Pregnancies resulting from fresh in vitro fertilization (IVF) cycles exposed to supraphysiologic estrogen levels have been associated with higher rates of low birth weight and small for gestational age babies. We identified GATA3, a transcription factor selectively expressed in the trophectoderm during the blastocyst stage of embryo development, in an upstream analysis of genes that were differentially methylated in chorionic villus samples between IVF and non-IVF infertility treatment pregnancies. In this study, we investigate the hypothesis that GATA3 is hormonally regulated and plays an important functional role in trophoblast migration, invasion, and placentation. We found that GATA3 expression was hormonally regulated by estradiol in HTR8/SVneo first trimester trophoblast cells; however, no change in expression was seen with progesterone treatment. Furthermore, GATA3 knockdown resulted in decreased HTR8/SVneo cell migration and invasion compared with controls. RNA sequencing of GATA3 knockdown cells demonstrated 96 differentially regulated genes compared with controls. Genes known to play an important role in cell-cell and cell-extracellular matrix interactions, cell invasion, and placentation were identified, including CTGF, CYR61, ADAMTS12, and TIMP3. Our results demonstrate estradiol down-regulates GATA3, and decreased GATA3 expression leads to impaired trophoblast cell migration and invasion, likely through regulation of downstream genes important in placentation. These results are consistent with clinical data suggesting that supraphysiologic estrogen levels seen in IVF pregnancies may play an important role in attenuated trophoblast migration, invasion, and impaired placentation. GATA3 appears to be an important regulator of placentation and may play a role in impaired outcomes associated with fresh IVF cycles.

Multiple long-term studies have demonstrated a propensity for breast cancer recurrences to develop near the site of the original breast cancer. Recognition of this local recurrence pattern laid the foundation for the development of accelerated partial breast irradiation (APBI) approaches designed to limit the radiation treatment field to the site of the malignancy. However, there is a paucity of data regarding the efficacy of APBI in general, and intraoperative radiotherapy (IORT), in particular, for the management of ductal carcinoma in situ (DCIS). As a result, use of APBI, remains controversial. A prospective nonrandomized trial was designed to determine if patients with pure DCIS considered eligible for concurrent IORT based on preoperative mammography and contrast-enhanced magnetic resonance imaging (CE-MRI) could be successfully treated using IORT with minimal need for additional therapy due to inadequate surgical margins or excessive tumor size. Between November 2007 and June 2014, 35 women underwent bilateral digital mammography and bilateral breast CE-MRI prior to selection for IORT. Patients were deemed eligible for IORT if their lesion was ≤4 cm in maximal diameter on both digital mammography and CE-MRI, pure DCIS on minimally invasive breast biopsy or wide local excision, and considered resectable with clear surgical margins using breast-conserving surgery (BCS). Postoperatively, the DCIS lesion size determined by imaging was compared with lesion size and surgical margin status obtained from the surgical pathology specimen. Thirty-five patients completed IORT. Median patient age was 57 years (range 42-79 years) and median histologic lesion size was 15.6 mm (2-40 mm). No invasive cancer was identified. In more than half of the patients in our study (57.1%), MRI failed to detect a corresponding lesion. Nonetheless, 30 patients met criteria for negative margins (i.e., margins ≥2 mm) whereas five patients had positive margins (<2 mm). Two of the five patients with positive margins underwent mastectomy due to extensive imaging-occult DCIS. Three of the five patients with positive margins underwent successful re-excision at a subsequent operation prior to subsequent whole breast irradiation. A total of 14.3% (5/35) of patients required some form of additional therapy. At 36 months median follow-up (range of 2-83 months, average 42 months), only two patients experienced local recurrences of cancer (DCIS only), yielding a 5.7% local recurrence rate. No deaths or distant recurrences were observed. Imaging-occult DCIS is a challenge for IORT, as it is for all forms of breast-conserving therapy. Nonetheless, 91.4% of patients with DCIS were successfully managed with BCS and IORT alone, with relatively few patients requiring additional therapy.

Background A prospective randomized controlled trial has established the efficacy of targeted intraoperative radiotherapy (TARGIT) in the management of invasive breast cancer treated with breast‐conserving surgery (BCS). The purpose of this analysis is to evaluate the efficacy of TARGIT in the management of ductal carcinoma in situ (DCIS). Methods A prospective nonrandomized trial was designed to evaluate the success of TARGIT in the management of DCIS, as measured by a low risk of requiring additional surgery or radiotherapy and an acceptable local recurrence rate (LRR). Results Fifty‐five patients with DCIS received BCS and TARGIT from November 2007 to March 2017. Median patient age was 57 years (range, 42‐83 years) and median histological lesion size was 14.4 mm (range, 2‐51 mm). Four patients required either re‐excision and/or whole breast irradiation, yielding a rate of additional therapy of 7.3% (4 of 55). Among 46 women administered TARGIT at the time of initial BCS, two local recurrences were observed yielding a 4.3% (2 of 46) LRR at 46 months median follow‐up (range, 4‐116 months). There were no clinically significant adverse events. Conclusions Preliminary evidence indicates TARGIT can be performed with a low risk of requiring additional therapy (7.3%) and an acceptable LRR (4.3%) when administered at the time of BCS.

suMMARY Of 95 boys treated for acute lymphoblastic leukaemia 25 have developed leukaemic infiltration of the testes. In 15 children relapse was apparently confined to the testes, and since treatment 7 of these boys remain in remission. The median duration of remission after testicular relapse was 72 weeks, considerably longer than that reported after other forms ofleukaemic relapse.

Preliminary bone scans have been performed on all patients with early breast cancer. The incidence of positive scans has been recorded and several factors determining scan status have been enumerated. Particular attention has been focused on the natrual history of scan positive and scan negative patients. Eighteen per cent of stage I and 41 per cent of stage II cancers had positive bone scans. Scan results were correlated with age, menopausal status, tumour position, tumour size and histological node status. Postmenopausal patients were found to have a significantly increased risk of being scan positive (P less than 0-01). Follow-up studies have confirmed that the lesions demonstrated by scanning actually represent metastatic foci. At 18 months 85-7 per cent of scan positive patients had evidence of disseminated disease compared with only 11-4 per cent of scan negative patients (P less than 0-01). Clinically overt advanced disease evolves from positive scan lesions. It is clear that a significant percentage of patients felt to have early breast cancer already have widely disseminated disease at the initial presentation. The biological significance of bone scan lesions makes a sensitive screening test for dissemination an essential part of the preliminary assessment of patients with breast cancer. Bone scans provide an excellent prognostic index at a patient's initial assessment.