Probes for INS

AIMS:

Verrucous carcinoma (VC) is a variant of well differentiated squamous cell carcinoma and is in the anal region regarded as synonymous with giant condyloma (Buschke-Löwenstein tumor) (BLT). Etiology, diagnostic criteria and clinical behavior of both lesions are controversial. Recent studies suggest that VC at other sites is not associated with human papillomaviruses (HPV). We hypothesized that anal VC is also not related to HPV, while BLT is a HPV-induced lesion.

METHODS AND RESULTS:

Ten cases of VC and 4 cases of BLT were included. Several techniques were used for HPV detection: in situ hybridization for HPV6, 11, 16 and 18, six different PCR protocols for detection of at least 89 HPV types from Alpha-, Beta-, Gamma- and Mu-PV genera, and in situ hybridization for high risk HPV E6/E7 mRNA. p16 immunohistochemistry and morphometric analysis were also performed. Alpha-, Gamma- and Mu-PVs were not found in any case of VC, while HPV6 was detected in all cases of BLT. p16 overexpression was not present in any of the lesions. Among microscopic features, only the absence of koilocytosis and enlarged spinous cells seem to be useful to distinguish VC from BLT.

CONCLUSIONS:

Our results suggest that anal VC, similarly to VC at other sites, is not associated with HPV infection and must be distinguished from BLT which is associated with low risk HPV. Only with well-set diagnostic criteria will it be possible to ascertain clinical behavior and optimal treatment for both lesions. 

Human Papillomavirus (HPV) is known as causative for squamous cell carcinoma (SCC) of the oropharynx, but is also not infrequently found in carcinomas of the sinonasal tract. Recently, a subset of these carcinomas was recognized to harbour HPV33 and have a significant morphological overlap with adenoid cystic carcinoma (ACC), a rare and aggressive carcinoma originating in the minor salivary glands. Termed HPV-related carcinoma with ACC-like features, only 9 cases have been reported. To clarify the occurrence of these tumours we screened a large material for presence of HPV-related ACC-like carcinoma. The identified tumours were characterized immunohistochemically and with fluorescence in situ hybridization and clinicopathologic information for all cases is presented.

METHODS AND RESULTS:

Forty-seven candidate cases were screened for presence of HPV. Six cases were identified and genotyped as HPV types 33, 35 and 56. All six cases had areas of dysplastic mucosal lining and showed remarkable heterogeneous morphologies. MYB, MYBL1, and NFIB genes were intact and, interestingly, staining for MYB protein was largely negative in contrast to what was found in ACC. One patient experienced a local recurrence 11 years after initial treatment and the remaining five patients were alive without evidence of disease.

CONCLUSION:

We report six new cases of HPV-related ACC-like carcinoma and found that, although in a small material, the prognosis for these patients seems more favourable than for ACC. For the distinction between ACC and HPV-related ACC-like carcinoma, p16, MYB immunohistochemistry, or investigation of MYB, MYBL1, and NFIB gene status are valuable. This article is protected by copyright. All rights reserved.

Abstract

BACKGROUND:

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing among older adults. It is unknown whether these trends can be explained by human papillomavirus (HPV) and whether HPV-related tumors remain associated with an improved prognosis among older patients.

METHODS:

In a retrospective study of OPSCCs diagnosed from 1995 to 2013 at 2 National Comprehensive Cancer Network-designated cancer centers, p16 immunohistochemistry and in situ hybridization (ISH) for HPV-16, high-risk DNA, and/or E6/E7 RNA were performed. The median age at diagnosis was compared by p16 and ISH tumor status. Trends in age were analyzed with nonparametric trends. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards models.

RESULTS:

Among 239 patients, 144 (60%) were p16-positive. During 1998-2013, the median age increased among p16-positive patients (Ptrend = .01) but not among p16-negative patients (Ptrend = .71). The median age of p16-positive patients increased from 53 years (interquartile range [IQR] in 1995-2000, 45-65 years) to 58 years (IQR for 2001-2013, 53-64 years). Among patients ≥ 65 years old, the proportion of OPSCCs that were p16-positive increased from 41% during 1995-2000 to 75% during 2007-2013 (Ptrend = .04). Among all age groups, including older patients, a p16-positive tumor status conferred improved overall survival in comparison with a p16-negative status.

CONCLUSIONS:

The median age at diagnosis for HPV-related OPSCC is increasing as the proportion of OPSCCs caused by HPV rises among older adults. The favorable survival conferred by an HPV-positive tumor status persists in older adults. Cancer 2018. © 2018 American Cancer Society.

Neurons are well suited for computations on millisecond timescales, but some neuronal circuits set behavioral states over long time periods, such as those involved in energy homeostasis. We found that multiple types of hypothalamic neurons, including those that oppositely regulate body weight, are specialized as near-perfect synaptic integrators that summate inputs over extended timescales. Excitatory postsynaptic potentials (EPSPs) are greatly prolonged, outlasting the neuronal membrane time-constant up to 10-fold. This is due to the voltage-gated sodium channel Nav1.7 (Scn9a), previously associated with pain-sensation but not synaptic integration. Scn9a deletion in AGRP, POMC, or paraventricular hypothalamic neurons reduced EPSP duration, synaptic integration, and altered body weight in mice. In vivo whole-cell recordings in the hypothalamus confirmed near-perfect synaptic integration. These experiments show that integration of synaptic inputs over time by Nav1.7 is critical for body weight regulation and reveal a mechanism for synaptic control of circuits regulating long term homeostatic functions.

Adaptation of liver to the postprandial state requires coordinated regulation of protein synthesis and folding aligned with changes in lipid metabolism. Here we demonstrate that sensory food perception is sufficient to elicit early activation of hepatic mTOR signaling, Xbp1 splicing, increased expression of ER-stress genes, and phosphatidylcholine synthesis, which translate into a rapid morphological ER remodeling. These responses overlap with those activated during refeeding, where they are maintained and constantly increased upon nutrient supply. Sensory food perception activates POMC neurons in the hypothalamus, optogenetic activation of POMC neurons activates hepatic mTOR signaling and Xbp1 splicing, whereas lack of MC4R expression attenuates these responses to sensory food perception. Chemogenetic POMC-neuron activation promotes sympathetic nerve activity (SNA) subserving the liver, and norepinephrine evokes the same responses in hepatocytes in vitro and in liver in vivo as observed upon sensory food perception. Collectively, our experiments unravel that sensory food perception coordinately primes postprandial liver ER adaption through a melanocortin-SNA-mTOR-Xbp1s axis.

Abstract