Predictors of toxicity in treating patients with neuroblastoma by radiolabeled metaiodobenzylguanidine

We searched for methods that would enable prescriptions of the maximum tolerable doses of iodine-131 metaiodobenzylguanidine (MIBG) and iodine-125 MIBG in the treatment of patients with neuroblastoma. We correlated doses, defined in different ways, with subsequent platelet levels in treated patients to determine accurate predictors of the most frequent toxicity, thrombocytopenia. Nine patients with neuroblastoma were given 131 I-MIBG (4.9–8.1 GBq or 132–220 mCi) and ten were given 125 I-MIBG (8.3-30.0 GBq or 224–809 mCi) as initial treatments. These therapies were sufficiently varied that correlations could be made between indices of the doses and the subsequent toxicity as reflected in circulating platelet levels. Predictors of toxicity were: whole-body absorbed dose of radiation (cGy) calculated from pretherapy tracer doses of 131 I-MIBG; GBq/kg of body weight; and GBq/m 2 of body surface area. Toxicity was recorded as the nadir of the platelet level and platelet/pretherapeutic level (platelet ratio). For treatments with 131 I-MIBG, the highest correlation was obtained between cGy and the logo 10 -transformed platelet ratio ( r =−0.86), but comparison of GBq/m2 and the platelet nadir ( r =−0.76) or the platelet ratio ( r =−0.74) or the log 10 − transformed platelet ratio ( r =−0.73) gave comparable and statistically significant results. For treatments with 125 I-MIBG, significant correlations were obtained between GBq/m 2 and the platelet ratio ( r =−0.81) or GBq/kg and the log 10 − -transformed platelet ratio; the correlation between cGy and any toxicity index was low. Per administered GBq, 131 I-MIBG was 2.6 times more potent than 125 I-MIBG in causing a platelet ratio of 0.1. Thus, in predicting toxicity, therapeutic doses of 131 I-MIBG expressed as GBq/m 2 performed satisfactorily and almost as well as whole-body cGy, and treatment doses of 125 I-MIBG expressed as GBq/m 2 or GBq/kg performed satisfactorily and much better than whole-body cGy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46835/1/259_2004_Article_BF00182305.pd

Dysplasia in Barrett esophagus

BACKGROUND Dysplasia in Barrett esophagus is a premalignant condition that is associated with an increased risk of developing esophageal adenocarcinoma. Unfortunately, clinical investigation aimed at prevention of progression to malignant disease has been hampered by the variable prevalence of dysplasia reported in the literature. The objective of the current study was to more accurately determine the prevalence of dysplasia among individuals with Barrett esophagus who would be available for enrollment in a chemoprevention trial. METHODS The pathology archives of 3 institutions were reviewed over a 5-year period for all reports of diagnoses of Barrett esophagus. Surgical cases, malignancies, and duplicate or referral cases were excluded from the analysis. RESULTS A total of 790 cases of Barrett esophagus were identified. Of these, 37 (4.7%) were cases of low-grade dysplasia (LGD), and 20 (2.5%) were cases of high-grade dysplasia. The University of Michigan Medical Center (Ann Arbor, MI) diagnosed 18 cases of LGD, Henry Ford Hospital (Detroit, MI) diagnosed 15 cases of LGD, and Brigham and Women's Hospital (Boston, MA) diagnosed 4 cases of LGD in patients with Barrett esophagus over the 5-year study period. CONCLUSIONS The confirmed low prevalence of cases of LGD will affect the design of future clinical trials of chemopreventive interventions for Barrett esophagus. Cancer 2004. © 2004 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34387/1/20149_ftp.pd

Dose escalation of a curcuminoid formulation

BACKGROUND: Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed. METHODS: A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C(3 )Complex™, Sabinsa Corporation). Healthy volunteers were administered escalating doses from 500 to 12,000 mg. RESULTS: Seven of twenty-four subjects (30%) experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg. CONCLUSION: The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent

Effects of Low Dose Aspirin (81 mg) on Proliferating Cell Nuclear Antigen and Amaranthus Caudatus Labeling in Normal-Risk and High-Risk Human Subjects for Colorectal Cancer

Epidemiological, experimental, and clinical observations provide support for a colorectal cancer chemopreventive role for aspirin. We have evaluated the effects of aspirin on proliferation biomarkers in normal-risk and high-risk human subjects for colorectal cancer. Colorectal biopsies were obtained at baseline and at 24h after 28 daily doses of 81mg of aspirin from 13 high-risk and 15 normal-risk subjects for colorectal cancer. We evaluated aspirin\u27s effects on proliferating cell nuclear antigen (PCNA) immunohistochemistry and epithelial mucin histochemistry using the lectin, Amaranthus caudatus agglutinin (ACA) in crypt sections from rectal biopsies. The baseline whole crypt PCNA LIs differed significantly between normal-risk and high-risk subjects. PCNA LIs are not affected by 28 days of aspirin at 81mg daily. ACA LIs are decreased by 28 days of aspirin at 81mg daily in both normal-risk and high-risk subjects. Aspirin\u27s effects on ACA LIs may have mechanistic and biological implications that deserve further attention. PCNA and ACA LIs are not useful as proliferation biomarkers for aspirin\u27s chemopreventive activity in morphologically normal human colorectal mucosa

Erythromycin breath test predicts oral clearance of cyclosporine in kidney transplant recipients

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109859/1/cptclpt1992174.pd

Clinical trials optimizing investigator and self-collection of buccal cells for RNA yield.

ObjectiveBuccal cells are an ideal surrogate tissue for studying biologic effects of carcinogens or drugs, however inherent fragility and salivary RNAses limit RNA yield. We conducted healthy volunteer trials to optimize collection conditions.MethodsWe conducted: (a) a single-arm crossover study evaluating four test conditions on RNA yield by buccal cytobrush; (b) a single-arm prospective study evaluating RNA yield by investigator vs self-collection.ResultsAntecedent toothbrushing, time of day, and number of cytobrush strokes did not significantly impact RNA yield. RNA yield was doubled by using 2 vs 1 cytobrush per buccal surface (P = .0054). Self-collection of buccal cells for RNA was feasible; 36 of 50 (72%) samples passed quality control.ConclusionRNA yield was doubled by using two cytobrushes per buccal surface. Healthy volunteers can self-collect sufficient buccal RNA for gene expression studies. Techniques from these pragmatic trials could enhance availability of a limited tissue for serial biomarker measurements.Level of evidence1b-Prognosis Study (Individual prospective cohort study)

Clinical trials optimizing investigator and self-collection of buccal cells for RNA yield.

ObjectiveBuccal cells are an ideal surrogate tissue for studying biologic effects of carcinogens or drugs, however inherent fragility and salivary RNAses limit RNA yield. We conducted healthy volunteer trials to optimize collection conditions.MethodsWe conducted: (a) a single-arm crossover study evaluating four test conditions on RNA yield by buccal cytobrush; (b) a single-arm prospective study evaluating RNA yield by investigator vs self-collection.ResultsAntecedent toothbrushing, time of day, and number of cytobrush strokes did not significantly impact RNA yield. RNA yield was doubled by using 2 vs 1 cytobrush per buccal surface (P = .0054). Self-collection of buccal cells for RNA was feasible; 36 of 50 (72%) samples passed quality control.ConclusionRNA yield was doubled by using two cytobrushes per buccal surface. Healthy volunteers can self-collect sufficient buccal RNA for gene expression studies. Techniques from these pragmatic trials could enhance availability of a limited tissue for serial biomarker measurements.Level of evidence1b-Prognosis Study (Individual prospective cohort study)