Nodal staging affects adjuvant treatment choices in elderly patients with clinically node-negative, estrogen receptor-positive breast cancer.

Background: In response to Choosing Wisely recommendations that sentinel lymph node biopsy (slnb) should not be routinely performed in elderly patients with node-negative (cN0), estrogen receptor-positive (er+) breast cancer, we sought to evaluate how nodal staging affects adjuvant treatment in this population. Methods: From a prospective database, we identified patients 70 or more years of age with cN0 breast cancer treated with surgery for er+ her2-negative invasive disease during 2012-2016. We determined rates of, and factors associated with, nodal positivity (pN+), and compared the use of adjuvant radiation (rt) and systemic therapy by nodal status. Results: Of 364 patients who met the inclusion criteria, 331 (91%) underwent slnb, with 75 (23%) being pN+. Axillary node dissection was performed in 11 patients (3%). On multivariate analysis, tumour size was the only factor associated with pN+ (p = 0.007). Nodal positivity rates were 0%, 13%, 23%, 33%, and 27% for lesions preoperatively sized at 0-0.5 cm, 0.5-1 cm, 1.1-2.0 cm, 2.1-5.0 cm, and more than 5.0 cm. Compared with patients assessed as node-negative, those who were pN+ were more likely to receive axillary rt (lumpectomy: 53% vs. 1%, p < 0.001; mastectomy: 43% vs. 2%, p < 0.001), and adjuvant systemic therapy (endocrine: 82% vs. 69%; chemotherapy plus endocrine: 7% vs. 2%, p = 0.002). Conclusions: Of elderly patients with cN0 er+ breast cancer, 23% were pN+ on slnb. Size was the primary predictor of nodal status, and yet significant rates of nodal positivity were observed even in tumours preoperatively sized at 1 cm or less. The use of rt and systemic adjuvant therapies differed by nodal status, although the long-term oncologic implications require further investigation. Multidisciplinary input on a case-by-case basis should be considered before omission of slnb.

Tyrosine kinase inhibitors significantly improved survival outcomes in patients with metastatic gastrointestinal stromal tumour: a multi-institutional cohort study.

Background: The real-world impact of tyrosine kinase inhibitors (tkis) in clinical practice for gastrointestinal stromal tumour (gist) has not been extensively reported. We sought to assess how outcomes have changed over the eras and to evaluate the effect of access to imatinib and sunitinib on survival in patients with unresectable or metastatic gist in British Columbia. Methods: Patients with metastatic or unresectable gist were allocated to one of three eras: pre-2002, 2002-2007, and post-2007 based on treatment availability (pre-imatinib, post-imatinib, and post-sunitinib). Overall survival (os) and progression-free survival (pfs) were compared between eras. Univariate and multivariate analyses were performed to determine the effects of tumour, patient, and treatment characteristics on survival outcomes. Results: Of 657 patients diagnosed with gist throughout British Columbia during 1996-2016, 196 had metastatic disease: 23 in the pre-imatinib era, 67 in the post-imatinib era, and 106 in the post-sunitinib era. A significant increase in os, by 53.6 months (p = 0.0007), and pfs, by 29.1 months (p = 0.044), was observed after the introduction of imatinib. The introduction of sunitinib did not significantly affect os or pfs. Conclusions: Implementation of tkis has drastically improved survival outcomes for patients with metastatic gist by up to 4.55 years in the real-world setting. Our study demonstrates that implementation of tkis in clinical practice has outperformed their benefit predicted in clinical trials.

Electronic Stopping of Slow Protons in Oxides: Scaling Properties.

Electronic stopping of slow protons in ZnO, VO_{2} (metal and semiconductor phases), HfO_{2}, and Ta_{2}O_{5} was investigated experimentally. As a comparison of the resulting stopping cross sections (SCS) to data for Al_{2}O_{3} and SiO_{2} reveals, electronic stopping of slow protons does not correlate with electronic properties of the specific material such as band gap energies. Instead, the oxygen 2p states are decisive, as corroborated by density functional theory calculations of the electronic densities of states. Hence, at low ion velocities the SCS of an oxide primarily scales with its oxygen density.

Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer.

OBJECTIVES: There is uncertainty surrounding the prognostic value and clinical utility of peritoneal cytology in endometrial cancer. Our primary objective was to determine if positive cytology is associated with disease-free and overall survival in women treated surgically for endometrial cancer, specifically those with low or intermediate risk disease. METHODS: This was a retrospective population-based cohort study of British Columbia Cancer Registry patients who underwent surgery with peritoneal washings for endometrioid-type endometrial cancer from 2003 to 2009. Low risk was defined as Stage IA grade 1 or 2, and intermediate risk defined as Stage IA grade 3, or Stage IB grade 1 or 2 tumours. Five-year overall and disease free-survival were assessed using Kaplan-Meier estimation. Potential covariates including peritoneal cytology, grade, depth of myometrial invasion, LVSI, age, and adjuvant therapy were evaluated in a multivariable Cox proportional hazards model. RESULTS: There were 849 patients, of whom 370 (43.6%) and 298 (35.1%) had low- and intermediate-risk disease, respectively. Overall, forty-nine (5.8%) patients had positive cytology, including 6 and 9 with low- and intermediate-risk respectively (2.2% within low and intermediate risk combined). Positive peritoneal cytology was not significantly associated with disease-free (HR 3.17, 95% CI 0.91-11.03) or overall survival (HR 1.33, 95% CI 0.47-3.76) in low and intermediate risk patients. Only age and extensive LVSI were associated with lower overall survival (HR 1.10, 95% CI 1.08-1.13, and HR 2.39, 95% CI 1.02-5.61, respectively). CONCLUSIONS: Positive peritoneal cytology was not associated with disease-free and overall survival in women with low and intermediate risk endometrial cancer.

Surgeon Volume, Patient Age, and Tumor-Related Factors Influence the Need for Re-Excision After Breast-Conserving Surgery.

BACKGROUND: Breast-conserving surgery (BCS) is the preferred surgical approach for the majority of patients with early-stage breast cancer. There are frequent issues regarding pathologic margin status, requiring margin re-excision, and, in the literature, there is significant variability in re-excision rates, suggesting this is a potential quality-of-care issue. Understanding the patient-, disease-, and physician-related factors influencing reoperation rates is of importance in an effort to minimize this occurrence. METHODS: A retrospective analysis of all patients referred to our cancer center over a 3-year period (1 January 2011-31 December 2013) was performed. Surgeon volume, and patient- and tumor-related factors were assessed for their impact on re-excision rates. Multivariate logistic regression analysis was performed to identify variables of significance influencing reoperation rates after attempted BCS. RESULTS: Overall, 594 patients underwent initial BCS, with 159 (26.8%) patients requiring at least one re-excision to ensure negative pathologic margins. On multivariate analysis, low surgeon case volume, patient age (under 46 years of age), tumor size (>2 cm), and lobular carcinoma were associated with an increased re-excision rate. CONCLUSION: Re-excisions are frequent after BCS and are influenced by surgeon volume, patient age, and tumor-related factors. These factors should be considered when counseling patients considering BCS, and also for quality assurance.

Breast cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK, 2000-2007: a population-based study.

BACKGROUND: We investigate whether differences in breast cancer survival in six high-income countries can be explained by differences in stage at diagnosis using routine data from population-based cancer registries. METHODS: We analysed the data on 257,362 women diagnosed with breast cancer during 2000-7 and registered in 13 population-based cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Flexible parametric hazard models were used to estimate net survival and the excess hazard of dying from breast cancer up to 3 years after diagnosis. RESULTS: Age-standardised 3-year net survival was 87-89% in the UK and Denmark, and 91-94% in the other four countries. Stage at diagnosis was relatively advanced in Denmark: only 30% of women had Tumour, Nodes, Metastasis (TNM) stage I disease, compared with 42-45% elsewhere. Women in the UK had low survival for TNM stage III-IV disease compared with other countries. CONCLUSION: International differences in breast cancer survival are partly explained by differences in stage at diagnosis, and partly by differences in stage-specific survival. Low overall survival arises if the stage distribution is adverse (e.g. Denmark) but stage-specific survival is normal; or if the stage distribution is typical but stage-specific survival is low (e.g. UK). International differences in staging diagnostics and stage-specific cancer therapies should be investigated.

Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995-2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data.

BACKGROUND: Cancer survival is a key measure of the effectiveness of health-care systems. Persistent regional and international differences in survival represent many avoidable deaths. Differences in survival have prompted or guided cancer control strategies. This is the first study in a programme to investigate international survival disparities, with the aim of informing health policy to raise standards and reduce inequalities in survival. METHODS: Data from population-based cancer registries in 12 jurisdictions in six countries were provided for 2·4 million adults diagnosed with primary colorectal, lung, breast (women), or ovarian cancer during 1995-2007, with follow-up to Dec 31, 2007. Data quality control and analyses were done centrally with a common protocol, overseen by external experts. We estimated 1-year and 5-year relative survival, constructing 252 complete life tables to control for background mortality by age, sex, and calendar year. We report age-specific and age-standardised relative survival at 1 and 5 years, and 5-year survival conditional on survival to the first anniversary of diagnosis. We also examined incidence and mortality trends during 1985-2005. FINDINGS: Relative survival improved during 1995-2007 for all four cancers in all jurisdictions. Survival was persistently higher in Australia, Canada, and Sweden, intermediate in Norway, and lower in Denmark, England, Northern Ireland, and Wales, particularly in the first year after diagnosis and for patients aged 65 years and older. International differences narrowed at all ages for breast cancer, from about 9% to 5% at 1 year and from about 14% to 8% at 5 years, but less or not at all for the other cancers. For colorectal cancer, the international range narrowed only for patients aged 65 years and older, by 2-6% at 1 year and by 2-3% at 5 years. INTERPRETATION: Up-to-date survival trends show increases but persistent differences between countries. Trends in cancer incidence and mortality are broadly consistent with these trends in survival. Data quality and changes in classification are not likely explanations. The patterns are consistent with later diagnosis or differences in treatment, particularly in Denmark and the UK, and in patients aged 65 years and older. FUNDING: Department of Health, England; and Cancer Research UK.

Utilisation of radiotherapy in rural and urban areas in British Columbia compared with evidence-based estimates of radiotherapy needs for patients with breast, prostate and lung cancer.

AIMS: To compare the existing model estimates of the appropriate rates of radiotherapy for lung, breast and prostate cancers with actual radiotherapy rates in rural, semi-urban and urban areas, and in areas with short and long drive distances to cancer clinics in British Columbia. MATERIALS AND METHODS: All registered cases of lung, breast and prostate cancer diagnosed in British Columbia between 1997 and 2007 were identified. The proportion of cancers treated within 1 (RT1Y) and 5 years (RT5Y) of diagnosis were calculated according to rural, semi-urban and urban area, and areas associated with short and long drive distances to cancer clinics in British Columbia. RESULTS: RT1Y for lung, breast and prostate in urban and rural areas were 47/45%, 57/46% and 31/30%, and for short and long drive times were 47/44%, 56/50% and 31/31% compared with model estimates for initial radiotherapy needs of 41-45%, 57-61% and 32-37%, respectively. RT5Y for lung, breast and prostate in urban and rural areas were 52/47%, 59/48% and 42/39%, and for short and long drive times were 51/47%, 57/50% and 42/42% compared with model estimates for overall radiotherapy needs of 66-83%, 57-61% and 60-61%, respectively. CONCLUSIONS: Radiotherapy rates vary between and within urban and rural areas in British Columbia. Radiotherapy rates for breast and lung cancer patients are higher, and closer to model estimates of need, in urban areas and short drive time areas. Radiotherapy rates do not vary with drive time or rural versus urban classification for patients with prostate cancer.

Predictors of positive radial margin status in a population-based cohort of patients with rectal cancer.

BACKGROUND: Surgical margin status is an important predictor of risk of relapse among patients with rectal cancer. METHODS: Patients referred to the British Columbia Cancer Agency for consideration of adjuvant therapy for rectal adenocarcinoma were included. Predictors of margin positivity were determined from uni- and multivariate analysis. RESULTS: Among 340 patients, 83% had negative resection margins. In 268 patients with resectable tumours, a significantly higher rate of margin positivity was observed in low rectal tumours (32.2%) as compared with mid-rectal (3.9%) and high rectal (14.3%) tumours. Among 59 patients with locally advanced rectal cancer treated with preoperative radiation (with or without chemotherapy), 32% with low tumours had margin positivity. Of patients with T4 tumours, 50% (11/22) had a positive resection margin. CONCLUSIONS: In a population cohort, distal-third rectal location, locally advanced presentation, and T4 cancer represent subgroups for whom further improvement in therapy is required.

Reasons for variation in coverage in the NHS cervical screening programme.

In order to investigate reasons for variation in coverage of cervical screening, data from standard Department of Health returns were obtained for all Health Authorities for 1998/1999. Approximately 80% of the variation between health authorities is explained by differences in age distribution and area classification. Considerable differences between Health Authority and Office of National Statistics (ONS) population figures in City and Urban (London) areas for the age group 25-29 years and for City (London) for age group 30-34 years, suggest an effect of list inflation in these groups. Coverage as a performance indicator may be more accurately represented using the age range 35-64 years. Using this narrower age range, the percentage of health authorities meeting the 80% 5-year coverage target increases from 87% to 90%.

Effect of NHS breast screening programme on mortality from breast cancer in England and Wales, 1990-8: comparison of observed with predicted mortality.

OBJECTIVE: To assess the impact of the NHS breast screening programme on mortality from breast cancer in women aged 55-69 years over the period 1990-8. DESIGN: Age cohort model with data for 1971-89 used to predict mortality for 1990-8 with assumption of no major effect from screening or improvements in treatment until after 1989. Effect of screening and other factors on mortality estimated by comparing three year moving averages of observed mortality with those predicted (by five year age groups from 50-54 to 75-79), the effect of screening being restricted to certain age groups. SETTING: England and Wales. SUBJECTS: Women aged 40 to 79 years. RESULTS: Compared with predicted mortality in the absence of screening or other effects the total reduction in mortality from breast cancer in 1998 in women aged 55-69 was estimated as 21.3%. Direct effect of screening was estimated as 6.4% (range of estimates from 5.4-11.8%). Effect of all other factors (improved treatment with tamoxifen and chemotherapy, and earlier presentation outside the screening programme) was estimated as 14.9% (range 12.2-14.9%). CONCLUSIONS: By 1998 both screening and other factors, including improvements in treatment, had resulted in substantial reductions in mortality from breast cancer. Many deaths in the 1990s will be of women diagnosed in the 1980s and early 1990s, before invitation to screening. Further major effects from screening and treatment are expected, which together with cohort effects should result in further substantial reductions in mortality from breast cancer, particularly for women aged 55-69, over the next 10 years.

Mediators of the ocular inflammatory response to interleukin-1 beta plus tumor necrosis factor-alpha.

BACKGROUND: Intravitreal injection of marginally inflammatory doses of interleukin-1 beta and tumor necrosis factor-alpha (IL-1 beta/TNF alpha) has been shown to produce intraocular inflammation distinctly different from that induced by higher intravitreal doses of either IL-1 or TNF alpha. Since cyclooxygenase inhibitors and platelet-activating factor (PAF)-receptor antagonists can reduce IL-1- or TNF alpha-induced uveitis, the present investigation was undertaken to determine whether cyclooxygenase metabolites of arachidonic acid and PAF are important mediators of IL-1 beta/TNF alpha-induced uveitis. METHODS: The cyclooxygenase inhibitor indomethacin and two structurally dissimilar PAF-receptor antagonists, SRI 63-441 and WEB 2086, were used to investigate the importance of cyclooxygenase metabolites and PAF in IL-1 beta/TNF alpha-induced uveitis. RESULTS: Based upon the effectiveness of indomethacin, the anterior uveitis induced by IL-1 beta/TNF alpha could be divided into two phases; a primary phase dependent upon generation of cyclooxygenase metabolites (the first 24 h) and a secondary phase largely independent of cyclooxygenase metabolite production (24-48 h). Posterior uveitis was also apparent at 48 h and was reduced by indomethacin. SRI 63-441 reduced the anterior uveitis at 24 h and to a lesser extent at 48 h; it also reduced the posterior uveitis at 48 h. However, although WEB 2086 was as effective as SRI 63-441 in reducing PAF-induced platelet aggregation, ex vivo, it did not significantly reduce IL-1 beta/TNF alpha-induced uveitis. CONCLUSIONS: Although the findings do not support an important role for PAF in TNF alpha/IL-1 beta-induced uveitis, it cannot be ruled out that more intensive treatment with a specific and long-acting PAF-receptor antagonist might yield more positive results.