Development of a Ki-67-based clinical trial assay for neoadjuvant endocrine therapy response monitoring in breast cancer.

Purpose The recent publication of the ACOSOG Z1031 trial results demonstrated that Ki-67 proliferation marker-based neoadjuvant endocrine therapy response monitoring could be used for tailoring the use of adjuvant chemotherapy in ER+HER2-negative breast cancer patients. In this paper, we describe the development of the Ki-67 clinical trial assay used for this study.Methods Ki-67 assay assessment focused on reproducing a 2.7% Ki-67 cut-point (CP) required for calculating the Preoperative Endocrine Prognostic Index and a 10% CP for poor endocrine therapy response identification within the first month of neoadjuvant endocrine treatment. Image analysis was assessed to increase the efficiency of the scoring process. Clinical outcome concordance for two independent Ki-67 scores was the primary performance metric.Results Discordant scores led to a triage approach where cases with complex histological features that software algorithms could not resolve were flagged for visual point counting (17%). The final Ki-67 scoring approach was run on T1/2 N0 cases from the P024 and POL trials (N = 58). The percent positive agreement for the 2.7% CP was 87.5% (95% CI 61.7-98.5%); percent negative agreement 88.9% (95% CI: 65.3-98.6%). Minor discordance did not affect the ability to predict similar relapse-free outcomes (Log-Rank P = 0.044 and P = 0.055). The data for the 10% early triage CP in the POL trial were similar (N = 66), the percentage positive agreement was 100%, and percent negative agreement 93.55% (95% CI: 78.58-99.21%). The independent survival predictions were concordant (Log-rank P = 0.0001 and P = 0.01).Conclusions We have developed an efficient and reproducible Ki-67 scoring system that was approved by the Clinical Trials Evaluation Program for NCI-supported neoadjuvant endocrine therapy trials. Using the methodology described here, investigators are able to identify a subgroup of patients with ER+HER2-negative breast cancer that can be safely managed without the need of adjuvant chemotherapy

Bayesian estimation of performance measures of screening tests in the presence of covariates and absence of a gold standard

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The sensitivity (S(e)) and the specificity (S(p)) are the two most common measures of the performance of a diagnostic test, where Se is the probability of a diseased individual to be correctly identified by the test while Sp is the probability of a healthy individual to be correctly identified by the same test. A problem appears when all individuals cannot be verified by a gold standard. This occurs when there is not a definitive test for detection of the disease or the verification by a gold standard is an impracticable procedure according to its cost, accessibility or risks. In this paper we develop a Bayesian analysis to estimate the disease prevalence, the sensitivity and specificity of screening tests in the presence of a covariate and in the absence of a gold standard. We use the Metropolis Hastings algorithm to obtain the posterior summaries of interest. We have as motivation for the investigation the LAMS (Latin American Screening) Study, an extensive project designed for comparing screening tools for cervical cancer in Brazil and Argentina. When applied to the analysis of data from LAMS Study, the proposed Bayesian method shows to be a useful alternative to estimate measures of performance of screening tests in the presence of covariates and when a gold standard is not available. An advantage of the method is the fact that the number of parameters to be estimated is not limited by the number of observations, as it happens with several frequentist approaches. However, it is important to point out that the Bayesian analysis requires informative priors in order for the parameters to be identifiable. The method can be easily extended for the analysis of other medical data sets.2316881Research European Committee of the European Economical Comunity [INCO DEV 4-CT-2001-10013]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Research European Committee of the European Economical Comunity [INCO DEV 4-CT-2001-10013]FAPESP [99/11264-0]CNPq [300354/01-0

Current physical therapy care of patients undergoing breast reconstruction for breast cancer: a survey of practice in the United Kingdom and Brazil

Background In both the United Kingdom (UK) and Brazil, women undergoing mastectomy should be offered breast reconstruction. Patients may benefit from physical therapy to prevent and treat muscular deficits. However, there are uncertainties regarding which physical therapy program to recommend. Objective The aim was to investigate the clinical practice of physical therapists for patients undergoing breast reconstruction for breast cancer. A secondary aim was to compare physical therapy practice between UK and Brazil. Methods Online survey with physical therapists in both countries. We asked about physical therapists’ clinical practice. Results 181 physical therapists completed the survey, the majority were from Brazil (77%). Respondents reported that only half of women having breast reconstruction were routinely referred to physical therapy postoperatively. Contact with patients varied widely between countries, the mean number of postoperative sessions was 5.7 in the UK and 15.1 in Brazil. The exercise programs were similar for different reconstruction operations. Therapists described a progressive loading structure over time: range of motion (ROM) was restricted to 90° of arm elevation in the first two postoperative weeks; by 2–4 weeks ROM was unrestricted; at 1–3 months muscle strengthening was initiated, and after three months the focus was on sports-specific activities. Conclusion Only half of patients having a breast reconstruction are routinely referred to physical therapy. Patients in Brazil have more intensive follow-up, with up to three times more face-to-face contact with a physical therapist than in the UK. Current practice broadly follows programs for mastectomy care rather than being specific to reconstruction surgery

Human Papillomavirus-specific Genotypes in Cervical Lesions of Women Referred for Smears With Atypical Glandular Cells or Adenocarcinoma In Situ

This study was designed to analyze whether specific human papillomavirus (HPV) genotypes may predict histologic outcomes in women with glandular abnormalities in their cervical smears. Of the 160 women included, I I I were diagnosed with atypical glandular cells, 35 had both atypical glandular cells and high-grade squamous intraepithelial lesions, whereas 14 women had AIS, in I case associated with high-grade squamous intraepithelial lesions. All women underwent colposcopic examinations and biopsy was performed in 129/160 (80.6%). Thirty-one women (19.3%) were considered negative for neoplasia and scheduled for follow-up. All specimens were tested for 27 HPV genotypes by Roche's polymerase chain reaction-reverse line blot assay. Histologic diagnoses were either cervical intraepithelial neoplasia or invasive carcinoma in 75 (58%) women, and negative for neoplasia in 54 (42%). The overall prevalence of HPV was 43%. HPV 16 was the most prevalent type followed by HPV 18. HPV 16 was significantly associated with squamous and glandular neoplasia and HPV 18 with glandular neoplasia. In women with cervical intraepithelial neoplasia 2 or 3, 11 different HPV genotypes were found, whereas in those who had invasive glandular or invasive carcinoma HPV 16 and HPV 18 were found predominantly. The detection of HPV 16 in women with glandular abnormalities in cervical smears did not help differentiating squamous from glandular lesions. However, the detection of HPV 53 in abnormal smears can predict squamous neoplasia, whereas HPV IS can predict glandular neoplasia as histologic diagnoses.28327227

Variants of human papillomavirus types 16 and 18: Histological findings in women referred for atypical glandular cells or adenocarcinoma in situ in cervical smear

Human papillomavitus (HPV) genotypes cannot fully explain the histological diagnosis of women with glandular abnormalities detected by cervical smear. Thus, this study was designed to analyze the distribution of HPV-16 and HPV-18 variants in women referred because of atypical glandular cells and adenocarcinoma in situ in their cervical smears and its association with histological results. Twenty-four women with HPV-16 and 6 with HPV-18, selected from 160 women with cervical smears suggestive of glandular abnormalities, were included. Histological results showed cervicitis (I case), squamous neoplasia (18 cases), glandular neoplasia (7 cases), and glandular neoplasia associated with a squamous component (4 cases). Among the 24 cases presenting HPV-16, the European variant was detected in 15 (62%) and the Asian American in 9 (38%). Among the 15 cases associated with the European variant, 14 (93%) presented squamous neoplasia and 1 (7%) invasive adenocarcinoma. Asian-American HPV-16 variants were significantly. associated with histological diagnosis of glandular neoplasia alone (odds ratio, 9.3 [1.4-60.2]) or associated with squamous neoplasia (odds ratio, 18.7 [1.5-232.3]). Adenocarcinomas were detected in 4 of 6 HPV-18-positive cases, being 2 cases had the European variant, 1 had the Asian Amerindian variant, and 1 had the African variant. The association of HPV-16 with squamous or glandular neoplasia is explained by its variants. In this study, squamous neoplasia Was related to the European variant of HPV-16, whereas glandular neoplasia was related to the Asian-American variant. Glandular neoplasia is associated with HPV-18, but the results of our analysis of its variants were inconclusive.25439339

DNA recovery from Hybrid Capture II samples stored in specimen transport medium with denaturing reagent, for the detection of human papillomavirus by PCR

The purpose of this Study was to examine the quality of DNA recovered for human papillomavirus (HPV) detection using polymerase chain reaction (PCR) in samples that had been collected for Hybrid Capture II (HCII), testing and stored in specimen transport medium (STM) with denaturing reagent at -20° C for 18 months. Endocervical tissue was collected from 92 women for HCII assay using the Digene STM, and a Papanicolaou smear was carried out in all cases. Seven women had normal colposcopy results. The remaining 85 patients underwent colposcopy-directed biopsy or cervical conization for histological investigation. Of the 92 samples tested, 84 were HCII-positive and 8 were negative. Quality control for amplification was carried out with β-globin primers G73 and G74, and HPV was tested using PGMY09 and PGMY11. DNA was recovered from 83 of the 92 samples (90%). Among the 84 samples HCII-positive initially, HPV was detected by PCR in 56 (67%). PCR did not detect HPV DNA in the eight samples that were HCII-negative, although five of them were positive for β-globin. This paper describes a novel DNA extraction technique that may permit exact HPV typing in stored samples collected originally for HCII testing, making it possible to carry out retrospective investigations to retrieve information on specific HPV types in large HCII series. © 2005 Elsevier B.V. All rights reserved.1264167119720

Prediction of high-grade cervical disease with human papillomavirus detection in women with glandular and squamous cytologic abnormalities

The objective of this study was to assess whether human papillomavirus (HPV) detection with hybrid capture II (HC II) can help predict the presence and the nature, glandular or squamous, of histologic cervical lesions in women referred due to atypical glandular cells (AGC) or high-grade squamous intraepithelial lesion (HSIL). A total of 247 women were included. Referral Pap smears comprised AGC (51 cases), AGC plus HSIL (28 cases), adenocarcinoma in situ (10 cases), and HSIL (158 cases). All patients were tested for high-risk HPV with HC II and had a histologic assessment of their cervix. Histologic analysis showed 38 women with (15.3%) cervicitis, 194 with (75.5%) squamous lesions, and 15 with (9.2%) glandular neoplasia. The overall rate of high-risk HPV detection was 77%. Almost 70% of AGC-HPV-negative patients did not have a pathologically proven cervical neoplasia, whereas 76% of women with AGC-HPV-positive result were diagnosed with a squamous or glandular neoplasia. Most (95%) of the lesions in patients with AGC-HSIL were of squamous nature, and HPV detection did not contribute to their differentiation from glandular lesions. We conclude that in women with AGC, HPV positivity strongly correlated with the presence of glandular or squamous cervical lesion but did not help distinguishing women with squamous from those with glandular neoplasia.1631055106

Incidence, predictive factors, and prognosis for winged scapula in breast cancer patients after axillary dissection

Axillary lymph node dissection is part of breast cancer surgery, and winged scapula is a possible sequela. Data regarding its incidence, predictive factors, and patient prognosis remains inconsistent. Ignorance of its diagnosis may lead to undertreatment with physical morbidity. Breast cancer patients with axillary lymph node dissection were prospectively recruited. Postoperative examinations by the physiotherapy staff were performed. One hundred eighty-seven patients were recruited during July-October 2012; 51 patients had a positive diagnosis (27.2 %), with 38 patients (86 %) who recovered completely from the winged scapula, while 6 patients (13 %) still had winged scapula at 6 months after surgery. One hundred thirty patients underwent mastectomy and 100 cases had immediate reconstruction. Age, BMI, previous shoulder joint morbidity, and breast surgery were not associated with winged scapula. Neoadjuvant treatment, mastectomy or conservative surgery, immediate reconstruction, tumor size, and nodal involvement also did not show any correlation. Breast reconstruction with prosthesis, even with serratus muscle dissection, does not increase the incidence of winged scapula. Winged scapula is not an uncommon incidence after breast cancer surgery. Physiotherapy is related to the complete recovery. The severity or grading of the winged scapula and the recovery time after physiotherapy should be investigated in the future studies.22616111617Umberto Veronesi Foundatio