Cryptococcus neoformans var grubii meningoencephalitis in a patient on fingolimod for relapsing-remitting multiple sclerosis: Case report and review of published cases.

INTRODUCTION: Fingolimod, a sphingosine-1-phosphate modulator used in the treatment of relapsing-remitting multiple sclerosis, has been associated with several cases of cryptococcosis. CASE REPORT: We present a case of Cryptococcal meningoencephalitis attributable to Cryptococcus neoformans var. grubii, in a 58-year-old bird-keeper from Australia, after 7 years of fingolimod therapy. We discuss this in the context of previously reported cases, our understanding of fingolimod immune modulation, and known Cryptococcus pathobiology. CONCLUSION: We suggest consideration of harm minimisation behaviours in patients requiring fingolimod, particularly in those with profound CD4 lymphopenia. Furthermore, we echo the call for improved post-marketing surveillance systems to determine the epidemiology of atypical infections with novel immunomodulatory treatments.

Evidence of state dependent learning of brightness discrimination in hypothermic mice.

Shock-elicited escape behavior of C57Bl mice in a brightness discrimination task was examined to investigate the effects of hypothermia on acquisition and reversal. Neither acquisition nor reversal was impaired by 7 degrees C or 13 degrees C decreases in central body temperature when body temperature remained at those levels throughout testing. However, body temperature changes from acquisition to reversal were accompanied by memory deficits during reversal if acquisition occurred at body temperature decreased by 13 degrees and reversal occurred at normal body temperature or body temperature decreased by 7 degrees and reversal at body temperature decreased by 13 degrees. This finding suggests the occurrence of a state dependent discrimination response: an instance of asymmetrical dissociation. In addition, during acquisition, latency of the escape response was longer in hypothermic animals than in controls, and should be interpreted as a performance deficit, rather than failure or delayed rate of learning. Depressed intertrial activity also was observed in hypothermic animals.

Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor.

Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAF(V600E) is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAF(V600E) signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of STAT3 serine-727 and tyrosine-705 phosphorylations is promoted by B-RAF(V600E) activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation. Consequently, suppression of STAT3 activity disrupted B-RAF(V600E)-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that STAT3 has a central role in the survival and contributes to chemoresistance of B-RAF(V600E) melanoma.

Suicide rates among cancer patients in Connecticut.

This study derives age-sex specific standardized mortality ratios (SMR's) among cancer (ca) patients with respect to population suicide rates. Suicide rates were derived for all 144,530 ca patients in the Connecticut Tumor Registry from 1940-1973. We also derived rates by number of years since diagnosis (y-s-dx) and by decade of dx. We hypothesized beforehand that suicide rates will (1) be higher in ca patients than the population; (2) be higher soon after dx than in later y-s-dx; (3) vary directly with spread of disease at dx, highest for metastatic, lowest for local. We address hypotheses (1) and (2) here. After collapsing age groups and y-s-dx in the observed 192 ca patient suicides, SMR's derived for age, sex and y-s-dx were tested with an exact Poisson distribution. Overall, SMR for males was significantly elevated (230, P less than 0.005), but not for females. In males, a test for trend in SMR's with y-s-dx showed a significant decline, supporting hypothesis (2) for males (chi2 = 4.0, df = 1, P less than 0.05). No trend was found for decade of dx. On combining decades, male SMR's were significantly elevated in 10 of the 25 cells of age by y-s-dx, while none of the female cells was significant. We conclude that both hypotheses were supported for males, and neither for females.

Psychological factors in the prognosis of malignant melanoma: a prospective study.

Sixty-four patients with Stage I or II malignant melanoma who were apparently disease free rated the amount of adjustment needed to cope with their illness on a scale of 1 to 100. The resultant figure was called the melanoma adjustment score. Twenty-nine patients who relapsed within 1 year of surgery reported a score of 53 +/- 31 (mean +/- SD); 35 nonrelapsers reported a score of 80 +/- 20, p less than 0.001. Based upon analysis of indivual melanoma adjustment scores in the first 31 patients, we predicted that subjects scoring greater or equal to 65 would stay in remission, whereas those scoring greater than 65 would relapse. Applying this prospectively to the next 33 patients we correctly identified 25 of 33 outcomes (76%), p less than 0.03. This psychological variable was independent of known biological prognostic factors, which did not predict 1 year survival. The melanoma adjustment score was also independent of the number of positive lymph nodes, which did correlate with outcome in these patients. The results suggest a role for psychological factors in the one year prognosis of this malignancy.