasing given the increasing number of cesarean sections being performed, along with increased detection due to widespread use of early endovaginal sonography. The normal sonographic and magnetic resonance findings of this phenomenon will be discussed, including the appearance of complications associated with abnormal placentation, such as the placenta accreta spectrum. Cases of CSEP at our institution will be illustrated, along with clinical presentations and treatment outcomes. The study included women who were diagnosed with a CSEP in the first trimester, which was confirmed by ultrasound. The clinical presentations, imaging findings, and treatment outcomes of these pregnancies were recorded. In our series, treatment ranged from no intervention with fetal demise on short-term follow-up ultrasound to viable near-term deliveries requiring cesarean section, urgent blood products, and emergent surgery. The majority of our cases 75% (15 of 20) underwent successful early first trimester termination by a combination of systemic methotrexate administration, ultrasound-guided injection of embryocidal agents, and/or surgery. Early imaging recognition and diagnosis of CSEP is critically important to minimize maternal complications, maintain treatment options, and potentially preserve future fertility.

Combined local blood-brain barrier opening and systemic methotrexate for the treatment of brain tumors.

Despite aggressive therapy, existing treatments offer poor prognosis for glioblastoma multiforme patients, in part due to poor penetration of most drugs across the blood-brain barrier (BBB). We propose a minimal-invasive combined treatment approach consisting of local BBB disruption in the tumor in parallel to systemic drug administration. Local BBB disruption is obtained by convection-enhanced delivery of a novel BBB disruption agent, enabling efficient/targeted delivery of the systemically administered drug by the tumors own vasculature. Various human serum albumin (HSA) analogs were synthesized and screened for BBB disruption efficacy in custom in vitro systems. The candidate analogs were then delivered into naïve rat brains by convection-enhanced delivery and screened for maximal BBB disruption and minimal brain toxicity. These studies found a noncationized/neutralized analog, ethylamine (EA)-HSA, to be the optimal BBB-opening agent. Immunocytochemical studies suggested that BBB disruption by EA-HSA may be explained by alterations in occludin expression. Finally, an efficacy study in rats bearing intracranial gliomas was performed. The rats were treated by convection-enhanced delivery of EA-HSA in parallel to systemic administration of Methotrexate, showing significant antineoplastic effects of the combined approached reflected in suppressed tumor growth and significantly (~x3) prolonged survival.

Transvaginal Aspiration of Ectopic Gestational Sac: A Novel Treatment Option in Tubal Ectopic Pregnancies

ABSTRACTObjectiveTo present five cases of unruptured tubal ectopic pregnancies treated with ultrasound-guided aspiration with local potassium chloride (KCl) or systemic methotrexate (MTX) administration.DesignCase series.SettingA hospital-based prospective study.PatientsFive women with unruptured tubal ectopic pregnancy.InterventionsTransvaginal ultrasound-guided aspiration of tubal ectopic pregnancy followed by local KCl or intramuscular injection of MTX (50 mg/m2).Main outcome measuresSuccessful conservative treatment of tubal ectopic pregnancies with preservation of fallopian tubes.ResultsFour (80%) out of five women weres uccessfully treated, without the need for operative intervention. One patient required salpingectomy for ruptured ectopic pregnancy during the course of treatment.ConclusionTransvaginal ultrasound-guided aspiration of ectopic gestational sac along with either local KCl or systemic methotrexate administration can be safely used to treat unruptured tubal ectopic pregnancies in selected patient population.How to cite this articleMishra VV, Choudhary S, Sharma U, Agarwal R. Transvaginal Aspiration of Ectopic Gestational Sac: A Novel Treatment Option in Tubal Ectopic Pregnancies. J South Asian Feder Obst Gynae 2015;7(1):1-4.

Successful Management of a Scary Case of Cesarean Scar Pregnancy with Combined Treatment using Methotrexate, Uterine Artery Embolization and Suction Evacuation

ABSTRACT Cesarean scar pregnancy (CSP) is the rarest type of ectopic pregnancy implanted in the myometrium at the site of the previous cesarean section scar. It may lead catastrophic complications like uterine rupture and uncontrollable hemorrhage.4 Early diagnosis can offer treatment options of avoiding uterine rupture and hemorrhage, thus, preserving the uterus and future fertility. The conservative treatment can be by local and/or systemic administration of methotrexate, dilatation and curettage, excision of trophoblastic tissues (laparoscopy/laparotomy), bilateral internal artery ligation with trophoblastic evacuation and uterine artery embolization7 combined with curettage and/ or methotrexate. We did successful treatment of a viable CSP by systemic injections of methotrexate followed by selective uterine artery embolization in combination with dilatation and curettage. How to cite this article Mehta P, Vishwanath U, Joseph S, Anitha M. Successful Management of a Scary Case of Cesarean Scar Pregnancy with Combined Treatment using Methotrexate, Uterine Artery Embolization and Suction Evacuation. J South Asian Feder Obst Gynae 2015;7(3):143-147.

Management of an 11-week cesarean scar pregnancy

Introduction: cesarean scar pregnancy is a lifethreatening condition, especially in the advanced gestational age. Optimal management has not yet been established because this is a rare condition. case report: A 30-year-old female, with a previous cesarean, diagnosed with a viable cesarean scar pregnancy with 11 weeks of gestation. successful termination of cesarean scar pregnancy was achieved with systemic and local (ultrasoundguided) methotrexate administration with subsequent dilatation and evacuation, under ultrasound guidance, in a two- stage procedure: rupture of the amniotic sac with partial removal of the fetus and one week later total evacuation of uterine content, with satisfactory hemostasis. conclusion: cesarean scar pregnancy is associated with a high morbidity and adverse consequences for future fertility. there is no optimal management established, because of the rarity of the condition. We present a case of successful termination of an advanced first trimester cesarean scar pregnancy.

Effect of methotrexate upon antigen-induced arthritis of the rabbit temporomandibular joint.

Juvenile idiopathic arthritis (JIA) of the temporomandibular joint (TMJ) can cause severe growth disturbances of the craniomandibular system. Antigen-induced arthritis (AIA) of the rabbit TMJ is simulating the inflammatory process of the TMJ in JIA. The aim of this study was to investigate the effect of a systemic administration of methotrexate (MTX) on AIA in rabbits by means of three different histological staining methods. After sensitization, a bilateral arthritis of the TMJ was induced by an intra-articular administration of ovalbumin in 12 New Zealand white rabbits aged 10 weeks. From the 13th week of age, six of the 12 rabbits received weekly intramuscular injections of MTX, and the other six animals remained without therapy. Another six animals served as controls, receiving no treatment or intra-articular injections at all. After euthanasia at the age of 22 weeks, all TMJs were retrieved en bloc. Sagittal sections were cut and stained with haematoxylin-eosin (H-E), Safranin-O for the evaluation of the Mankin score and tartrate-resistant acid phosphatase (TRAP). In the arthritis group, a chronic inflammation with degeneration of the articular cartilage was visible. In the MTX group, the signs of cartilage degeneration were significantly reduced compared with the arthritis group. In contrast, the joints in the control group were inconspicuous. A correlation between the Mankin score and TRAP-positive cells could be found. Systemic administration of MTX seems to have a positive effect upon the inflammatory process in the rabbit TMJ but fails to eliminate the sign of arthritis completely.

Three-dimensional computed tomographic angiography in the diagnosis and conservative management of cesarean scar pregnancy with prominent neovascularization

ObjectiveCesarean scar pregnancy (CSP) is a rare potentially life-threatening form of ectopic gestation. However, optimal management has not yet been established. Furthermore, there are limited reports on the diagnostic value of three-dimensional computed tomographic angiography (3D-CTA) for the conservative management of this disorder. Case reportA 33-year-old woman (gravida 3, para 2), with two previous deliveries by low segmental transverse cesarean section, was referred after 5 weeks of amenorrhea. Her serum beta-human chorionic gonadotropin (β-hCG) value was 2921 mIU/mL. Cesarean scar pregnancy was diagnosed by ultrasonography and magnetic resonance imaging. On 3D-CTA, a prominent uteroplacental neovascularized mass was identified. It was supplied by the left uterine artery and a thick draining left ovarian vein. After three cycles of systemic methotrexate (MTX) administration, the serum β-hCG value decreased to 142 mIU/mL. However, the gestational sac enlarged and peritrophoblastic blood flow persisted. In contrast to the ultrasonographic findings, marked reduction of uteroplacental neovascularization at the CSP site with regression of the draining ovarian vein was evident on 3D-CTA. The gestational products were thereafter successfully resected by hysteroscopic surgery without hemorrhagic complications. Fifty-seven days after the initial MTX administration, serum β-hCG reached a normal level. ConclusionThis case emphasizes that, when selecting the method of intervention, 3D-CTA is potentially useful for evaluating uteroplacental neovascularization in a hemodynamically stable CSP.

Skin-penetrating methotrexate alleviates imiquimod-induced psoriasiform dermatitis via decreasing IL-17-producing gamma delta T cells.

Accumulating evidence has shown that the Toll-like receptor 7 agonist imiquimod (IMQ) induces psoriasiform skin inflammation in mice and that this inflammation is dependent on the IL-23/IL-17 axis. Moreover, it has been demonstrated that the main source of IL-17 is not Th17 but is dermal gamma delta (γδ) T cells in mouse psoriasiform skin. Recent advances in the understanding of immunopathogenesis of psoriasis led to an alteration in the treatment paradigm to the use of highly efficacious biologics. However, their high cost impedes the extensive use of these agents. Thus, inexpensive and safe medications are still considered valuable. In this study, we introduce the therapeutic efficacy of a newly formulated methotrexate (MTX), a chemical conjugate of MTX with cell permeable peptide, for the treatment of psoriasis. Topically applied skin-penetrating (SP)-MTX reduced the psoriasiform skin phenomenon, epidermal thickness and infiltrating immune cells into the dermis. IL-17A-producing dermal γδ T cells in the cellular infiltrate that contribute IL-23/IL-17 axis were well abrogated by SP-MTX. Furthermore, SP-MTX had no toxic effects on liver, kidney or myeloid cells, unlike systemic administration of MTX. In conclusion, topically applied SP-MTX ameliorated psoriasiform skin inflammation in mice with the criteria of clinical phenomenon, histopathology and immunology, without inducing systemic toxic effects.

帝王切開瘢痕部妊娠に対しMTX全身投与、UAE、子宮鏡下妊卵除去術を行い、 腹腔鏡下子宮形成術後、生児を得た一例

A cesarean scar pregnancy (CSP) is one of the most dangerous forms of ectopic pregnancy. We report a case of a 33-year-old gravida 5 para 3 who was referred to our hospital at 6 weeks, 2 days of gestation from another facility with a diagnosis of CSP. A sagittal view of a transvaginal ultrasonogram imaged a gestational sac 32 mm in diameter in the anterior wall of the uterine isthmus, a fetus with a fetal heart beat, and abundant vascular flow around the gestational sac. The serum hCG level was 64,999 IU/l. It increased for a short interval to 125,512 IU/l after the systemic administration of methotrexate (MTX). We performed uterine artery embolization (UAE). Subsequently, the serum hCG level gradually declined, and we identified the disappearance of the fetal heart beat and vascular flow around the gestational sac. After another UAE, we performed a hysteroscopic resection when the serum hCG level declined to < 10,000 IU/l. The serum hCG level showed a negative conversion 60 days after the first MTX administration. During the follow-up period the thickness of the muscular layer of the uterine isthmus became remarkably thin; therefore, we performed a laparoscopic repair of the uterine scar. The patient subsequently achieved a normal pregnant and delivered a live infant at 30 weeks, 0 days of gestation by cesarean section. We stress that it is extremely important to avoid situations such as hemorrhage or rupture during treatment of a CSP. Therefore, we must carefully employ a combination of MTX administration, UAE, and hysteroscopic resection. This case suggests that laparoscopic repair of a uterine scar is a useful procedure, which leads to a better prognosis for future pregnancy, particularly in cases in which the muscular layer is extremely thin. Further study of CSPs is needed.

Recurrent Ipsilateral Cornual Pregnancy with High bHCG Level Successfully Treated with Single Dose of Methotrexate Injection: A Case Report

Cornual pregnancy is a type of ectopic pregnancy with the highest incidence of mortality. The incidence of recurrent cornual pregnancy is not known. We report a rare case of recurrent ipsilateral cornual ectopic pregnancy with bHCG level >7000 IU/L, which was managed successfully using a single dose of systemic methotrexate injection. A 33 year old lady had recurrent ipsilateral cornual pregnancy after previous salpingectomy and cornual resection. The size of cornual pregnancy was small and unruptured. The initial bHCG level was 7299 IU/L. She was given medical treatment by a single-dose intramuscular methotrexate injection and the cornual pregnancy was resolved after 5 weeks. In conclusion, systemic administration of methotrexate can be considered in unruptured cornual pregnancy in a haemodynamically stable patient even with high level of initial bHCG level of over 7000.

Management of Cesarean Scar Pregnancy

To evaluate the diagnosis and treatment and long term follow up of cesarean scar pregnancy. Methods: From January 2008 to December 2013, 12 cases of Cesarean scar pregnancy were diagnosed using transvaginal grey scale and color doppler ultrasound and managed by various approaches. Incidence, gestational age, ulrasound findings, serum beta-human chorionic gonadotropin ( beta-hCG) levels, flow profiles of transvaginal color doppler ultrasound, and different methods of treatment were recorded. Results: The incidence of cesarean scar pregnancy was 1:2051. Gestational age at diagnosis ranged from 5 weeks + 2days to 10weeks + 4 weeks. The time interval from the last cesarean section to the diagnosis of Cesarean scar pregnancy ranged from 5 months to 8 years. Patients were treated by different methods as follows: transvaginal ultrasound-guided injection of methotrexate(MTX) into the gestational sac (n = 1), systemic methotrexate administration alone (n = 2), dilatation and curettage (n = 3), or local resection of the gestation mass (n =6 ). After local or systemic MTX, high-velocity and low-impedance subtrophoblastic flow (resistance index (RI) = 0.35) persisted until beta-hCG returned to normal. One of 3 patients, treated by dilatation and curettage, underwent a hysterectomy because of uncontrolled profuse vaginal bleeding. The scar pregnancy mass took 2 months to 8 months for regression after treatment. None of the patient had uterine rupture. Conclusion: Sonography guided methotrexate injection and/or systemic methotrexate are the treatment of choice to manage cesarean scar pregnancy less than 6-8 week's gestation without fetal heart activity. Dilatation and curettage leads to profuse vaginal bleeding and not recommended for cesarean scar pregnancy due to high morbidity. Those patients having persistent pain and recurrent bleeding, surgical resection for removal of mass and repair of defective site should be recommended.

Neurocognitive and Neuroradiologic Central Nervous System Late Effects in Children Treated on Pediatric Oncology Group (POG) P9605 (Standard Risk) and P9201 (Lesser Risk) Acute Lymphoblastic Leukemia Protocols (ACCL0131)

Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin rescue, and frequency of systemic MTX administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system (CNS)-directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with "standard-risk" acute lymphoblastic leukemia, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. Magnetic resonance imaging scans and standard neuropsychological tests were performed ≥2.6 years after the end of treatment. Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. Children on both studies had significant attention problems, but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive MTX exposure as a major contributor to CNS late effects.

Pivotal points in interstitial pregnancy: New insights in conservative medical treatment of non-ruptured interstitial pregnancy

We report the efficacy of a minimally invasive approach of the multidose protocol with methotrexate (MTX) in the management of three cases of interstitial pregnancy (IP), with elevated serum β-hCG in two cases. New considerations and management strategies are discussed. Successful termination of IP and in one case, a subsequent successful pregnancy, was achieved. The process led to the development of an enhanced understanding of diagnostic modalities and their limitations, with regard to the particular entities under discussion. We also focused attention on pivotal points and anatomical features in the management of this dangerous occurrence. Long-term results with careful follow-up were analysed by instrumental procedure. This hazardous type of ectopic pregnancy can be managed with systemic administration of MTX, also in patients with elevated β-hCG values. The present report underlines that an integrated approach in early diagnosis, multidose treatment and close follow-up, are essential forms of medical management.

Engineering Human T Cells for Resistance to Methotrexate and Mycophenolate Mofetil as an In Vivo Cell Selection Strategy

Gene transfer and drug selection systems that enforce ongoing transgene expression in vitro and in vivo which are compatible with human pharmaceutical drugs are currently underdeveloped. Here, we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic/immunosuppressive drugs methotrexate (MTX) and mycophenolate mofetil (MMF) in a multicistronic lentiviral vector for in vivo T lymphocyte selection. We found that co-expression of human dihydrofolate reductase (DHFRFS; L22F, F31S) and inosine monophosphate dehydrogenase II (IMPDH2IY; T333I, S351Y) conferred T cell resistance to the cytocidal and anti-proliferative effects of these drugs at concentrations that can be achieved clinically (up to 0.1 µM MTX and 1.0 µM MPA). Furthermore, using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells, in vivo selection studies demonstrate that huEGFRt+DHFRFS+IMPDH2IY+ T cells could be enriched following adoptive transfer either by systemic administration of MTX alone (4.4 -fold), MMF alone (2.9-fold), or combined MTX and MMF (4.9-fold). These findings demonstrate the utility of both DHFRFS/MTX and IMPDH2IY/MMF for in vivo selection of lentivirally transduced human T cells. Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients.

Abruptio Placentae in Subsequent Pregnancy after Conservative Management of Hemorrhagic Cesarean Scar Pregnancy by Transcatheter Arterial Chemoembolization

IntroductionCesarean scar pregnancy is a rare but dangerous type of ectopic pregnancy in which implantation occurs within the fibrous tissue of a cesarean scar defect. Conservative management of cesarean scar pregnancy is challenging, especially when future fertility preservation is a significant concern. Furthermore, reports on significant maternal morbidity in subsequent pregnancies after successful conservative management of cesarean scar pregnancy are limited.Case reportA 31-year-old woman with previous history of 2 cesarean sections transferred due to massive uterine hemorrhage 7 weeks after dilatation and curettage performed under the diagnosis of missed abortion at 7 weeks of gestation. Cesarean scar pregnancy was diagnosed and was conservatively managed by emergent transcatheter arterial chemoembolization (TACE) followed by multiple doses of systemic methotrexate administration. Seven months after TACE, she spontaneously conceived. At 36 weeks and 5 days of pregnancy, emergency cesarean section was performed due to sudden massive hemorrhage. Abruptio placentae was diagnosed when hysterotomy was performed. After manual removal of the placenta, a healthy infant was delivered. The postoperative course was uneventful.ConclusionThe pregnancy course should be carefully monitored for early detection of maternal morbidity associated with placental abnormalities to achieve successful outcome in subsequent gestations after conservative management of cesarean scar pregnancy.

Cervico-isthmic pregnancy successfully treated with bipolar resection following methotrexate administration: case report and literature review

Cervico-isthmic pregnancy is a rare form of ectopic pregnancy associated with a high morbidity and mortality rate. Recent advances in high-resolution ultrasound have made the diagnosis of early cervico-isthmic pregnancies easier. Early diagnosis allows a more conservative therapeutic approach that avoids hysterectomy and preserves fertility. Here is reported a case of viable cervico-isthmic pregnancy successfully treated with resectoscopy after failed systemic and local (hysteroscopic) methotrexate administration. The resectoscopic excision of the cervico-isthmic pregnancy was carried out with the technique of slicing, using a 27 bipolar resectoscope with a 4-mm loop. The procedure was successful with the complete removal of the ectopic pregnancy, while maintaining satisfactory haemostasis. A literature review shows that no consensus exists for the treatment of cervico-isthmic pregnancies.We report a case of viable cervico-isthmic pregnancy successfully treated with resectoscopy after failed systemic and local (hysteroscopical) methotrexate administration. The resectoscopic excision of cervico-isthmic pregnancy was carried out with the technique of slicing, using a 27 bipolar resectoscope with a 4-mm loop. The procedure was successful with the complete removal of the ectopic pregnancy, while maintaining satisfactory haemostasis.