Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks

Purpose: MG98 is a second generation phosphorothioate antisense oligodeoxynucleotide which is a highly specific inhibitor of translation of the mRNA for human DNA MeTase I (DNMT 1). This phase I study examined the toxicity and pharmacologic profile of MG98 administered as a continuous 21-day intravenous infusion every 4 weeks. Patients and methods: Fourteen patients with solid cancers received a total of 25 cycles of MG98 at doses ranging from 40 to 240 mg/m²/day. Steady-state concentrations of MG98 were measured as were several pharmacodynamic assessments including mRNA of the target gene, DNMT1, in PBMC. In addition, other potential surrogate markers of drug effects were explored, including hemoglobin F, Vimentin and GADD45. Results: Dose limiting effects were drug-related reversible transaminase elevation and fatigue seen at doses of 240, 200 and 160 mg/m²/day. The dose level of 80 mg/m²/day was felt to be safe and tolerable when delivered on this schedule. No evidence of antitumor activity was observed. Although pharmacokinetic analysis revealed that at the higher dose levels, mean Css values of MG98 were approximately 10-fold times the IC₅₀ values associated with target inhibition in vitro, the extent of MG98 penetration into target tumors in this trial was not determined. No consistent, dose-related changes in correlative markers including DNMT1 mRNA, hemoglobin F, Vimentin and GADD45, were observed. Conclusions: This schedule of MG98 given as a 21-day continuous intravenous infusion every 4 weeks was poorly tolerated in the highest doses; therefore, further disease-site specific evaluation of the efficacy of this agent will utilize a more favorable, intermittent dosing schedule. Pharmacodynamic evaluations undertaken in an attempt to explore and validate the biological mechanisms of MG98 did not show dose-related effects.     

Can subjective global assessment of nutritional status predict survival in ovarian cancer?

Background

Malnutrition is a significant problem in patients with ovarian cancer. The goal of this study was to investigate the prognostic role of Subjective Global Assessment (SGA) in patients with ovarian cancer treated in an integrative cancer treatment setting.

Methods

We evaluated a case series of 132 ovarian cancer patients treated at Cancer Treatment Centers of America^® from Jan 2001 to May 2006. SGA was used to assess nutritional status at baseline. Using SGA, patients were classified as well nourished (SGA A), moderately malnourished (SGA B) or severely malnourished (SGA C). Kaplan Meier method was used to calculate survival. Cox proportional hazard models were constructed to evaluate the prognostic effect of SGA independent of other factors.

Results

Of 132 patients, 24 were newly diagnosed while 108 had received prior treatment. 15 had stage I disease at diagnosis, 8 stage II, 85 stage III and 17 stage IV. The median age at presentation was 54.4 years (range 25.5 – 82.5 years). 66 patients were well-nourished (SGA A), 35 moderately malnourished (SGA B) and 31 severely malnourished (SGA C). Well nourished patients had a median survival of 19.3 months (95% CI: 14.1 to 24.5), moderately malnourished 15.5 months (95% CI: 5.8 to 25.1), and severely malnourished 6.7 months (95% CI: 4.1 to 9.3); the difference being statistically significant (p = 0.0003). Multivariate Cox modeling, after adjusting for stage at diagnosis and prior treatment history found that moderately malnourished and severely malnourished status were associated with a relative risk of 2.1 (95% CI: 1.2 to 3.6, p = 0.008) and 3.4 (95% CI: 1.9 to 5.8, p < 0.001) respectively as compared to well nourished status.

Conclusion

Univariate and multivariate survival analyses found that low SGA scores (i.e. well-nourished status) are associated with better survival outcomes. This study lends support to the role of aggressive nutritional intervention in improving patient outcomes in cancer care.     

Fetal cardiac malposition: incidence and outcome of associated cardiac and extracardiac malformations

Cardiac malposition is a rare but important finding when detected on fetal ultrasound. The purpose of this study was to evaluate the incidence of fetal cardiac malposition, associated abnormalities, and clinical outcome in a tertiary-care medical center. Records of fetuses (1993 to 2006) with dextroposition, dextrocardia, mesocardia, ectopia cordis, or heterotaxy were reviewed. The presence of congenital heart disease (CHD), extracardiac anomalies, and outcome were noted. Cardiac malposition was present in 101 fetuses among a total of 3313 (3%) pregnancies. In 78 (78%) patients, the heart was positioned in the right hemithorax. Of those, 26 (33%) had dextrocardia (CHD = 21), and 52 (67%) had dextroposition (CHD = 14). Sixteen (16%) patients had mesocardia (CHD = 8), and 7 (7%) had ectopia cordis (CHD = 6). The majority (58%) of fetal cardiac malposition was caused by intrathoracic masses. Concomitant CHD occurred in 50%. Outcome was available in 97%. The perinatal and neonatal mortality rate was 30%; the elective termination rate was 4%. Patients with CHD had higher mortality rates. The highest mortality rates occurred in ectopia cordis and combined disease of diaphragmatic hernia and CHD.     

Contraception for the transplant patient

Patients who have had an organ transplant have a need for highly effective contraception. Intrauterine devices, depo-medroxyprogesterone acetate, and implantable etonorgestrel have the highest efficacy combined with the least chance of interaction with antirejection medication regimens. Combined hormonal contraceptives and progestin-only pills are also acceptable methods for patients who do not have other contraindications to their use. Barrier method use should be advocated for any patient who is entering a new sexual relationship and as an adjunct to other methods. Consultation with a gynecologist experienced with the provision of contraceptives to medically complicated patients is advised for all women of reproductive age who have received an organ transplant.     

Effect of Concussion on Reaction Time and Neurocognitive Factors: Implications for Subsequent Lower Extremity Injury

BackgroundRecent evidence has demonstrated that athletes are at greater risk for a lower extremity injury following a return-to-sport (RTS) after sport-related concussion (SRC). The reason for this is not completely clear, but it has been hypothesized that persistent deficits in neurocognitive factors may be a contributing factor.Hypothesis/PurposeThis study assessed simple reaction time, processing speed, attention, and concentration in a group of athletes, post-concussion upon clearance for RTS for potential deficits that may result in slower reaction time, processing speed, attention, and concentration. The researchers hypothesized that the concussion group would demonstrate worse scores on both assessments compared to a sex-, age-, and sport-matched cohort.Study DesignCase-controlled studyMethodsTwelve participants who had suffered a SRC and eight healthy individuals who were matched to the concussed group by age, sex, and sport were evaluated. Those with a concussion had been cleared for RTS by a licensed healthcare provider. Each participant underwent neurocognitive tests that included a simple reaction time test (SRT) and the King-Devick Test (K-D). Independent t-tests were performed to compare the groups with significance set a priori at p<0.05.ResultsThere was a significant difference (p =0.024) between groups for SRT with the concussed group demonstrating a better SRT than the control group. There were no significant differences (p =0.939) between the groups for the K-D.ConclusionWith no significant differences between groups in the K-D assessment and, surprisingly, the concussed group having a better SRT compared to the healthy group, our hypothesis was not supported.Clinical RelevanceThese specific measures, compounded with extensive post-concussion time lapse until RTS clearance, may have limited capacity in revealing potential persistent deficits in relevant neurocognitive characteristics.Level of EvidenceLevel of Evidence 3     

Spontaneous rupture of the liver

A patient with systemic lupus erythematosus developed an acute surgical abdomen secondary to spontaneous rupture of the liver and died. Postmortem examination revealed an arteritis of the liver, pancreas, adrenal gland, skeletal muscle, and spleen. It appeared that an arteritis of the liver produced areas of infarction that ruptured and caused the clinical findings.