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Background Studies showed that axillary lymph node dissection can be safely omitted in presence of positive sentinel lymph node(s) in breast cancer patients treated with breast conserving therapy. Since the outcome of the sentinel lymph node biopsy has no clinical consequence, the value of the procedure itself is being questioned. The aim of the BOOG 2013–08 trial is to investigate whether the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients treated with breast conserving therapy. Methods The BOOG 2013–08 is a Dutch prospective non-inferiority randomized multicentre trial. Women with pathologically confirmed clinically node negative T1–2 invasive breast cancer undergoing breast conserving therapy will be randomized for sentinel lymph node biopsy versus no sentinel lymph node biopsy. Endpoints include regional recurrence after 5 (primary endpoint) and 10 years of follow-up, distant-disease free and overall survival, quality of life, morbidity and cost-effectiveness. Previous data indicate a 5-year regional recurrence free survival rate of 99% for the control arm and 96% for the study arm. In combination with a non-inferiority limit of 5% and probability of 0.8, this result in a sample size of 1.644 patients including a lost to follow-up rate of 10%. Primary and secondary endpoints will be reported after 5 and 10 years of follow-up. Discussion If the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients undergoing breast conserving therapy, this study will cost-effectively lead to a decreased axillary morbidity rate and thereby improved quality of life with non-inferior regional control, distant-disease free survival and overall survival. Trial registration The BOOG 2013–08 study is registered in ClinicalTrials.gov since October 20, 2014, Identifier: NCT02271828. https://clinicaltrials.gov/ct2/show/NCT02271828

BackgroundSeroma formation is a common complication after mastectomy. This review aims to elucidate which surgical techniques are most effective in reducing the dead space and therefore seroma formation in patients undergoing mastectomy.MethodsA literature search was performed to identify clinical studies comparing any form of flap fixation to conventional closure technique in patients undergoing mastectomy with or without axillary clearance. Studies were eligible for inclusion if outcome was described in terms of seroma formation and/or complications of seroma formation. Studies on animal research or breast reconstruction with tissue expanders or flap harvesting (latissimus dorsi) were excluded.ResultsA total of nine articles were eligible for inclusion. Five were retrospective studies and four were prospective. Retrospective and prospective studies have demonstrated the higher incidence of seroma formation in patients not undergoing mechanical flap fixation. The incidence of seroma-related complications in these studies vary. Four out of the nine studies demonstrate that patients undergoing flap fixation, need significantly fewer seroma aspirations. There are very few studies on the use of tissue glues preventing seroma formation.ConclusionThe scientific body of evidence favoring flap fixation after mastectomy is convincing. Mechanical flap fixation seems to reduce seroma formation and seroma aspiration after mastectomy. There are, however, no well-powered randomized controlled trials evaluating all aspects of seroma formation and its sequelae. Further research should elucidate whether flap fixation using sutures or tissue glue is superior.

Background Seroma formation is a common complication after mastectomy and is associated with delayed wound healing, infection, skin flap necrosis, patient discomfort and repeated visits to the out patient clinic to deal with seroma and its sequelae. Closing the dead space after mastectomy seems to be key in reducing seroma and its complications. Various methods have been described to reduce the dead space after mastectomy: closed suction drainage, quilting of the skin flaps and application of adhesive tissue glues. The aim of this trial is to compare seroma formation and its sequelae in the various methods of flap fixation. Methods This is a multicenter, double-blind, randomized controlled trial in female breast cancer patients undergoing mastectomy, with or without axillary clearance. Exclusion criteria consist of breast conserving therapy, direct breast reconstruction and incapacity to comprehend implications and extent of study and unable to sign for informed consent. A total of 336 patients will be randomized. Patients will be randomly allocated to one of three treatment arms consisting of flap fixation using ARTISS tissue glue with a low suction drain, flap fixation using sutures and a low suction drain or conventional wound closure (without flap fixation) and low suction drainage. Follow up will be conducted up to twelve months post surgery. The primary outcome is the number of seroma aspirations and secondary outcomes consist of number of out patient clinic visits, surgical skin infection rate, shoulder function, cosmesis, health-related quality of life and costs and cost-effectiveness (cost/QALY). Discussion This is the first study of its kind to evaluate the effect of flap fixation and its sequelae (ie seroma aspirations, number of out patient clinic visits, infection, shoulder function, patient assessed cosmesis, quality of life and cost-effectiveness) in a double blind randomized controlled trial. Trial registration This trial was approved by the hospitals’ joint medical ethical committee ( 14-T-21, 2 June 2014). The SAM Trial is registered in ClinicalTrials.gov since October 2017, Identifier: NCT03305757 .

Purpose Omitting sentinel lymph node biopsy (SLNB) in breast cancer treatment results in patients with unknown positive nodal status and potential risk for systemic undertreatment. This study aimed to investigate whether gene expression profiles (GEPs) can lower this risk in cT1-2N0 ER+ HER2– breast cancer patients treated with BCT. Methods Patients were included if diagnosed between 2011 and 2017 with cT1-2N0 ER+ HER2– breast cancer, treated with BCT and SLNB, and in whom GEP was applied. Adjuvant chemotherapy recommendations based on clinical risk status (Dutch breast cancer guideline of 2020 versus PREDICT v2.1) with and without knowledge on SLNB outcome were compared to GEP outcome. We examined missing adjuvant chemotherapy indications, and the number of GEPs needed to identify one patient at risk for systemic undertreatment. Results Of 3585 patients, 2863 (79.9%) had pN0 and 722 (20.1%) pN + disease. Chemotherapy was recommended in 1354 (37.8% guideline-2020) and 1888 patients (52.7% PREDICT). Eliminating SLNB outcome ( n  = 722) resulted in omission of chemotherapy recommendation in 475 (35.1% guideline-2020) and 412 patients (21.8% PREDICT). GEP revealed genomic high risk in 126 (26.5% guideline-2020) and 82 patients (19.9% PREDICT) in case of omitted chemotherapy recommendation in the absence of SLNB. Extrapolated to the whole group, this concerns 3.5% and 2.3%, respectively, resulting in the need for 28–44 GEPs to identify one patient at risk for systemic undertreatment. Conclusion If no SLNB is performed, clinical risk status according to the guideline of 2020 and PREDICT predicts a very low risk for systemic undertreatment. The number of GEPs needed to identify one patient at risk for undertreatment does not justify its standard use.

Breast cancer guidelines advise sentinel lymph node biopsy (SLNB) in patients with ductal carcinoma in situ (DCIS) on core biopsy at high risk of invasive cancer or in case of mastectomy. This study investigates the incidence of SLNB and SLN metastases and the relevance of indications in guidelines and literature to perform SLNB in order to validate whether SLNB is justified in patients with DCIS on core biopsy in current era. Clinically node negative patients diagnosed from 2004 to 2013 with only DCIS on core needle biopsy were selected from a national database. Incidence of SLN biopsy and metastases was calculated. With Fisher exact tests correlation between SLNB indications and actual presence of SLN metastases was studied. Further, underestimation rate for invasive cancer and correlation with SLN metastases was analysed. 910 patients were included. SLNB was performed in 471 patients (51.8 %): 94.5 % had pN0, 3.0 % pN1mi and 2.5 % pN1. Patients undergoing mastectomy had 7 % SLN metastases versus 3.5 % for breast conserving surgery (BCS) ( p  = 0.107). The only factors correlating to SLN metastases were smaller core needle size ( p  = 0.01) and invasive cancer ( p  < 0.001). Invasive cancer was detected in 16.7 % by histopathology with 15.6 % SLN metastases versus only 2 % in pure DCIS. SLNB showed metastases in 5.5 % of patients; 3.5 % in case of BCS (any histopathology) and 2 % when pure DCIS was found at definitive histopathology (BCS and mastectomy). Consequently, SLNB should no longer be performed in patients diagnosed with DCIS on core biopsy undergoing BCS. If definitive histopathology shows invasive cancer, SLNB can still be considered after initial surgery.

Background Trials failed to demonstrate additional value of completion axillary lymph node dissection in case of limited sentinel lymph node metastases in breast cancer patients undergoing breast conserving therapy. It has been suggested that the low regional recurrence rates in these trials might partially be ascribed to accidental irradiation of part of the axilla by whole breast radiation therapy, which precludes extrapolation of results to mastectomy patients. The aim of the randomized controlled BOOG 2013–07 trial is therefore to investigate whether completion axillary treatment can be safely omitted in sentinel lymph node positive breast cancer patients treated with mastectomy. Design This study is designed as a non-inferiority randomized controlled multicentre trial. Women aged 18 years or older diagnosed with unilateral invasive clinically T1-2 N0 breast cancer who are treated with mastectomy, and who have a maximum of three axillary sentinel lymph nodes containing micro- and/or macrometastases, will be randomized for completion axillary treatment versus no completion axillary treatment. Completion axillary treatment can consist of completion axillary lymph node dissection or axillary radiation therapy. Primary endpoint is regional recurrence rate at 5 years. Based on a 5-year regional recurrence free survival rate of 98 % among controls and 96 % for study subjects, the sample size amounts 439 per arm (including 10 % lost to follow-up), to be able to reject the null hypothesis that the rate for study and control subjects is inferior by at least 5 % with a probability of 0.8. Results will be reported after 5 and 10 years of follow-up. Discussion We hypothesize that completion axillary treatment can be safely omitted in sentinel node positive breast cancer patients undergoing mastectomy. If confirmed, this study will significantly decrease the number of breast cancer patients receiving extensive treatment of the axilla, thereby diminishing the risk of morbidity and improving quality of life, while maintaining excellent regional control and without affecting survival. Trial registration The BOOG 2013–07 study is registered in the register of ClinicalTrials.gov since April 10, 2014, Identifier: NCT02112682 .

Several independent randomized controlled trials are initiated to investigate whether sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients with negative axillary ultrasound findings, who are treated with breast conserving therapy. A consequence of omitting sentinel lymph node biopsy is absence of pathological lymph node status information. We aimed to investigate the impact of omitting sentinel lymph node biopsy on adjuvant systemic treatment recommendations. Data from all consecutive patients with invasive breast cancer and negative axillary ultrasound findings treated with breast conserving therapy and sentinel lymph node biopsy between 2008 and 2012 were collected from a prospective database. Two methods, Adjuvant! Online and the Dutch breast cancer guideline 2012, were used to determine the adjuvant systemic treatment recommendations of every patient. At first, each patient was considered to be lymph node negative, and secondly the patients’ true pathological lymph node status was used. A total of 303 patients were consecutively included. Pathological lymph node status was pN0 in 72.3 %, pN0(i+) in 12.9 %, pN1mi+ in 5.6 %, pN1 in 7.3 %, and pN2 in 2.0 % of the patients. The decision to recommend adjuvant systemic treatment changed due to the pathological lymph node status in 1.0 % of the patients (3/303) when using Adjuvant! Online and in 3.6 % (11/303) when using the 2012 Dutch breast cancer guideline. The impact of the pathological lymph node status on adjuvant systemic treatment recommendations in clinically node negative breast cancer patients with negative axillary ultrasound findings treated with breast conserving therapy is limited. The safety of omitting the sentinel lymph node biopsy should be confirmed by the initiated randomized controlled trials.

Abstract Seroma formation after axillary dissection is a common problem in breast cancer surgery. We report the case of a 68-year-old female with breast cancer who underwent a wide local excision and axillary clearance due to stage III breast cancer. Patient received post-operative whole breast irradiation therapy and developed a painful, infected seroma one month after surgery. This was treated with antibiotic therapy after which the infection subsided. One year after surgery patient presented with a painful persisting seroma in the left axilla. We decided to surgically treat the seroma by removing the fibrous seroma capsula and closing of the dead space with a latissimus dorsi flap. Six weeks after surgery, patient was pain and seroma free and was happy with the surgical result. Latissimus dorsi flap harvesting is an ideal way to treat persisting fibrous encapsulated seroma pockets after axillary clearance in the treatment of breast cancer.

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes ( CLCN4 , CNKSR2 , FRMPD4, KLHL15 , LAS1L , RLIM and USP27X ) and potentially deleterious variants in 2 novel candidate XLID genes ( CDK16 and TAF1 ). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4 −/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Considerable evidence indicates that glucocorticoid hormones enhance the consolidation of long-term memories for emotionally arousing experiences but not that for less arousing or neutral information. However, previous studies have not determined the basis of such arousal-induced selectivity. Here we report the finding that endogenous noradrenergic activation of the basolateral complex of the amygdala (BLA) induced by emotional arousal is essential in enabling glucocorticoid memory enhancement. Corticosterone administered immediately after object recognition training enhanced 24-h memory of naive male rats but not that of rats previously habituated to the training context in order to reduce novelty-induced emotional arousal. The β-adrenoceptor antagonist propranolol administered either systemically or into the BLA blocked the corticosterone-induced memory enhancement. Further, in habituated rats, corticosterone activated BLA neurons, as assessed by phosphorylated cAMP response element binding (pCREB) immunoreactivity levels, and enhanced memory only when norepinephrine release was stimulated by administration of the α₂-adrenoceptor antagonist yohimbine. These findings strongly suggest that synergistic actions of glucocorticoids and emotional arousal-induced noradrenergic activation of the BLA constitute a neural mechanism by which glucocorticoids may selectively enhance memory consolidation for emotionally arousing experiences.