Postoperative radiotherapy omission in selected patients with early breast cancer following preoperative breast MRI (PROSPECT): primary results of a prospective two-arm study.

BACKGROUND: Adjuvant breast radiotherapy as a standard component of breast-conserving treatment for early cancer can overtreat many women. Breast MRI is the most sensitive modality to assess local tumour burden. The aim of this study was to determine whether a combination of MRI and pathology findings can identify women with truly localised breast cancer who can safely avoid radiotherapy. METHODS: PROSPECT is a prospective, multicentre, two-arm, non-randomised trial of radiotherapy omission in patients selected using preoperative MRI and postoperative tumour pathology. It is being conducted at four academic hospitals in Australia. Women aged 50 years or older with cT1N0 non-triple-negative breast cancer were eligible. Those with apparently unifocal cancer had breast-conserving surgery (BCS) and, if pT1N0 or N1mi, had radiotherapy omitted (group 1). Standard treatment including excision of MRI-detected additional cancers was offered to the others (group 2). All were recommended systemic therapy. The primary outcome was ipsilateral invasive recurrence rate (IIRR) at 5 years in group 1. Primary analysis occurred after the 100th group 1 patient reached 5 years follow-up. Quality-adjusted life-years (QALYs) and cost-effectiveness of the PROSPECT pathway were analysed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000810011). FINDINGS: Between May 17, 2011, and May 6, 2019, 443 patients with breast cancer underwent MRI. Median age was 63·0 years. MRI detected 61 malignant occult lesions separate from the index cancer in 48 patients (11%). Of 201 group 1 patients who had BCS without radiotherapy, the IIRR at 5 years was 1·0% (upper 95% CI 5·4%). In group 1, one local recurrence occurred at 4·5 years and a second at 7·5 years. In group 2, nine patients had mastectomy (2% of total cohort), and the 5-year IIRR was 1·7% (upper 95% CI 6·1%). The only distant metastasis in the entire cohort was genetically distinct from the index cancer. The PROSPECT pathway increased QALYs by 0·019 (95% CI 0·008-0·029) and saved AU$1980 (95% CI 1396-2528) or £953 (672-1216) per patient. INTERPRETATION: PROSPECT suggests that women with unifocal breast cancer on MRI and favourable pathology can safely omit radiotherapy. FUNDING: Breast Cancer Trials, National Breast Cancer Foundation, Cancer Council Victoria, the Royal Melbourne Hospital Foundation, and the Breast Cancer Research Foundation.

Contrast-enhanced mammography for surveillance in women with a personal history of breast cancer.

PURPOSE: Women with a personal history of breast cancer have an increased risk of subsequent breast malignancy and may benefit from more sensitive surveillance than conventional mammography (MG). We previously reported outcomes for first surveillance episode using contrast-enhanced mammography (CEM), demonstrating higher sensitivity and comparable specificity to MG. We now report CEM performance for subsequent surveillance. METHODS: A retrospective study of 1,190 women in an Australian hospital setting undergoing annual surveillance following initial surveillance CEM between June 2016 and December 2022. Outcome measures were recall rate, cancer detection rate, contribution of contrast to recalls, false positive rate, interval cancer rate and characteristics of surveillance detected and interval cancers. RESULTS: 2,592 incident surveillance episodes were analysed, of which 93% involved contrast-based imaging. Of 116 (4.5%) recall episodes, 40/116 (34%) recalls were malignant (27 invasive; 13 ductal carcinoma in situ), totalling 15.4 cancers per 1000 surveillance episodes. 55/116 (47%) recalls were contrast-directed including 17/40 (43%) true positive recalls. Tumour features were similar for contrast-directed recalls and other diagnoses. 8/9 (89%) of contrast-directed invasive recalls were Grade 2-3, and 5/9 (56%) were triple negative breast cancers. There were two symptomatic interval cancers (0.8 per 1000 surveillance episodes, program sensitivity 96%). CONCLUSION: Routine use of CEM in surveillance of women with PHBC led to an increase in the detection of clinically significant malignant lesions, with a low interval cancer rate compared to previous published series. Compared to mammographic surveillance, contrast-enhanced mammography increases the sensitivity of surveillance programs for women with PHBC.

Contrast-Enhanced Mammography in Local Staging of Screen-Detected Breast Cancer.

BACKGROUND: BreastScreen Australia, the population mammographic screening program for breast cancer, uses two-view digital screening mammography ± ultrasound followed by percutaneous biopsy to detect breast cancer. Secondary breast imaging for further local staging, not performed at BreastScreen, may identify additional clinically significant breast lesions. Staging options include further mammography, bilateral ultrasound, and/or contrast-based imaging (CBI) [magnetic resonance imaging (MRI) or contrast-enhanced mammography (CEM)]. CBI for local staging of screen-detected cancer was introduced at an academic hospital breast service in Melbourne, VIC, Australia. We report findings for otherwise occult disease and resulting treatment changes. MATERIAL AND METHODS: Patients staged using CEM between November 2018 and April 2022 were identified from hospital records. Data were extracted from radiology, pathology, and breast unit databases. CEM-detected abnormalities were documented as true positive (TP) for invasive cancer or ductal carcinoma in situ (DCIS), or otherwise false positive (FP). The impact on surgical decisions was assessed. RESULTS: Of 202 patients aged 44-84 years, 60 (30%) had 74 additional findings [34 (46%) TP, 40 (54%) FP]. These were malignant in 29/202 (14%) patients (79% invasive cancers, 21% DCIS). CEM resulted in surgical changes in 43/202 (21%) patients: wider resection (24/43), conversion to mastectomy (6/43), contralateral breast surgery (6/43), additional ipsilateral excision (5/43), and bracketing (2/43). Additional findings were more common for patients with larger index lesions and for invasive cancer, but there was no significant variation by age, breast density, or index lesion grade. CONCLUSIONS: CEM for local staging of screen-detected breast cancers identified occult malignancy in 14% of patients. CEM improves local staging and may facilitate appropriate management of screen-detected breast cancers.

Is de-escalation of treatment by omission of radiotherapy associated with fear of cancer recurrence in women with early breast cancer? An exploratory study.

PURPOSE: Safe de-intensification of adjuvant radiotherapy (RT) for early breast cancer (BC) is currently under evaluation. Little is known about the patient experience of de-escalation or its association with fear of cancer recurrence (FCR), a key issue in survivorship. We conducted a cross-sectional study to explore this association. METHODS: Psychometrically validated measures including the Fear of Cancer Recurrence Inventory-Short Form were completed by three groups of women with early BC: Women in the PROSPECT clinical trial who underwent pre-surgical MRI and omitted RT (A), women who underwent pre-surgical MRI and received RT (B); and women who received usual care (no MRI, received RT; C). Between group differences were analysed with non-parametric tests. A subset from each group participated in a semi-structured interview. These data (n = 44) were analysed with directed content analysis. RESULTS: Questionnaires from 400 women were analysed. Significantly lower FCR was observed in Group A (n = 125) than in Group B (n = 102; p = .002) or Group C (n = 173; p = .001), and when participants were categorized by RT status (omitted RT vs received RT; p < .001). The proportion of women with normal FCR was significantly (p < .05) larger in Group A (62%) than in Group B (35%) or Group C (40%). Two qualitative themes emerged: 'What I had was best' and 'Coping with FCR'. CONCLUSIONS: Omitting RT in the setting of the PROSPECT trial was not associated with higher FCR than receiving RT. Positive perceptions about tailored care, lower treatment burden, and trust in clinicians appear to be protective against FCR.

Contrast enhanced mammography in breast cancer surveillance.

PURPOSE: Mammography (MG) is the standard imaging in surveillance of women with a personal history of breast cancer or DCIS (PHBC), supplemented with ultrasound. Contrast Enhanced Mammography (CEM) has higher sensitivity than MG and US. We report the performance of CEM compared with MG ± US. METHODS: A retrospective study of patients undergoing their first surveillance CEM in an Australian hospital setting between June 2006 and October 2020. Cases where a patient was recalled for assessment were identified, recording radiology, pathology and treatment details. Blinded re-reading of recalled cases was performed to determine the contribution of contrast. Use of surveillance US across the board was assessed for the period. RESULTS: 73/1191 (6.1%) patients were recalled. 35 (48%) were true positives (TP), with 26 invasive cancers and 9 cases of DCIS, while 38 (52%) were false positive (FP) with a positive predictive value (PPV) 47.9%. 32/73 were recalled due to MG findings, while 41/73 were only recalled due to Contrast. 14/73 had 'minimal signs' with a lesion identifiable on MG with knowledge of the contrast finding, while 27/73 were visible only with contrast. 41% (17/41) recalled due to contrast were TP. Contrast-only TPs were found with low and high mammographic density (MD). Screening breast US reduced by 55% in the year after CEM was implemented. CONCLUSION: Compared to MG, CEM as a single surveillance modality for those with PHBC has higher sensitivity and comparable specificity, identifying additional malignant lesions that are clinically significant. Investigation of interval cancer and subsequent round outcomes is warranted.

Utility of cephalic drains in infants receiving extracorporeal membrane oxygenation.

INTRODUCTION: The addition of cephalic drains (CDs) in extracorporeal membrane oxygenation (ECMO) to augment venous drainage may offer benefit, though their use is varied. Our objective was to describe our institution's experience with CDs including flow rates and patency. We also compared complication rates between patients with and without a CD. METHODS: This retrospective cohort study included infants <12 months of age cannulated for ECMO between January 1, 2010 and September 30, 2019 at a single institution. Flow data were obtained for those with a CD. Demographic and complication rates were obtained for all. RESULTS: Of 264 patients in the final cohort, 220 (83%) had a CD of which 93.2% remained patent to decannulation. CDs typically provided 30% or more of ECMO flow throughout the ECMO run. The median time to CD clot was 139 h (range 48-635 h). Patients with a clotted CD had longer ECMO runs than those whose CD remained patent (median 382 h [IQR 217-538] vs 139 h [IQR 91-246], p < 0.001). Survival to discharge was lower for those with clotted versus patent CD (14% vs 70%, p < 0.001). Mechanical complications were more common in patients with CD (p = 0.005). Seizures were more common in those without a CD (p = 0.021). CONCLUSIONS: In this cohort, the majority of CDs placed remained patent at decannulation and provided substantial additional venous drainage. Mechanical problems were common in patients with CDs, but without clinical sequelae. Further study is warranted to elucidate CD impact on short- and long-term outcomes.

Treatment Intensity Differences After Early-Stage Breast Cancer (ESBC) Diagnosis Depending on Participation in a Screening Program.

BACKGROUND: While population mammographic screening identifies early-stage breast cancers (ESBCs; ductal carcinoma in situ [DCIS] and invasive disease stages 1-3A), commentaries suggest that harms from overdiagnosis and overtreatment may outweigh the benefits. Apparent benefits to patients with screen-detected cancers may be due to selection bias from exclusion of interval cancers (ICs). Treatment intensity is rarely discussed, with an assumption that all ESBCs are treated similarly. We hypothesized that women diagnosed while in a screening program would receive less-intense treatment than those never or not recently screened (NRS). METHODS: This was a retrospective analysis of all women aged 50-69 years managed for ESBC (invasive or DCIS) during the period 2007-2013 within a single service, comparing treatment according to screening status. Data on demographics, detection, pathology, and treatment were derived from hospital, cancer registry, and screening service records. RESULTS: Overall, 622 patients were active screeners (AS) at diagnosis (569 screen-detected and 53 ICs) and 169 patients were NRS. AS cancers were smaller (17 mm vs. 26 mm, p < 0.0001), less likely to involve nodes (26% vs. 48%, p < 0.0001), and lower grade. For invasive cancer, NRS patients were more likely to be recommended for mastectomies [35% vs. 16%; risk ratio(RR) 2.2, p < 0.0001], axillary dissection (43% vs. 19%; RR 2.3, p < 0.0001), adjuvant chemotherapy (65% vs. 37%; RR 1.7, p < 0.0001), and postmastectomy radiotherapy (58% vs. 39%; RR 1.5, p = 0.04). CONCLUSION: Participants in population screening diagnosed with ESBC receive substantially less-intense treatment than non-participants. Differences persist when potential overdiagnosis is taken into account; these differences should be factored into debates around mammographic screening.

Quality of Life Outcomes Associated With Optimization of Treatment by Omitting Radiotherapy in Early Breast Cancer.

PURPOSE: Improved prognosis of early breast cancer (EBC) has created opportunities for treatment optimization but reducing morbidity should not inadvertently compromise quality of life (QoL). PROSPECT1 used pre-operative MRI and pathology findings to identify women suitable for radiotherapy (RT) omission following breast conserving surgery. We retrospectively explored the association between de-escalation by omission of RT and QoL in women with EBC. MATERIALS AND METHODS: Three groups were recruited: PROSPECT participants who omitted RT following preoperative MRI (A); participants who received RT following preoperative MRI (B); and women who received usual care - No MRI, received RT (C). Measures included the EORTC QLQ-C30 and BR23, BCTOS, DASS-21 and a measure of decision regret. Between group differences were assessed using ANOVA or nonparametric equivalents. Semi-structured interviews were analyzed with qualitative description (n = 44). RESULTS: Data from 400 women were analyzed (125A, 102B, 173C). Group A had fewer symptoms and better body image (breast symptoms: A-B P = .003, A-C P = <.001; arm symptoms: A-B P = .004, A-C P = .011; body image: A-C P = .041) and fewer differences between the treated and untreated breasts (cosmetic: A-B P < .001, A-C P < .001; functional: A-C P = .011; breast specific pain: A-B P < .001, A-C P < .001). Two qualitative themes were found: Treatment with the biggest impact on QoL, and Specific impact of RT on QoL. CONCLUSIONS: Omission of RT was associated with better QoL and functional and cosmetic outcomes. It was highly acceptable to patients. Clinicians should consider the potential for preserved QoL associated with treatment optimization via omission of RT in treatment planning for patients with EBC.

Expanding Medicaid Payment for Pasteurized Donor Human Milk in High-Risk Neonates.

Pasteurized donor human milk (PDHM) is associated with a reduced incidence of necrotizing enterocolitis in very low birth weight (VLBW) infants. Absence of Medicaid and private insurance payment for PDHM use in neonatal intensive care units contributes to disparities based on state of birth and socioeconomic level. Before 2017, 5 states had policies for PDHM coverage, incorporating less than 30% of VLBW infants born nationally. In this case study, we outline the partnership of local American Academy of Pediatrics (AAP) chapters with the national AAP Section on Neonatal-Perinatal Medicine to create a PDHM Advocacy Toolkit to facilitate Medicaid PDHM coverage. Over 5 years, neonatologist-led advocacy, incentivized via AAP funds, contributed to 5 additional states providing Medicaid payment for PDHM, resulting in over 55% of VLBW infants born nationally in states with funded coverage. Partnerships with state AAP chapters, pilot grant funding with deliverables, emphasis on advocacy coaching, and modification of the generalized toolkit to suit local needs were essential in engineering Medicaid PDHM payment. Together these actions provide a template for other pediatric subspecialists to help advance niche-focused advocacy issues at the state level.

Changing populations being treated with ECMO in the neonatal period - who are the others?

Extracorporeal life support via extracorporeal membrane oxygenation (ECMO) has served the sickest of neonates for almost 50 years. Naturally, the characteristics of neonates receiving ECMO have changed. Advances in care have averted the need for ECMO for some, while complex cases with uncertain outcomes, previously not eligible for ECMO, are now considered. Characterizing the disease states and outcomes for neonates on ECMO is challenging as many infants do not fall into classic categories, i.e. meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS), or congenital diaphragmatic hernia (CDH). Since 2017, over one third of neonatal respiratory ECMO runs reported to the Extracorporeal Life Support Organization Registry are grouped as Other, a catch-all that encompasses those with a diagnosis not included in the classic categories. This review summarizes the historical neonatal ECMO population, reviews advances in therapy and technology impacting neonatal care, and addresses the unknowns in the ever-growing category of Other.

Characteristics and outcomes of a multi-institution cohort of infants with necrotizing enterocolitis totalis.

OBJECTIVE: To characterize the presentation, management and outcomes of infants with necrotizing enterocolitis totalis (tNEC) vs surgical non-totalis NEC (sNEC). STUDY DESIGN: This retrospective study identified infants undergoing surgery for NEC through The Children's Hospitals Neonatal Database. Demographic, surgical and mortality characteristics were compared. RESULTS: Of 1059 infants, 161 (15.2%) had tNEC. Perinatal characteristics did not differ. tNEC infants were older and were less likely to have pneumoperitoneum at referral (5.6% vs 13.1%, p < 0.001) or intestinal perforation at surgery (38.5% vs 66.7%, p < 0.001). Infants with tNEC were more acidotic preoperatively (7.1, [IQR 7, 7.3] vs 7.3, [IQR 7.2, 7.4], p < 0.001). Mortality was 96.9% for tNEC and 26.5% for sNEC (p < 0.001). tNEC cases varied by center, accounting for 0-43% of all surgical NEC cases. CONCLUSIONS: Mortality is high for tNEC infants, who present at older age, with greater illness severity but are less likely to have intestinal perforation than sNEC infants.

US state policies for Medicaid coverage of donor human milk.

Donor human milk is recommended by the American Academy of Pediatrics for high-risk infants when mother's own milk is absent or insufficient in quantity. Several factors may contribute to the inequitable use of or access to donor human milk, including a limited knowledge of its effects, cost, reimbursement, and regulatory barriers. The American Academy of Pediatrics and the United States Surgeon General have called for investigating barriers that prevent use of donor human milk for high-risk infants and for changes to public policy known to improve availability and affordability. We review the current legislative, regulatory, and economic landscape surrounding donor human milk use in the United States, as well as suggest state- and federal-level solutions to increase access to donor human milk.

Outcomes of screening-detected ductal carcinoma in situ treated with wide excision alone.

BACKGROUND: Ductal carcinoma in situ (DCIS) is commonly identified on screening mammography. Standard treatment for localized DCIS is wide local excision (WLE) and adjuvant radiotherapy. This approach represents overtreatment in many cases, where the DCIS would never have become clinically significant, or where less intensive treatment would have been satisfactory. We reviewed the medium-term outcome of a cohort of screen detected DCIS patients treated mainly with WLE without radiotherapy. METHODS: All patients diagnosed with DCIS at NorthWestern BreastScreen between January 1994 and December 2005 were identified from a prospective database. Demographic, pathological, treatment, and outcome data were collected and analyzed. Survival and local recurrence (LR) rates were determined, and associations between various factors and recurrence were analyzed. RESULTS: A total of 422 patients were diagnosed with DCIS. There were 400 patients treated with WLE, and 27 of these received adjuvant radiotherapy. The 5- and 8-year overall and breast cancer specific survival rates were 96.1 and 91.3%, and 99.6 and 99.3%, respectively. The local recurrence rate was 15.4 and 17.1% at 5 and 8 years. Of 56 local recurrences, 34 had WLE after recurrence, 16 of which had adjuvant radiotherapy. No single factor was statistically significantly associated with local recurrence, although combining factors revealed groups where the LR rate was less than 5%. CONCLUSIONS: Breast cancer specific mortality was very low in this cohort of older patients with screen-detected DCIS. There was a moderate rate of local recurrence that could usually be salvaged with breast conservation. Decisions regarding adjuvant radiotherapy should take these findings into account.

Relationships of Pubertal Development Among Early Adolescents to Sexual and Nonsexual Risk Behaviors and Caregivers' Parenting Behaviors.

Using a school-based sample of Washington, DC, fifth graders (mean age 10.38, SD = 0.66) and their parents (N = 408), we examined associations of pubertal development with early adolescents' sexual and nonsexual risk behaviors and their caregivers' parenting behaviors; and of these risk behaviors with parenting behaviors. Youths reporting signs of pubertal development were more likely to engage in these risk behaviors than students reporting no signs. Pubertal development was not related to parenting behaviors; however, parents of youths who reported multiple nonsexual risk behaviors reported more parent-child communication about sexual topics. These results highlight the need to begin risk prevention efforts early, prior to pubertal development. Research is needed to understand how parents can help youths better cope with pubertal development to avoid involvement in sexual and nonsexual risk behaviors.

Multicentre evaluation of magnetic technology for localisation of non-palpable breast lesions and targeted axillary nodes.

BACKGROUND: Magseed technology is a recently introduced localisation technique for impalpable breast lesions with possible advantages over traditional techniques. These include improved theatre logistics, flexibility in incision placement and improved patient experience. This multicentre study evaluates the experience of introducing Magseed technology into routine surgical practice. METHODS: A prospective multicentre study of Magseed localised procedures was performed. Insertion data were recorded by the radiologist including lesion characteristics and Magseed insertion accuracy. The surgical team recorded time from insertion to operation, operating time and surgical satisfaction. Pathology results were reviewed for specimen weight and margins. RESULTS: Between February 2019 and June 2020, 100 patients were enrolled. Magseed localised procedures included 18 excisional biopsies, 23 wide local excisions (WLE), 50 WLE with axillary surgery and four cases of Magseed localised breast WLE with Magseed localised axillary surgery. There were three therapeutic mammoplasties and two cases of Magseed localised targeted axillary node dissection alone. A total of 90% of Magseeds were radiologically placed within 5 mm of the target lesion/node. Time between incision and specimen removal was 17 min (range 6-40 min). All breast and axillary Magseeds were successfully identified and retrieved during surgery. The target lesion was identified in the specimen in all cases. A total of 10% of cases required further surgery for pathologically positive margins. Overall, surgeons reported that Magseed localisation was "easy" or "very easy" in 77% of cases. CONCLUSION: Magseed is a reliable, safe and accurate surgical technique that provides logistical advantages and flexibility of surgical approach. The method was well-accepted by all users.

Transfusion-related Gut Injury and Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) accounts for 10% of deaths in neonatal intensive care units. Several causal mechanisms are likely to lead to a final common disease phenotype. This article summarizes recent data on NEC following red blood cell (RBC) transfusion, with a focus on the most recent literature and ongoing trials. It highlights potential mechanisms from preclinical and human physiologic studies. It also discusses the role of feeding during RBC transfusion and the risk of NEC. Ongoing randomized trials will provide important data on how liberal or conservative approaches to RBC transfusion influence the risk of NEC.

Patent Ductus Arteriosus of the Preterm Infant.

Postnatal ductal closure is stimulated by rising oxygen tension and withdrawal of vasodilatory mediators (prostaglandins, nitric oxide, adenosine) and by vasoconstrictors (endothelin-1, catecholamines, contractile prostanoids), ion channels, calcium flux, platelets, morphologic maturity, and a favorable genetic predisposition. A persistently patent ductus arteriosus (PDA) in preterm infants can have clinical consequences. Decreasing pulmonary vascular resistance, especially in extremely low gestational age newborns, increases left-to-right shunting through the ductus and increases pulmonary blood flow further, leading to interstitial pulmonary edema and volume load to the left heart. Potential consequences of left-to-right shunting via a hemodynamically significant patent ductus arteriosus (hsPDA) include increased risk for prolonged ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis or focal intestinal perforation, intraventricular hemorrhage, and death. In the last decade, there has been a trend toward less aggressive treatment of PDA in preterm infants. However, there is a subgroup of infants who will likely benefit from intervention, be it pharmacologic, interventional, or surgical: (1) prophylactic intravenous indomethacin in highly selected extremely low gestational age newborns with PDA (<26 + 0/7 weeks' gestation, <750 g birth weight), (2) early targeted therapy of PDA in selected preterm infants at particular high risk for PDA-associated complications, and (3) PDA ligation, catheter intervention, or oral paracetamol may be considered as rescue options for hsPDA closure. The impact of catheter-based closure of hsPDA on clinical outcomes should be determined in future prospective studies. Finally, we provide a novel treatment algorithm for PDA in preterm infants that integrates the several treatment modalities in a staged approach.