Individualized Mycophenolate Mofetil Dosing Based on Drug Exposure Significantly Improves Patient Outcomes After Renal Transplantation

Efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic monitoring of its active metabolite, mycophenolic acid (MPA). In this 12-month study, 137 renal allograft recipients from 11 French centers receiving basiliximab, cyclosporine A, MMF and corticosteroids were randomized to receive either concentration-controlled doses or fixed-dose MMF. A novel Bayesian estimator of MPA AUC based on three-point sampling was used to individualize doses on posttransplant days 7 and 14 and months 1, 3 and 6. The primary endpoint was treatment failure (death, graft loss, acute rejection and MMF discontinuation). Data from 65 patients/group were analyzed. At month 12, the concentration-controlled group had fewer treatment failures (p = 0.03) and acute rejection episodes (p = 0.01) with no differences in adverse event frequency. The MMF dose was higher in the concentration-controlled group at day 14 (p < 0.0001), month 1 (p < 0.0001) and month 3 (p < 0.01), as were median AUCs on day 14 (33.7 vs. 27.1 mg*h/L; p = 0.0001) and at month 1 (45.0 vs. 30.9 mg*h/L; p < 0.0001). Therapeutic MPA monitoring using a limited sampling strategy can reduce the risk of treatment failure and acute rejection in renal allograft recipients 12 months posttransplant with no increase in adverse events.     

Adjuvant chemotherapy in completely resected non-small-cell lung cancer.

Surgery alone has long been the standard treatment for patients with operable non-small-cell lung cancer (NSCLC). However, despite complete resection, 5-year survival rates have been disappointing, with about 50% of patients eventually suffering relapse and death from disease. Randomized trials conducted in the 1980s hinted at a survival benefit for postoperative cisplatin-based regimens, but they were underpowered. A meta-analysis published in 1995 found a nonsignificant 13% reduction in the risk of death associated with cisplatin-based chemotherapy, with an increase of survival of 5% at 5 years. This led to renewed interest in adjuvant chemotherapy in resected NSCLC. Thousands of patients have been included in a new generation of randomized trials in the last 10 years. Most of these recent studies have now been reported and several have demonstrated a clear survival advantage for patients treated with platin-based adjuvant therapy. These results also suggest a greater benefit with modern two-drug regimens. In view of the most recent data, postoperative platin-based chemotherapy can now be considered the standard of care for completely resected NSCLC patients with good performance status.     

Does systemic inflammation trigger local exercise-induced oxidative stress in COPD?

Inflammatory abnormalities may be involved in the inadequate basal oxidant/antioxidant balance and local exercise-induced oxidative stress in chronic obstructive pulmonary disease (COPD) patients. The time course of oxidative stress and inflammation was investigated in 10 COPD patients and seven healthy subjects before and after local dynamic quadriceps endurance exercise at 40% of maximal strength. Venous samples were collected before, immediately after and up to 48 h after exercise. At rest, levels of an oxidant released by stimulated phagocytes, the superoxide anion, were significantly higher in patients, as were plasma levels of C-reactive protein, tumour necrosis factor-alpha and interleukin-6, inflammatory markers. An inverse relationship was found between baseline C-reactive protein levels and endurance time in patients. Six hours after exercise, superoxide anion release and levels of protein oxidation products, an index of oxidative stress, increased similarly in both groups, whereas thiobarbituric acid reactive substance levels, another index of oxidative stress, increased significantly only in patients. Plasma nonenzymatic antioxidant and inflammatory cytokine levels were unchanged by the exercise protocol. The increased baseline systemic inflammation in chronic obstructive pulmonary disease patients could be related to disturbed oxidant/antioxidant balance, and, together, these may have triggered the exercise-induced oxidative stress. The absence, however, of local exercise-induced systemic inflammation suggests that additional mechanisms explain local exercise-induced oxidative stress.     

Diagnosis of diffuse and localized arrhythmogenic right ventricular dysplasia by gated blood-pool SPECT.

This study aimed to assess the ability of global and local systolic parameters measured with gated blood-pool SPECT (GBPS) to diagnose and characterize the severity of diffuse or localized arrhythmogenic right ventricular dysplasia (ARVD). METHODS: Fifty-nine subjects with symptomatic ventricular arrhythmias were prospectively included in the study. With the International Society and Federation of Cardiology criteria for ARVD as a gold standard, these subjects were classified as subjects without ARVD (21 control subjects) and patients with localized ARVD (16 patients) or diffuse ARVD (22 patients). Right ventricular volumes, right ventricular ejection fractions (EF), the SD of local EF (sigma-EF), and the SD of the local times of end systole (sigma-TES) were computed from GBPS data and compared among the groups in the study population. RESULTS: sigma-EF did not differ between control subjects and patients with diffuse or localized ARVD. Right ventricular EF and volumes differed between patients with diffuse ARVD and control subjects, with similar areas under the receiver-operating-characteristic curves, but right ventricular EF and volumes failed to differentiate patients with localized ARVD. In contrast, sigma-TES differed between patients with diffuse or localized ARVD and control subjects. Regression analysis showed that the systolic parameter most strongly associated with the diagnosis of ARVD was sigma-TES. The probabilities of a randomly chosen patient in the diffuse ARVD group and of a randomly chosen patient in the localized ARVD group having sigma-TES values greater than that of a randomly chosen control subject were 98.5% and 96.7%, respectively. For the diagnosis of localized ARVD, a threshold of 80 ms for sigma-TES corresponded to sensitivity, specificity, and positive and negative predictive values of 100%, 81%, 80%, and 100%, respectively. CONCLUSION: With GBPS, both diffuse ARVD and localized ARVD can be accurately diagnosed by computing sigma-TES for all of the pixels on the surface of the right ventricle.     

De novo esophageal neoplasia after liver transplantation.

The purpose of the study was to determine the incidence, risk factors, treatment, and influence on survival of patients with de novo esophageal cancer after liver transplantation (LT). From 1988 to 2006, 1,926 patients underwent LT in our institution. A total of 9 patients (0.5%) developed a de novo esophageal cancer and 1 patient a cancer of the cardia (0.05%). A retrospective analysis was performed to reveal underlying diseases, timeframes between LT and appearance of cancer, predisposing factors, cancer therapy, complications, immunosuppressive regimens, and survival. Of our 10 patients, 7 (70%) suffered from esophageal squamous cell carcinoma (SCC) and 3 patients (30%) developed an adenocarcinoma, including the patient with cancer of the cardia. A total of 9 patients were transplanted due to alcoholic cirrhosis; 1 patient suffered from hepatocellular carcinoma in nonA-nonB hepatitis-related cirrhosis. Median time to tumor diagnosis was 51 months after transplantation. A total of 5 patients were treated conservatively with combined radiochemotherapy and 5 underwent surgical resection. Patients with radiochemotherapy showed a mean survival of 14.8 months vs. 24.8 months for the patients of the surgery group. No major postoperative complication has been observed. A total of 2 patients of the surgery group are still alive after a follow-up of 15 and 89 months. In conclusion, de novo esophageal and cancer of the cardia after LT is a rare event. In spite of immunosuppression, no increased complication rate has been observed. Patients may have a survival benefit from surgical resection.     

Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves' ophthalmopathy.

BACKGROUND: Intravenous methylprednisolone pulses (IVMP) are more efficacious and better tolerated than oral prednisone in Graves' ophthalmopathy (GO) patients. However, acute and severe liver damage has been reported in sporadic cases during IVMP, resulting in fatal acute liver failure in four patients so far. The mechanism causing the liver damage is incompletely understood. DESIGN: We performed a prospective observational study in 13 patients with dysthyroid optic neuropathy (group A) and in 14 patients with moderately severe GO (group B) who were treated with high-dose (group A) or low-dose (group B) IVMP; cumulative steroid doses were 8.45 g in group A and 4.5 g in group B, and follow-up time was 24 weeks. MAIN OUTCOME: Slight increases in serum aminotransferases (in alanine aminotransferase [ALAT] more than in aspartate aminotransferase [ASAT]) were observed, in seven patients exceeding the upper normal limit of 40 U/L. These changes were more prominent in group A than in group B as was also evident from a decrease in ASAT/ALAT ratio in group A but not in group B. Changes in serum aminotransferases occurred especially in the first 6 weeks of IVMP, becoming smaller thereafter with the decrease in steroid dosage. Pretreatment liver steatosis or diabetes were not related to liver damage, but preexistent viral hepatitis was. CONCLUSION: IVMP in GO patients causes dose-dependent liver damage by a direct toxic effect of glucocorticoids on hepatocytes. Nevertheless, IVMP seems to be pretty safe if cumulative doses exceeding 8 g are avoided and liver function is checked before and at regular intervals during pulse therapy.     

Comparative study of 3 therapeutic methods for Pouteau Colles' fracture. Apropos of 97 cases

Results of three therapeutic modalities used for the treatment of a homogeneous series of patients with a Pouteau Colles fracture are analyzed. Orthopedic treatment provided deceiving results. Pinning was, on the contrary, very effective, intrafocal pinning with immediate mobilization of the wrist appearing perfectly effective. Few complications were reported in contrast to plastered immobilizations. Good results were obtained in 80% of cases and functional recovery was rapid, indicating that this method represents undoubted progress when compared with conventional therapies.     

In vitro cytotoxicity of a remineralizing resin-based calcium phosphate cement.

Recently, a resin-based calcium phosphate cement (RCPC) has been reported as a remineralizing pulp-capping or lining cement. RCPC consists mainly of tetracalcium and dicalcium phosphates, ethoxylated bisphenol A dimethacrylate and pyromellitic glycerol dimethacrylate monomers and photo- and chemical initiators. OBJECTIVES: Here, the cytotoxic effects of RCPC were evaluated. The hypothesis was that RCPC induced only minor cytotoxic response in immortalized murine odontoblast and pulp cells, comparable to that produced by similar dimethacrylates due to unpolymerized dimethacrylate monomer present after curing. METHODS: Cytotoxicity was determined following the changes in cell succinate dehydrogenase activity after 24 h exposure to the cement components and after a 24 h recovery period. A fourfold range of concentrations was tested of the monomers, the eluate of cured RCPC leached in Dulbecco's modified Eagle's medium, and crushed cured cement in dimethyl sulfoxide. RESULTS: The monomers themselves had cytotoxicities similar to those reported for other dimethacrylates, although they are significantly less toxic than Bis-GMA. Differential cell sensitivity was demonstrated, with the pulp cells having greater sensitivity to the unpolymerized monomer than the odontoblast-like cells. The leached components have cytotoxicity similar to that of the free monomers. The crushed material demonstrated no apparent cytotoxicity at the dilutions tested. SIGNIFICANCE: These data demonstrate that RCPC has an in vitro cytotoxicity that is comparable to other materials containing dimethacrylate monomers and suggest that the material may be suitable for use in dental restorations. The data also indicate that the pulp cells appear more sensitive to dimethacrylates than the odontoblasts.     

Surgical epicardial left ventricular lead versus coronary sinus lead placement in biventricular pacing.

OBJECTIVE: Biventricular pacing has demonstrated improvement in cardiac function in treating congestive heart failure (CHF). Two different operative strategies (coronary sinus vs. epicardial stimulation) for left ventricular (LV) pacing were compared. METHODS: Since April 1999, a total of 86 patients (pts, age: 63+/-10 years) with depressed systolic LV function (mean ejection fraction 24+/-9%), left bundle-branch-block (mean QRS 182+/-22 ms) and congestive heart failure NYHA III or higher were enrolled. For biventricular stimulation coronary sinus (CS) leads were placed in 79 pts. Nine of these devices were converted to surgical epicardial LV-leads, because of CS-lead failure. In 7 patients epicardial LV-leads were initially implanted surgically, accounting for a total of 16 pts with surgical placed epicardial steroid-eluting LV-leads. For these, a limited left-lateral thoracotomy (7+/-4 cm) was used. Thirty-three (38%) pts had an indication for a defibrillator. The mean follow-up time was 16.4+/-15.4 months (0.1-45 months), representing 107.1 patient-years. RESULTS: In the biventricular pacing mode, QRS duration decreased to 143+/-16 ms (P<0.001). Threshold capture of the CS-leads increased significantly compared to surgically placed epicardial leads (18 month control: 2.2+/-1.4V/0.5 ms vs. 0.7+/-0.3V/0.5 ms), which had no increase in threshold (P<0.001). At the 18 month follow-up 7 CS-leads had a threshold of >4V/0.5 ms vs. epicardial leads which were under 1.1V/0.5 ms, except for one (1.8V/0.5 ms). After CS-lead implantation 25 LV-lead related complications occurred, (failed implantation, CS-dissection, loss of pacing capture, diaphragm stimulation or lead dislodgment), vs. one dislodgement after surgical epicardial lead placement (P<0.05). Correct lead positioning (obtuse marginal branch area) was achieved in all surgical epicardial placements but only in 70% with CS-leads (P<0.03). In the follow up period, 9 pts died (4 cardiac related). Heart transplantation was necessary in 4 pts due to deterioration of the cardiomyopathy. CONCLUSIONS: Surgical epicardial lead placement revealed excellent long-term results and a lower LV-related complication rate compared to CS-leads. Although, the approach via limited thoracotomy for biventricular pacing is associated with 'more surgery', it is a safe and reliable technique and should be considered as an equal alternative.