Multiple primary malignancies in patients with Merkel cell carcinoma1

Background Merkel cell carcinoma (MCC) is a rare malignant cutaneous tumour, the incidence of which is increasing. Second malignancies have been reported to occur with high incidence in these patients. Objectives We report the rate and nature of multiple malignancies in patients with MCC treated over a 10 year period in Addenbrooke’s Hospital in Cambridge, United Kingdom, as well as the temporal relationship of these additional malignancies to the diagnosis of MCC. Results The 27 patients had an approximately equal sex incidence with a median age at diagnosis of 79 years. Seventy percent (n=19) of patients had a second primary malignant tumour; and 7 of these patients had two or more tumours in addition to the MCC. Eighteen patients had additional cutaneous malignancies: melanoma, squamous cell carcinoma and basal cell carcinoma, and 8 patients presented non‐cutaneous malignancy including colorectal, haematological and breast tumours. Of the 28 additional tumours in our patients, half were diagnosed prior to presentation of MCC, 32% within 6 months of diagnosis, and 18% between 6 months and 3 years after diagnosis. Possible reasons for the high rate of additional tumours in this population are discussed. Conclusions Our figures reflect a higher incidence of multiple malignancies in those with Merkel cell tumour than has previously been reported. This has important implications for the care and surveillance of these patients.     

Meningitis and midline facial deformity

A baby with unilateral cleft lip, midline cleft palate and hypertelorism developed meningitis in the first 48 h of life. Examination of the nasopharynx showed a soft tissue mass, which was confirmed as a basal encephalocele by computed tomography. There was also congenital hydrocephalus and the corpus callosum was absent. Surgical treatment included repair of the anterior basal skull defect, repair of the lip and palate, and ventriculo-peritoneal shunt. There is currently evidence of developmental delay and right-sided visual impairment due to Morning Glory syndrome. This case demonstrates that basal encephalocele should be considered in any baby with midline facial deformity who develops meningitis.     

Multisensory auditory-visual interactions during early sensory processing in humans: a high-density electrical mapping study

Integration of information from multiple senses is fundamental to perception and cognition, but when and where this is accomplished in the brain is not well understood. This study examined the timing and topography of cortical auditory-visual interactions using high-density event-related potentials (ERPs) during a simple reaction-time (RT) task. Visual and auditory stimuli were presented alone and simultaneously. ERPs elicited by the auditory and visual stimuli when presented alone were summed ('sum' ERP) and compared to the ERP elicited when they were presented simultaneously ('simultaneous' ERP). Divergence between the 'simultaneous' and 'sum' ERP indicated auditory-visual (AV) neural response interactions. There was a surprisingly early right parieto-occipital AV interaction, consistent with the finding of an earlier study [J. Cogn. Neurosci. 11 (1999) 473]. The timing of onset of this effect (46 ms) was essentially simultaneous with the onset of visual cortical processing, as indexed by the onset of the visual C1 component, which is thought to represent the earliest cortical visual evoked potential. The coincident timing of the early AV interaction and C1 strongly suggests that AV interactions can affect early visual sensory processing. Additional AV interactions were found within the time course of sensory processing (up to 200 ms post stimulus onset). In total, this system of AV effects over the scalp was suggestive of both activity unique to multisensory processing, and the modulation of 'unisensory' activity. RTs to the stimuli when presented simultaneously were significantly faster than when they were presented alone. This RT facilitation could not be accounted for by probability summation, as evidenced by violation of the 'race' model, providing compelling evidence that auditory-visual neural interactions give rise to this RT effect.     

Activation timecourse of ventral visual stream object-recognition areas: high density electrical mapping of perceptual closure processes

Object recognition is achieved even in circumstances when only partial information is available to the observer. Perceptual closure processes are essential in enabling such recognitions to occur. We presented successively less fragmented images while recording high-density event-related potentials (ERPs), which permitted us to monitor brain activity during the perceptual closure processes leading up to object recognition. We reveal a bilateral ERP component (N(cl)) that tracks these processes (onsets approximately 230 msec, maximal at approximately 290 msec). Scalp-current density mapping of the N(cl) revealed bilateral occipito-temporal scalp foci, which are consistent with generators in the human ventral visual stream, and specifically the lateral-occipital or LO complex as defined by hemodynamic studies of object recognition.     

Loss of tumor-promoting activity of unleaded gasoline in N- nitrosodiethylamine-initiated ovariectomized B6C3F1 mouse liver

Unleaded gasoline (UG) vapor (2056 ppm) increased the incidence of liver tumors in a chronic bioassay and exhibited tumor-promoting activity in N-nitrosodiethylamine (DEN)-initiated female mouse liver. Estrogen inhibited mouse liver tumor development and the hepatocarcinogenic and tumor-promoting dose of UG produced uterine changes suggestive of estrogen antagonism. To directly test the hypothesis that UG-induced tumor-promoting ability is secondary to its interaction with the mouse liver tumor inhibitor, estrogen, we compared the tumor-promoting ability of UG in ovariectomized (Ovex) mice with the hepatic tumor-promoting ability of UG in intact mice. Ovaries were surgically removed at 4 weeks of age. Exposure to wholly vaporized UG (2018 ppm) under bioassay and tumor-promoting conditions began at 8 weeks of age. After 4 months of exposure, UG increased relative liver weight and hepatic microsomal cytochrome P450 pentoxyresourfin-O- dealkylase and ethoxyresorufin-O-deethylase activity to a similar extent in intact and Ovex mice. Non-focal hepatocyte proliferation, as measured by the incorporation of bromo-deoxyuridine, was not changed by UG exposure and was similar in all treatment groups. After 4 months of exposure to DEN-initiated mice, UG significantly increased the volume fraction of liver occupied by foci (three-fold) as compared to control intact mice. As expected, volume of foci was elevated in DEN/Ovex/control mice as compared to DEN/intact/control mice. In DEN/Ovex mice UG did not significantly increase the focal volume fraction. Thus, the tumor promoting activity of UG, as demonstrated by increased volume fraction of liver occupied by hepatic foci in intact mice, is greatly attenuated in Ovex mice. The volume fraction data in Ovex mice support the hypothesis that the tumor promoting activity of UG is dependent upon the interaction of UG with ovarian hormones. These data also indicate that hepatic microsomal cytochrome P450 PROD and EROD induction, hepatomegaly and non-focal hepatic LI are not specific markers of hepatic tumor promoting activity of UG.      

Chemoprevention of spontaneous tumorigenesis in nullizygous p53- deficient mice by dehydroepiandrosterone and its analog 16alpha-fluoro- 5-androsten-17-one

Transgenic mice with both alleles of the p53 tumor suppressor gene product 'knocked out' by gene targeting are susceptible to early development of tumors, chiefly lymphomas and sarcomas. Compared with the control group, administration of dehydroepiandrosterone (DHEA) at 0.3% of the diet to male p53-deficient mice extended their lifespan by delaying death due to neoplasms (from 105 to 166 days on study, P = 0.002), primarily by suppressing lymphoblastic lymphoma (from 45 to 6% of neoplastic deaths, P = 0.010). Treatment with a synthetic DHEA analog, 16alpha-fluoro-5-androsten-17-one (compound 8354), at 0.15% of the diet also increased lifespan, to 140 days for mice that developed tumors (P = 0.037). The effects of these steroids on lifespan and tumor development did not appear to be strongly related to inhibition of food consumption and weight gain, in that a group pair-fed with control diet to the reduced food consumption of the DHEA-treated group developed and died of the same types of neoplasms at the same rate as the controls fed ad libitum. The chemopreventive effect of these steroids has been proposed to be due to suppression of DNA synthesis by inhibition of glucose 6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway. Although DHEA and its analog are strong non- competitive inhibitors of this enzyme in vitro, treatment with DHEA did not deplete cellular nucleotide pools in the liver, as would have been predicted. The chemopreventive effect of DHEA in this model may be due to steroid-induced thymic atrophy and suppression of T cell lymphoma, permitting these mice to survive long enough to develop tumors with longer latency.