Leptomeningeal disease as a presenting feature of gestational trophoblastic neoplasia: A review and recommendations for management.

OBJECTIVES: Gestational Trophoblastic Neoplasia (GTN) is a rare group of malignant placental-related tumours requiring systemic anti-cancer treatment. Leptomeningeal disease (LMD) related to GTN is not well reported with no consensus in optimal treatment. We offer recommendations for management of these patients. METHODS: We discuss five patients with GTN who presented with features of LMD and were diagnosed with gadolinium-enhanced MRI brain, all of whom received low dose induction etoposide-cisplatin (EP) followed by either EP-etoposide, methotrexate (CNS) and actinomycin-D (EMA) or EMA(CNS)-cyclophosphamide and vincristine (CO). RESULTS: Four out of the five patients additionally received intrathecal methotrexate. Four patients had complete hCG response to first line multi-agent chemotherapy, one patient required second line paclitaxel, cisplatin alternating with paclitaxel, etoposide (TP/TE), where paclitaxel was substituted with nab-paclitaxel due to anaphylaxis, followed by hysterectomy. One of the four initial complete hCG responders relapsed in the lung requiring further systemic treatment with subsequent lobectomy. Patient reported outcomes indicate persistent neurological symptoms are mild and do not affect functionality and quality of life. CONCLUSION: With a follow-up range of 2-6 years, all five patients remain cured demonstrating excellent survival outcomes with the avoidance of whole-brain radiotherapy in all cases.

Risk adapted single-agent dactinomycin or carboplatin for second-line treatment of methotrexate resistant low-risk gestational trophoblastic neoplasia.

OBJECTIVE: To evaluate the outcome of patients treated with second-line chemotherapy for methotrexate-resistant low-risk GTN at the Sheffield Centre, UK between 2001 and 2015, including the novel use of single-agent carboplatin as a strategy to reduce exposure to combination chemotherapy. METHODS: 392 low-risk GTN patients were treated with first-line methotrexate. The selection of chemotherapy regimen following methotrexate-resistance depended on the volume of residual disease as indicated by the serum hCG value at the time, with patients switching to either single-agent dactinomycin at an hCG level<150IU/L from 2001-2010 and <300IU/L since 2010, or to combination treatment with etoposide/dactinomycin (EA) above these thresholds. In order to reduce exposure to more toxic combination chemotherapy regimens, our treatment policy was revised in 2011, with the recommendation of single-agent carboplatin as an alternative to EA at hCG levels >300IU/L. RESULTS: 136 (35%) of 392 received second-line chemotherapy following methotrexate-resistance. 59 patients received single-agent dactinomycin with 53 (90%) patients achieving complete hCG response, 3 patients requiring combination chemotherapy or surgery, and 3 patients subsequently spontaneously resolving. 56 patients received EA chemotherapy with hCG complete response in 50 (89%) patients, and the remaining 6 patients were cured with further multi-agent chemotherapy or surgery. With carboplatin, 17/21 (81%) achieved an overall complete hCG response rate, with 4 patients requiring third-line EA. Carboplatin was well tolerated with no significant alopecia; myelosuppression was the most significant toxicity. Overall survival for all patients was 100%. CONCLUSION: These data show the continued excellent outcomes for methotrexate-resistant low-risk patients treated with single-agent dactinomycin or EA. Our experience with carboplatin is promising and provides an alternative regimen for methotrexate-resistant low-risk disease that avoids alopecia and in-patient treatment.

Ability grouping in secondary schools: effects on pupils' self-concepts.

BACKGROUND: Current pressure on secondary schools to increase ability grouping has raised concerns about the impact of setting on pupils' self-concepts. Evidence from previous research is conflicting. A multidimensional measure and multilevel modelling promise to clarify the effects. AIMS: This paper aims to examine the effects of structured ability grouping on year 9 pupils' self-concepts. SAMPLES: The sample comprises over 3000 year 9 pupils (aged 13-14 years) in 45 mixed secondary comprehensive schools in England. The schools represent three levels of ability grouping in the lower school (years 7 to 9). METHODS: Pupils responded to a multidimensional self-concept scale measuring academic and general facets of the self-concept. Measures of attainment were collected in English, mathematics and science. Multilevel modelling was used to examine the effect of the type of school on the general facets of the pupils' self-concept and the effects of setting in each curriculum subject on the academic facets of the self-concept. RESULTS: Pupils' general self-concept was higher in the group of schools with moderate levels of setting. The degree of setting in mathematics and science had no effect on the corresponding academic self-concepts but setting in English tended to lower the self-concepts of the higher attaining pupils and raise the self-concepts of lower attaining pupils. Gender differences were consistent with previous research, with boys having significantly higher self-concept scores than girls, except in English. These findings indicate that the degree of stratification in schools can have an impact on adolescents' self-esteem and views of themselves in school.

Scintillation proximity assay to study the interaction of epidermal growth factor with its receptor.

Scintillation Proximity Assay (SPA), which does not require the physical separation of receptor bound and free ligand, was applied to study the interaction of Epidermal Growth Factor (EGF) with its receptor (EGFR) in membrane preparations from human placenta. Fluomicrospheres to which the monoclonal anti-EGFR antibody R1 was coupled, were used. Kinetic binding data of the association of 125I-labeled EGF binding to the receptor at 20 degrees C could be fitted according to a double exponential model, which is consistent with the presence of fast and slow associating EGF binding sites. Dissociation kinetics revealed that perturbation of equilibrium conditions rapidly occurs upon washing. Multiple point Scatchard analysis of equilibrium 125I-labeled EGF binding data revealed curvilinearity, indicating the presence of both high and low affinity EGF binding sites. We conclude that SPA is an interesting new tool in the exploration of the interaction of ligands with their receptors, which allows detailed ligand-receptor studies under precise in situ conditions.

Inhibition of trypsin by t-butyloxycarbonyl-alpha-aza-(4-aminophenyl)alanine phenyl ester.

t-Butyloxycarbonyl-alpha-aza-(4-aminophenyl)alanine phenyl ester (III: R = NH2) has been synthesized. The rate of inhibition of trypsin (EC 3.4.21.4) by this compound (due to acylation followed by slower deacylation) shows a marked pH maximum at approximately 6. The shape of the pH-rate curve is discussed in terms of (i) the normal pH-activity curve of trypsin reacting with a charged substrate, i.e. the protonated form of the amino compound, (ii) the deprotonation of the 4-amino group with pKa 4.3, and (iii) the lower rate of reaction of the enzyme with the uncharged, deprotonated form of the ester.

Utilization of static and kinetic information for depth by young Malawians.

The utilization of static and kinetic information for depth by Malawian children and young adults in making monocular relative size judgments was investigated. Subjects viewed pairs of objects or photographic slides of the same pairs and judged which was the larger of each pair. The sizes and positions of the objects were manipulated such that the more distant object subtended a visual angle equal to, 80% of, or 70% of the nearer object. Motor parallax information was manipulated by allowing or preventing head movement. All subjects displayed sensitivity to static information for depth when the two objects subtended equal visual angles. When the more distant object was larger but subtended a smaller visual angle than the nearer object, subjects tended to base their judgments on retinal size. Motion parallax information increased accuracy of judgments of three-dimensional displays but reduced accuracy of judgments of pictorial displays. Comparisons are made between these results and those for American subjects.

Utilization of static and kinetic information for depth by young Malawians

The utilization of static and kinetic information for depth by Malawian children and young adults in making monocular relative size judgments was investigated. Subjects viewed pairs of objects or photographic slides of the same pairs and judged which was the larger of each pair. The sizes and positions of the objects were manipulated such that the more distant object subtended a visual angle equal to; 80 percent of; or 70 percent of the nearer object. Motor parallax information was manipulated by allowing or preventing head movement. All subjects displayed sensitivity to static information for depth when the two objects subtended equal visual angles. When the more distant object was larger but subtended a smaller visual angle than the nearer object; subjects tended to base their judgments on retinal size. Motion parallax information increased accuracy of judgments of three- dimensional displays but reduced accuracy of judgments of pictorial displays. Comparisons are made between these results and those for American subjects

Cytosine deaminase: structural modifications studies.

Structural modification studies have been shown that a cysteine, a histidine and possibly an arginine residue are involved in the catalytic process. The enzyme gave a single band on polyacrylamide gel electrophoresis, and the amino acid analysis showed it to contain a high proportion of hydrophobic residues, which was in agreement with the chemical modification results.

The reaction of an alpha-aza-amino acid derivative with chymotrypsin and its use as a ligand for covalent affinity purification.

1. Chymotrypsin is inactivated by N-acetyl-alpha-azaphenylalanine phenyl ester (phenyl N(2)-acetyl-N(1)-benzylcarbazate) in a stoicheiometric reaction. 2. The inactivation is reversible spontaneously (first-order rate constant is 1.2x10(-4)s(-1)) and accelerated by the presence of hydroxylamine. 3. Polymers based on polyacrylamide and carrying ligands containing the alpha-azaphenylalanine phenyl ester group were prepared. 4. Chymotrypsin reacts with these polymers and is removed by them from solution. Trypsin reacts less rapidly. 5. Chymotrypsin is slowly released from the polymer spontaneously and more rapidly on treatment with hydroxylamine. 6. The reaction of trypsin can be inhibited by competitive inhibitors. 7. Chymotrypsin was separated from trypsin by the selective bonding of chymotrypsin on to and its subsequent liberation from one of the polymers described.

A comparison of the antinociceptive actions of cholinomimetic and morphine-like drugs.

1. The antinociceptive activity of morphine, nalorphine, oxotremorine and eserine has been examined in mice in electroshock and phenylbenzoquinone writhing tests.2. The effectiveness of these drugs alone, in combination with each other, and in combination with the muscarinic antagonist atropine sulphate, and with the narcotic antagonist naloxone has also been investigated.3. In both tests morphine was effective and antagonized by naloxone.4. Nalorphine was active in the phenylbenzoquinone test but only slightly active in the electroshock test: it was antagonized by naloxone in both tests.5. Morphine was potentiated by nalorphine in the phenylbenzoquinone test. but antagonized by it in the electroshock test.6. Oxotremorine was effective in both tests, and was antagonized by atropine sulphate.7. Eserine was active only in the phenylbenzoquinone test, and was antagonized by atropine sulphate.8. Oxotremorine was potentiated by eserine in the phenylbenzoquinone test, but antagonized by it in the electroshock test.9. Crossed agonist and partial agonist experiments produced enhancement.10. No antagonism was seen in the crossed antagonist experiments.11. The similarities between the effects of the two classes of drugs are discussed, and the conclusion drawn that they act by separate mechanisms.