Increased TGF-ß: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?

Survivors of severe congenital diaphragmatic hernia (CDH) present significant respiratory morbidity despite lung growth induced by fetal tracheal occlusion (TO). We hypothesized that the underlying mechanisms would involve changes in lung extracellular matrix and dysregulated transforming growth factor (TGF)-ß pathway, a key player in lung development and repair. Pulmonary expression of TGF-ß signaling components, downstream effectors, and extracellular matrix targets were evaluated in CDH neonates who died between birth and the first few weeks of life after prenatal conservative management or TO, and in rabbit pups that were prenatally randomized for surgical CDH and TO vs. sham operation. Before tissue harvesting, lung tissue mechanics in rabbits was measured using the constant-phase model during the first 30 min of life. Human CDH and control fetal lungs were also collected from midterm onwards. Human and experimental CDH did not affect TGF-ß/Smad2/3 expression and activity. In human and rabbit CDH lungs, TO upregulated TGF-ß transcripts. Analysis of downstream pathways indicated increased Rho-associated kinases to the detriment of Smad2/3 activation. After TO, subtle accumulation of collagen and α-smooth muscle actin within alveolar walls was detected in rabbit pups and human CDH lungs with short-term mechanical ventilation. Despite TO-induced lung growth, mediocre lung tissue mechanics in the rabbit model was associated with increased transcription of extracellular matrix components. These results suggest that prenatal TO increases TGF-ß/Rho kinase pathway, myofibroblast differentiation, and matrix deposition in neonatal rabbit and human CDH lungs. Whether this might influence postnatal development of sustainably ventilated lungs remains to be determined.

The risk of non-sentinel metastases in primary breast cancer.

BACKGROUND: Sentinel node biopsy (SNB) has been established as standard of surgical care in primary breast cancer. If the sentinel node (SN) is negative, axillary dissection (ALND) is not necessary, but if the SN is positive ALND is warranted. This analysis evaluated associated risk factors for non-sentinel metastases in the case of a positive SN. PATIENTS AND METHODS: A retrospective analysis of all SNB performed between 10/1999 and 07/2005 was carried out. RESULTS: A total of 406 patients were included: 214 patients (51%) had SNB with ALND while 197 patients (49%) had SNB only. In 41 of 109 nodal-positive patients, the SN was the only nodal metastasis. In the multivariate analysis, the number of positive SN and the presence of lymphatic vessel infiltration were significant risk factors for additional non-sentinel metastases (p = 0.05 and 0.047, respectively). The risk for non-sentinel metastases was 25.9% without and 59.2% with these risk factors, respectively. CONCLUSION: If the SN is positive, ALND remains obligatory.