Dissecting the biological heterogeneity of HER2-positive breast cancer

HER2-positive (HER2+) breast cancer (BC) is a heterogenous and multifaceted disease, with interesting therapeutic implications. First, all intrinsic molecular subtypes can be identified in HER2+ tumors, with the HER2-enriched being the most frequent. Such subtypes do not differ much from their counterparts in HER2-negative disease, apart for the high expression of genes in/near the HER2 amplicon on chromosome 17. Intrinsic subtyping, along with the quantification of ERBB2 mRNA levels, is associated with higher rates of pathologic complete response across neoadjuvant trials of dual HER2 blockade and might help select patients for de-escalation and escalation treatment strategies. Secondly, HER2+ tumors have a broad range of DNA alterations. ERBB2 mutations and alterations in the PI3K/Akt/mTOR pathway are among the most frequent and might predict benefit from potent pan-HER, PI3K and mTOR inhibitors. Moreover, HER2+ tumors are usually infiltrated by lymphocytes. These tumor infiltrating-lymphocytes (TILs) predict response to neoadjuvant anti-HER2-based treatment and exert a prognostic role. PD-L1, detected in ∼42 % of HER2+ BC, might also be useful to define patients responding to novel anti-PD1/PD-L1 immunotherapies. New multiparametric clinicopathologic and genomic tools accounting for this complexity, such as HER2DX, are under development to define more tailored treatment approaches. Finally, HER2-targeted antibody-drug conjugates (ADC) such as trastuzumab deruxtecan might be active in tumors with low expression of HER2. Overall, there is a need to molecularly characterize and develop novel targeted therapies for HER2+ disease.     

Hormone exposure and its suppressive effect on risk of high-grade gliomas among patients with breast cancer

BackgroundPrior reports demonstrate the expression of estrogen and progesterone receptors in high-grade gliomas (HGGs), but the relationship between hormone receptor-positive disease and risk of HHGs in patients with breast cancer (BC) remains uncharacterized.MethodsUsing the SEER 18 registries (2000–2017), we examined the temporal trend of the incidence of HGGs and BC. The standardized incidence ratio was calculated to assess the risk of subsequent HGG in BC patients.ResultsDuring the study period, the incidence of BC and HGGs remained comparable for men and women. Among 976,134 patients with BC, we found a decreased incidence of HGGs in females, but not in males. Female BC patients with hormone receptor-positive disease were at a lower risk of developing glioblastoma and anaplastic astrocytoma.ConclusionOur study findings allude to the protective role of hormone exposure in the development of HGGs, which may lead to the development of therapies targeting hormonal pathways.     

The Current Pediatric Surgery Job Market: A Perspective of Recent Fellowship Graduates

PurposeThis study describes the job market from the perspective of recent pediatric surgery graduates.MethodsAn anonymous survey was circulated to the 137 pediatric surgeons who graduated from fellowships 2019–2021.ResultsThe survey response rate was 49%. The majority of respondents were women (52%), Caucasian (72%), and had a median student debt burden of $225,000. Considering job opportunities, respondents strongly emphasized camaraderie (93%), mentorship (93%), case mix (85%), geography (67%), faculty reputation (62%), spousal employment (57%), compensation (51%), and call frequency (45%). 30% were satisfied with the employment opportunities available, and 21% felt strongly prepared to negotiate for their first job. All respondents were able to secure a job. Most jobs were university-based (70%) or hospital employed (18%) positions where surgeons covered median of two hospitals. 49% wanted protected research time, and 12% of respondents were able to secure substantial, protected research time. The median compensation for university-based jobs was $12,583 below the median AAMC benchmark for assistant professors for the corresponding year of graduation.ConclusionThese data highlight the ongoing need for assessment of the pediatric surgery workforce and for professional societies and training programs to further assist graduating fellows in preparing to negotiate their first job.Type of studySurveyLevel of EvidenceLevel V.     

Efficacy of percutaneous and transcutaneous tibial nerve stimulation in women with idiopathic overactive bladder: A prospective randomised controlled trial

BackgroundDifferent studies have reported the efficacy of percutaneous tibial nerve stimulation (PTNS) and transcutaneous tibial nerve stimulation (TTNS) in treating idiopathic overactive bladder (OAB). However, no study has compared the effectiveness of PTNS and TTNS added to bladder training (BT) in idiopathic OAB.ObjectiveTo compare the efficacy of PTNS and TTNS added to BT in women with idiopathic OAB.MethodsWe randomised 60 women with idiopathic OAB into 3 groups. Group 1 (n = 19) received BT, Group 2 (n = 19) received PTNS in addition to BT, and Group 3 (n = 20) received TTNS in addition to BT. PTNS and TTNS were performed 2 days a week, for 30 min a day, for a total of 12 sessions for 6 weeks. Patients were evaluated by incontinence severity (pad test), a 3-day voiding diary (frequency of voiding, incontinence episodes, nocturia and number of pads used), symptom severity, quality of life, treatment success (positive response rate), treatment satisfaction (Likert scale), discomfort level and preparation time for stimulation (sec).ResultsAt the end of treatment; severity of incontinence, frequency of voiding, incontinence episodes, nocturia, number of pads used, symptom severity and quality of life were significantly improved in Groups 2 and 3 versus Group 1 (P < 0.0167). Treatment success and treatment satisfaction were higher in Groups 2 and 3 than Group 1 (P < 0.001 and P < 0.0167, respectively). Level of discomfort was lower, treatment satisfaction was higher and preparation time for stimulation was shorter in Group 3 than Group 2 (P < 0.05).ConclusionBoth the PTNS plus BT and TTNS plus BT were more effective than BT alone in women with idiopathic OAB. These 2 tibial nerve stimulation methods had similar clinical efficacy but with slight differences: TTNS had shorter preparation time, less discomfort level and higher patient satisfaction than PTNS.     

Exclusion of Patients With Brain Metastases in Published Phase III Clinical Trials for Advanced Breast Cancer

Metastatic HER2-positive (HER2+) and triple-negative breast cancer (TNBC) confer a 30% or higher risk of developing brain metastases (BrM), but BrM is typically an exclusion criteria for clinical trials, which limits the generalizability of trial results to these patients. We therefore analysed trends in the enrollment of patients with BrM, as well as the use of outcomes specific to the central nervous system (CNS), in phase III clinical trials evaluating systemic therapy for patients with advanced HER2+ and/or TNBC. Notably, 10 of the 34 trials (29%, 95% confidence interval = 15.1%-47.5%) evaluated CNS-specific outcomes and trials that completely excluded patients with BrM were significantly less likely to meet their primary endpoint (n = 6/17, 35%) than those that permitted conditional enrollment (n = 13/15, 87%) (P = .005), suggesting that enrollment of patients with BrM is not detrimental to trial success.     

The effect of immediate postpartum levonorgestrel contraceptive implant use on breastfeeding and infant growth: a randomized controlled trial

Objective

This study assessed whether immediate postpartum insertion of levonorgestrel contraceptive implants is associated with a difference in infant growth from birth to 6 months, onset of lactogenesis, or breastfeeding continuation at 3 and 6 months postpartum compared to delayed insertion at 6 to 8 weeks postpartum.