Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice.

Epilepsy and autism spectrum disorder (ASD) are common comorbidities of one another. Despite the prevalent correlation between the two disorders, few studies have been able to elucidate a mechanistic link. We demonstrate that forebrain specific Tsc1 deletion in mice causes epilepsy and autism-like behaviors, concomitant with disruption of 5-HT neurotransmission. We find that epileptiform activity propagates to the raphe nuclei, resulting in seizure-dependent hyperactivation of mTOR in 5-HT neurons. To dissect whether mTOR hyperactivity in 5-HT neurons alone was sufficient to recapitulate an autism-like phenotype we utilized Tsc1flox/flox;Slc6a4-cre mice, in which mTOR is restrictively hyperactivated in 5-HT neurons. Tsc1flox/flox;Slc6a4-cre mice displayed alterations of the 5-HT system and autism-like behaviors, without causing epilepsy. Rapamycin treatment in these mice was sufficient to rescue the phenotype. We conclude that the spread of seizure activity to the brainstem is capable of promoting hyperactivation of mTOR in the raphe nuclei, which in turn promotes autism-like behaviors. Thus our study provides a novel mechanism describing how epilepsy can contribute to the development of autism-like behaviors, suggesting new therapeutic strategies for autism.

Patterns of skin metastases: a review of 25 years' experience at a single cancer center.

BACKGROUND: Skin metastases can be defined as the spread of a tumor from its site of primary origin to the skin. Skin metastasis may be the first sign of advanced cancer or an indicator of cancer recurrence. OBJECTIVES: To review patient data of 401 skin metastases available from our institution and compare this information to previously published studies. METHODS: Patient data from the Cancer Registry at RPCI database was reviewed for skin metastasis using vendor software. We included all cases of carcinoma, melanoma, sarcomas, and hematologic malignancies entered during a 25-year period from January 4, 1985, to March 1, 2010. Data identifying the relationship of tumor incidence, morphology, and skin metastasis was reviewed. A total of 401 patients who had skin metastases at the time of cancer diagnosis or had skin metastases as a recurrent site were included in this study. Extensive literature review was conducted using PubMed for articles relating to skin metastases and its clinical presentation and histological features. RESULTS: Breast cancer was the most common cancer to metastasize to the skin (32.7% of all skin metastases seen) followed by bronchus and lung (13.2%), skin (melanoma; 9.5%), lymph nodes (7.5%), oral cavity/pharynx/larynx (6.2%), blood and bone marrow (5.5%), and colorectal (4.2%). The most common histological types of tumors were identified as adenocarcinoma (infiltrating ductal carcinoma [22.7%]), lobular carcinoma (4.7%), and non-adenocarcinoma (squamous cell carcinoma [12.2%] and malignant melanoma [5.2%]). CONCLUSIONS: This is the largest review of skin metastases in the United States in the past 25 years. We found the primary cancers that metastasize to the skin have changed in frequency from previous studies. Our data are helpful in indicating which cancers have the strongest predilection for skin metastasis. Identification of these cancers can help both the clinician and patient detect early signs of metastases, which may allow for earlier diagnosis, implementation of therapy, and possible prolonged survival.

The presentation, pathology, and current management strategies of cutaneous metastasis.

Skin metastases are rare in the routine clinical practice of dermatology, but are of major clinical significance because they usually indicate advanced disease. We reviewed the literature on skin metastasis regarding recent trends in clinical presentation and diagnosis of the most common cutaneous lesions. An extensive literature review was conducted using PubMed from May 26, 2011 to July 16, 2013 relating cutaneous metastases. Articles chosen for reference were queried with the following prompts: "Cutaneous metastases", "clinical presentation", "histological features", and "immunohistochemistry". Further searches included "treatment" and "management" options for "metastatic breast", "metastatic colorectal", "metastatic melanoma", "metastatic lung", and "hematologic cancers." We also reviewed the literature on the current management of melanoma as a model for all cutaneous metastatic disease. Our own clinical findings are presented and compared to the literature. Additionally, we highlight the most useful immunohistochemical studies that aid in diagnoses. Several novel therapies and combination therapies such as electrochemotherapy, vemurafenib, and imiquimod will be discussed for palliative treatment of cancers that have been found to improve cutaneous lesions. We review these notable findings and developments regarding skin metastases for the general dermatologist.