Breast Carcinoma in Young Women: No Evidence of Increasing Rates of Metastatic Breast Carcinoma in a Single Tertiary Center Review

Breast carcinoma in young women aged less than 40 years attracts a high level of mainstream media coverage, and there is a gap between societal perceptions of the disease as a growing problem and epidemiological trends. Several population studies have reported that the overall incidence of breast carcinoma in young women is stable, while one recent article suggested that the relative proportion of breast carcinoma in young women that is metastatic at diagnosis is growing. We sought to establish whether these trends were apparent at our institution. In this study, the clinical database at a breast carcinoma tertiary center was reviewed in terms of clinicopathologic data on patient age, diagnosis, clinical and pathologic stage, hormone receptor status, and HER‐2 overexpression status for the period 2000–2011. Over the study period, young patients represented a decreasing proportion of all breast carcinoma cases (10.8% [2000–2003] to 8.7% [2008–2011]; p < 0.0001) treated at our institution. Young patients were more likely than patients aged 40 years or older to present with metastatic (M1) disease (5.4% versus 4.4%; p = 0.009), to be triple negative (21.6% versus 13%; p < 0.001), or to be HER‐2 positive (24.3% versus 14.8%; p < 0.01). Young patients with HER‐2‐positive cancers were significantly more likely to present with metastatic disease (8.3% versus 4.8%; p = 0.004). This study showed no demonstrable increase in the relative proportion of breast cancer occurring in patients aged <40 years over the 12‐year period 2000–2011 and no increase in the proportion of young patients presenting with metastatic disease.     

Human sperm express a functional androgen receptor: effects on PI3K/AKT pathway

BACKGROUND: Results from mice lacking the androgen receptor (AR) showed that it is critical for the proper development and function of the testes. The aim of this study was to investigate whether a functional AR is present in human sperm. METHODS: The expression of AR and its effects on sperm were evaluated by RT-PCR, Western Blot, Immunocytochemistry, PI3Kinase and DNA laddering assays. RESULTS: We showed in human sperm that AR is located at the head region. Dihydrotestosterone (DHT), in a dose-dependent manner, leads to the rapid phosphorylation of the AR on tyrosine, serine and threonine residues and this effect was reduced by the AR antagonist hydroxyflutamide (OH-Flut). The effects of AR were evaluated on the phosphoinositide-3 kinase/protein kinase B (PI3K/AKT) pathway. Specifically, 0.1 and 1 nM DHT stimulated PI3K activity, whereas 10 nM DHT decreased PI3K activity and levels of p-AKT S473 and p-AKT T308, p-BCL2, and enhanced phosphatase and tensin homologue (PTEN) phosphorylation. In addition, 10 nM DHT was able to induce the cleavage of caspases 8, 9 and 3 and cause DNA laddering, and these effects were reversed either by casodex or OHFlut. By using wortmannin, a specific PI3K inhibitor, the cleavage of caspase 3 was reproduced, confirming that in sperm the PI3K/AKT pathway is involved in caspase activation. CONCLUSIONS: Human sperm express a functional AR that have the ability to modulate the PI3K/AKT pathway, on the basis of androgen concentration.     

Reply: The human sex ratio in New York City did not change after 11 September 2001

Sir, We thank Professor Lydersen for carefully considering our work(Catalano et al., 2006). He argues that we misled readers whenwe concluded that the sex ratio of 0.9995 observed in New YorkCity in January 2002 (the lowest among the 91 monthly cohortswe studied) would not be expected from history. He bases hisargument, as we understand it, on the assumption that we repeatedour test three, perhaps more, times and should not cite theP-value from only one test     

The intraspleen huPBL NOD/SCID model to study the human HIV-specific antibody response selected in the course of natural infection

The intrasplenic injection of human peripheral blood mononuclear cells (PBMCs) into severely immune deficient NOD/SCID mice, causes a massive and transient dominant expansion of human B cells in the spleen. This permits the easy isolation of human monoclonal antibodies specific for different antigens by a Kohler and Milstein-based method. Here we studied the human HIV-specific antibody response in the circulation of mice after intrasplenic transfer of PBMC from untreated HIV-infected patients with detectable to high viral load as well as from HAART-treated and from untreated patients, who kept an undetectable viral load (the latter referred to as “natural suppressors”). Excellent B cell expansion was obtained for all PBMC. High level replication of virus was observed after transfer of PBMC of untreated viremic patients only. A strong and multispecific HIV-specific antibody response was observed after transfer of PBMC of untreated viremic patients and natural suppressors. In contrast, only a weak and pauci-specific antibody response was detected in mice reconstituted with PBMC from successfully treated patients. Based on these observations we conclude that the use of the intraspleen mouse model confirmed a) the presence of HIV-specific circulating memory B cells in untreated patients and natural suppressors; b) the nearly complete absence of circulating memory B cells in patients receiving highly active antiretroviral therapy. Using the intraspleen model we generated large numbers of immortalized B cells and isolated two anti-p24 human monoclonal antibodies. We further conclude that the intraspleen huPBL NOD/SCID model is a small animal model useful for the analysis of the antibody response against HIV found in patients.     

Respiratory and hemodynamic perioperative adverse events in intravenous versus inhalational induction in pediatric anesthesia: A systematic review and meta‐analysis

Perioperative respiratory and hemodynamic adverse events are still a cause of morbidity and mortality in pediatric anesthesia. It has been suggested that volatile agents might be associated with more respiratory adverse events compared to intravenous agents (eg, propofol), which have been associated with a higher risk of bradycardia compared to volatile agents. We performed a systematic review and meta‐analysis to evaluate the risk of perioperative hemodynamic and respiratory adverse events, comparing intravenous induction with inhalational induction in pediatric anesthesia. We searched PubMed, Embase, and Medline up to February 12, 2020. Randomized controlled trials were included. A quality assessment was carried out using a modified version of the “Cochrane Risk of Bias Tool for Randomized Controlled Trials.” Of the 1602 applicable publications, four were included in the final review. Two studies found no significant differences in perioperative respiratory or hemodynamic adverse events. Two studies found a higher risk of respiratory perioperative adverse events in inhalation versus intravenous induction, with a relative risk varying from 1.64 to 3.83. Data were heterogenous, and pooled estimates may not be reliable. The present systematic review and meta‐analysis revealed no significant difference in the occurrence of perioperative respiratory adverse events between inhalation and intravenous induction. More respiratory adverse events during and after inhalation induction were found, in particular in children with multiple risk factors for respiratory adverse events. This did not reach significance. Future research should include a large randomized controlled trial comparing inhalation and intravenous induction with respiratory and hemodynamic adverse events as primary outcome and adequately blinded outcome assessors.     

TMPRSS2-ERG Fusions Are Strongly Linked to Young Patient Age in Low-grade Prostate Cancer

Based on next-generation sequencing of early-onset prostate cancer (PCa), we earlier demonstrated that PCa in young patients is prone to rearrangements involving androgen-regulated genes—such as transmembrane protease, serine 2 (TMPRSS2)–v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion—and provided data suggesting that this situation might be caused by increased androgen signaling in younger men. In the same study, an accumulation of chromosomal deletions was found in cancers of elderly patients. To determine how age-dependent molecular features relate to cancer phenotype, an existing data set of 11 152 PCas was expanded by additional fluorescence in situ hybridization analyses of phosphatase and tensin homolog (PTEN), 6q15 and 5q21. The results demonstrate that the decrease in TMPRSS2–ERG fusions with increasing patient age is limited to low-grade cancers (Gleason ≤3 + 4) and that the significant increase in the deletion frequency with age was strictly limited to ERG-negative cancers for 6q15 and 5q21 but to ERG-positive cancers for PTEN. These data suggest that the accumulation of non–androgen-linked genomic alterations with advanced patient age may require an appropriate microenvironment, such as a positive or negative ERG status. The strong link of ERG activation to young patient age and low-grade cancers may help to explain a slight predominance of low-grade cancers in young patients.