Wound healing after trauma may predispose to lung cancer metastasis: review of potential mechanisms.

Inflammatory oncotaxis, the phenomenon in which mechanically injured tissues are predisposed to cancer metastases, has been reported for a number of tumor types, but not previously for histologically proven lung cancer. We review clinical and experimental evidence and mechanisms that may underlie inflammatory oncotaxis, and provide illustrative examples of two patients with squamous cell carcinoma of the lung who developed distant, localized metastatic disease at sites of recent physical trauma. Trauma may predispose to metastasis through two distinct, but not mutually exclusive, mechanisms: (1) physical trauma induces tissue damage and local inflammation, creating a favorable environment that is permissive for seeding of metastatic cells from distant sites; and/or (2) micrometastatic foci are already present at the time of physical injury, and trauma initiates changes in the microenvironment that stimulate the proliferation of the metastatic cells. Further exploration of post-traumatic inflammatory oncotaxis may elucidate fundamental mechanisms of metastasis and could provide novel strategies to prevent cancer metastasis.

Minimal evidence for a direct involvement of twisted gastrulation homolog 1 (TWSG1) gene in human holoprosencephaly.

Holoprosencephaly (HPE) is the most common disorder of human forebrain and facial development. Presently understood etiologies include both genetic and environmental factors, acting either alone, or more likely, in combination. The majority of patients without overt chromosomal abnormalities or recognizable associated syndromes have unidentified etiologies. A potential candidate gene, Twisted Gastrulation Homolog 1 (TWSG1), was previously suggested as a contributor to the complex genetics of human HPE based on (1) cytogenetic studies of patients with 18p deletions, (2) animal studies of TWSG1 deficient mice, and (3) the relationship of TWSG1 to bone morphogenetic protein (BMP) signaling, which modulates the primary pathway implicated in HPE, Sonic Hedgehog (SHH) signaling. Here we present the first analysis of a large cohort of patients with HPE for coding sequence variations in TWSG1. We also performed fine mapping of 18p for a subset of patients with partial 18p deletions. Surprisingly, minimal evidence for alterations of TWSG1 was found, suggesting that sequence alterations of TWSG1 are neither a common direct cause nor a frequent modifying factor for human HPE pathologies.

Holoprosencephaly and agnathia spectrum: Presentation of two new patients and review of the literature.

Holoprosencephaly (HPE), the most common developmental disorder of the human forebrain, is occasionally associated with the spectrum of agnathia, or virtual absence of the mandible. This condition results in a constellation of structural cerebral and craniofacial abnormalities. Here we present two new patients and review 30 patients from the literature with HPE and variants of agnathia. The majority of these patients are female and have the most severe forms of HPE, with cyclopia present more frequently than is usually observed in cohorts of patients with HPE. Also, many patients have additional clinical findings not typical in patients with classic HPE, particularly situs abnormalities. Recent animal studies suggest that the association of HPE and agnathia may relate to alterations in signaling from forebrain and foregut endoderm organizing centers and subsequent first pharyngeal arch development, although present models are inadequate to explain all of the clinical findings of this enigmatic human syndrome. Further research is required to better elucidate the causal and pathogenic basis of this association.

Holoprosencephaly: recommendations for diagnosis and management.

PURPOSE OF REVIEW: This review presents recent advances in our understanding and clinical management of holoprosencephaly (HPE). HPE is the most common developmental disorder of the human forebrain and involves incomplete or failed separation of the cerebral hemispheres. The epidemiology, clinical features, causes, diagnostic approach, management, and outcomes of HPE are discussed. RECENT FINDINGS: Chromosomal abnormalities account for the most commonly identified cause of HPE. However, there are often unidentifiable causes in patients with nonsyndromic, nonchromosomal forms of HPE. The prevalence of HPE may be underestimated given that patients with mild forms often are not diagnosed until they present with severely affected children. Pregestational maternal diabetes mellitus is the most recognized risk factor for HPE, as supported by recent large-scale epidemiological studies. Genetic studies using microarray-based comparative genomic hybridization technology have resulted in better characterization of important HPE loci. SUMMARY: HPE encompasses a wide spectrum of forebrain and midline defects, with an accompanying wide spectrum of clinical manifestations. A coordinated, multidisciplinary care team is required for clinical management of this complex disorder. Further research will enable us to better understand the pathogenesis and causes of HPE, and thus to improve the genetic counseling of patients and their families.