Transcription factor defects in inborn errors of immunity with atopy.

Transcription factors (TFs) are critical components involved in regulating immune system development, maintenance, and function. Monogenic defects in certain TFs can therefore give rise to inborn errors of immunity (IEIs) with profound clinical implications ranging from infections, malignancy, and in some cases severe allergic inflammation. This review examines TF defects underlying IEIs with severe atopy as a defining clinical phenotype, including STAT3 loss-of-function, STAT6 gain-of-function, FOXP3 deficiency, and T-bet deficiency. These disorders offer valuable insights into the pathophysiology of allergic inflammation, expanding our understanding of both rare monogenic and common polygenic allergic diseases. Advances in genetic testing will likely uncover new IEIs associated with atopy, enriching our understanding of molecular pathways involved in allergic inflammation. Identification of monogenic disorders profoundly influences patient prognosis, treatment planning, and genetic counseling. Hence, the consideration of IEIs is essential for patients with severe, early-onset atopy. This review highlights the need for continued investigation into TF defects to enhance our understanding and management of allergic diseases.

Influence of germline BRCA genotype on the survival of patients with triple-negative breast cancer.

The presence of BRCA pathogenic variants (PVs) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared to carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I-III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). The recurrence-free (RFS) and overall survival (OS) were compared according to mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9-12del CNV and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% (95% CI 72.3-84.6%), with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95%CI: 78.7-90.0%), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and non-carriers (100% vs. 78.6% and 84.7%; log-rank p=0.037 and p=0.051, respectively). This study suggests that BRCA1 ex9-12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers.

Outcomes of Hispanic women with lymph-node positive, HER2 positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab in Mexico.

INTRODUCTION: Evidence regarding the outcomes of Hispanic women with breast cancer is lacking. We analyzed women with HER2+ disease treated with trastuzumab-based neoadjuvant chemotherapy in Mexico. METHODS: 244 patients were included. Outcomes were compared between patients who achieved pathologic complete response (pCR) (n = 119), or less than pCR (n = 125). Patients with noninvasive (ypT0/is, ypN0) residual disease were also analyzed. RESULTS: 119 (48.8%) patients achieved pCR. pCR was the only factor associated with improved 3 year survival (98.1% vs 92.3%: P = 0.02). Survival was better in patients with ypT0/is, ypN0 response than in those with residual invasive disease (p < 0.01). 3 year survival was 98.1% for patients with pCR and 92.6% for patients with ypTis, ypN0 response (p = 0.64). CONCLUSIONS: Response rates to trastuzumab based neoadjuvant chemotherapy in Hispanics mimic that of other ethnic groups. This underlines the fact that access to treatment, rather than ethnicity, is the main prognostic factor in this population.

Legality and age influence end of life decisions in Mexican physicians.

PURPOSE: To test in two groups of physicians-in-training a simplified questionnaire exploring their acceptance of Physician Assisted Death (PAD), Therapy Withdrawal upon family request (WD), and Personalized PAD (PPAD) on whether the participant would seek PAD for him/herself. MATERIAL AND METHODS: A 4-item questionnaire was answered by 212 residents in different stages of training and grouped as beginners (1st and 3d year internal medicine residents, n = 76) and advanced (5th to 8th year residents of different internal medicine or oncology subspecialties, n = 136). The response options to the PAD and WD questions included a conditioned yes (CYes) dealing with legalization of PAD or the existence of a patient's previous written agreement to WD. RESULTS: Beginners had significantly more Yes plus C-Yes answers than advanced for questions regarding PAD (82 vs. 55%), WD (95 vs. 75%) and PPAD (76 vs. 56%). The importance of legal aspects implied in the conditioned answers can be seen in two findings: a) A sizable 29% of participants conditioned their Yes answers for both questions whereas only 9% gave an unconditioned Yes to both. b) A cross-classification of the PAD and WD answers showed that 13% of participants reversed their No in PAD to C-Yes in WD. CONCLUSIONS: Our simplified questionnaire operated well and was able to confirm the increase in acceptance of PAD and WD by young Mexican physicians, and the need of legislation regarding end of life decisions in our country.

Physician-assisted death. Opinions of Mexican medical students and residents.

BACKGROUND AND AIMS: To explore opinions of young residents and medical students on physician-assisted death (PAD). METHODS: A questionnaire was answered by 140 residents at the beginning of their residency and 99 third- or fourth-year medical students (46 attended religiously administered medical schools [RAMS] and 53 lay-administered medical schools [LAMS]). Main questions were agreement with PAD, therapy withdrawal (TW) and personalized PAD (PPAD) on whether participants themselves would seek help to die. RESULTS: There were no differences of acceptance between residents and students but LAMS students had significantly higher agreement than RAMS students for PAD (68 vs. 33%), TW (79 vs. 39%) and PPAD (57 vs. 48%). LAMS students were also more willing to agree to a physician prescribe/inject a lethal drug, even if PAD were not legalized. However, legality was also an important issue, i.e., 25-58% of those unsure or opposed to PAD would reverse the decision if PAD were legalized, and 42-54% of those unwilling to TW would also reverse if written consent of the patient existed. Overall acceptance of residents and students was significantly higher than our previous study in nearly 1,000 older physicians (50 vs. 39% for PAD and 58 vs. 48% for TW). CONCLUSIONS: PAD and TW acceptability seems to be increasing in Mexico, probably as a result of evolving social attitudes that appeared to be counteracted by a more conservative upbringing at home in our young RAMS students.