Objectives To assess ultrasound characteristics of ipsilateral axillary lymph nodes after two doses of four different COVID-19 vaccination protocols, to determine whether these parameters differed with age, and to describe how they changed on follow-up imaging. Methods A total of 247 volunteer employees from our center who had received two doses of COVID-19 vaccination were recruited and followed prospectively. Axillary ultrasound of the ipsilateral vaccinated arm was performed the week after receiving the second dose to analyze lymph node features (number, long-axis, cortical thickness, morphology, and vascular imaging). Axillary lymphadenopathy resulting from four vaccination protocols-mRNA (BNT162b2, mRNA-1273), ChAdOx1-S, and mix-and-match-was compared. Analysis was conducted using the Kruskal-Wallis test and post hoc analysis with Bonferroni corrections. Nodal reactogenicity was evaluated for two age groups: young (< 45 years old) and middle-aged ( >= 45 years old). All parameters were compared between both groups using an unpaired-sample Student t test. A p value < 0.05 was considered statistically significant. Results Significantly higher values for total number of visible nodes, cortical thickness, Bedi's classification (p < 0.001), and vascularity (p < 0.05) were observed in mRNA vaccine recipients compared to full ChAdOx1-S protocol recipients. Moreover, mix-and-match protocol recipients showed greater nodal cortical thickness and higher Bedi's classification than full ChAdOx1-S recipients (p < 0.001). Analyses between age groups revealed greater cortical thickness, Bedi's classification, and color Doppler signal in younger patients (p < 0.05). Conclusions Nodal parameters of Bedi's classification and cortical thickness were more often increased in mRNA and mix-and-match vaccine recipients when compared to ChAdOx1-S vaccine alone, especially in younger patients.

Purpose: To evaluate the feasibility, early toxicity, and clinical outcomes of early-breast cancer patients in a single-arm, phase I/II study of an ultra-accelerated, four-fraction schedule of minimal breast irradiation (4f-AMBI) using a multicatheter, minimally-invasive, intraoperative tumor bed implant (MITBI) during breast-conserving surgery (BCS). Methods and materials: Eligible women aged >40 years with clinically and radiologically confirmed, unifocal invasive or in situ ¿3 cm tumors were considered as potential candidates for MITBI during BCS. After the pathology report, patients who met APBI criteria received ultra-accelerated four-fractions irradiation (6.2 Gy BID x 4fx over 2 days) with perioperative HDR-brachytherapy (PHDRBT). Early complications, toxicity, clinical outcomes, and cosmetic results were analyzed. Results: Of 89 patients initially implanted, 60(67.4%) were definitively included in the 4f-AMBI-protocol. The median age was 64.4 years; the median CTV was 32.1 cc (6.9-75.4 cc), and the external-V100 was 43.1 cc (12.87-107 cc), representing 5% of the breast tissue irradiated with a median CTV D90 of 6.2 Gy (5.6-6.28 Gy). The entire local treatment (BCS&MITBI-4f-AMBI) was completed at a median of 8 days (4-10 days). The rate of early complications was 11%. There were no major complications. Acute skin-subcutaneous G1 toxicity was reported in 11.7%, and late G1 toxicity on 36.7%. After a median follow-up of 27 months (11-51 months), the local, elsewhere, locoregional and distant-control rates were 100%, 98.3%, 100%, and 100% respectively. The early-cosmetic evaluation was excellent-good in 94.5% of patients evaluated. Conclusions: Ultra-accelerated, four-fraction, minimal breast irradiation (4f-AMBI) using a minimally-invasive tumor bed implant procedure is safe, dosimetrically feasible, and shows small irradiated volumes. This program provides low toxicity rates and excellent short-term clinical and cosmesis outcomes.

Objectives This study was conducted in order to investigate COVID-19 vaccine influence on unilateral axillary lymph nodes, comparing nodal basal features with their characteristics after the first and second vaccination dose. Methods Ninety-one volunteer employees from our center who participated in the BNT162b2 (Pfizer-BioNTech) vaccination campaign were prospectively recruited. A total of three axillary ultrasound evaluations of the ipsilateral vaccinated arm were performed: before vaccination, the week after the first dose and the week after the second dose. The following findings were recorded: the total number of visible nodes, the maximum measurements of the diameter and cortex, Bedi's classification, and color Doppler evaluation. The collected data were compared using paired-sample Student's t-test for quantitative continuous variables and Wilcoxon rank-sum test for ordinal variables. Additional analyses were performed after classifying patients according to the previous history of COVID-19 disease. Differences among both groups were evaluated with the Mann-Whitney U test. Variables with a p value < 0.05 were considered statistically significant. Results Comparative analyses between the three US examinations showed a statistically significant augmentation of total visible nodes, maximum diameter, cortical thickness, grade of Bedi's classification, and Doppler signal (p < 0.001). Analyses between patients with and without previous COVID-19 infection showed a higher lymph node response in naive patients compared to those who were previously infected. Conclusions According to our results, both doses of COVID-19 vaccine induced an increase of all axillary lymph node parameters with statistically significant differences, especially in coronavirus-naive patients.

Gene expression is finely and dynamically controlled through the tightly coordinated and interconnected activity of epigenetic modulators, transcription and splicing factors and post-translational modifiers. We have recently identified the splicing factor SLU7 as essential for maintaining liver cell identity and genome integrity and for securing cell division both trough transcriptional and splicing mechanisms. Now we uncover a new function of SLU7 controlling gene expression at the epigenetic level. We show that SLU7 is required to secure DNMT1 protein stability and a correct DNA methylation. We demonstrate that SLU7 is part in the chromatome of the protein complex implicated in DNA methylation maintenance interacting with and controlling the integrity of DNMT1, its adaptor protein UHRF1 and the histone methyl-transferase G9a at the chromatin level. Mechanistically, we found that SLU7 assures DNMT1 stability preventing its acetylation and degradation by facilitating its interaction with HDAC1 and the desubiquitinase USP7. Importantly, we demonstrate that this DNMT1 dependency on SLU7 occurs in a large panel of proliferating cell lines of different origins and in in vivo models of liver proliferation. Overall, our results uncover a novel and non-redundant role of SLU7 in DNA methylation and present SLU7 as a holistic regulator of gene expression.

Purpose: To evaluate our institutional experience of minimally invasive tumor bed implantation (MITBI) during breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) to deliver peri-operative high-dose-rate brachytherapy (PHDRBT) as accelerated minimal breast irradiation (AMBI) or anticipated boost (A-PHDRBT-boost). Material and methods: Patients older than 40, with clinical and radiological unifocal DCIS < 3 cm were considered potential candidates for accelerated partial breast irradiation (APBI) and were implanted during BCS using MITBI-technique. Patients who in final pathology reports showed free margins and no other microscopic tumor foci, received AMBI with PHDRBT (3.4 Gy BID in 5 days). Patients with adverse features received A-PHDRBT-boost with post-operative external beam radiotherapy (EBRT). Results: Forty-one patients were implanted, and 36 were treated and analyzed. According to final pathology, 24 (67%) patients were suitable for AMBI and 12 (33%) were qualified for A-PHDRBT-boost. Reoperation rate for those with clear margins was 16.6% (6/36); this rate increased to 33% (4/12) for G3 histology, and 66% (4/6) were rescued using AMBI. Early complications were documented in 5 patients (14%). With a median follow-up of 97 (range, 42-138) months, 5-year rates of local, elsewhere, locoregional, and distant control were all 97.2%. 5-year ipsilateral breast tumor recurrence rates (IBTR) were 5.6% (2/36), 8.3% (2/24) for AMBI, and 0% (0/12) for A-PHDRBT-boost patients. Both instances of IBTR were confirmed G3 tumors in pre-operative biopsies; no IBTR was documented in G1-2 tumors. Cosmetic outcomes were excellent/good in 96% of AMBI vs. 67% in A-PHDRBT-boost (p = 0.034). Conclusions: The MITBI-PHDRBT program allows selection of patients with excellent prognoses (G1-2 DCIS with negative margins and no multifocality), for whom AMBI could be a good alternative with low recurrence rate, decrease of unnecessary radiation, treatment logistics improvement, and over-treatment reduction. Patients whose pre-operative biopsy showed G3 tumor, presents with inferior local control and more risk of reoperation due to positive margins.

Background Recently, a new mammography system to perform contrast-enhanced mammography has become available in the market. For the high-energy acquisition, it uses a titanium filter instead of a copper one, reducing the tube load while maintaining image quality. Purpose To retrospectively evaluate the accuracy of contrast-enhanced mammography with a titanium filter (TiCEM) in three readers with different grades of experience. Material and Methods IRB-approved retrospective multicentric lesion by lesion study with 200 lesions, all of them initially classified as BI-RADS categories 0/3/4/5 on mammography and/or ultrasound and with pathological confirmation, in 135 patients. Three readers with different levels of experience (expert, resident, intermediate) blinded to the final diagnosis, retrospectively evaluated the low-energy (LE) images and the combination of LE and recombined (subtracted) images and classified the lesions according to the BI-RADS categories. Reader 1 also categorized the breast density. ROC curves were performed for each reader. Results Out of the 200 lesions, 82 were benign and 118 malignant (20 DCIS, 10 ILC, 88 IDC). The AUCs of LE versus TiCEM for were: Reader 1: 0.7 vs. 0.88, P < 0.001; Reader 2: 0.63 vs. 0.83, P < 0.001; and Reader 3: 0.63 vs. 0.84, P < 0.001. For the three readers, the AUCs of LE versus TiCEM were significantly superior in both dense and non-dense breasts (P < 0.001). Comparing the AUC of LE for Reader 1 (expert) versus the AUC of TiCEM for Reader 2 (resident) there were significant differences (0.7 vs. 0.83, P < 0.001). Conclusion The accuracy of TiCEM was significantly better for all the readers, in both dense and non-dense breasts. The accuracy of a resident reading a TiCEM study was better than the accuracy of an expert radiologist reading LE images.

AimsImmunotherapy is a rising alternative to traditional treatment in breast cancer (BC) patients in order to transform cold into hot immune enriched tumours and improve responses and outcome. A computational modelling approach was applied to quantify modulation effects of immunotherapy and chemotherapy response on tumour shrinkage and progression-free survival (PFS) in naive BC patients. MethodsEighty-three Her2-negative BC patients were recruited for neoadjuvant chemotherapy with or without immunotherapy based on dendritic cell vaccination. Sequential tumour size measurements were modelled using nonlinear mixed effects modelling and linked to PFS. Data from another set of patients (n=111) were used to validate the model. ResultsTumour size profiles over time were linked to biomarker dynamics and PFS. The immunotherapy effect was related to tumour shrinkage (P < .05), with the shrinkage 17% (95% confidence interval: 2-23%) being higher in vaccinated patients, confirmed by the finding that pathological complete response rates in the breast were higher in the vaccinated compared to the control group (25.6% vs 13.6%; P=.04). The whole tumour shrinkage time profile was the major prognostic factor associated to PFS (P < .05), and therefore, immunotherapy influences indirectly on PFS, showing a trend in decreasing the probability of progression with increased vaccine effects. Tumour subtype was also associated with PFS (P < .05), showing that luminal A BC patients have better prognosis. ConclusionsDendritic cell-based immunotherapy is effective in decreasing tumour size. The semi-mechanistic validated model presented allows the quantification of the immunotherapy treatment effects on tumour shrinkage and establishes the relationship between the dynamics of tumour size and PFS.

Background: The use of preoperative breast MRI remains controversial despite being the most sensitive technique for the detection of breast malignancies. Purpose: To evaluate the benefit of preoperative breast MRI after performing the three conventional techniques (DM, US, DBT). To analyze the influence of breast density in the sensitivity of the different imaging techniques. Material and methods: Retrospective review of 280 histologically confirmed breast cancers in 192 women. We reviewed the medical records and evaluated the change of treatment induced by MRI. Also, we assessed the reports of DM and the combination of the different imaging techniques, and categorized them according to ACR density (a-d) and as negative (BI-RADS 1-3) or positive (BIRADS 4 or 5). The gold standard was the pathologic assessment of the surgical specimen. The sensitivity of the different techniques was compared using McNemar test. Results: Among these 192 women the use of MRI did not significantly increase the mastectomy rate (from 16.6% to 17.6%; p = 0.5). The addition of any technique demonstrated a higher sensitivity than DM alone. The sensitivity of DM alone was 52.5% while using all the techniques, including MRI, was 94.3% (p < 0.001). Regardless of breast density pattern, the addition of any technique significantly increased the sensitivity of DM (p < 0.001). Conclusions: The addition of MRI to the three conventional techniques increased the sensitivity but did not significantly modify the rate of mastectomies. Additional techniques increased the sensitivity of DM in both dense and non-dense breasts.

Debido a las limitaciones de la mamografía de cribado, especialmente en mamas densas, ha surgido una nueva técnica complementaria: la tomosíntesis. Esta técnica, al ser tomográfica, permite aumentar la detección de cánceres ocultos en la mamografía a la vez que puede disminuir los resultados falsos positivos provocados por superposición de imágenes. En este artículo revisamos el papel de la tomosíntesis en el cribado, analizando los 3 principales ensayos clínicos prospectivos que han tenido lugar en Europa: el ensayo OSLO, el ensayo STORM y el ensayo MALMÖ. Aunque la técnica mamográfica empleada es diferente en el estudio MALMÖ, los 3 han demostrado un significativo aumento de la sensibilidad (32, 34 y 43%, respectivamente), existiendo más diferencias en cuanto a las rellamadas (+32%, ¿27%, +43%). A pesar de que el tiempo de lectura se incrementa, parece que la técnica es coste-efectiva y contribuye poco al sobrediagnóstico, por lo que la tomosíntesis está llamada a jugar un papel importante en el cribado del cáncer de mama.

Our aim was to evaluate the diagnostic accuracy of magnetic resonance imaging (MRI) fused with prone 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in primary tumour staging of patients with breast cancer. METHODS: This retrospective study evaluated 45 women with 49 pathologically proven breast carcinomas. MRI and prone PET-CT scans with time-of-flight and point-spread-function reconstruction were performed with the same dedicated breast coil. The studies were assessed by a radiologist and a nuclear medicine physician, and evaluation of fused images was made by consensus. The final diagnosis was based on pathology (90 lesions) or follow-up¿¿¿24 months (17 lesions). RESULTS: The study assessed 72 malignant and 35 benign lesions with a median size of 1.8 cm (range 0.3-8.4 cm): 31 focal, nine multifocal and nine multicentric cases. In lesion-by-lesion analysis, sensitivity, specificity, positive and negative predictive values were 97%, 80%, 91% and 93% for MRI, 96%, 71%, 87%, and 89% for prone PET, and 97%. 94%, 97% and 94% for MRI fused with PET. Areas under the curve (AUC) were 0.953, 0.850, and 0.983, respectively (p¿<¿0.01). CONCLUSIONS: MRI fused with FDG-PET is more accurate than FDG-PET in primary tumour staging of breast cancer patients and increases the specificity of MRI.