Sunitinib in combination with gemcitabine for advanced solid tumours: a phase I dose-finding study.

BACKGROUND: This phase I, dose-finding study determined the maximum tolerated dose (MTD), safety, and pharmacokinetics of sunitinib plus gemcitabine in patients with advanced solid tumours. METHODS: Two schedules with sunitinib (25-50 mg per day) and IV gemcitabine (750-1250 mg m(-2)) in escalating doses were studied. First, patients received sunitinib on a 4-weeks-on-2-weeks-off schedule (Schedule 4/2) plus gemcitabine on days 1, 8, 22, and 29. Second, patients received sunitinib on a 2-weeks-on-1-week-off schedule (Schedule 2/1) plus gemcitabine on days 1 and 8. The primary endpoint was determination of MTD and tolerability. RESULTS: Forty-four patients received the combination (Schedule 4/2, n=8; Schedule 2/1, n=36). With no dose-limiting toxicities (DLTs) at maximum dose levels on Schedule 2/1, MTD was not reached. Grade 4 treatment-related AEs and laboratory abnormalities included cerebrovascular accident, hypertension, and pulmonary embolism (n=1 each), and neutropenia (n=3), thrombocytopenia and increased uric acid (both n=2), and lymphopenia (n=1). There were no clinically significant drug-drug interactions. Antitumor activity occurred across dose levels and tumour types. In poor-risk and/or high-grade renal cell carcinoma patients (n=12), 5 had partial responses and 7 stable disease ≥ 6 weeks. CONCLUSION: Sunitinib plus gemcitabine on Schedule 2/1 with growth factor support was well tolerated and safely administered at maximum doses of each drug, without significant drug-drug interactions.

An ex vivo culture model for orthodontically induced root resorption.

OBJECTIVES: Root resorption is a ubiquitous although undesirable sequela to orthodontic treatment. Current methods to investigate the pathophysiology have certain limitations. In pursuit to understand and develop treatment modalities for orthodontically induced root resorption, the ability to manipulate cells within their natural extracellular matrix in a three dimensional organotypic model is invaluable. The study aimed to develop a laboratory-based organotypic model to investigate the effect of orthodontic forces on the periodontium. METHODS: Mandibular slices of male Wistar rats were maintained in Trowel-typed cultures at 37°C in 5% carbon dioxide in air for 7 days with test specimens subjected to compressive forces at 50 g and 100g by stainless steel springs. Tissue architecture and cell viability were maintained under culture conditions. RESULTS: Osteoclast numbers increased significantly in both test groups whilst odontoclasts increased in the 50 g group. Immunohistochemistry demonstrated increased dentine sialoprotein expression in both test groups, suggesting changes in mineralization-related activity due to mechanical strain. CONCLUSION: The study showed initial cellular and molecular changes of key markers that relate to root resorption in response to mechanical loading. CLINICAL SIGNIFICANCE: Severe root resorption may occur when forces applied are heavy or transmitted over an extended period and could lead to mobility and tooth loss. This ex vivo model can be used to investigate cellular and molecular processes during orthodontic tooth movement which may advance the clinical management of root resorption.

Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure.

AIMS: To assess the antitumour activity, safety, pharmacokinetics and pharmacodynamics of continuous daily sunitinib dosing in patients with imatinib-resistant/intolerant gastrointestinal stromal tumour (GIST) and to assess morning dosing versus evening dosing. PATIENTS AND METHODS: In this open-label phase II study, patients were randomised to receive morning or evening dosing of sunitinib 37.5mg/day. The primary end-point was clinical benefit rate (CBR; percent complete responses+partial responses [PRs]+stable disease [SD] 24 weeks). Secondary end-points included progression-free survival (PFS), overall survival (OS), safety, pharmacokinetic parameters and plasma biomarker levels. RESULTS: Sixty of 61 planned patients received treatment (30 per dosing group); 26 completed the study. Overall, the CBR was 53% (95% exact CI, 40-66): eight patients (13%) achieved objective PRs; 24 (40%) achieved SD 24 weeks. Median PFS was 34 weeks (95% CI, 24-49); median OS was 107 weeks (95% CI, 72 - not yet calculable). Most adverse events (AEs) were of grade 1 or 2 in severity, and were manageable through dose modification or standard interventions. No new AEs were apparent compared with the approved intermittent dosing schedule. Antitumour activity and safety were generally similar with morning and evening dosing. Continuous daily sunitinib dosing achieved and sustained effective drug concentrations without additional accumulation across cycles. Decreases from baseline in plasma levels of soluble KIT after 20 and 24 weeks of dosing correlated with longer OS. CONCLUSION: For patients with imatinib-resistant/intolerant GIST, continuous daily sunitinib dosing appears to be an active alternative dosing strategy with acceptable safety.

A Phase II trial of cisplatin plus WR-2721 (amifostine) for metastatic breast carcinoma: an Eastern Cooperative Oncology Group Study (E8188).

BACKGROUND: Cisplatin has minimal antitumor activity when used as second- or third-line treatment of metastatic breast carcinoma. Older reports suggest an objective response rate of 8% when 60-120 mg/m2 of cisplatin is administered every 3-4 weeks. Although a dose-response effect has been observed with cisplatin, the dose-limiting toxicities associated with cisplatin (e.g., nephrotoxicity, ototoxicity, and neurotoxicity) have limited its use as a treatment for breast carcinoma. WR-2721 or amifostine initially was developed to protect military personnel in the event of nuclear war. Amifostine subsequently was shown to protect normal tissues from the toxic effects of alkylating agents and cisplatin without decreasing the antitumor effect of the chemotherapy. Early trials of cisplatin and amifostine also suggested that the incidence and severity of cisplatin-induced nephrotoxicity, ototoxicity, and neuropathy were reduced. METHODS: A Phase II study of the combination of cisplatin plus amifostine was conducted in patients with progressive metastatic breast carcinoma who had received one, but not more than one, chemotherapy regimen for metastatic disease. Patients received amifostine, 910 mg/m2 intravenously over 15 minutes. After completion of the amifostine infusion, cisplatin 120 mg/m2 was administered over 30 minutes. Intravenous hydration and mannitol was administered before and after cisplatin. Treatment was administered every 3 weeks until disease progression. RESULTS: Forty-four patients were enrolled in the study of which 7 (16%) were ineligible. A median of 2 cycles of therapy was administered to the 37 eligible patients. Six partial responses were observed for an overall response rate of 16%. Most patients (57%) stopped treatment because of disease progression. Neurologic toxicity was reported in 52% of patients. Seven different life-threatening toxicities were observed in patients while receiving treatment. CONCLUSIONS: The combination of cisplatin and amifostine in this study resulted in an overall response rate of 16%. Neither a tumor-protective effect nor reduced toxicity to normal tissues was observed with the addition of amifostine to cisplatin in this trial.

Modulation of cytochrome P4501A1 activity by ascorbigen in murine hepatoma cells.

Modulation of cytochrome P4501A1 (CYP1A1) activity is a mechanism whereby indoles present in cruciferous vegetables could affect the metabolism of xenobiotics. Ascorbigen (ASG) is the predominant indole formed during the degradation of glucobrassicin, although the mechanism by which ASG modulates CYP1A1 activity is not known. The major focus of this study was to examine the mechanism of CYP induction by ASG using a murine hepatoma-derived cell line (Hepa 1c1c7). ASG was shown to induce the activity of 7-ethoxyresorufin O-deethylase, a marker for CYP1A1, in a concentration-responsive manner with a maximum induction at 700 microM. Maximum ASG induction after 24-hr treatment was 7% of maximal CYP1Al activity induced by the well-known potent CYP1A1 inducer, indolo[3,2-b]carbazole (ICZ) (1 microM), and the EC50 values differed by 2-fold. The CYP1A1 activity increased continuously up to 72 hr, where ASG showed an induction efficiency in the same range as for the positive control (1 microM ICZ) after 24 hr, whereas the CYP1A1 protein level, measured by Western blot analysis, was maximally induced after 24 hr. ASG significantly inhibited CYP1A1 activity in whole cells at concentrations above 1 microM. ASG increased the chloramphenicol acetyl transferase (CAT) activity via a CAT reporter construct containing a dioxin-responsive element in Hepa 1c1c7 cells, indicating involvement of the aryl hydrocarbon receptor. ASG was shown to be transformed into ICZ, or a compound with the same chromatographic mobility as ICZ, in the medium. Taken together, the results indicate that ASG inhibits CYP1A1 activity at low concentrations, but induces the same activity at higher concentrations.

Inhibition of bacteriophage T7 RNA polymerase in vitro transcription by DNA-binding pyrrolo[2,1-c][1,4]benzodiazepines.

The interactions of several pyrrolo[2, 1-c][1,4]benzodiazepine (PBD) antitumor antibiotics with linearized plasmid pGEM-2-N-ras DNA have been analyzed by quantitative in vitro transcription (QIVT) and in vitro transcription footprinting (IVTF) methods. A concentration-dependent inhibitory effect of the PBDs on transcription is observed using both techniques. The rank order for overall inhibition of transcription by the QIVT method is found to be: sibiromycin > tomaymycin > anthramycin > DC-81 > neothramycin, whereas the IVTF experiments show a different ranking: sibiromycin > anthramycin > neothramycin > tomaymycin. In addition, stimulation of transcription was observed at low PBD concentrations in both the QIVT and IVTF experiments. These results demonstrate unequivocally that the formation of PBD-DNA adducts at AGA-5' base sequences on the transcribed strand results in transcription blockage for all PBDs examined. Furthermore, the sequence of flanking base pairs appears to influence the degree of blocking, with the sequences ACAGAAA-5', AAAGATG-5', AGAGATA-5', and CAAGAAC-5' providing the most pronounced blocks for all PBDs studied in this system. Neothramycin and tomaymycin cause additional blocks at some GGA-5' and TGA-5' sequences. Parallel MPE-Fe(II) footprinting studies have revealed PBD binding sites on both the transcribing and nontranscribing strands, although all transcription blocks determined from the IVTF assays are due to drug bound on the transcribing DNA template strand.

Prospective audit of mucosal biopsy specimens of the gastrointestinal tract.

AIMS: To determine why mucosal biopsy specimens of the gastrointestinal tract were taken and whether they were justified on clinical or pathological grounds. METHODS: A prospective audit of 190 consecutive biopsy specimens received in a university hospital histology department over six weeks. RESULTS: The 31 separate presenting symptoms included diarrhoea (34%), abdominal pain (16%) and rectal bleeding (15%). In 41% (78/190) the histology was normal, 28% (53/190) showed inflammatory changes and 11% 21/190) carcinoma. A clear justification for the procedure was identified in over 90% (171/190) of patients. In 36% (68/190) there was a change in patient management on receipt of biopsy reports and further investigations were ordered in 29% (55/190). The mean time taken to report biopsy specimens was 4.7 working days and there was no difference between the reporting time of a pathologist compared with a consultant or a trainee. CONCLUSIONS: There is no evidence that mucosal biopsy specimens are taken unnecessarily.

Changes in locus-of-control attitudes about drug misuse in a self-help group in a methadone maintenance clinic.

Clients of a methadone-maintenance clinic in Brooklyn, New York participating in a clinically-guided self-help (CGSH) program plus standard treatment (methadone maintenance plus individual counseling) demonstrated statistically significant changes in locus-of-control beliefs, from external to internal causation, about personal responsibility for drug misuse. Members of two control groups--one participating in a didactic lecture program plus standard treatment and the other receiving only standard treatment--failed to demonstrate similar changes. This increase in internal locus of control in the CGSH group suggests the potential efficacy of CGSH as a relapse-prevention therapeutic technique.

Selective toxicity of compounds naturally present in food toward the transformed phenotype of human colorectal cell line HT29.

It has previously been observed that allyl isothiocyanate, a compound naturally present in the diet, is more cytotoxic toward the human colorectal adenocarcinoma cell line HT29 in its control transformed state than after exposure to sodium butyrate or to dimethylformamide, which slow growth and induce differentiation (detransformation). In the present study, a range of other dietary compounds were assayed for such selective toxicity. These compounds were chosen as constituents of foodstuffs that have been identified from epidemiologic studies as being potentially antitumorigenic and also as having anticarcinogenic activity in experimental models. Benzyl and phenethyl isothiocyanate, benzyl thiocyanate, and quercetin showed decreased toxicity towards HT29 after detransformation of the cells by one or both treatments, whereas no change was observed in the sensitivity to diallyl sulfide or diallyl disulfide. It is proposed that the presence of such selectively toxic compounds in the diet may inhibit the development of tumors by interfering with the growth of preneoplastic lesions while having little effect on normal cells. The cumulative effects of these inhibitions may contribute to the chemopreventive properties of the parent foodstuffs observed in epidemiologic studies.

Cytotoxic and clastogenic effects of benzyl isothiocyanate towards cultured mammalian cells.

Benzyl isothiocyanate (BITC), a compound found in cruciferous vegetables present in the human diet, has previously been shown to induce chromosome aberrations in an Indian muntjac cell line. The results of this study show that it also induces both chromosome aberrations and sister chromatid exchanges (SCEs) in Chinese hamster ovary (CHO) cells in the absence of an exogenous metabolic activation system and induces DNA strand breaks as measured by the single-cell gel electrophoresis assay. However, whereas it increased the number of aberrations four-fold, it was not able to raise SCE levels by more than 50% and there was a levelling-off in the dose-response curve. Whereas the survival curve of CHO cells exposed to BITC was linear in shape, that of the human colorectal adenocarcinoma cell line HT29 was found to fit the exponential model (with an alpha equivalent of 0.28 and a beta equivalent of 2.80, where the concentration of BITC is measured in micrograms/ml). This pattern of clastogenic and cytotoxic activities is reminiscent of that generated by ionizing radiation and certain radiomimetic chemotherapeutic agents.

Computing for synchrotron radiation experiments.

Computing provision is of major concern to synchrotron radiation researchers. An overview is presented of the computing facilities for synchrotron radiation work at the Synchrotron Radiation Source, Daresbury Laboratory. Data acquisition, reduction and analysis are seen as an integrated activity essential for full utilization of beam time. We discuss the evolution of data-acquisition systems from stand-alone systems of limited computing power, to a unified project computing village using state-of-the-art equipment for combined-technique, high-data-rate experiments. A brief account of software packages for data reduction and analysis is also given.

Dental management of fibrous dysplasia.

This report describes two patients with monostotic fibrous dysplasia affecting maxillary alveolar processes. The long-term care for patient ML between ages 6 and 28 years included the transplantation of a premolar and a third molar tooth into the affected area, but the transplanted tooth 14 had to be extracted 6 years later. The patient JW, who presented at age 5 with an asymptomatic swelling in the left deciduous molar and first permanent molar region, was followed for 15 years. Teeth 24, 25, and 26 were developmentally absent. The roots of the deciduous teeth of both patients resorbed normally, and were replaced by tissue with the same radiographic appearance as fibrous dysplasia.

Recovery of Salmonella from shell eggs.

A preenrichment procedure and a direct selective enrichment procedure were compared for recovery of Salmonella artificially inoculated into liquid whole egg, egg yolk, and egg albumen. For liquid whole egg and egg yolk, the 2 procedures were comparable. With egg albumen, however, preenrichment in lactose broth gave significantly higher recoveries than did direct selective enrichment in either selenite cystine or tetrathlonate broths. The lactose preenrichment procedure was used to determine the survival of S. enteritidis in egg yolk and egg albumen over a period of 7 days. As shown by most probably number determinations, counts of S. enteritidis inoculated into egg albumen decreased by 3 log units, whereas those in egg yolk did not change significantly. It is recommended, therefore, that only the egg yolk be examined for this pathogen. In a comparison of 5 different preenrichment media (lactose broth, brain heart infusion broth, trypticase soy broth, buffered peptone water, and nutrient broth), lactose broth was somewhat less productive than the other 4 media for the recovery of Salmonella from egg yolks. Trypticase soy broth gave the highest recovery.

Exposure of the hip using a modified anterolateral approach.

This report outlines an exposure to the hip using one curved skin incision, permitting retention of the femoral neck, and allowing access to both the anterior and posterior aspects of the hip, the whole of the proximal femur, and the circumference of the acetabulum. This approach is useful in revision surgery. The anterior abductors are mobilized using partial sharp release. A review of postoperative abductor function is presented, demonstrating satisfactory function after partial sharp release.

In vitro cleavage of an N-ras messenger-like RNA by a ribozyme.

A cDNA library was constructed in lambda gt10 from T-15 cells, a transformed mouse fibroblast line. The transforming N-ras sequence was recovered and subsequently used as a substrate for ribozyme cleavage. The design of the ribozyme was based on that of the hammerhead structure of the satellite tobacco ringspot autolytic processing sequence. Specificity to the N-ras substrate was conferred by 10 nucleotides homologous to the target site on the mRNA positioned on either side of the catalytic unit. The cleavage reaction was most efficient at higher temperatures but efficiency at lower temperatures was improved by the inclusion of urea in the reaction mixture. The ribozyme failed to cut an antisense ras sequence even at high temperature or in the presence of urea.

Intraocular histiocytic lymphoma: a pediatric case presentation.

An 11-year-old white female with a 5-month history of stage IV systemic histiocytic lymphoma presented in relapse with a red, painful left eye with a decrease in visual acuity. A diagnostic anterior chamber paracentesis was performed revealing cells consistent with the systemic diagnosis of histiocytic lymphoma. Also, at that time, central nervous system involvement was found. This is the youngest patient to our knowledge to have documented intraocular involvement from histiocytic lymphoma. She is also unusual in that the ocular involvement was predominantly localized to the anterior segment.

High esophageal stricture: a complication of "inlet patch" mucosa.

High esophageal stricture associated with a circumferential "inlet patch" of heterotopic gastric mucosa is reported in 2 patients. Biopsy specimens taken from the strictures demonstrated inflamed or ulcerated gastric fundal-type mucosa in both cases. Dilatation of the strictures followed by treatment with histamine H2-antagonists produced almost complete resolution of dysphagia in both patients.

Angina bullosa haemorrhagica: lesional immunostaining and haematological findings.

The aetiology of angina bullosa haemorrhagica remains obscure. Fourteen patients with clinical features suggestive of angina bullosa haemorrhagica were investigated. Haemostatic function tests were carried out on an initial 5 patients and immunostain studies on a total of 12 patients. The results indicate that the aetiology of angina bullosa haemorrhagica is associated with neither a haemostatic defect, nor an immunopathogenic basis, and the cause is, as yet, unclear.

Angina bullosa haemorrhagica: clinical and laboratory features in 30 patients.

Angina bullosa haemorrhagica (ABH) is a relatively recently recognized bullous disorder in which recurrent oral blood blisters appear in the absence of any identified systemic disorder. This study has examined the clinical, histologic, immunologic, and hemostatic features of 30 British patients and demonstrates that ABH is predominantly a localized disorder of middle-aged or elderly patients of either sex that is evident mainly as blood blisters on the soft palate. Trauma appears to be the most common identifiable precipitating factor, but the essential tissue defect is as yet unidentified.