Do we have a robust method for preoperative tumour depth assessment for oral cavity tumours with clinically negative necks?

Tumour depth is an important prognostic factor in head and neck cancer and has recently been included in the eighth edition of the Union for International Cancer Control TNM classification of malignant tumours for oral squamous cell carcinoma (OSCC). It is important to appraise the accuracy of depth assessments; however, there is little current evidence in the literature. Accurate depth assessment is particularly pertinent in cT1-T2N0 OSCC where it may influence neck management. A retrospective study was performed at two tertiary referral centres, in which surgically treated patients with cT1-T4N0 OSCC were audited. Preoperative tumour depth assessments from multimodality radiological staging scans were compared with the final histopathological depth. The predictive accuracy of intraoral ultrasound (IOUS), computed tomography (CT), and magnetic resonance imaging (MRI) for tumour depth was evaluated. Accuracy to within 3mm of the histopathological depth was seen in 56.7% of MRI scans and 57.1% of CT scans. IOUS appeared to have superior prediction, with 78.2% of measurements within 3mm. Over one third of CT and MRI imaging failed to detect a lesion; IOUS scans detected the lesions in all of these case. In conclusion, the reliability of preoperative imaging assessment of tumour depth should be considered when recommending treatment.

The views of older women towards mammographic screening: a qualitative and quantitative study.

BACKGROUND: Mammographic screening has improved breast cancer survival in the screened age group. This improved survival has not been seen in older women (>70 years) where screening uptake is low. This study explores the views, knowledge and attitudes of older women towards screening. METHODS: Women (>70 years) were interviewed about breast screening. Interview findings informed the development of a questionnaire that was sent to 1000 women (>70 years) to quantify their views regarding screening. RESULTS: Twenty-six women were interviewed and a questionnaire was designed. The questionnaire response rate was 48.3% (479 out of 992). Over half (52.9%, 241 out of 456) of the respondents were unaware that they could request a mammography by voluntary self-referral and were unaware how to arrange this. Most (81.5%, 383 out of 470) had not attended breast screening since turning 70 years. Most (75.6%, 343 out of 454) felt screening was beneficial and would attend if invited. Most (90.1%, 412 out of 457) felt screening should be offered to all women regardless of age or health. CONCLUSIONS: There is a lack of knowledge about screening in older women. The majority felt that invitation to screening should be extended to the older age group regardless of age or health. The current under-utilised system of voluntary self-referral is not supported by older women.

High levels of the MDM2 oncogene in paediatric rhabdomyosarcoma cell lines may confer multidrug resistance.

The MDM2 protein is known to be overexpressed in some sarcomas including rhabdomyosarcoma. However, the extent to which the MDM2 protein influences sensitivity to chemotherapeutic drugs is unclear. We have analysed this further using stable transfection of the mdm2 gene into 4 well-characterised human paediatric rhabdomyosarcoma cell lines. Transfection with the mdm2 gene resulted in increased levels of the MDM2 protein in all the cell lines. In 2 of the lines, SCMC and RD, the mdm2 gene caused between 2-fold and 61-fold increase in resistance to vincristine, etoposide and doxorubicin but not to cisplatin. In these lines there was an increase in expression of the mdr-1 gene which encodes P-glycoprotein, but not the mrp1 gene which encodes the multidrug resistance protein (MRP). The resistance was reversible using the MDR modulator PSC833, confirming the presence of P-glycoprotein. We conclude that MDM2 overexpression may be a mechanism by which multidrug resistance is regulated in some rhabdomyosarcomas.

In vitro prevention of the emergence of multidrug resistance in a pediatric rhabdomyosarcoma cell line.

We have established preclinical models for the development of drug resistance to vincristine (a major drug used in the treatment of pediatric rhabdomyosarcoma) using cell lines. The RD cell line has a mutant P53 phenotype and does not have detectable P-glycoprotein (P-gp) or multidrug resistance-related protein (MRP) despite expressing low levels of mdr-1 mRNA, which encodes P-gp and mrp1 mRNA. Resistant variants of RD were derived by exposure to increasing concentrations of vincristine. This was repeated on six occasions, resulting in three cell lines which could tolerate 64 x the IC(50) concentration. Six independent agents were tested for their ability to prevent the development of resistance in this model. Despite at least 10 attempts, resistance did not develop in the presence of the multidrug resistance (MDR) modulators PSC833, VX710, and XR9576. This strongly suggests that these agents may delay or even prevent the development of resistance to vincristine. This was also confirmed in a second rhabdomyosarcoma cell line, Rh30. In contrast, the agents indomethacin (MRP1 modulator), CGP41251 (protein kinase C inhibitor), and dexrazoxane (putative MDR prevention agent) did not affect the development of resistance in the RD model. Characterization of the resistant cell lines indicated the presence of increased mdr-1 and P-gp expression, which resulted in resistance to the agents doxorubicin, etoposide, and vincristine but not cisplatin. The resistance could be modulated using PSC833 or VX710, confirming that functional P-gp is present. No apparent differences were seen between the resistant cell lines derived in the absence and presence of the various agents. These experiments strongly suggest that the development of MDR may be preventable using modulators of MDR and merit clinical studies to test this hypothesis.

Characterization and modulation of drug resistance of human paediatric rhabdomyosarcoma cell lines.

The role of multidrug resistance (MDR) and p53 functional status in the treatment of paediatric rhabdomyosarcoma is unclear. We have characterized a panel of seven human rhabdomyosarcoma cell lines for MDR and p53 phenotype. None of the cell lines had P-glycoprotein (P-gp) or multidrug resistance-related protein (MRP) detectable by Western blotting, whereas immunohistochemistry suggested that very low levels of MDR proteins may be present in some of the lines. RT-PCR studies indicated that mdr-1, mrp-1 and Irp mRNA was present in 5/7, 7/7 and 5/7 lines respectively. The function of p53 is compromised in six of the lines, either through mutation of the p53 gene or by overexpression of mdm-2. The sensitivity of many of the cell lines to vincristine could be modulated above 2-fold and as high as 16-fold using two modulating agents, PSC833 and VX710 (with VX710 being a significantly more potent modulator of the rhabdomyosarcoma lines). PSC833 also increased vincristine accumulation in all of the lines from 1.2- to 2.2-fold. These results suggest that some of these cell lines have low levels of multidrug resistance. The level of MDR proteins is very low and therefore difficult to detect, but may be sufficient to confer low-level, but clinically relevant, resistance to some cytotoxic agents, especially vincristine. These cell lines will therefore provide a suitable model to test new strategies in treatment and for further understanding relationships between protein expression and drug resistance.

Occurrence of Leuconostoc mesenteroides and leuconostoc-like organisms in Lagos, Nigeria.

A total of 91 catalase--negative Gram-positive coccal isolates obtained from 245 clinical specimens in Lagos were characterized. Ten (11.0%) of the isolates were vancomycin resistant, they fermented glucose, sucrose, fructose, lactose, mannose, mannitol, ribose, salicin, sorbitol, arabinose and xylose with acid production. One of the isolates produced in addition gas inclusive and ethanol, thus identified as Leuconostoc mesenteroides. The ten vancomycin-resistant Gram-positive coccal organisms (VRGPC) showed variable sensitivity patterns to penicillin, tetracycline, erythromycin, ampicillin, streptomycin, chloramphenicol, cloxacillin and co-trimoxazole. The possible role of Leuconostoc spp. and VRGPC in clinical infections in hospital setting is still to be defined.