Ki67 and breast cancer mortality in women with invasive breast cancer.

BACKGROUND: The percentage of cells staining positive for Ki67 is sometimes used for decision-making in patients with early invasive breast cancer (IBC). However, there is uncertainty regarding the most appropriate Ki67 cut points and the influence of interlaboratory measurement variability. We examined the relationship between breast cancer mortality and Ki67 both before and after accounting for interlaboratory variability and 8 patient and tumor characteristics. METHODS: A multicenter cohort study of women with early IBC diagnosed during 2009-2016 in more than 20 NHS hospitals in England and followed until December 31, 2020. RESULTS: Ki67 was strongly prognostic of breast cancer mortality in 8212 women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early IBC (Ptrend < .001). This relationship remained strong after adjustment for patient and tumor characteristics (Ptrend < .001). Standardization for interlaboratory variability did little to alter these results. For women with Ki67 scores of 0%-5%, 6%-10%, 11%-19%, and 20%-29% the corresponding 8-year adjusted cumulative breast cancer mortality risks were 3.3% (95% confidence interval [CI] = 2.8% to 4.0%), 3.7% (95% CI = 3.0% to 4.4%), 3.4% (95% CI = 2.8% to 4.1%), and 3.4% (95% CI = 2.8% to 4.1%), whereas for women with Ki67 scores of 30%-39% and 40%-100%, these risks were higher, at 5.1% (95% CI = 4.3% to 6.2%) and 7.7% (95% CI = 6.6% to 9.1) (Ptrend < .001). Similar results were obtained when the adjusted analysis was repeated with omission of pathological information about tumor size and nodal involvement, which would not be available preoperatively for patients being considered for neoadjuvant therapy. CONCLUSION: Our findings confirm the prognostic value of Ki67 scores of 30% or more in women with ER-positive, HER2-negative early IBC, irrespective of interlaboratory variability. These results also suggest that Ki67 may be useful to aid decision-making in the neoadjuvant setting.

Healthcare service disruption in 14 Latin American and Caribbean countries during the COVID-19 pandemic: Analysis of household phone surveys, 2020-2021.

Background: The coronavirus 2019 (COVID-19 pandemic) and associated responses have significantly disrupted healthcare. We aimed to estimate the magnitude of and reasons for households reporting healthcare disruption in 14 Latin America and the Caribbean (LAC) region countries from mid-2020 to mid-2021, and its relationship with country contextual factors. Methods: We used COVID-19 high-frequency phone surveys (HFPS) conducted in 14 LAC countries in three rounds in 2020 and one in 2021. We classified the reasons reported for healthcare disruption into four groups: concerns about contracting COVID-19, healthcare supply constraints, financial reasons, and public health measures (PHMs). We used bivariate and multivariate regressions to examine correlates of reported healthcare disruption with the above groups and country context as control variables. Results: On average, 20% of households reported a disruption in May-June 2020 (45% to 10% at country level), dropping to 9% in June-July 2020 (31% to 3%) and July-August 2020 (26% to 3%), and declining to 3% in May-July 2021 (11% to 1%). The most common reason reported for disruption was healthcare supply constraints, followed by concerns about contracting COVID-19, PHM, and financial reasons. In multivariable regression analyses, we found that a higher incidence of new COVID-19 cases (regression coefficient (ß) = 0.018, P < 0.01), stricter PHM (ß = 0.002, P < 0.01), fewer hospital beds per population (ß = -0.011, P < 0.01), and lower out-of-pocket health spending (ß = -0.0008, P < 0.01) were associated with higher levels of disrupted care. A higher care disruption was associated with a lower gross domestic product (GDP) per person (ß = -0.00001, P < 0.01) and lower population density (ß = -0.056, P < 0.01). Conclusions: Healthcare services for households in LAC were substantially disrupted during the COVID-19 pandemic. Findings about supply and financial constraints can inform the recovery of postponed healthcare services, while public health and contextual factors findings can inform future health system resilience efforts in LAC and elsewhere.

Central Endocrine Complications Among Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review.

PURPOSE: Children who receive cranial radiation therapy (RT) as a component of treatment for malignancy are often at risk of long-term central endocrine toxicity secondary to radiation to the hypothalamic-pituitary axis (HPA). A comprehensive analysis was performed of central endocrine late effects in survivors of childhood cancer treated with RT as part of the Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium. METHODS AND MATERIALS: A systematic review of the risk of RT-related central endocrine effects was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A total of 4629 publications were identified, of which 16 met criteria for inclusion in dose modeling analysis, with a total of 570 patients in 19 cohorts. Eighteen cohorts reported outcomes for growth hormone deficiency (GHD), 7 reported outcomes for central hypothyroidism (HT), and 6 reported outcomes for adrenocorticotropic hormone (ACTH) deficiency. RESULTS: Normal tissue complication probability modeling for GHD (18 cohorts, 545 patients) yielded D50 = 24.9 Gy (95% CI, 20.9-28.0) and γ50 = 0.5 (95% CI, 0.27-0.78). The normal tissue complication probability model fit for whole brain irradiation in children with a median age of >5 years indicated a 20% risk of GHD for patients who receive a mean dose of 21 Gy in 2-Gy fractions to the HPA. For HT, among 7 cohorts (250 patients), D50 = 39 Gy (95% CI, 34.1-53.2) and γ50 = 0.81 (95% CI, 0.46-1.35), with a 20% risk of HT in children who receive a mean dose of 22 Gy in 2-Gy fractions to the HPA. For ACTH deficiency (6 cohorts, 230 patients), D50 = 61 Gy (95% CI, 44.7-119.4) and γ50 = 0.76 (95% CI, 0.5-1.19); there is a 20% risk of ACTH deficiency in children who receive a mean dose of 34 Gy in 2-Gy fractions to the HPA. CONCLUSIONS: RT dose to the HPA increases the risk of central endocrine toxicity, including GHD, HT, and ACTH deficiency. In some clinical situations, these toxicities may be difficult to avoid, and counseling of patients and families with respect to anticipated outcomes is important.

Breast cancer mortality in 500 000 women with early invasive breast cancer diagnosed in England, 1993-2015: population based observational cohort study.

OBJECTIVES: To describe long term breast cancer mortality among women with a diagnosis of breast cancer in the past and estimate absolute breast cancer mortality risks for groups of patients with a recent diagnosis. DESIGN: Population based observational cohort study. SETTING: Routinely collected data from the National Cancer Registration and Analysis Service. PARTICIPANTS: All 512 447 women registered with early invasive breast cancer (involving only breast and possibly axillary nodes) in England during January 1993 to December 2015, with follow-up to December 2020. MAIN OUTCOME MEASURES: Annual breast cancer mortality rates and cumulative risks by time since diagnosis, calendar period of diagnosis, and nine characteristics of patients and tumours. RESULTS: For women with a diagnosis made within each of the calendar periods 1993-99, 2000-04, 2005-09, and 2010-15, the crude annual breast cancer mortality rate was highest during the five years after diagnosis and then declined. For any given time since diagnosis, crude annual breast cancer mortality rates and risks decreased with increasing calendar period. Crude five year breast cancer mortality risk was 14.4% (95% confidence interval 14.2% to 14.6%) for women with a diagnosis made during 1993-99 and 4.9% (4.8% to 5.0%) for women with a diagnosis made during 2010-15. Adjusted annual breast cancer mortality rates also decreased with increasing calendar period in nearly every patient group, by a factor of about three in oestrogen receptor positive disease and about two in oestrogen receptor negative disease. Considering just the women with a diagnosis made during 2010-15, cumulative five year breast cancer mortality risk varied substantially between women with different characteristics: it was <3% for 62.8% (96 085/153 006) of women but ≥20% for 4.6% (6962/153 006) of women. CONCLUSIONS: These five year breast cancer mortality risks for patients with a recent diagnosis may be used to estimate breast cancer mortality risks for patients today. The prognosis for women with early invasive breast cancer has improved substantially since the 1990s. Most can expect to become long term cancer survivors, although for a few the risk remains appreciable.

Adjuvant and neoadjuvant breast cancer treatments: A systematic review of their effects on mortality.

BACKGROUND: Adjuvant and neoadjuvant breast cancer treatments can reduce breast cancer mortality but may increase mortality from other causes. Information regarding treatment benefits and risks is scattered widely through the literature. To inform clinical practice we collated and reviewed the highest quality evidence. METHODS: Guidelines were searched to identify adjuvant or neoadjuvant treatment options recommended in early invasive breast cancer. For each option, systematic literature searches identified the highest-ranking evidence. For radiotherapy risks, searches for dose-response relationships and modern organ doses were also undertaken. RESULTS: Treatment options recommended in the USA and elsewhere included chemotherapy (anthracycline, taxane, platinum, capecitabine), anti-human epidermal growth factor 2 therapy (trastuzumab, pertuzumab, trastuzumab emtansine, neratinib), endocrine therapy (tamoxifen, aromatase inhibitor, ovarian ablation/suppression) and bisphosphonates. Radiotherapy options were after breast conserving surgery (whole breast, partial breast, tumour bed boost, regional nodes) and after mastectomy (chest wall, regional nodes). Treatment options were supported by randomised evidence, including > 10,000 women for eight treatment comparisons, 1,000-10,000 for fifteen and < 1,000 for one. Most treatment comparisons reduced breast cancer mortality or recurrence by 10-25%, with no increase in non-breast-cancer death. Anthracycline chemotherapy and radiotherapy increased overall non-breast-cancer mortality. Anthracycline risk was from heart disease and leukaemia. Radiation-risks were mainly from heart disease, lung cancer and oesophageal cancer, and increased with increasing heart, lung and oesophagus radiation doses respectively. Taxanes increased leukaemia risk. CONCLUSIONS: These benefits and risks inform treatment decisions for individuals and recommendations for groups of women.

Associations between Feeding Behaviors Collected from an Automated Milk Feeder and Neonatal Calf Diarrhea in Group Housed Dairy Calves: A Case-Control Study.

The objective of this case-control study was to determine if feeding behavior data collected from an automated milk feeder (AMF) could be used to predict neonatal calf diarrhea (NCD) in the days surrounding diagnosis in pre-weaned group housed dairy calves. Data were collected from two research farms in Ontario between 2017 and 2020 where calves fed using an AMF were health scored daily and feeding behavior data (milk intake (mL/d), drinking speed (mL/min), number of rewarded or unrewarded visits) was collected. Calves with NCD were pair matched to healthy controls (31 pairs) by farm, gender, and age at case diagnosis to assess for differences in feeding behavior between case and control calves. Calves were first diagnosed with NCD on day 0, and a NCD case was defined as calves with a fecal score of ≥2 for 2 consecutive days, where control calves remained healthy. Repeated measure mixed linear regression models were used to determine if there were differences between case and control calves in their daily AMF feeding behavior data in the days surrounding diagnosis of NCD (-3 to +5 days). Calves with NCD consumed less milk on day 0, day 1, day 3, day 4 and day 5 following diagnosis compared to control calves. Calves with NCD also had fewer rewarded visits to the AMF on day -1, and day 0 compared to control calves. However, while there was a NCD status x day interaction for unrewarded visits, there was only a tendency for differences between NCD and control calves on day 0. In this study, feeding behaviors were not clinically useful to make diagnosis of NCD due to insufficient diagnostic ability. However, feeding behaviors are a useful screening tool for producers to identify calves requiring further attention.

Exposure of the oesophagus in breast cancer radiotherapy: A systematic review of oesophagus doses published 2010-2020.

BACKGROUND AND PURPOSE: Breast cancer radiotherapy can increase the risk of subsequent primary oesophageal cancer, with risk increasing according to oesophagus radiation dose. We describe oesophagus exposure from modern breast cancer regimens and discuss the risks of oesophageal cancer for women irradiated recently. MATERIALS AND METHODS: A systematic review was undertaken of oesophagus doses from breast cancer radiotherapy regimens published during 2010-2020. Mean and maximum oesophagus doses were described for different target regions irradiated and different radiotherapy techniques. RESULTS: In 112 published regimens from 18 countries, oesophagus doses varied with target region. For partial breast irradiation, average mean oesophagus dose was 0.2 Gy (range 0.1-0.4) in four regimens; maximum dose was not reported. For breast or chest wall radiotherapy, average oesophagus doses were mean 1.8 Gy (range 0.1-10.4) in 24 regimens and maximum 6.7 Gy (range 0.4-14.3) in seven regimens. For radiotherapy including a nodal region, average oesophagus doses were higher: mean 11.4 Gy (range <0.1-29.3) in 61 regimens and maximum 34.4 Gy (range 3.4-51.3) in 55 regimens. Average mean oesophagus doses were >10 Gy for intensity modulated nodal radiotherapy, but lower for other node techniques. CONCLUSIONS: Mean oesophagus doses from partial breast and breast/chest wall regimens were usually less than 2 Gy, hence radiation-risks will be very small. However, for radiotherapy including lymph nodes, average mean oesophagus dose of 11.4 Gy may nearly double oesophageal cancer risk. Consideration of oesophageal exposure during nodal radiotherapy planning may reduce the risks of radiation-related oesophageal cancer for women irradiated today.

Use of a noncycloplegic autorefractor to perform vision screening in preschools.

Early detection and treatment of vision disorders in children are important to avoid lifelong visual impairment; however, preschool vision-screening rates are low. Traditional methods of screening lack the precision of objective tests and are difficult to administer in preschoolers. This study adopted a method using school nurses to conduct vision screening in preschoolers with a portable autorefractor. In addition, the effectiveness of the school nurse in conducting follow-up was evaluated. In a sample of 600 children, more than 98% completed the screening, and 7% were referred for follow-up evaluation. Seventeen percent of parents had plans to follow-up after receiving a brochure indicating that their child would benefit from a comprehensive eye exam. However, after a conversation with the school nurse, 86% had plans to schedule an evaluation with an eye care professional. Of the 15 students with known follow-up, 10 received glasses. The described method is effective in identifying young children with potential vision problems and facilitating their correction after contact made by the school nurse.