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HPV FOCAL is a randomized trial comparing high-risk HPV [Hybrid Capture 2 (HC2)] vs. liquid-based cytology (LBC) for primary cervical screening.The present study objective was to compare Aptima HPV (AHPV) and HC2 assay performance at the intervention arm baseline and 48 mo. screens in relation to the rates of cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+).Women enrolled after December 2010 (n = 3475) were screened at baseline with both AHPV and HC2 (AHPV was blinded). Women with CIN2+ exited the trial; HC2 negative (-) women and those HC2 positive (+) withCIN2 returned for 48 mo. screening with AHPV, HC2, and LBC.At baseline, 7.2% were AHPV + vs. 8.4% for HC2 (p = 0.06). Round 1 AHPV CIN2+ sensitivity (relative to HC2) was 96.0% (95%CI: 86.5-99.0; p = 0.15) and 100% (95%CI: 82.4-100) for CIN3+. AHPV and HC2 specificities (CIN2) were 94.1% vs. 93.0% respectively (p = 0.05). At 48 mo., 4.8% and 5.2% were AHPV+ and HC2+ respectively (p = 0.41), and both tests had the same CIN2+ and CIN3+ sensitivities (87.5% and 85.0% respectively). AHPV specificity (95.8%) was higher, but not significantly, than HC2 (95.3%; p = 0.38). Of 3226 baseline AHPV- women, 12/2,858 (0.4%) had CIN2+ vs. 13/2821 (0.5%) for the 3184 baseline HC2- women.There was no significant difference in CIN2+ detection for AHPV vs. HC2 at baseline or at 48 mo. Baseline AHPV- and HC2- women had similar CIN2+ rates at 48 mo., demonstrating the safety of a four year screening interval for AHPV- women.

Introduction Projection of the effect of cancer screening interventions are frequently conducted using complex simulation models. It is important that such models demonstrate their ability to replicate observational results on the effect of screening. We present results using the OncoSim-CRC microsimulation model to replicate results from four randomized trials (RCTs) of sigmoidoscopy screening for colorectal cancer (CRC). Methods The published results of four RCTs of sigmoidoscopy were reviewed. Two key outcomes were identified: the intention-to-treat hazard ratios (HR) for CRC incidence and CRC mortality for the screening versus control arms. Each RCT study arm was simulated within OncoSim-CRC using the study specific entry criteria, follow-up and observed participation and compliance rates. The ratio of predicted cases (deaths) between intervention arm and control arm was used to estimate the HRs. Results The RCTs differed in the implementation of sigmoidoscopy screening and only one (PLCO) used more than one cycle. All four RCTs found significant reductions, HR Conclusions OncoSim-CRC predicted reductions in CRC incidence and mortality agreed well with observed in RCTs of sigmoidoscopy screening.

Background Immunochemical faecal testing (FIT) is used in Canada for colorectal cancer (CRC) screening. The threshold for FIT abnormality is under operator control and this study uses a simulation model to predict the effect of threshold selection on outcomes including years-of-life gained, CRC incidence and mortality, and direct health system costs. Method The OncoSim Model was used to predict outcomes of biennial screening between ages 50–74 years in a cohort aged 45 years followed until death for eight FIT threshold values between 50 and 225 ng/ml. The literature on FIT performance was reviewed and seven parameter sets of sensitivity and specificity values by FIT threshold were created to span published variation in test performance in subjects with CRC, adenomas or no colorectal neoplasia. Results Reducing the FIT threshold reduced both projected CRC incidence and mortality for all parameter sets, although cost impacts and cost-effectiveness varied compared to no screening. Biennial FIT was projected to be cost-effective at all thresholds considered with a maximum of CAD$ 5400 per QALY over the seven parameter sets and a maximum of CAD$ 6800 per QALY for a one level change in the eight threshold levels considered. Demand for colonoscopy varied strongly with FIT threshold and was greatest for the lowest threshold (50 ng/ml) but the magnitude varied across the 7 parameter sets. Conclusions Compared to no screening, all thresholds of FIT examined were predicted to be cost-effective in the prevention and management of CRC. Threshold choice strongly influences predicted demand placed upon colonoscopy resources.

Background Cervical cancer screening programs are switching from Pap screening to high-risk HPV testing. Objectives To compare the Aptima HPV Assay (AHPV) with the Hybrid Capture® 2 High-Risk HPV DNA Test® (HC2) for primary cervical screening. Study design HPV FOCAL is a randomized trial comparing HC2 to liquid-based cytology (LBC) for screening women aged 25–65. AHPV and HC2 were compared at the baseline screen (n = 3473). Genotyping was by the Aptima HPV 16 18/45 Genotype Assay. We assessed HPV genotyping and reflex LBC for colposcopy triage. Results AHPV/HC2 agreement was 96.5% (kappa 0.76); positive agreement was 77.4%. The AHPV positive rate was 7.2% vs. 8.4% for HC2 (p = 0.06). Based on HC2 screening, round 1 CIN2 and CIN3+ rates were 9.2/1000 and 5.2/1000 respectively. Using HC2 as the comparator test, AHPV CIN2+ and CIN3+ relative sensitivities were 0.96 and 1.00 (p = 1.00) respectively. High-grade reflex LBC and HPV 16 infection were significantly associated with CIN3+. AHPV specificity was 0.94 vs. 0.93 (p = 0.05) for HC2. Compared with triage of HC2+ with abnormal cytology or HPV persistence for 12 months, colposcopy referral would be significantly reduced (38.3/1000 vs. 60.8/1000; p Conclusions AHPV vs. HC2 screening had equivalent CIN2+ and CIN3+ detection. Triage of AHPV+ by abnormal reflex LBC and the presence of HPV 16/18/45 would result in a significantly lower colposcopy referral rate with similar CIN2+ and CIN3+ detection rates as the overall HC2+ referral algorithm.

Objective To estimate the impact of implementing primary human papilloma virus liquid-based cytology (LBC) screening on four-year rates of referral for colposcopy in the British Columbia screening program. Methods We used data on referral for colposcopy from an RCT (HPV FOCAL) comparing HPV testing every four years with LBC testing every two years. We also used data from population screening with conventional cytology among women aged 25 to 69. The predicted effect of adoption of either trial protocol on rates of referral for colposcopy was estimated using trial age-specific result and screening result-specific rates weighted by their screening program distribution. The cumulative age-specific rates of referral for colposcopy over four years were calculated. Results Use of HPV testing initially increased rates of referral for colposcopy in the trial, but over four years the cumulative rates of referral were similar to those for LBC except in women aged 25 to 29, in whom a substantial excess persisted. Four-year rates of referral for colposcopy declined with age in women screened with HPV testing, LBC, and conventional cytology. Extrapolating the trial results to the distribution in the provincial screening program, implementation of either HPV or LBC throughout the provincial population would approximately double the current rates of referral for colposcopy. Conclusion Compared with LBC screening, primary screening for HPV increased rates of referral for colposcopy only among women aged 25 to 29. In contrast to current practice, referral for colposcopy was largely driven by the trial protocol recommendations for the management of abnormal results and not by which screening test was used.

There is little cost-effectiveness evidence for breast cancer screening with mammography in women under the age of 50 years, or over the age of 70 years, and available estimates vary widely. The Canadian Task Force on Preventive Health Care (CTFPHC) took cost-effectiveness into account in their recent recommendations on breast cancer screening, but no data are available from a Canadian setting. We constructed a microsimulation model using data from the Screening Mammography Program of British Columbia (BC) and the BC Cancer Registry. Eight screening strategies with varying age ranges and frequencies were compared to a reference strategy of no screening. Local screening, diagnostic, and treatment costs, and utility weights from the literature were applied to health states. Cost-effectiveness was expressed as incremental cost-effectiveness ratios (ICER) and cost-effectiveness acceptability curves, using the results of probabilistic sensitivity analysis. The most cost-effective strategies were biennial screening from ages 50 to 69, with an ICER of $28,921/QALY, and biennial screening from 40 to 69, with an ICER of $86,029/QALY. Screening women ages 40–49 was more cost-effective than screening women ages 70–74, which conflicts with the recommendations of the CTFPHC. There was, however, considerable uncertainty around these cost-effectiveness results. Regardless of willingness-to-pay, no single strategy was significantly more likely to be cost effective than the others. There is value in reducing the uncertainty around these cost-effectiveness estimates, to better inform future screening policy.

Background British Columbia (BC) introduced a school-based HPV vaccine program in September 2008. As part of the HPV vaccine program evaluation, we determined the type-specific HPV prevalence in a population-based sample of women presenting for routine cervical cancer screening in the province. Methods From June 2010 to February 2011, a total of 1100 physicians from all health regions in BC were invited to return ten sequential cytobrushes used during routine office-based Pap screening to the Provincial Health Services Authority Laboratories for HPV type-specific testing. Client age was the only identifier provided. Specimens were screened by the Digene Hybrid Capture® 2 High-Risk (hr) HPV DNA Test (HC2). HC2 positive specimens were then genotyped using the Roche cobas® 4800 HPV Test, the Roche Linear Array (LA) HPV Genotyping Test and the Digene® HPV Genotyping LQ Test. Results Overall, 12.2% of the 4330 specimens with valid HC2 results were hrHPV positive. Age range was 15–69 (median 39.0). By age group, the proportion HC2 hrHPV positive was: 15–19, 25.7%; 20–24, 33.2%; 25–29, 21.9%; 30–34, 12.6%; 35–39, 9.5%; 40–44, 8.4%; ≥45, 3.4%. Overall hrHPV prevalence was 10.1% by Roche cobas® 4800, 10.5% by Roche LA and 10.3% by Digene LQ. For HPV 16/18, rates by age group by Roche LA were: 15–19, 5.1%/2.8%; 20–24, 9.5%/3.9%; 25–29, 6.2%/1.0%; 30–34, 2.4%/1.7%; 35–39, 1.2%/1.0%; 40–44, 1.6%/0.2%; ≥45, 0.3%/0.2%. Similar HPV 16/18 rates were obtained with the Digene LQ and Roche cobas® 4800 methods. Agreement between the three genotyping methods for HPV 16 and 18 was high. Conclusions Comparable to other evaluations, hrHPV positivity was highest among younger women and HPV 16 was the most frequent genotype detected. These baseline estimates will be useful for monitoring the effectiveness of the HPV vaccine in BC. Type-specific analyses repeated at regular intervals over time may determine whether the use of HPV vaccine results in hrHPV genotype replacement in the province.

The first organized breast cancer service screening program in Canada was established in 1988 in British Columbia. The pilot project was successful in showing that screening could be conducted at a unit cost of US$38; now US$41. Screening is conducted in dedicated centers and diagnostic work-ups done in the community. The current annual volume is 235,000. Stepwise expansion is ongoing and is determined by community specific service requirements. Prognostic factors of cancers detected consistently exceed internationally recommended targets. Since the inception of the program the age standardized breast cancer mortality rate per 100,000 has dropped in British Columbia from the highest to the lowest in Canada for provinces with similar populations.

The aim of this study was to detect neuroendocrine differentiation (NE), to determine its association with major clinicopathological parameters of breast cancer, and to study the prognostic significance of NE differentiation in a group of breast carcinomas by using tissue microarray (TMA) methodology. NE differentiation was studied by using 3 markers, synaptophysin (Syn), chromogranin A (ChA), and neuron-specific enolase (NSE) in a group of 334 patients with breast carcinoma. TMA blocks were made by using duplicate 0.6-mm-diameter tissue cores from each paraffin block. Results of immunostaining were scored on a 4-point scale, that is, as negative, weak, intermediate, and strong immunoreactivity. Positive staining of breast cancers for any of the 3 NE markers was detected in 19.5% of cases. Expression of a single marker was present in 16.2% of cases, and expression of 2 or 3 markers in combination was detected in 3.3% of cases. There was no statistically significant correlation of NE phenotype with tumor morphology, except mucinous carcinoma (3 of 6 cases positive), estrogen receptor, progesterone receptor, or nodal status. A weak correlation was noted between synaptophysin staining and higher tumor grade (P = 0.029). Analysis of disease-specific and overall survival based on up to 20 years of follow-up data showed a correlation between NSE expression and improved disease-specific (P = 0.043) and overall survival (P = 0.03) in univariate but not in multivariate analysis. The expression of Syn and ChA, as well as coexpression of multiple NE markers, had no prognostic significance.

Optimal drug regimens for cancer chemotherapy are determined when knowledge is only available on the behaviour of the tumour and the drugs used, over a population of patients. The case of two drugs is investigated where they are equivalent on average. Our calculations indicate that the optimal regimen has both drugs given initially but then sequences the two drugs. Our calculations also indicate that as tumour heterogeneity increases, the benefit to be gained from the optimal regimen can decrease in comparison to reasonable regimens. This has the effect of complicating the calculation of optimal regimens in a clinical setting, and may explain why results in experimental oncology fail to carry over to clinical oncology.

Objective To examine population data to see whether survival from breast cancer has improved differentially in screened and unscreened women and examine published studies on mammographic screening to determine whether there is evidence that screening is no longer effective. Methods Data was reviewed on trends in breast cancer specific survival among women participating and not participating in the British Columbia Breast Screening Program. Population studies of mammographic screening published between 2000 and 2010 with breast cancer mortality as the outcome were also reviewed. Results Breast cancer specific survival in British Columbia improved more in screening participants than non-participants, HR = 0.74 (0.58,0.93) between the periods 1990–4 and 2000–4. Among the published studies of mortality between 2000 and 2010 selected from different jurisdictions all had found a reduction in breast cancer mortality although this was not always statistically different from zero. Studies had used a range of designs and evaluative methods which may have contributed to the magnitude of the effect reported. Conclusion No evidence was found in the British Columbia data and the published studies reviewed, that treatment or other changes, had caused mammographic screening to become ineffective.

Recently, there has been a growing number of studies applying image processing techniques to analyze melanocytic lesions for atypia and possible malignancy and for total-body mole mapping. However, such lesions can be partially obscured by body hairs. None of these studies has fully addressed the problem of human hairs occluding the imaged lesions. In our previous study we designed an automatic segmentation program to differentiate skin lesions from the normal healthy skin, and learned that the program performed well with most of the images, the exception being those with hairs, especially dark thick hairs, covering part of the lesions. These thick dark hairs confused the program, resulting in unsatisfactory segmentation results. In this paper, we present a method to remove hairs from an image using a pre-processing program we have called DullRazor. This pre-processing step enables the segmentation program to achieve satisfactory results. DullRazor can be downloaded as shareware from http:/(/)www.derm.ubc.ca.

A sensitive and specific quantitative assay for total doxorubicin concentrations in plasma containing liposome-encapsulated doxorubicin hydrochloride (TLC D-99) was developed, with solvent extraction and reversed-phase high-performance liquid chromatography (HPLC). Separation of doxorubicin from its metabolites was accomplished with a 15 cm x 3.9 mm i.d., microBondapak phenyl analytical HPLC column. Optimum chromatographic conditions, obtained with a mobile phase gradient from 85 to 50% (v/v) 16 mM ammonium formate buffer in tetrahydrofuran at a flow rate of 2 mL/min, gave a detection limit of 0.3 pmol/injection. Eleven-point standard curves with from 0.00595 to 29.8 microM TLC D-99 and 0.1 microM internal standard in plasma were analyzed on three separate occasions to formally validate this assay. An overall correlation coefficient of 0.9985 was found for the logarithmic transformed data. The pharmacokinetic characteristics of doxorubicin were investigated after administration of TLC D-99 to 12 non-small-cell lung cancer patients as an intravenous infusion at doses of 60 and 75 mg/m2. The data are best described by a three-compartment model with alpha, beta, and gamma elimination half-lives of 0.0721, 2.84, and 25.2 h for the 60-mg/m2 group and 0.103, 2.56, and 14.9 h for the 75-mg/m2 patients. A mean plasma clearance of 9.89 L/h (range: 1.95 to 23.4 L/h) was found for the 60-mg/m2 patients, with that from the 75-mg/m2 group being within these values. Mean area under the plasma concentration versus time curve estimates of 37.1 and 47.9 microM/h were observed for the patients receiving 60 and 75 mg/m2, respectively. The plasma concentration-time course for total doxorubicin following administration of TLC D-99 suggests that the disposition of the liposomal formulation is determined more by the pharmacokinetics of the liposome than the encapsulated drug.

Complete remissions of the androgen-dependent Shionogi mouse mammary carcinoma are observed after androgen withdrawal but invariably the disease recurs and is refractory to further hormonal manipulations. To determine the proportions of androgen-dependent (AD) and -independent (AI) tumorigenic stem cells in parent and recurrent tumors and in vivo limiting dilution assay was developed. There was a marked enrichment of stem cells in the recurrent tumors ( 1 200 tumor cells) relative to the parent tumors ( 1 4000 tumor cells) when assayed in male hosts. By assaying tumor takes in female mice, the proportion of AI stem cells was found to be 1 370,000 tumor cells in the parent vs 1 800 tumor cells in the recurrent carcinoma; a 500-fold increase in AI stem cells resulting from androgen-withdrawal. Unexpectedly, no enrichment of AI stem cells was evident in regressing parent tumors; rather, the proportion of such cells was very small ( 1 2,200,000 tumor cells). This finding implies that the AI cells which survive androgen withdrawal may result from the ability of small number of initially AD stem cells to adapt to an altered hormonal environment. This adaptive process was further defined in terms of the disappearance of androgen receptors from the nucleus and the expression of androgen-repressed genes including the proto-oncogenes, c-fos and c-myc, and the cell death gene, TRPM-2; all of which are constitutively active in recurrent AI tumor cells. Overall, our results indicate: (1) the tumor mass consists mainly of differentiated cells; (2) stem cells initially are AD but at most the killing effect of androgen-withdrawal will be limited to 2–3 logarithms before compensatory adaptive mechanisms supervene; and (3) progression of stem cells to an AI state, in which they are resistant to the killing effects of cell death genes, might be prevented by the inhibition of androgen-repressed adaptive mechanisms which come into play when androgens are withdrawn.

Hryniuk has recently advanced the proposal that the dose intensity of a therapeutic regimen, defined as the ratio of cumulative drug dose to therapeutic period, is an important predictor of the therapeutic outcome. We discuss two simple models of chemotherapeutic effect in cancer treatment and show how they lead to consideration of a time-dependent function, the dose-intensity function, which is a generalization of Hryniuk's dose intensity. Both models show that the therapeutic outcome is dependent upon the dose-intensity function; however, the nature of the dependence varies with the model selected.

A stem cell compartment model is utilized to simulate the growth of human tumors. This model is used to explore the effect of cell differentiation and loss on the development of spontaneous drug resistance. Cellular differentiation is found to increase the rate of development of single drug resistance, although this is balanced by the likehood that such resistant cells will subsequently become extinct. Overall the probability that singly resistant cells will develop and persist is found to be independent of the rate of cellular differentiation. Conversely, when two drugs are available, the probability that cells resistant to both drugs will persist is proportional to the rate of cellular differentiation. Approximate formulae relating the net overall mutation rate to the intrinsic mutation rates and net growth rates of the stem cell compartment are developed.