Inequities in referrals to a breast cancer risk assessment and prevention clinic: a mixed methods study.

BACKGROUND: Inequitable access to personalized breast cancer screening and prevention may compound racial and ethnic disparities in outcomes. The Breast Cancer Personalized Risk Assessment, Education and Prevention (B-PREP) program, located within the Brigham and Women's Hospital (BWH) Comprehensive Breast Health Center (BHC), provides care to patients at high risk for developing breast cancer. We sought to characterize the differences between BWH primary care patients referred specifically to B-PREP for risk evaluation and those referred to the BHC for benign breast conditions. Through interviews with primary care clinicians, we sought to explore contributors to potentially inequitable B-PREP referral patterns. METHODS: We used electronic health record data and the B-PREP clinical database to identify patients referred by primary care clinicians to the BHC or B-PREP between 2017 and 2020. We examined associations with likelihood of referral to B-PREP for risk assessment. Semi-structured interviews were conducted with nine primary care clinicians from six clinics to explore referral patterns. RESULTS: Of 1789 patients, 78.0% were referred for benign breast conditions, and 21.5% for risk assessment. In multivariable analyses, Black individuals were less likely to be referred for risk than for benign conditions (OR 0.38, 95% CI:0.23-0.63) as were those with Medicaid/Medicare (OR 0.72, 95% CI:0.53-0.98; OR 0.52, 95% CI:0.27-0.99) and those whose preferred language was not English (OR 0.26, 95% CI:0.12-0.57). Interviewed clinicians described inconsistent approaches to risk assessment and variable B-PREP awareness. CONCLUSIONS: In this single-site evaluation, among individuals referred by primary care clinicians for specialized breast care, Black, publicly-insured patients, and those whose preferred language was not English were less likely to be referred for risk assessment. Larger studies are needed to confirm these findings. Interventions to standardize breast cancer risk assessment in primary care may improve equity.

Wearable-Triggered Ecological Momentary Assessments Are Feasible in People With Advanced Cancer and Their Family Caregivers: Feasibility Study from an Outpatient Palliative Care Clinic at a Cancer Center.

Background: Emerging digital health approaches could play a role in better personalized palliative care. Aim: We conducted a feasibility study testing wearable sensor (WS)-triggered ecological momentary assessments (EMAs) and electronic patient-reported outcomes in community palliative care with patient-caregiver dyads. Design: All wore consumer-grade WS for five weeks. Sensor-detected "stress" (heart rate variability algorithm) that passed individualized thresholds triggered a short smartphone survey. Daily sleep surveys, weekly symptom surveys (Integrated Palliative care Outcome Scale), and a poststudy experience survey were conducted. Setting/Participants: Fifteen dyads (n = 30) were recruited from an outpatient palliative care clinic for people with cancer. Results: Daytime sensor wear-time had 73% adherence. Participants perceived value in this support. Quantity and severity of "stress" events were higher in patients. Sleep disturbance was similar but for different reasons: patients (physical symptoms) and caregivers (worrying about the patient). Conclusions: EMAs are feasible and valued in community palliative care.

Rates of pathologic nodal disease among cN0 and cN1 patients undergoing routine axillary ultrasound and neoadjuvant chemotherapy.

PURPOSE: Routine axillary ultrasound (AxUS) in patients receiving neoadjuvant chemotherapy (NAC) remains controversial. Here, we report rates of AxUS-detected nodal disease among patients with normal clinical exams, and rates of pathologic nodal disease after NAC based on method of nodal disease detection. METHODS: Clinicopathologic findings were prospectively collected for stage I-III breast cancer patients selected for NAC. All patients had pre-treatment AxUS, suspicious nodes were biopsied. The following four patient cohorts were examined: patients with suspicious exam or AxUS but negative biopsy (Suspicious cN0); those with normal exam and normal AxUS (Not Suspicious cN0); those with normal exam but suspicious AxUS and positive biopsy (AxUS-detected cN1); and those with abnormal exam and positive biopsy (exam-detected cN1). Sentinel (SLN) and non-sentinel lymph nodes (non-SLN) were evaluated by immunohistochemistry; nodal metastases of any size were considered positive. RESULTS: 500 patients were included. Of 310 patients with normal axillary exams, 160 had suspicious AxUS, 65 were biopsy-negative (Suspicious cN0) and 95/310 (30.6%) were biopsy-positive (AxUS-detected cN1). Of 190 with abnormal axillary exams, 166 were biopsy-proven node-positive (exam-detected cN1) and 24 were AxUS or biopsy-negative (Suspicious cN0). Rates of pathologic nodal disease were 20/150 (13.3%) among Not Suspicious cN0 patients, 12/89 (13.5%) among Suspicious cN0 (p = 0.97). Rates of residual nodal disease were 55/95 (57.9%) among AxUS-detected cN1 patients, 102/166 (61.4%) among exam-detected cN1 (p = 0.57). CONCLUSION: AxUS detected nodal disease in 30.6% of patients with normal clinical exams selected for NAC. Rates of pathologic nodal disease were similar among AxUS-detected and exam-detected cN1 patients.

Impact of the Histologic Pattern of Residual Tumor After Neoadjuvant Chemotherapy on Recurrence and Survival in Stage I-III Breast Cancer.

BACKGROUND: Additional risk-stratification measures are needed in breast cancer patients with residual disease after neoadjuvant chemotherapy (NAC). We aimed to describe oncologic outcomes in a modern cohort treated with NAC, and evaluate the prognostic value of histologic pattern of residual tumor. PATIENTS AND METHODS: We included patients with stage I-III breast cancer treated with NAC and surgery from 2004 to 2014. Histologic pattern of residual tumor was evaluated by central pathology review when slides were available. Multivariable Cox regression was performed to evaluate factors associated with locoregional recurrence (LRR), recurrence-free survival (RFS), and overall survival (OS). RESULTS: Among 975 patients, median follow-up was 74.0 months and 10-year rates of LRR, RFS, and OS were 9.8%, 67.6% and 74.4%, respectively. Biologic subtype, pathologic node-positive disease, and pathologic complete response (pCR) were associated with outcomes. Among 666 (68.3%) patients with central pathology review, pattern of residual disease was not significantly associated with LRR. However, both scattered residual tumor and no/minimal response relative to a concentric pattern of response were significantly associated with inferior RFS (scattered: hazard ratio 2.0, p = 0.015; no/minimal response: hazard ratio 2.2, p = 0.021) and OS (scattered: hazard ratio 2.2, p = 0.026; no/minimal response: hazard ratio 2.5, p = 0.023). This finding was most prominent in patients with triple-negative breast cancer. CONCLUSIONS: Patients with a scattered relative to concentric pattern of residual tumor after NAC had inferior RFS and OS, nearly as poor as those with no/minimal response. Histologic pattern of residual tumor may represent a novel prognostic measure, particularly in the triple-negative breast cancer population.

How Often Does Retrieval of a Clipped Lymph Node Change Adjuvant Therapy Recommendations? A Prospective, Consecutive, Patient Cohort Study.

BACKGROUND: Prior studies examining sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NAC) for cN1 patients have demonstrated that 20% of biopsied, clipped lymph nodes (cLNs) are nonsentinel lymph nodes (non-SLNs). Our goal was to determine how often the cLN was a non-SLN among both cN0 and cN1 patients and how often cLN pathology impacted management. METHODS: Overall, 238 patients treated with NAC and surgery January 2019 to June 2020 were prospectively examined. Patients underwent routine axillary ultrasound, biopsy of suspicious nodes, and clip placement. Radioactive iodine-125 seed localization of the cLN was performed in cN1 patients only. Isolated tumor cells (ITCs) were considered node positive (ypN+) for both cN0 and cN1 cohorts. Chart review was performed to determine if cLNs were non-SLN and their ypN status. RESULTS: Of 118 cN0 patients, 115 of 118 (97%) underwent successful SLNB, 33 of whom had a cLN present; 21 of 33 (64%) cLNs were non-SLNs. Overall, 9 of 118 (8%) were ypN+; no cLN was ypN+ without additional +SLNs. Of 120 cN1 patients, 104 of 120 (87%) converted to cN0, 98 of 104 (94%) of which had attempted SLNB, and 95 of 98 (97%) successfully mapped. The cLN was a non-SLN in 18 of 95 (19%). Overall, 58 of 104 (56%) cN1 patients were ypN+. One patient had a positive cLN in the absence of +SLNs. This patient underwent axillary lymph node dissection (ALND); adjuvant treatment recommendations were unchanged. CONCLUSIONS: The cLN was a non-SLN in 19% of cN1 patients. cLN pathology did not impact adjuvant therapy recommendations, calling into question the utility of routinely clipping biopsied lymph nodes.

Serial step sections at narrow intervals with immunohistochemistry are required for accurate histological assessment of sentinel lymph node biopsy in oral squamous cell carcinoma.

BACKGROUND: Sentinel lymph node (SLN) biopsy is an accurate staging modality in early oral squamous cell carcinoma (OSCC), but its accuracy relies on labor-intensive histopathology protocols. We sought to determine whether serial step sections with immunohistochemistry (SSSIHC) at narrow intervals of the entire SLN are required to accurately exclude metastasis. METHODS: Consecutive SLN biopsies over a 13-year period were retrospectively evaluated. If the index section was negative for carcinoma, the entire SLN was subjected to SSSIHC at 150 µm intervals. The first section level and total number of section levels to contain carcinoma were recorded. RESULTS: One hundred and eighteen SLN+ from 90 patients were included. SSSIHC upstaged the nodal status in 19.5% of patients. Metastasis was identified in 16.7% and 10.2% beyond section levels 4 and 6, respectively. Among SLNs requiring SSSIHC, 47.5% contained carcinoma in a single section level. CONCLUSION: SSSIHC of the entire SLN at 150 µm intervals are required to identify occult metastasis in OSCC.

Comparison of Breast Cancer Staging Systems After Neoadjuvant Chemotherapy.

BACKGROUND: No consensus exists for optimal staging following neoadjuvant chemotherapy (NAC). We compared the performance of the American Joint Committee on Cancer (AJCC) pathologic prognostic staging system, Residual Cancer Burden (RCB) Index, and the Neo-Bioscore in breast cancer patients after NAC. METHODS: Patients with stage I-III breast cancer who received NAC at Dana-Farber Cancer Institute from 2004 to 2014 were identified. Kaplan-Meier curves were used to estimate disease-free survival (DFS) and overall survival (OS), and model fits were compared by receiver operator characteristic (ROC) curve using the c-statistic and DeLong's test. RESULTS: Overall, 802 patients with a median age of 48 years received NAC. Most patients presented with cT2 (n = 470, 58.6%) and cN1 (n = 422, 52.6%) disease. The subtype was estrogen receptor (ER)- and/or progesterone receptor (PR)-positive/human epidermal growth factor receptor 2 (HER2)-negative in 296 (36.9%) patients, HER2-positive in 261 (32.5%) patients, and triple-negative in 245 (30.5%) patients. Median follow-up was 79.5 months. There were 174 recurrences (30 local, 25 regional, 145 distant), with 676 (76.8%) patients alive at last follow-up. AJCC pathologic prognostic staging and RCB had better discrimination for estimated 7-year DFS and OS compared with the Neo-Bioscore. The ROC c-statistics for DFS model fit were similar for AJCC pathologic prognostic stage (0.72) and RCB (0.71, p = non-significant); both had improved model fit versus the Neo-Bioscore (0.65, p < 0.01). The c-statistics for OS were 0.74, 0.71, and 0.70 for AJCC pathologic prognostic stage, RCB, and Neo-Bioscore, respectively (p = non-significant). CONCLUSIONS: These results validate the ability of these staging systems to stratify survival outcomes in NAC patients, with best discrimination achieved using AJCC pathologic prognostic stage or RCB.

Clinico-pathologic predictors of patterns of residual disease following neoadjuvant chemotherapy for breast cancer.

Among breast cancer patients treated with neoadjuvant chemotherapy (NAC) who do not experience a pathologic complete response (pCR), the pattern of residual disease in the breast varies. Pre-treatment clinico-pathologic features that predict the pattern of residual tumor are not well established. To investigate this issue, we performed a detailed review of histologic sections of the post-treatment surgical specimens for 665 patients with stage I-III breast cancer treated with NAC followed by surgery from 2004 to 2014 and for whom slides of the post-NAC surgical specimen were available for review. This included 242 (36.4%) patients with hormone receptor (HR)+/HER2- cancers, 216 (32.5%) with HER2+ tumors, and 207 (31.1%) with triple negative breast cancer (TNBC). Slide review was blinded to pre-treatment clinico-pathologic features. pCR was achieved in 7.9%, 37.0%, and 37.7%, of HR+/HER2- cancers, HER2+ cancers, and TNBC respectively (p < 0.001). Among 389 patients with residual invasive cancer in whom the pattern of residual disease could be assessed, 287 (73.8%) had a scattered pattern and 102 (26.2%) had a circumscribed pattern. In both univariate and multivariate analyses, there was a significant association between tumor subtype and pattern of response. Among patients with HR+/HER2- tumors, 89.4% had a scattered pattern and only 10.6% had a circumscribed pattern. In contrast, among those with TNBC 52.8% had a circumscribed pattern and 47.2% had a scattered pattern (p < 0.001). In addition to subtype, histologic grade and tumor size at presentation were also significantly related to the pattern of residual disease in multivariate analysis, with lower grade and larger size each associated with a scattered response pattern (p = 0.002 and p = 0.01, respectively). A better understanding of the relationship between pre-treatment clinico-pathologic features of the tumor and pattern of residual disease may be of value for helping to guide post-chemotherapy surgical management.

Pharmaceutical procurement among public sector procurers in CARICOM / Compras farmacéuticas por parte de organismos del sector público de CARICOM / Aquisição de produtos farmacêuticos por compradores do setor público da CARICOM

ABSTRACT Objective. To examine multiple aspects of the medicines in CARICOM procurement markets, including manufacturer headquarters location, regulatory history, and type (innovator versus generic); the proportion of World Health Organization (WHO) essential medicines; and the most expensive medicines procured. Methods. An analysis of procurement information from selected CARICOM procurers. Four public sector procurement lists were obtained based on public availability or sharing of data from public sector procurers. Analyses were based on parameters available or deduced from these data. Results. The majority of products come from manufacturers headquartered in North America and Europe (63%-67%). The percentage of medicines procured from generic companies is 60%-87%; and 25%-50% of medicines procured are on the WHO Essential Medicines List. Wide price variations exist in the most expensive medicines purchased. Conclusions. The analysis identifies vulnerabilities and opportunities in the procurement situation of CARICOM states, particularly related to quality and rational use of medicines. This analysis represents a baseline that governments and other stakeholders can use in the future.

RESUMEN Objetivo. Revisar los múltiples aspectos de los medicamentos en los mercados de compras y los proveedores de CARICOM, como la ubicación de la sede del fabricante, el historial de regulación, el tipo (patentado versus genérico); la proporción de medicamentos esenciales de la Organización Mundial de la Salud (OMS); y los medicamentos comprados más caros. Métodos. Se analizó información sobre la compra por parte de determinados organismos de CARICOM. La información procedía de cuatro listas de organismos del sector público que realizan las compras, que se consiguieron en función de su disponibilidad pública o de los datos distribuidos por los organismos del sector público que realizan las compras. Los análisis estaban basados en los parámetros disponibles o derivados de estos datos. Resultados. La mayoría de los productos proviene de fabricantes radicados en América del Norte y Europa (entre 63% y 67%). El porcentaje de medicamentos que se compra de empresas genéricas oscila entre 60% y 87%; y de 25% a 50% de los medicamentos que se compran están en la Lista de Medicamentos Esenciales de la OMS. Hay una gran divergencia de precios entre los medicamentos comprados más caros. Conclusiones. En el análisis se han encontrado vulnerabilidades y oportunidades con respecto a la situación de las compras de medicamentos de los Estados de CARICOM, especialmente en cuanto a la calidad y al uso racional de los medicamentos. Este análisis representa una línea de base que los gobiernos u otros interesados directos pueden utilizar en el futuro.

RESUMO Objetivo. Examinar vários aspectos relacionados aos mercados e fornecedores de produtos farmacêuticos da CARICOM, incluindo a localização da sede do laboratório fabricante, histórico regulatório e tipo de produtos (inovadores versus genéricos); proporção de medicamentos adquiridos que constam da relação de medicamentos essenciais da Organização Mundial da Saúde (OMS); e medicamentos mais caros comprados. Métodos. Foi realizada uma análise de informação sobre compras feitas por compradores selecionados da CARICOM. Quatro listas de compras do setor público foram obtidas com informação de acesso público ou compartilhada pelos compradores. As análises foram feitas com base em parâmetros disponíveis ou inferidos a partir dos dados. Resultados. A maioria dos produtos farmacêuticos é proveniente de laboratórios com sedes na América do Norte e Europa (63%-67%). Do total, 60%-87% dos medicamentos adquiridos são de laboratórios de produtos genéricos e 25%-50% constam da relação de medicamentos essenciais da OMS. Existe uma ampla variação nos preços dos medicamentos mais caros comprados. Conclusões. Foram identificadas fragilidades e oportunidades na situação de compras dos países da CARICOM, em particular relacionadas à qualidade dos produtos e ao uso racional dos medicamentos. Esta análise serve de referência a ser usada futuramente pelos governos e outras partes interessadas.

Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis.

YAP1 is a transcriptional coactivator and the principal effector of the Hippo signaling pathway, which is causally implicated in human cancer. Several YAP1 gene fusions have been identified in various human cancers and identifying the essential components of this family of gene fusions has significant therapeutic value. Here, we show that the YAP1 gene fusions YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, and YAP1-SS18 are oncogenic in mice. Using reporter assays, RNA-seq, ChIP-seq, and loss-of-function mutations, we can show that all of these YAP1 fusion proteins exert TEAD-dependent YAP activity, while some also exert activity of the C'-terminal fusion partner. The YAP activity of the different YAP1 fusions is resistant to negative Hippo pathway regulation due to constitutive nuclear localization and resistance to degradation of the YAP1 fusion proteins. Genetic disruption of the TEAD-binding domain of these oncogenic YAP1 fusions is sufficient to inhibit tumor formation in vivo, while pharmacological inhibition of the YAP1-TEAD interaction inhibits the growth of YAP1 fusion-expressing cell lines in vitro. These results highlight TEAD-dependent YAP activity found in these gene fusions as critical for oncogenesis and implicate these YAP functions as potential therapeutic targets in YAP1 fusion-positive tumors.

Models of endometriosis and their utility in studying progression to ovarian clear cell carcinoma.

Endometriosis is a common benign gynaecological condition affecting at least 10% of women of childbearing age and is characterized by pain--frequently debilitating. Although the exact prevalence is unknown, the economic burden is substantial (∼$50 billion a year in the USA alone) and it is associated with considerable morbidity. The development of endometriosis is inextricably linked to the process of menstruation and thus the models that best recapitulate the human disease are in menstruating non-human primates. However, the use of these animals is ethically challenging and very expensive. A variety of models in laboratory animals have been developed and the most recent are based on generating menstrual-like endometrial tissue that can be transferred to a recipient animal. These models are genetically manipulable and facilitate precise mechanistic studies. In addition, these models can be used to study malignant transformation in epithelial ovarian carcinoma. Epidemiological and molecular evidence indicates that endometriosis is the most plausible precursor of both clear cell and endometrioid ovarian cancer (OCCA and OEA, respectively). While this progression is rare, understanding the underlying mechanisms of transformation may offer new strategies for prevention and therapy. Our ability to pursue this is highly dependent on improved animal models but the current transgenic models, which genetically modify the ovarian surface epithelium and oviduct, are poor models of ectopic endometrial tissue. In this review we describe the various models of endometriosis and discuss how they may be applicable to developing our mechanistic understanding of OCCA and OEA.

Family carers providing support to a person dying in the home setting: A narrative literature review.

BACKGROUND: This study is based on people dying at home relying on the care of unpaid family carers. There is growing recognition of the central role that family carers play and the burdens that they bear, but knowledge gaps remain around how to best support them. AIM: The aim of this study is to review the literature relating to the perspectives of family carers providing support to a person dying at home. DESIGN: A narrative literature review was chosen to provide an overview and synthesis of findings. The following search terms were used: caregiver, carer, 'terminal care', 'supportive care', 'end of life care', 'palliative care', 'domiciliary care' AND home AND death OR dying. DATA SOURCES: During April-May 2013, Cumulative Index to Nursing and Allied Health Literature (CINAHL), MEDLINE, PsycINFO, Pubmed, Cochrane Reviews and Citation Indexes were searched. Inclusion criteria were as follows: English language, empirical studies and literature reviews, adult carers, perspectives of family carers, articles focusing on family carers providing end-of-life care in the home and those published between 2000 and 2013. RESULTS: A total of 28 studies were included. The overarching themes were family carers' views on the impact of the home as a setting for end-of-life care, support that made a home death possible, family carer's views on deficits and gaps in support and transformations to the social and emotional space of the home. CONCLUSION: Many studies focus on the support needs of people caring for a dying family member at home, but few studies have considered how the home space is affected. Given the increasing tendency for home deaths, greater understanding of the interplay of factors affecting family carers may help improve community services.

'Malnutrition Universal Screening Tool' predicts mortality and length of hospital stay in acutely ill elderly.

Malnutrition and its impact on clinical outcome may be underestimated in hospitalised elderly as many screening procedures require measurements of weight and height that cannot often be undertaken in sick elderly patients. The 'Malnutrition Universal Screening Tool' ('MUST') has been developed to screen all adults, even if weight and/or height cannot be measured, enabling more complete information on malnutrition prevalence and its impact on clinical outcome to be obtained. In the present study, 150 consecutively admitted elderly patients (age 85 (sd 5.5) years) were recruited prospectively, screened with 'MUST' and clinical outcome recorded. Although only 56 % of patients could be weighed, all (n 150) could be screened with 'MUST'; 58 % were at malnutrition risk and these individuals had greater mortality (in-hospital and post-discharge, P<0.01) and longer hospital stays (P=0.02) than those at low risk. Both 'MUST' categorisation and component scores (BMI, weight loss, acute disease) were significantly related to mortality (P<0.03). Those patients with no measured or recalled weight ('MUST' subjective criteria used) had a greater risk of malnutrition (P=0.01) and a poorer clinical outcome (P<0.002) than those who could be weighed and, within both groups, clinical outcome was worse in those at risk of malnutrition. The present study suggests that 'MUST' predicts clinical outcome in hospitalised elderly, in whom malnutrition is common (58 %). In those who cannot be weighed, a higher prevalence of malnutrition and associated poorer clinical outcome supports the importance of routine screening with a tool, like 'MUST', that can be used to screen all patients.

Malnutrition in hospital outpatients and inpatients: prevalence, concurrent validity and ease of use of the 'malnutrition universal screening tool' ('MUST') for adults.

The 'malnutrition universal screening tool' ('MUST') for adults has been developed for all health care settings and patient groups, but ease of use and agreement with other published tools when screening to identify malnutrition requires investigation. The present study assessed the agreement and the prevalence of malnutrition risk between 'MUST' and a variety of other tools in the same patients and compared the ease of using these tools. Groups of patients were consecutively screened using 'MUST' and: (1) MEREC Bulletin (MEREC) and Hickson and Hill (HH) tools (fifty gastroenterology outpatients); (2) nutrition risk score (NRS) and malnutrition screening tool (MST; seventy-five medical inpatients); (3) short-form mini nutritional assessment (MNA-tool; eighty-six elderly and eighty-five surgical inpatients); (4) subjective global assessment (SGA; fifty medical inpatients); (5) Doyle undernutrition risk score (URS; fifty-two surgical inpatients). Using 'MUST', the prevalence of malnutrition risk ranged from 19-60% in inpatients and 30% in outpatients. 'MUST' had 'excellent' agreement (kappa 0.775-0.893) with MEREC, NRS and SGA tools, 'fair-good' agreement (kappa 0.551-0.711) with HH, MST and MNA-tool tools and 'poor' agreement with the URS tool (kappa 0.255). When categorisation of malnutrition risk differed between tools, it did not do so systematically, except between 'MUST' and MNA-tool (P=0.0005) and URS (P=0.039). 'MUST' and MST were the easiest, quickest tools to complete (3-5 min). The present investigation suggested a high prevalence of malnutrition in hospital inpatients and outpatients (19-60% with 'MUST') and 'fair-good' to 'excellent' agreement beyond chance between 'MUST' and most other tools studied. 'MUST' was quick and easy to use in these patient groups.