NFATc1 promotes prostate tumorigenesis and overcomes PTEN loss-induced senescence.

Despite recent insights into prostate cancer (PCa)-associated genetic changes, full understanding of prostate tumorigenesis remains elusive owing to complexity of interactions among various cell types and soluble factors present in prostate tissue. We found the upregulation of nuclear factor of activated T cells c1 (NFATc1) in human PCa and cultured PCa cells, but not in normal prostates and non-tumorigenic prostate cells. To understand the role of NFATc1 in prostate tumorigenesis in situ, we temporally and spatially controlled the activation of NFATc1 in mouse prostate and showed that such activation resulted in prostatic adenocarcinoma with features similar to those seen in human PCa. Our results indicate that the activation of a single transcription factor, NFATc1 in prostatic luminal epithelium to PCa can affect expression of diverse factors in both cells harboring the genetic changes and in neighboring cells through microenvironmental alterations. In addition to the activation of oncogenes c-MYC and STAT3 in tumor cells, a number of cytokines and growth factors, such as IL1ß, IL6 and SPP1 (osteopontin, a key biomarker for PCa), were upregulated in NFATc1-induced PCa, establishing a tumorigenic microenvironment involving both NFATc1 positive and negative cells for prostate tumorigenesis. To further characterize interactions between genes involved in prostate tumorigenesis, we generated mice with both NFATc1 activation and Pten inactivation in prostate. We showed that NFATc1 activation led to acceleration of Pten null-driven prostate tumorigenesis by overcoming the PTEN loss-induced cellular senescence through inhibition of p21 activation. This study provides direct in vivo evidence of an oncogenic role of NFATc1 in prostate tumorigenesis and reveals multiple functions of NFATc1 in activating oncogenes, in inducing proinflammatory cytokines, in oncogene addiction, and in overcoming cellular senescence, which suggests calcineurin-NFAT signaling as a potential target in preventing PCa.

Toxicity of photodynamic therapy after combined external beam radiotherapy and intraluminal brachytherapy for carcinoma of the upper aerodigestive tract.

BACKGROUND AND OBJECTIVE: To describe the toxicity of photodynamic therapy (PDT) in patients with carcinoma of the upper aerodigestive tract who received prior treatment with external beam irradiation and intraluminal brachytherapy (IB). STUDY DESIGN/MATERIALS AND METHODS: Hospital records of PDT patients were reviewed. Three patients who received prior treatment with external beam irradiation and IB were identified. Two patients had esophageal carcinoma treated with combined chemotherapy and external beam irradiation (55.8 and 50.4 Gy) followed by IB (12 Gy and 35 Gy at 1 cm). These patients then received PDT for treatment of recurrence (2 mg/kg Photofrin injection and 2 light applications: 630 nm, 150--200 J/cm, 200--400 mW/cm). One patient had non-small cell lung cancer treated with external beam irradiation (60 Gy) followed by IB (36.1 Gy at 1 cm) and then received PDT for recurrence (1 mg/kg Photofrin injection and one light application: 630 nm, 150 J/cm, 200 mW/cm). RESULTS: One patient with esophagus cancer had formation of a tracheoesophageal fistula, which required stent placement. The other esophageal cancer patient developed quadriplegia due to an epidural abscess arising from a fistula with the diseased portion of the esophagus. The lung cancer patient had massive hemoptysis after the procedure and died 2 days later. Autopsy showed necrotizing arteritis of the right pulmonary artery. CONCLUSION: Patients with upper aerodigestive tract carcinoma who have received treatment with both external beam irradiation and IB seem to be at higher risk for complications when treated with PDT.

Comparison between isotropic and nonisotropic dosimetry systems during intraperitoneal photodynamic therapy.

BACKGROUND AND OBJECTIVE: On-line monitoring of light fluence during intraperitoneal photodynamic therapy (IP PDT) is crucial for safe light delivery. A flat photodiode-based dosimetry system is compared with an isotropic detector-based system in patients undergoing IP PDT. STUDY DESIGN/MATERIALS AND METHODS: Flat photodiodes and spherical detectors were placed side by side in the abdomen, for simultaneous light dosimetry in 19 patients. Tissue phantom experiments were performed to provide a preliminary estimate of the tissue optical properties of the peritoneum. RESULTS: The conversion factor between systems for 630-nm light was found to be 1.7 +/- 0.12. The mu(eff) of the tissues in the abdomen is estimated to vary between 0.5 cm(-1) to 1.4 cm(-1) assuming a mu(s)' = 7 cm(-1). CONCLUSIONS: The measured conversion factor should allow for comparison of light fluences with future clinical protocols that use an isotropic-based detector system. Differences in the optical properties of the underlying tissues may contribute to the variability in light measurements.

Prospective study on the occurrence of withdrawal in critically ill children who receive fentanyl by continuous infusion.

OBJECTIVE: To determine the occurrence of narcotic withdrawal in critically ill children who receive continuous infusions of fentanyl. DESIGN: Prospective case series. SETTING: A university hospital pediatric intensive care unit. PATIENTS: Twenty-three children, aged 1 wk to 22 months (mean 6 months), who required assisted mechanical ventilation and who received continuous infusions of fentanyl for > 24 hrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total fentanyl dose received, length of infusion, and peak infusion rate were recorded. Patients were evaluated for narcotic withdrawal by the Neonatal Abstinence Scoring System of Finnegan. Children with scores of > or = 8 were considered to have narcotic withdrawal. Withdrawal was observed in 13 (57%) of 23 infants. Total fentanyl dose (2.96 +/- 4.10 vs. 0.53 +/- 0.37 mg/kg, p < .005) and length of fentanyl infusion (13.1 +/- 11.3 vs. 3.8 +/- 1.5 days, p < .0001) were significantly greater in those infants with narcotic withdrawal than in those infants with no withdrawal, respectively. Peak fentanyl infusion rate (9.9 +/- 7.8 vs. 9.2 +/- 4.4 micrograms/kg/hr) did not differ significantly between the two groups. A total fentanyl dose of > 2.5 mg/kg or a duration of infusion of > 9 days was 100% predictive of withdrawal. CONCLUSIONS: Continuous infusions of fentanyl produce a high occurrence rate of narcotic withdrawal when administered to critically ill children. This effect is both dose- and duration-dependent.

Neonatal gangrene in the newborn infant of a diabetic mother.

The newborn daughter of a diabetic mother developed neonatal gangrene of an upper extremity with massive muscle necrosis of the forearm, and required early dorsal and volar fasciotomies with subsequent debridements to salvage the limb. Decreased perfusion and local ischemia resulting in neonatal gangrene may result from the greater propensity for intravascular thrombosis in infants whose mothers have diabetes mellitus. While previous investigators have suggested that surgical intervention should be avoided in neonatal gangrene, in more severe cases early fasciotomy may be required to salvage a limb and avoid life-threatening complications.