SUMMARY It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 Profiling, we find that mitochondria of many adult somatic tissues, including brain, heart and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities.

Most data regarding survival in patients with chondrosarcoma are limited to case studies and small series performed at single institutions. A systematic review was performed to study the relationship between proposed prognostic factors and survival. Every study published in the English literature was reviewed. The mortality rates in these patients were analyzed according to modality of treatment, treatment history, histological subtype, and histological grade. A total of 560 patients with cranial chondrosarcoma were analyzed. Median follow-up time was 60 months. The 5-year mortality among all patients was 11.5% with median survival of 24 months. Mortality at 5 years was significantly greater for patients with tumors of higher grade or of the mesenchymal subtype, or had received surgical resection alone, when compared to their respective counterparts. The results of our systematic review provide useful data in predicting survival among cranial chondrosarcoma patients.

Previous experiments in anesthetized or decerebrate cats showed that the vestibular system participates in adjusting blood pressure during postural changes. The present experiments tested the hypothesis that removal of vestibular inputs in awake cats would affect orthostatic tolerance. Before the lesion, blood pressure typically remained within 10 mmHg of baseline values during nose-up-pitch body rotations of up to 60 degrees in amplitude. In contrast, bilateral peripheral vestibular lesions altered the pattern of orthostatic responses in all animals, and blood pressure fluctuated >10 mmHg from baseline values during most 60 degrees nose-up tilts in five of six animals. The deficit in correcting blood pressure was particularly large when the animal also was deprived of visual cues indicating position in space. During this testing condition, either a decrease or increase in blood pressure >10 mmHg in magnitude occurred in >80% of tilts. The deficit in adjusting blood pressure after vestibular lesions persisted for only 1 wk, after which time blood pressure remained stable during tilt. These data show that removal of vestibular inputs alters orthostatic responses and are consistent with the hypothesis that vestibular signals are one of several inputs that are integrated to elicit compensatory changes in blood pressure during movement.

Recordings were made from the vestibular nuclei of decerebrate cats that had undergone a combined bilateral labyrinthectomy and vestibular neurectomy 49-103 days previously and allowed to recover. Responses of neurons were recorded to tilts in multiple vertical planes at frequencies ranging from 0.05 to 1 Hz and amplitudes up to 15 degrees. Many spontaneously active neurons were present in the vestibular nuclei; the mean firing rate of these cells was 43 +/- 5 (SEM) spikes/s. The spontaneous firing of the neurons was irregular: the coefficient of variation was 0.86 +/- 0.14. The firing of 27% of the neurons was modulated by tilt. The plane of tilt that elicited the maximal response was typically within 25 degrees of pitch. The response gain was approximately 1 spikes/s/degree across stimulus frequencies. The response phase was near stimulus position at low frequencies, and lagged position slightly at higher frequencies (average of 35 +/- 9 degrees at 0.5 Hz). The source of the inputs eliciting modulation of vestibular nucleus activity during tilt in animals lacking vestibular inputs is unknown, but could include receptors in the trunk or limbs. These findings show that activation of vestibular nucleus neurons during vertical rotations is not exclusively the result of labyrinthine inputs, and suggest that limb and trunk inputs may play an important role in graviception and modulating vestibular-elicited reflexes.

The literature regarding recurrences in patients with cranial chondrosarcoma is limited to small series performed at single institutions, raising the question if these data precisely reflect the true recurrence of this tumor for guiding the clinician in the management of these patients. An extensive systematic review of the English literature was performed. The patients were stratified according to treatment modality, treatment history, histological subtype, and histological grade, and the recurrence rates were analyzed. A total of 560 patients treated for cranial chondrosarcoma were included. Five-year recurrence rate among all patients was 22% with median follow-up of 60 months and median disease-free interval of 16 months. Tumor recurrence was more common in patients who only received surgery or had mesenchymal subtype tumors. Our systematic review closely reflects the actuarial recurrence rate and provides predictive factors in the recurrence of cranial chondrosarcoma.