An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma.

PURPOSE: A topical Toll-like receptor 7 (TLR7) agonist induces regression of cutaneous melanocytic neoplasms. We explored antitumor activity of a systemically administered TLR7 agonist, 852A, in patients with metastatic melanoma. EXPERIMENTAL DESIGN: We undertook a phase II, multicenter, open-label study in patients with chemotherapy-refractory metastatic melanoma. Patients received i.v. 852A, starting at 0.6 mg/m(2) and increasing to 0.9 mg/m(2) based on tolerance, thrice per week for 12 weeks. Clinical response was determined by Response Evaluation Criteria in Solid Tumors. Immune effects of 852A were monitored by measuring serum type I IFN and IP-10 together with assessment of immune cell markers in peripheral blood. RESULTS: Twenty-one patients were enrolled. Thirteen patients completed the initial 12-week treatment cycle, with two discontinuing for adverse events considered to be possibly related to study drug. Four (19%) patients had disease stabilization for >100 days. One patient had a partial remission after two treatment cycles, but progressed during the third. Dose-limiting toxicity was observed in two patients. Serum type I IFN and IP-10 increased in most patients on 852A administration. Serum type I IFN increases were greater after dosing with 852A 0.9 mg/m(2) than after 0.6 mg/m(2) (P = 0.009). The maximal increase in IP-10 compared with baseline correlated with the maximal increase in type I IFN (P = 0.003). In the eight patients with immune cell marker data, CD86 expression on monocytes increased significantly post-first dose (P = 0.007). CONCLUSION: Intravenous 852A was well tolerated and induced systemic immune activation that eventually resulted in prolonged disease stabilization in some patients with stage IV metastatic melanoma who had failed chemotherapy.     

Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy.

BACKGROUND: Radiation dose distributions created by two dimensional (2D) treatment planning are responsible for partial volumes receiving >107% of the prescribed dose in a proportion of patients prescribed whole breast radiotherapy after tumour excision of early breast cancer. These may contribute to clinically significant late radiation adverse effects. AIM: To test three dimensional (3D) intensity modulated radiotherapy (IMRT) against 2D dosimetry using standard wedge compensators in terms of late adverse effects after whole breast radiotherapy. METHODS: Three hundred and six women prescribed whole breast radiotherapy after tumour excision for early stage cancer were randomised to 3D IMRT (test arm) or 2D radiotherapy delivered using standard wedge compensators (control arm). All patients were treated with 6 or 10MV photons to a dose of 50Gy in 25 fractions to 100% in 5 weeks followed by an electron boost to the tumour bed of 11.1Gy in 5 fractions to 100%. The primary endpoint was change in breast appearance scored from serial photographs taken before radiotherapy and at 1, 2 and 5 years follow up. Secondary endpoints included patient self-assessments of breast discomfort, breast hardness, quality of life and physician assessments of breast induration. Analysis was by intention to treat. RESULTS: 240 (79%) patients with 5-year photographs were available for analysis. Change in breast appearance was identified in 71/122 (58%) allocated standard 2D treatment compared to only 47/118 (40%) patients allocated 3D IMRT. The control arm patients were 1.7 times more likely to have a change in breast appearance than the IMRT arm patients after adjustment for year of photographic assessment (95% confidence interval 1.2-2.5, p=0.008). Significantly fewer patients in the 3D IMRT group developed palpable induration assessed clinically in the centre of the breast, pectoral fold, infra-mammary fold and at the boost site. No significant differences between treatment groups were found in patient reported breast discomfort, breast hardness or quality of life. CONCLUSION: This analysis suggests that minimisation of unwanted radiation dose inhomogeneity in the breast reduces late adverse effects. Incidence of change in breast appearance was statistically significantly higher in patients in the standard 2D treatment arm compared with the IMRT arm. A beneficial effect on quality of life remains to be demonstrated.     

Positive Impact of a Shelter-based Hepatitis B Vaccine Program in Homeless Baltimore Children and Adolescents

Homeless youth are at increased risk for hepatitis B virus (HBV) infection and HBV vaccine coverage is poor in this group. The purpose of our study was to determine if a shelter-based HBV vaccine program in children and adolescents 2–18 years of age with a randomized controlled trial using a culturally appropriate HBV video could increase HBV vaccine coverage rates. Subjects were randomized to an 8 min HBV video or a control, smoking prevention video. Before exposure to the videos, HBV knowledge, and demographics were assessed in caregivers and adolescents. HBV vaccine no. 1 was offered to all subjects who did not produce a vaccine record; subsequently, an accurate HBV vaccine history was obtained from medical providers. Subjects were asked to return 1 and 3 months after visit 1, HBV vaccine was offered to all with incomplete coverage, and HBV knowledge was reassessed. There were 328 children and adolescents cared for by 170 caregivers enrolled in the study. One hundred and four had incomplete HBV vaccine coverage. Data are reported for all family units with at least one subject needing vaccine. There were 53 children and adolescents randomized to the HBV video vs. 51 to the smoking video. HBV knowledge scores of caregivers improved at Visit no. 2 vs. no. 1 in the HBV video group (p = 0.01) but not in the smoking group (p = 0.82). Similar results were observed for adolescents in the HBV video group (p = 0.05) but not in the smoking group (p = 0.40). Exposure to the HBV video vs the smoking video had a significant effect on return rates for vaccine at Visit no. 2 (59 vs. 31%; p = 0.05) but not at Visit no. 3 (47 vs. 18%, p = 0.06). The shelter-based vaccine program was very effective in increasing HBV coverage rates in the entire group of 328 children and adolescents enrolled in the study, from 68% coverage at baseline to 85% at the conclusion of the study. We conclude that shelter-based HBV vaccine programs can be highly effective in increasing vaccine coverage rates in older children and adolescents. A brief exposure to a culturally appropriate HBV video improves HBV knowledge and may improve return rates for vaccine.     

Human aflatoxin albumin adducts quantitatively compared by ELISA, HPLC with fluorescence detection, and HPLC with isotope dilution mass spectrometry

Essential to the conduct of epidemiologic studies examining aflatoxin exposure and the risk of heptocellular carcinoma, impaired growth, and acute toxicity has been the development of quantitative biomarkers of exposure to aflatoxins, particularly aflatoxin B(1). In this study, identical serum sample sets were analyzed for aflatoxin-albumin adducts by ELISA, high-performance liquid chromatography (HPLC) with fluorescence detection (HPLC-f), and HPLC with isotope dilution mass spectrometry (IDMS). The human samples analyzed were from an acute aflatoxicosis outbreak in Kenya in 2004 (n = 102) and the measured values ranged from 0.018 to 67.0, nondetectable to 13.6, and 0.002 to 17.7 ng/mg albumin for the respective methods. The Deming regression slopes for the HPLC-f and ELISA concentrations as a function of the IDMS concentrations were 0.71 (r(2) = 0.95) and 3.3 (r(2) = 0.96), respectively. When the samples were classified as cases or controls, based on clinical diagnosis, all methods were predictive of outcome (P < 0.01). Further, to evaluate assay precision, duplicate samples were prepared at three levels by dilution of an exposed human sample and were analyzed on three separate days. Excluding one assay value by ELISA and one assay by HPLC-f, the overall relative SD were 8.7%, 10.5%, and 9.4% for IDMS, HPLC-f, and ELISA, respectively. IDMS was the most sensitive technique and HPLC-f was the least sensitive method. Overall, this study shows an excellent correlation between three independent methodologies conducted in different laboratories and supports the validation of these technologies for assessment of human exposure to this environmental toxin and carcinogen.     

Burkitt's Lymphoma in a Child with Aids

Few systemic lymphomas have been reported in children with AIDS. We report a case of disseminated Burkitt's lymphoma with lung involvement occurring in a 33-month-old child with acquired immunodeficiency syndrome. Lymphoid interstitial pneumonia was diagnosed by lung biopsy at 23 months of age, but lymphoma was not diagnosed before autopsy.     

Antitachycardia pacing therapies and arrhythmia monitoring diagnostics for the treatment of atrial fibrillation

The case of a patient with frequent episodes of atrial fibrillation that organizes into atrial flutter following implantation of a dual chamber, rate adaptive pacemaker is reported. The atrial flutter was effectively pace-terminated following activation of the atrial antitachycardia pacing therapies in the pacemaker. This resulted in a decrease in atrial fibrillation burden over time. The present case also illustrates the value of diagnostic data retrieved from pacemakers for monitoring atrial fibrillation frequency over time and evaluating the efficacy of pacing and drug therapy.     

Parathyroid hormone-related protein as a novel tumor marker in pancreatic adenocarcinoma

INTRODUCTION: Parathyroid hormone-related protein (PTHrP) can act as an oncoprotein to regulate the growth and proliferation of many common malignancies, including pancreatic cancer. Previous studies have shown that PTHrP is produced by human pancreatic cancer cell lines, can be shown in the cytoplasm and nucleus of paraffin-embedded pancreatic adenocarcinoma tumor specimens, and is secreted into the media of cultured pancreatic adenocarcinoma cells. We hypothesized that PTHrP could serve as a tumor-marker for growth of pancreatic cancer in vivo. AIM AND METHODOLOGY: To test this hypothesis, we used an orthotopic model developed in our laboratory of the PTHrP-producing human pancreatic cancer line, BxPC-3. This tumor was stably transduced with green fluorescence protein (GFP) to facilitate visualization of tumor growth and metastases. At early (5 weeks) and late (13 weeks) time points after surgical orthotopic implantation, serum PTHrP was measured and primary and metastatic tumor burden was determined for each mouse by assessing GFP expression. RESULTS: By 5 weeks after surgical orthotopic implantation (early group), the mean serum PTHrP level was 33.3 pg/mL. In contrast, by 13 weeks after surgical orthotopic implantation (late group), the mean serum PTHrP level increased to 158.5 pg/mL. These differences were highly significant (p < 0.001, Student t test). Numerous metastatic lesions were readily visualized by GFP in the late group. Serum PTHrP levels measured by immunoassay correlated with primary pancreatic tumor weights and serum calcium levels (p <0.01). PTHrP levels were not detectable (<21 pg/mL) in any of the 10 control mice with no tumor. Western blotting of BxPC-3-GFP tumor lysates confirmed the presence of PTHrP. BxPC-3-GFP tumor tissue stained with antibody to PTHrP. CONCLUSION: These results indicate that PTHrP can serve as a tumor marker in animal models of pancreatic cancer and may be a useful tumor marker for clinical pancreatic adenocarcinoma.     

Using counterconditioning to treat behavioural distress during subcutaneous injections in a paediatric rehabilitation patient

A counterconditioning-based intervention was conducted to supplement topical anaesthesia during repeated parent-administered subcutaneous injections performed on a 7-year-old girl for anticoagulation post-stroke. Preferred activities were paired with in vivo exposure to medical stimuli, first during simulated, then actual injections. Differential positive reinforcement was provided contingent on engagement with preferred activities, button pressing in response to an auditory stimulus, and general compliance with adult instructions. Child distress was measured by direct observations and intervention effects examined using an A-B, single-subject case study design with an interrupted time-series statistical analysis for brief single-subject data. Child distress decreased significantly when behavioural intervention was provided. Parent ratings indicated that treatment effects were maintained after the intervention was turned over to the mother and continued at home. Heart rate data provided physiological evidence of counterconditioning. The results are discussed in relation to the application of conditioning and counterconditioning theory in the paediatric rehabilitation setting.     

Melatonin and prostate cancer cell proliferation: interplay with castration,epidermal growth factor,and androgen sensitivity

BACKGROUND: Potential modulatory effects of melatonin on the proliferation of androgen-sensitive LNCaP and androgen-insensitive PC-3 and DU 145 prostate cancer cells were reported recently. In this study, we investigated the effects of combined melatonin and castration on LNCaP tumor growth in vivo, the interactions between melatonin and epidermal growth factor (EGF) on LNCaP cell proliferation, and melatonin actions on the proliferation of PC-3 and DU 145 cells. METHODS: Tumor development and growth in castrated nude mice inoculated with LNCaP cells or in intact animals inoculated with DU 145 cells, with or without daily melatonin treatment, were monitored by observation and caliper measurement. MT(1) receptor expression in native or transfected prostate cancer cell lines was examined by immunocytochemistry or 2-[(125)I]iodomelatonin binding. Cyclin D1 expression in LNCaP cells was assessed by Western blotting, and cell proliferation was measured by thymidine incorporation and/or cell count. RESULTS: Melatonin treatment was associated with further decreases in LNCaP tumor incidence and growth rate in castrated nude mice. Melatonin and 2-iodomelatonin (a melatonin receptor agonist) attenuated EGF-stimulated increases in LNCaP cell proliferation and cyclin D1 levels. Melatonin had no effect on the proliferation or growth of MT(1) receptor-expressing DU 145 cells, and of PC-3 cells in which MT(1) receptor protein was undetectable. The proliferation of transfected PC-3 cells expressing MT(1) receptor was unaffected by 2-iodomelatonin. CONCLUSION: Together with previous data, the present results indicate synergistic action of melatonin and castration in inhibiting the growth of androgen-sensitive LNCaP tumor. Androgen-sensitive prostate cancer cell proliferation may be modulated by opposite changes in cyclin D1 levels induced by activated MT(1) and EGF receptors. In androgen-insensitive prostate cancer cells, MT(1) receptor-mediated signal transduction may become defective not only through changes in membrane receptor protein expression and/or functions, but also by means of alterations in downstream postreceptor signaling events.