Second breast-conserving therapy with interstitial brachytherapy (APBI) as a salvage treatment in ipsilateral breast tumor recurrence: a retrospective study of 40 patients

Purpose: breast-conserving treatment (BCT) have emerged as an alternative to mastectomy in patients with ipsilateral breast tumor recurrence (IBTR). We evaluated survival outcomes and treatment-related toxicity in a series of 40 patients with IBTR, who underwent tumorectomy plus interstitial brachytherapy (APBI) as a salvage treatment. Material and methods: retrospective analysis included 40 patients diagnosed with IBTR and treated with intraoperative (26 patients) or post-operative (14 patients) multicatheter brachytherapy for APBI at our institution between June 2002 and October 2017. We assessed cosmesis, toxicity, overall survival (OS), and cancer-specific survival (CSS). Results: tumorectomy was performed in all cases, including intraoperative tumor margin assessment and sentinel node biopsy. Median age was 65 years (range, 41-92). The total prescribed dose was 32 Gy (8 fractions) in 19 patients and 34 Gy (10 fractions) in 20 patients. One elderly patient (age 92) received a single fraction of 16 Gy. Median follow-up was 61.5 months (range, 6-153). A median of 14 tubes were inserted. Mean treated V100 was 115 cc. Two patients developed a second relapse at 3 and 5 years after salvage treatment: one patient underwent salvage mastectomy and remains alive 10 years after brachytherapy, and the second one developed both local relapse and bone metastasis. The disease is stable at present. Five-year OS and CSS rates were 85.3% and 97.5%, respectively. Two patients died from cancer-related causes. Acute and late toxicity rates were low; seven patients developed acute infectious mastitis. Late fibrosis > grade 3 and late mastitis were observed in 14 and 6 cases, respectively. Conclusions: second BCT with APBI as a salvage treatment in ipsilateral breast recurrence achieves good local disease control, with a satisfactory toxicity profile compared to mastectomy. This approach seems to be safe and effective, although more data from randomized trials are needed

Advantages of intraoperative implant for interstitial brachytherapy for accelerated partial breast irradiation either frail patients with early-stage disease or in locally recurrent breast cancer

Purpose: to describe the intraoperative multicatheter implantation technique for accelerated partial breast irradiation (APBI) delivered with high-dose-rate brachytherapy (HDR-BT). Secondarily, to evaluate outcomes and toxicity in a series of 83 patients treated with this technique at our institution. Material and methods: retrospective analysis of a series of patients treated with HDR-BT APBI after intraoperative multicatheter interstitial implant between November 2006 and June 2017 at our institution. We assessed cosmesis, toxicity, overall survival (OS), and disease-free survival (DFS). Results: eighty-three patients were included: 59 patients (71.1%) with primary early-stage breast cancer and 24 (28.9%) with locally recurrent breast cancer. Tumorectomy was performed in all cases, with intraoperative tumor margin assessment and sentinel node biopsy. Median age was 82 years (range, 44-92). The total prescribed dose was 32 Gy (8 treatment fractions) in 60 patients (72.3%), and 34 Gy (10 fractions) in 23 patients (27.7%). Median follow-up was 40 months (range, 1-136 months). Three-year OS and DFS in the recurrent and primary cancer groups were 87% vs. 89%, and 96 % vs. 97.8%, respectively. Five patients died from non-cancer related causes. No local relapses were observed. Rates of acute and late toxicity were low in both groups. The cosmesis was good or excellent in most of patients treated for primary disease; in patients who underwent salvage brachytherapy for local recurrence, cosmesis was good in 49 patients and fair in 6. Conclusions: this technique, although time-consuming, achieves good local disease control with a satisfactory toxicity profile in both early-stage and local recurrent breast cancer patients. It may be especially suitable for frail patients

Using critical source areas for targeting cost-effective best management practices to mitigate phosphorus and sediment transfer at the watershed scale

The impact of implementing different best management practices (BMPs) at the small watershed scale were examined for the Petzenkirchen catchment in Austria and Lake Vico in Italy, in terms of data needs, hydrological processes, tools and models involved. Identification of critical source areas for targeting soil and phosphorus losses turned out to be crucial for correct allocation of BMPs. Comparison of environmental effectiveness and costs, both calculated using various modelling approaches, enabled us to compare different levels of introducing BMPs ecologically and economically. Within each catchment, small areas of land tended to be the source of disproportionately large amounts of pollution . Therefore, confining mitigation to these areas costs less than targeting wider areas. This suggests that a policy for environmental programmes should be focussed on hydrological units and critical source areas within these units instead of introducing universal controls - the ‘watering can’ principle - as practised today

La Piquera in central Iberian Peninsula : A new key vertebrate locality for the Early Pliocene of western Europe

Altres ajuts: CERCA Programme/Generalitat de CatalunyaWe introduce the new vertebrate site of La Piquera (Duero Basin, central Iberian Peninsula), provide a detailed description of the lithostratigraphy and present a preliminary faunal list. The fossil vertebrate association includes amphibians (with representatives of the families Salamandridae, Alytidae, Pelodytidae, and Bufonidae), squamate reptiles (with members of the families Agamidae, Lacertidae, Anguidae, Scincidae, Blanidae, ?Erycidae, and Colubridae/Psammophiidae), and mammals (with representatives of the families Soricidae, Erinaceidae, Muridae, Cricetidae, Gerbillidae, Gliridae, Sciuridae, Vespertilionidae, Rhinolophidae, Miniopteridae, Megadermatidae, Leporidae, Prolagidae, and Bovidae). The association indicates an intermediate biostratigraphic position between the southern Iberian sites of Sifón-413 (at about 5.33-5.23 Ma) and Botardo-D (between 4.79 and 4.63 Ma), the new locality being correlated with the earliest Ruscinian (lower part of the MN14 unit). The ecological affinities of the identified small vertebrates suggest the presence of a landscape dominated by open herbaceous meadows in the surroundings of the fossil-site during the earliest Pliocene, with the occasional presence of woodland patches and stable water bodies under relatively dry and warm environmental conditions. La Piquera therefore enhances our knowledge on the vertebrate community recorded in central Iberian Peninsula during the earliest Pliocene. With more than 1200 remains, La Piquera becomes a key locality for the Early Pliocene of southwestern Europe, central Spain, where this time-span is poorly represented

Five-year results of accelerated partial breast irradiation: a single institution retrospective review of 289 cases

Purpose: the purpose of the study was to describe our institutional experience with accelerated partial breast irradiation (APBI) using multicatheter brachytherapy with high-dose-rate. We report 5-year survival outcomes, cosmesis, and treatment-related toxicity. Methods and materials: this included a retrospective review of patients who underwent breast-conserving surgery followed by APBI at our institution from 2004 to 2017. Results: a total of 289 patients were evaluated. Median followup was 72 months. Median age was 70 years. APBI was the only primary treatment in 86.2% of cases with early-stage breast cancer and a second conservative treatment in 13.8%. The implant was performed postoperatively in 213 patients (73.7%) and intraoperatively in 76 (26.3%). The most common radiation schemes were 10 fractions of 3.4 Gy and eight fractions of 4 Gy. Elderly or frail patients (10%) received a single 16 Gy dose. Of the 289 patients, 215 met Groupe Europ een de Curieth erapie-European Society for Radiotherapy and Oncology criteria for APBI; in this group, late side effects included Grade 2 (G2) fibrosis (14.8%), skin discoloration at the catheter points (8.8%), and telangiectasia (0.5%). The cosmetic result was considered excellent or good in 88.3% of cases. Five-year local control, disease-free, cancer-specific, and overall survival rates were 98.9%, 96.7%, 99.1%, and 95.6%, respectively. Conclusions: local control and survival outcomes at 5 years of followup in this group of well-selected patients were excellent, with low rates of treatment-related toxicity. These findings confirm the safety and effectiveness of APBI, even in elderly and frail patients. These results provide further support for the clinical use of APBI in suitable patients. 2021 Published by Elsevier Inc. on behalf of American Brachytherapy Society

Changes in peripheral immune cells after intraoperative radiation therapy in low-risk breast cancer

A detailed understanding of the interactions and the best dose-fractionation scheme of radiation to maximize antitumor immunity have not been fully established. In this study, the effect on the host immune system of a single dose of 20 Gy through intraoperative radiation therapy (IORT) on the surgical bed in low-risk breast cancer patients undergoing conserving breast cancer has been assessed. Peripheral blood samples from 13 patients were collected preoperatively and at 48 h and 3 and 10 weeks after the administration of radiation. We performed a flow cytometry analysis for lymphocyte subpopulations, natural killer cells (NK), regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs). We observed that the subpopulation of NK CD56+high CD16+ increased significantly at 3 weeks after IORT (0.30-0.42%, P < 0.001), while no changes were found in immunosuppressive profile, CD4+CD25+Foxp3+Helios+ Treg cells, granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (Mo-MDSCs). A single dose of IORT may be an effective approach to improve antitumor immunity based on the increase in NK cells and the non-stimulation of immunosuppressive cells involved in immune escape. These findings support future combinations of IORT with immunotherapy, if they are confirmed in a large cohort of breast cancer patients

Axillary lymph node dissection versus radiotherapy in breast cancer with positive sentinelnodes after neoadjuvant therapy (ADARNAT trial)

Introduction: Breast cancer surgery currently focuses on de-escalating treatment without compromising patient survival. Axillary radiotherapy (ART) now replaces axillary lymph node dissection (ALND) in patients with limited sentinel lymph node (SLN) involvement during the primary surgery, and this has significantly reduced the incidence of lymphedema without worsening the prognosis. However, patients treated with neoadjuvant systemic treatment (NST) cannot benefit from this option despite the low incidence of residual disease in the armpit in most cases. Data regarding the use of radiotherapy instead of ALND in this population are lacking. This study will assess whether ART is non-inferior to ALND in terms of recurrence and overall survival in patients with positive SLN after NST, including whether it reduces surgery-related adverse effects. Methods and analyses: This multicenter, randomized, open-label, phase 3 trial will enroll 1660 patients with breast cancer and positive SLNs following NST in approximately 50 Spanish centers over 3 years. Patients will be stratified by NST regimen and nodal involvement (isolated tumoral cells or micrometastasis versus macrometastasis) and randomly assigned 1:1 to ART without ALND (study arm) or ALND alone (control arm). Level 3 and supraclavicular radiotherapy will be added in both arms. The primary outcome is the 5-year axillary recurrence determined by clinical and radiological examination. The secondary outcomes include lymphedema or arm dysfunction, quality of life based (EORTC QLQ-C30 and QLQ-BR23 questionnaires), disease-free survival, and overall survival. Discussion: This study aims to provide data to confirm the efficacy and safety of ART over ALND in patients with a positive SLN after NST, together with the impact on morbidity. Ethics and dissemination: The Research Ethics Committee of Bellvitge University Hospital approved this trial (Protocol Record PR148/21, version 3, 1/2/2022) and all patients must provide written informed consent. The involvement of around 50 centers across Spain will facilitate the dissemination of our results

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA-affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement

Axillary lymph node dissection versus radiotherapy in breast cancer with positive sentinel nodes after neoadjuvant therapy (ADARNAT trial)

IntroductionBreast cancer surgery currently focuses on de-escalating treatment without compromising patient survival. Axillary radiotherapy (ART) now replaces axillary lymph node dissection (ALND) in patients with limited sentinel lymph node (SLN) involvement during the primary surgery, and this has significantly reduced the incidence of lymphedema without worsening the prognosis. However, patients treated with neoadjuvant systemic treatment (NST) cannot benefit from this option despite the low incidence of residual disease in the armpit in most cases. Data regarding the use of radiotherapy instead of ALND in this population are lacking. This study will assess whether ART is non-inferior to ALND in terms of recurrence and overall survival in patients with positive SLN after NST, including whether it reduces surgery-related adverse effects.Methods and analysesThis multicenter, randomized, open-label, phase 3 trial will enroll 1660 patients with breast cancer and positive SLNs following NST in approximately 50 Spanish centers over 3 years. Patients will be stratified by NST regimen and nodal involvement (isolated tumoral cells or micrometastasis versus macrometastasis) and randomly assigned 1:1 to ART without ALND (study arm) or ALND alone (control arm). Level 3 and supraclavicular radiotherapy will be added in both arms. The primary outcome is the 5-year axillary recurrence determined by clinical and radiological examination. The secondary outcomes include lymphedema or arm dysfunction, quality of life based (EORTC QLQ-C30 and QLQ-BR23 questionnaires), disease-free survival, and overall survival.DiscussionThis study aims to provide data to confirm the efficacy and safety of ART over ALND in patients with a positive SLN after NST, together with the impact on morbidity.Ethics and disseminationThe Research Ethics Committee of Bellvitge University Hospital approved this trial (Protocol Record PR148/21, version 3, 1/2/2022) and all patients must provide written informed consent. The involvement of around 50 centers across Spain will facilitate the dissemination of our results.Trial registrationClinicalTrials.gov, identifier number NCT04889924