Trials and tribulations: obstacles to clinical trial recruitment.
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Clinical Trials as Topic↗
Biomedical subjects
N Siddiqui
Publications and source records attributed to N Siddiqui.
Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer.
PURPOSE: Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts. PATIENTS AND METHODS: We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 x 10(9) plaque forming units (pfu), 1 x 10(10) pfu, 3 x 10(10) pfu, and 1 x 10(11) pfu. RESULTS: The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 x 10(10) pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 10(11) pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication. CONCLUSION: This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.
Adenoviridae↗
Guidelines on using guidelines.
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Evidence-Based Medicine↗
An African male with cough, haemoptysis, weight loss and hypercalcaemia: TB or not TB?
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Antineoplastic Combined Chemotherapy Protocols↗
Primary scleral buckling in open-globe injury involving the posterior segment.
PURPOSE: To determine whether scleral buckle placement at the time of primary repair of open-globe injury of the posterior segment is beneficial. DESIGN: Retrospective, comparative, nonrandomized interventional study. PARTICIPANTS: One hundred twenty-five open-globe injuries treated at the Duke University Medical Center from June 1980 to May 1997. METHODS: Open-globe injuries were classified with the Open-globe Injury Classification. Eyes that had zone 2 and 3 injuries that had a primary buckle placed were compared with those that did not. MAIN OUTCOME MEASURES: Subsequent retinal detachment, visual outcome, and need for subsequent scleral buckling. RESULTS: The rate of retinal detachment and the visual outcome were similar in the two groups. More than half of those who did not have a primary buckle placed had subsequent scleral buckling surgery. CONCLUSIONS: Many open-globe injuries of the posterior segment require eventual scleral buckle. There may be a role for placement of a scleral buckle at the time of primary repair.
Adolescent↗
Rapid fold and structure determination of the archaeal translation elongation factor 1beta from Methanobacterium thermoautotrophicum.
The tertiary fold of the elongation factor, aEF-1beta, from Methanobacterium thermoautotrophicum was determined in a high-throughput fashion using a minimal set of NMR experiments. NMR secondary structure prediction, deuterium exchange experiments and the analysis of chemical shift perturbations were combined to identify the protein fold as an alpha-beta sandwich typical of many RNA binding proteins including EF-G. Following resolution of the tertiary fold, a high resolution structure of aEF-1beta was determined using heteronuclear and homonuclear NMR experiments and a semi-automated NOESY assignment strategy. Analysis of the aEF-1beta structure revealed close similarity to its human analogue, eEF-1beta. In agreement with studies on EF-Ts and human EF-1beta, a functional mechanism for nucleotide exchange is proposed wherein Phe46 on an exposed loop acts as a lever to eject GDP from the associated elongation factor G-protein, aEF-1alpha. aEF-1beta was also found to bind calcium in the groove between helix alpha2 and strand beta4. This novel feature was not observed previously and may serve a structural function related to protein stability or may play a functional role in archaeal protein translation.
Archaeal Proteins↗
Gestational trophoblastic disease: does central nervous system chemoprophylaxis have a role?
In the UK there are standardized surveillance procedures for gestational trophoblastic disease. However, there are differences in practice between the two treatment centres in terms of definition of persistent gestational trophoblastic disease, prognostic risk assessment and chemotherapeutic regimens. The role of prophylactic chemotherapy for cerebral micrometastatic disease in persistent gestational trophoblastic disease is unclear. We have analysed the outcome of 69 patients with lung metastases who elsewhere might have received prophylactic intrathecal chemotherapy. Of the 69 patients, 67 received intravenous chemotherapy only. The other two patients had cerebral metastases at presentation. One patient who received only intravenous chemotherapy subsequently developed a cerebral metastasis, but this patient's initial treatment was compromised by non-compliance. This experience supports our current policy of not treating patients with pulmonary metastases, without clinical evidence of central nervous system (CNS) involvement, with prophylactic intrathecal therapy.
Adolescent↗
Carboplatin and paclitaxel, alone and in combination: dose escalation, measurement of renal function, and role of the p53 tumor suppressor gene.
In this pharmacokinetic and dose-escalation study of the carboplatin/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combination, patients were randomly assigned to receive paclitaxel either as a 1-hour or a 3-hour infusion. The 1-hour infusion was feasible, with maximum tolerated doses similar to those previously reported for a 3-hour infusion. Using patients' age, height, plasma creatinine, and plasma creatine kinase provided an improved estimate of the glomerular filtration rate compared with the more traditional creatinine-based formulas according to population analysis of data derived from glomerular filtration rate estimates performed by an isotope method. Studies of the p53 gene sequence of ovarian tumors at diagnosis suggest that p53 mutations are a potent predictor of response to subsequent treatment with carboplatin.
Antineoplastic Agents, Phytogenic↗
Imaging quiz case 2. Tuberculous mastoiditis causing a facial palsy.
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Aged↗
Low HIV and high STD among commercial sex workers in a brothel in Bangladesh: scope for prevention of larger epidemic.
The present study documents the first systematic assessment of a brothel in Bangladesh in terms of sexually transmitted disease (STD) and human immunodeficiency virus (HIV). A cross sectional study was undertaken on brothel-based commercial sex workers (CSWs) selected systematic random sampling to assess the prevalence of STDs and HIV among CSWs in a brothel setting. Two hundred and ninety-six CSWs were selected from a brothel with a population of 593 women. Following informed consent, endocervical and blood samples were obtained for the diagnosis of genital chlamydia, gonorrhoea, HIV and syphilis respectively. In addition, another 170 consecutive blood samples were collected from the total CSW population for HIV tests. All blood samples for HIV testing were made anonymous by removing patient identifiers before testing. Endocervical specimens were tested by polymerase chain reaction (PCR) for the diagnosis of genital chlamydia and gonorrhoea. Syphilis and HIV infections were diagnosed by serology. One hundred and sixty-nine (57.1%) of the women were Treponema pallidum haemagglutination (TPHA)-positive, 20 (6.8%) of the women were Venereal Disease Research Laboratory (VDRL)-positive at a greater than 1:8 dilution. Eighty-two (28%) of the women were found to be infected either by gonorrhoea or chlamydia. No HIV antibody was found in any of the 466 blood samples. A high prevalence of STDs and low prevalence of HIV in the CSWs in Bangladesh suggest potential for the rapid spread of HIV once it is introduced in this high-risk population. The opportunity to control STD and HIV infection in this population should not be missed, in order to prevent a large epidemic in the future.
Bangladesh↗
A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate.
LY231514 is a novel antifolate that principally inhibits thymidylate synthase, but with additional folate-dependent enzyme targets. A Phase I study of single-agent LY231514 administered as a daily i.v. infusion over 10 minutes for 5 days, repeated every 3 weeks, was conducted to evaluate the maximum tolerated dose, pharmacokinetic profile, and antitumor activity of the drug using this schedule. Thirty-eight patients with advanced malignancies that were refractory or not amenable to standard therapy were treated with a total of 116 courses of LY231514, escalating treatment doses through 10 dose levels, from 0.2-5.2 mg/m2/day. No objective clinical responses were observed, although minor antitumor activity not fulfilling the response criteria was seen in three patients. A maximum tolerated dose of 4.0 mg/m2/day was determined, with neutropenia as the predominant dose-limiting toxicity. Reversible disturbances of liver biochemistry, fulfilling the protocol definitions of dose-limiting toxicity, were also observed. Other toxicities included diarrhea, mucositis, skin rash, and fatigue. Pharmacokinetic studies were performed at all treatment levels. Analysis showed a linear relation between administered dose and both maximum plasma concentration (Cmax) and area under the plasma concentration/time curve. The drug was cleared with a day 1 total body clearance of 108.9 +/- 38.8 ml/min/m2, with plasma concentrations declining with a mean harmonic terminal half-life of 1.4 +/- 0.98 h. When given by this schedule, LY231514 is tolerable, and Phase II studies are in progress.
Adult↗
Results of middle ear ventilation with 'Mangat' T-tubes.
Tympanostomy tube placement has been shown to be an effective treatment for recurrent acute otitis media and chronic otitis media with effusion. The Senior author, (K.S. Mangat), considered stiffness and the longer inner limbs of the Goode (Xomed) or Treace (Treace Medical) T-tubes as important factors in the high incidence of complications, and used smaller soft silicone. Mangat-tube (Xomed) with shorter inner limbs. A prospective study was undertaken over a five year period (July 1987-July 1992) which was a continuation of a previous retrospective study of Goode and Treace T-tubes (Mangat, K.S., Morrison, G.A.J., and Ganiwalla, T.M. (1993) Int. J. Pediatr. Otorhinolaryngol. 25, 119-125). 322 Mangat tubes (M-tubes) were inserted in 191 patients with persistent otitis media with effusion. The peak ages for insertion were between 4 and 6 years. Spontaneous extrusion occurred in 240 ears (66.5%; 154 patients) at a mean time of 29.3 months. Of these, there were 60 perforations at three months follow-up (18.6%) which fell to 31 perforations after six months (9.6%). Surgical extraction of the M-tube was necessary in 82 ears (22.7%; 50 patients) following persistent otorrhoea or resolution of the condition. Otorrhoea, requiring treatment, was noted in 36 ears (11%). No association was found between the occurrence of infection and the incidence of perforation persisting after a year. There was a higher incidence of persistent perforation in those requiring surgical extraction. The overall persistent perforation rate of only 9.6% would appear to be less than that experienced with Goode or Treace T-tubes.
Adolescent↗
Structure of the human gene (COX6A2) for the heart/muscle isoform of cytochrome c oxidase subunit VIa and its chromosomal location in humans, mice, and cattle.
We have mapped the gene for the heart/muscle isoform of cytochrome c oxidase (COX) subunit VIa in three mammalian species and isolated the human COX6AH gene (HGMW-approved symbol COX6A2). The bovine gene was mapped by somatic cell hybrid mapping panels to bovine chromosome BTA 25 with 94-95% concordance. The mouse gene (Cox6ah) was mapped using an interspecific backcross panel from the cross (C57BL/6J x Mus spretus)F1 x Mus spretus probed with the mouse COX VIa-H cDNA. Cox6ah was located on distal chromosome 7, between D7Mit8 and D7Mit13. From the regions of known gene conservation among these three species, we predicted that human COX6AH would be located on chromosome 16p. We hybridized a human x rodent mapping panel of somatic cell hybrids with the human cDNA to confirm this assignment. These data taken together indicated that the human COX6AH gene is located on the short arm of chromosome 16 and facilitated the isolation of the human gene from a chromosome 16-enriched library. The human COX6AH gene spans about 1 kb and contains three exons and two small introns. The sequences of the proximal 5' flanking regions of COX6AH genes are highly conserved between human, bovine, and rodent.
Amino Acid Sequence↗
Ectopic expression of Bcl-2, but not Bcl-xL rescues Ramos B cells from Fas-mediated apoptosis.
The human Burkitt lymphoma Ramos B cell line can be induced to undergo apoptosis in response to a variety of different agents, including calcium ionophores, anti-immunoglobulin (Ig) and macromolecular synthesis inhibitors. In addition, following up-regulation of the Fas (CD95) surface receptor by CD40 ligation, these cells also become susceptible to apoptosis induction by Fas ligation. We have previously shown that protection from calcium ionophore- and macromolecular synthesis inhibitor-induced apoptosis by CD40 ligation is associated with a rapid up-regulation of Bcl-xL followed by a more moderate and delayed up-regulation of Bcl-2. We show here that overexpression of Bcl-xL, like Bcl-2, protects Ramos cells from apoptosis induction in response to calcium ionophore, anti-Ig and macromolecular synthesis inhibition. However, in contrast to Bcl-2, ectopic overexpression of Bcl-xL does not rescue from Fas-mediated apoptosis. Thus, in Ramos B cells, the Fas apoptotic pathway exhibits differential sensitivity to inhibition by Bcl-2 family members. These findings also suggest that CD40 signaling provides a switch which renders the cells susceptible to Fas-ligand mediated apoptosis through up-regulation of Fas whilst affording protection from anti-Ig-induced apoptosis through up-regulation of Bcl-xL.
Apoptosis↗
Day-case adenoidectomy: how popular and safe in a rural environment?
In spite of previously favourable reports on day-case adenoidectomy, there are still worries amongst otolaryngologists that such practice is unsafe, especially in a rural environment. A national survey was therefore carried out which shows that only 41 per cent of respondents perform adenoidectomy routinely as day-case, and even fewer in rural areas. A regional audit on day-case adenoidectomy, covering five hospitals, was conducted in East Anglia. Between 1994 to 1995, 73 day-case adenoidectomies were performed and the outcome was compared to those of 183 in-patient adenoidectomies during the same period. The children in the day-case group recovered post-operatively even better than the in-patient group. None of them stayed overnight or required re-admission. There was no increased in post-operative consultation to the general practitioner. The parents in the day-case group were mostly in favour of the day-case arrangement (88 per cent). The results suggest that day-case adenoidectomy is safe and popular with parents even in a rural environment.
Adenoidectomy↗
A clinical and pharmacokinetic study of the combination of carboplatin and paclitaxel for epithelial ovarian cancer.
The aim of this phase I study was to determine the maximum tolerated dose of a 3-h infusion of paclitaxel, combined with carboplatin at a fixed AUC of 7 mg ml-1 min every 4 weeks for up to six cycles and to evaluate any possible pharmacokinetic interaction. Twelve chemonaive patients with ovarian cancer were treated with paclitaxel followed by a 30-min infusion of carboplatin. Paclitaxel dose was escalated from 150 mg m-2 to 225 mg m-2 in cohorts of three patients. Carboplatin dose was based on renal function. Pharmacokinetic studies were performed in nine patients (at least two at each dose level). A total of 66 courses were evaluable for assessment. Grade 3 or 4 neutropenia was seen in 70% of the courses, however hospitalization was not required. Grade 3 or 4 thrombocytopenia occurred in 24% of the courses. Alopecia, myalgia and peripheral neuropathy were common but rarely severe. The pharmacokinetics of paclitaxel was non-linear and did not appear to be influenced by co-administration of carboplatin. The AUC of carboplatin was 7.0 +/- 1.4 mg ml-1 min, indicating that there was no pharmacokinetic interaction. The combination of carboplatin and paclitaxel may be administered as first-line treatment for advanced ovarian cancer. Although myelosuppression is the dose-limiting toxicity of the component drugs, the severity of thrombocytopenia was less than anticipated. The results of this study, with only a small number of patients, need to be confirmed in future investigations.
Adult↗
Evidence for response set effects in structured research interviews.
The Addiction Severity Index and NIMH Diagnostic Interview Schedule data of 20 methadone-maintained subjects with "fake bad" invalid profiles on the Personality Assessment Inventory, 15 methadone-maintained subjects with "fake good" invalid profiles, and 158 methadone-maintained subjects with valid profiles were compared. The findings revealed a number of significant group differences on both measures with the highest scores for the fake bad subjects and lowest scores for the fake good subjects. These findings suggest that the response sets exhibited in response to the Personality Assessment Inventory questionnaire extended to performance during the two semi-structured interviews. There was no indication that interviewers were aware of misrepresentation. The limitations of the findings and alternative interpretations of the data are considered.
Adult↗
Carboplatin in combination with paclitaxel in advanced ovarian cancer: dose determination and pharmacokinetic and pharmacodynamic interactions.
Data from various phase I/II studies of carboplatin in combination with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have suggested that the degree of thrombocytopenia seen is less than that expected when carboplatin is given alone. However, some studies also have suggested that the area under the plasma concentration-time curve (AUC) of carboplatin is lower than that expected, raising the possibility of a pharmacokinetic interaction. Patients with advanced epithelial ovarian cancer were treated with first-line carboplatin (AUC = 7, using the 51Cr EDTA [edetic acid] clearance method) and escalating doses of paclitaxel. Thrombocytopenia was mild and was significantly less when the paclitaxel dose was 175 mg/m2 versus 150 mg/m2. Paclitaxel kinetics were nonlinear, as previously reported. The achieved carboplatin AUC was 7 +/- 1 mg/mL.min, indicating that the pharmacokinetics of carboplatin are not affected by paclitaxel. Glomerular filtration rates measured in 184 patients using the 51Cr EDTA clearance method were compared with rates estimated from the plasma creatinine level using the Cockcroft-Gault or Jeliffe formulas and showed a significant bias of these two formulas. Clearances above 50 mL/min were underestimated by an amount that became greater as the clearance increased and was approximately 25% to 35% for patients with clearances in the normal range. Since creatinine-based methods have been used in many previous studies, care is needed in interpreting the predicted AUC values from these studies. Carboplatin and paclitaxel may be given safely in combination at full doses, and the thrombocytopenia seen is significantly less than that observed with single-agent carboplatin. No evidence exists of a pharmacokinetic interaction, and the observation in some studies that the carboplatin AUC was lower than expected was probably due to the methodology used to estimate the glomerular filtration rate.
Adult↗