SB-649915-B, a novel 5-HT1A/B autoreceptor antagonist and serotonin reuptake inhibitor, is anxiolytic and displays fast onset activity in the rat high light social interaction test.

Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (+/-) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT(1A/B) receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED(50) of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [(3)H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (p<0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.     

A phase I trial of pre-operative radiotherapy for prostate cancer: Clinical and translational studies

BACKGROUND AND PURPOSE: Selected patients undergoing radical prostatectomy for localized prostate cancer can be at high-risk for pT3 disease and require subsequent radiotherapy. In a phase I trial, we investigated the feasibility of pre-operative radiotherapy for this patient subset. MATERIALS AND METHODS: Eligibility criteria were: T1/T2N0M0 tumors plus (i) Gleason >or=7, PSA>10 ng/ml and <35 ng/ml, or (ii), PSA >15 ng/ml and less <35 ng/ml (any Gleason). Patients received 25 Gy in five fractions of radiotherapy followed by radical prostatectomy. Trial endpoints included intra-operative morbidity and late toxicity following combined treatment. We also stained pre- and post-radiotherapy prostate samples for DNA damage response proteins. RESULTS: Between 2001 and 2004, 15 patients were entered on trial. Thirteen patients completed combined-modality treatment. Only one patient had signs of intra-operative inflammation. No patient had post-operative complication. There was no severe late gastrointestinal toxicity. Late genitourinary toxicity consisted of severe urinary incontinence in 2 of 13 patients. From a translational standpoint, irradiated prostate tumor tissues had long-term activation of the CDK-inhibitor p21(WAF) associated with reduced cell proliferation. CONCLUSION: Intra-operative morbidity is low following short-course, pre-operative radiotherapy. A phase II trial is planned to fully document biochemical response with this combined-modality approach.     

An initial report of a radiation dose-escalation trial in patients with one to five sites of metastatic disease

PURPOSE: Previous investigations have suggested that a subset of patients with metastatic cancer in a limited number of organs may benefit from local treatment. We investigated whether cancer patients with limited sites of metastatic disease (oligometastasis) who failed standard therapies could be identified and safely treated at one to five known sites of low-volume disease with radiotherapy. EXPERIMENTAL DESIGN: Patients with one to five sites of metastatic cancer with a life expectancy of >3 months and good performance status received escalating doses of radiation to all known sites of cancer with hypofractionated radiation therapy. Patients were followed radiographically with computed tomography scans of the chest, abdomen, and pelvis and metabolically with [18F]fluorodeoxyglucose-positron emission tomography 1 month following treatment and then every 3 months. Acute toxicities were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and late toxicities were scored using the Radiation Therapy Oncology Group late toxicity scoring system. RESULTS: Twenty-nine patients with 56 metastatic lesions were enrolled from November 2004 to March 2007, with a median follow-up of 14.9 months. Two patients experienced acute (radiation pneumonitis and nausea) and one experienced chronic (gastrointestinal hemorrhage) grade > or =3 toxicity. Fifty-nine percent of patients responded to protocol therapy. Twenty-one percent of patients have not progressed following protocol treatment. Fifty-seven percent of treated lesions have not progressed at last follow-up. Progression was amenable to further local therapy in 48% of patients. CONCLUSIONS: Patients with low-volume metastatic cancer can be identified, safely treated, and may benefit from radiotherapy.     

A decade of paediatric lymphangiomas

Lymphangiomas are uncommon, benign developmental tumours of the lymphatic system. Though usually symptomless, lymphangiomas can cause problems through pressure effects and may sometimes be life-threatening, especially in newborn infants with massive lesions involving the neck and mediastinum. The literature is reviewed with 33 additional cases presented. Despite the advent of more recent and innovative treatments, surgical excision is associated with the least number of complicatons and is still the most widely used and successful method of treatment.     

The correlation between sperm cell morphology and fertilization after zona pellucida slitting in subfertile males

OBJECTIVE: This work was undertaken to evaluate the correlation between sperm cell morphology and fertilization after zona pellucida slitting in subfertile males. DESIGN: Twenty-two couples who failed at least one in vitro fertilization attempt because of lack of oocytes fertilization underwent a zona-slitting micromanipulative procedure. A total of 245 oocytes were retrieved and inseminated by three different modes: 151 oocytes underwent micromanipulation, 2 were damaged, and the remaining 149 inseminated by the husband's sperm (group A). Fifty-five oocytes were not manipulated and inseminated by the husband's sperm (group B), and 39 oocytes were not manipulated and inseminated by a donor sperm (group C). RESULTS: Fertilization rates were 26.8%, 5.5%, and 53.8% in groups A, B, and C, respectively, and differed significantly between group A and group B. The cleavage rates were lower for oocytes fertilized by the husband's sperm (48.6%) than that obtained by donor (90%), suggesting a sperm factor contributing to this phenomenon. The procedure was most efficient in patients with a total motile sperm count after preparation of greater than or equal to 5 million and with either normal sperm morphology or defects localized to the acrosome or tail region only. Sperm with nuclear morphological abnormalities demonstrated a marked reduction in fertilization potential. CONCLUSION: It is concluded that the zona-slitting technique enhances fertilization of severely subfertile sperm, and its efficacy is affected by sperm morphology and a threshold concentration of motile cells.     

The Recognition Failure and Graphic Success of Idiot-Savant Artists

Three groups of subjects, an idiot-savant group, a group of mentally handicapped subjects matched for IQ, and normal artistically gifted children, were compared for their recognition and graphic reproduction abilities. It was found that, independent of input modality, level of intelligence determined recognition performance, while graphic ability independent of IQ was the determining factor in reproduction accuracy.     

Determination of the allelic frequencies of an L-myc and a p53 polymorphism in human lung cancer

The L-myc and p53 genes have been implicated in lung cancer.Both of these genes have restriction fragment length polymorphisms(RFLPs) that could account for differential expression or activityof variant forms. An EcoRI restriction site in the L-myc genewas previously reported to be a predictor of poor prognosisin Japanese lung cancer patients. There are several RFLPs inthe p53 gene. In exon 4 there is a polymorphism that codes foreither an arginine or proline residue at codon 72. We previouslyreported the frequency of DNA-RFLPs at these gene loci revealedby EcoRI and AccII respectively. Here we report results froma study comparing lung cancer cases (n = 31) with chronic obstructivepulmonary disease controls (n = 49). No association was foundbetween these RFLPs and disease status. Previous observationsthat the frequencies of these RFLPs varied by race were confirmed.The p53 arginine allele was found to be more common in Caucasians(0.71) than African Americans (0.50). The EcoRI restrictionsite present allele in L-myc was more frequent in African-Americans(0.71) than Caucasians (0.49). Thus, the allelic frequency forL-myc was similar in African Americans to that reported forJapanese, and the allelic frequency for p53 was similar in Caucasiansto that reported for Japanese.     

Defining functional drug-interaction domains on topoisomerase II by exploiting mechanistic differences between drug classes

Topoisomerase II is the primary cellular target for a variety of antineoplastic drugs that are active against human cancers. These drugs exert their cytotoxic effects by stabilizing covalent topoisomerase II-cleaved DNA complexes that are fleeting intermediates in the catalytic cycle of the enzyme. Despite this common feature of drug action, a number of mechanistic differences between drug classes have been described. These mechanistic differences (including effects on DNA cleavage/religation, DNA strand passage, and adenosine triphosphate hydrolysis) were used as the basis for a series of competition experiments to determine whether different compounds share a common site of action on topoisomerase II or interact at distinct sites. Results of the present study strongly suggest that at least four structurally disparate antineoplastic drugs, etoposide, amsacrine, genistein, and the quinolone CP-115,953, share an overlapping interaction domain on the enzyme.Paper presented at the Topoisomerase Inhibitors Conference, University of Maryland Cancer Center, 27–30 October 1993, Monterey, California, USA. Supported in part by Bristol Myers Oncology Division     

Defective oocytes: a new subgroup of unexplained infertility.

OBJECTIVE: To define a new category of unexplained infertility and its potential treatment. DESIGN: Normal infertile couples underwent prospectively, cross-fertilization attempts in which the wife's oocytes were inseminated by the husband and donor semen. After recurrent failure of fertilization, cross insemination of donor oocytes was attempted with the husband sperm. SETTING: In vitro fertilization unit at a teaching hospital. PATIENTS: Three couples who were diagnosed as suffering of unexplained infertility and treated by in vitro fertilization (IVF). RESULTS: The female partner of these couples produced morphologically normal oocytes that were demonstrated to be functionally defective and failed to fertilize in vitro with both husband and donor sperm. Donated oocytes inseminated by the husband's sperm were fertilized in all patients, demonstrating the normal fertilizing ability of the husbands' semen. One patient conceived and delivered after an oocyte donation. CONCLUSIONS: Conclusive diagnosis of defective oocytes as a cause of infertility may be made only after IVF and oocyte donation.     

Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment.

OBJECTIVE: To overview the world literature on ovarian hyperstimulation syndrome (OHSS) and modes of prevention and treatment of OHSS. STUDY SELECTION: All the pertinent literature on OHSS, its prevention, and strategies for treatment were reviewed. PREVENTION: Key to prevention is proper identification of the population at risk, which includes women with either the hormonal or the morphological signs of polycystic ovarian disease, high serum estradiol (E2) before human chorionic gonadotropin (hCG) administration (E2 greater than 4,000 pg/mL), multiple follicular response (greater than 35), younger age, and lean habitus. When a high risk situation is recognized, ovulatory dose of hCG may be reduced, avoided (with cycle cancellation), or substituted by gonadotropin-releasing hormone or its agonist. Luteal support with hCG is to be bypassed. To minimize risk of OHSS, endogenous pregnancy-drived hCG may be eluded by judicious cryopreservation of all embryos. Last, follicular aspiration will allow higher levels of E2 and larger number of follicles to be matured with lesser risk of OHSS than conventional ovulation induction without follicular aspiration. TREATMENT: In-house for the severe and intensive care for the critical form. Meticulous fluid and electrolyte balance using both crystalloids and colloids (albumin) until hemoconcentration abates. Paracentesis is indicated for tight ascites, deteriorating kidney functions, and symptomatic relief. Diuretics may be prudently used once hemodilution is achieved. Dopamine drip may be used as a renal rescue, whereas heparin is indicated for thromboembolic phenomena and surgery reserved for abdominal catastrophies. Therapeutic interruption of an early gestation may be lifesaving when all other measures have failed. CONCLUSIONS: Although severe and critical OHSS may not be completely avoided, early recognition of high-risk factors, judicious prevention schemes, and treatment strategies should reduce the complication and long-term sequelae of this iatrogenic syndrome.