Response to pneumococcal vaccine in patients with early rheumatoid arthritis receiving infliximab plus methotrexate or methotrexate alone

OBJECTIVE: We assessed whether the addition of anti-tumor necrosis factor (TNF) agent to methotrexate (MTX) therapy might alter the response of patients with rheumatoid arthritis (RA) to pneumococcal vaccination. METHODS: Seventy patients with early RA (n = 20, 36, and 14 in the infliximab 3 mg/kg plus MTX, infliximab 6 mg/kg plus MTX, and placebo plus MTX groups, respectively) were included in an analysis of patients enrolled in an ASPIRE substudy. Patients received 0.5 ml pneumococcal vaccine (Pneumovax) 34 weeks after initiation of study treatment; patient sera were collected 4 weeks later (week 38). Antibody responses were tested using enzyme immunoassay methods for reactivity to a panel of 12 serotypes of the pneumococcal vaccine. RESULTS: No significant difference in response to Pneumovax was observed between the infliximab plus MTX and placebo plus MTX groups. Roughly 80%-85% of patients responded to at least one serotype; however, only 20%-25% of patients in the different treatment groups responded to at least 6 different serotypes. Comparable proportions of patients in the 3 treatment groups responded to an increasing number (> or = 1 to > or = 6) of different serotypes. Patients < 45 years of age and those receiving oral corticosteroids generally appeared to respond better than those age 45 to 65 years and those not receiving oral corticosteroids. CONCLUSION: All treatment groups in this study had lower responses to vaccine than would be expected in the normal population. However, the addition of the anti-TNF agent infliximab to MTX therapy did not appear to affect the response of patients with RA to pneumococcal vaccination.     

Multiple fourth ventricular hydatidosis

Hydatid disease caused by ingestion of eggs of the cestode Echinococcus granulosus is endemic in the Middle East, Mediterranean countries, South America, North Africa and Australia.¹ Infratentorial occurrence of hydatid cyst is rare. We present a report of an extremely rare case of multiple exclusive fourth ventricular hydatid cysts, both primary and secondary, and discuss problems with the diagnosis and management of this condition.     

Plasma C5 glucose-to-2H2O ratio does not provide an accurate assessment of gluconeogenesis during hyperinsulinemic-euglycemic clamps in either nondiabetic or diabetic humans

OBJECTIVE—Measurement of plasma C2 glucose enrichment is cumbersome. Therefore, the plasma C5 glucose–to–²H₂O rather than the plasma C5-to-C2 glucose ratio commonly has been used to measure gluconeogenesis and glycogenolysis during hyperinsulinemic-euglycemic clamps. The validity of this approach is unknown.RESEARCH DESIGN AND METHODS—Ten nondiabetic and 10 diabetic subjects ingested ²H₂O the evening before study. The following morning, insulin was infused at a rate of 0.6 mU · kg⁻¹ · min⁻¹ and glucose was clamped at ∼5.3 mmol/l for 5 h. Plasma C5 glucose, C2 glucose, and ²H₂O enrichments were measured hourly from 2 h onward.RESULTS—Plasma C2 glucose and plasma ²H₂O enrichment were equal in both groups before the clamp, resulting in equivalent estimates of gluconeogenesis and glycogenolysis. In contrast, plasma C2 glucose and plasma C5 glucose enrichments fell throughout the clamp, whereas plasma ²H₂O enrichment remained unchanged. Since the C5 glucose concentration and, hence, the C5 glucose–to–²H₂O ratio is influenced by both gluconeogenesis and glucose clearance, whereas the C5-to-C2 glucose ratio is only influenced by gluconeogenesis, the C5 glucose–to–²H₂O ratio overestimated (P < 0.01) gluconeogenesis during the clamp. This resulted in biologically implausible negative (i.e., calculated rates of gluconeogenesis exceeding total endogenous glucose production) rates of glycogenolysis in both the nondiabetic and diabetic subjects.CONCLUSIONS—Plasma C5 glucose–to–²H₂O ratio does not provide an accurate assessment of gluconeogenesis in nondiabetic or diabetic subjects during a traditional (i.e., 2–3 h) hyperinsulinemic-euglycemic clamp. The conclusions of studies that have used this approach need to be reevaluated.Measurement of gluconeogenesis in humans is difficult. The deuterated water method is widely used for this purpose (1–17). This method relies on the fact that the fifth carbon of glucose is labeled during gluconeogenesis, whereas the second carbon of glucose is labeled with deuterium during equilibration of glucose-6-phosphate and fructose-6-phoshate (1,2). Therefore, at steady state, the ratio of plasma glucose with deuterium on the fifth carbon (C5 glucose) to plasma glucose labeled on the second carbon (C2 glucose) equals the percentage of plasma glucose derived from gluconeogenesis (1,2). Measurement of C2 glucose enrichment is cumbersome. Since ²H₂O and C2 glucose enrichments are equal at steady state, many investigators have used the plasma C5 glucose–to–²H₂O ratio to calculate gluconeogenesis after an overnight fast (4–7,9–12,18). The C5 glucose–to–²H₂O ratio has also been used to measure gluconeogenesis during glucose clamps (4,6,7,11,12,18). However, the validity of this approach is uncertain. We have reported that the rate of gluconeogenesis measured during the final hour of a 3-h hyperinsulinemic-euglycemic clamp in lean nondiabetic subjects using the C5-to-C2 glucose ratio correlated with that measured in the same subjects using the C5 glucose–to–²H₂O ratio (7). However, in those as well as other glucose clamp experiments (4,6,7,11,12,18), gluconeogenesis calculated using the C5 glucose–to–²H₂O ratio commonly exceeded total endogenous glucose production. Since endogenous glucose production equals the sum of glucose derived via gluconeogenesis and glycogenolysis, this result was biologically implausible.Plasma C5 glucose concentrations are determined both by the rate of appearance of C5 glucose into and the rate of disappearance of C5 glucose from the plasma pool. Therefore, the use of the C5 glucose–to–²H₂O ratio during a clamp is only accurate when C5 glucose has achieved a new steady state. Since hyperinsulinemic clamps typically are relatively short (e.g., 2–3 h) and the glucose pool large, we became concerned that plasma C5 glucose concentration was artificially elevated because the clearance was not sufficiently rapid for C5 glucose concentration to have reachieved a steady state at a lower concentration. If so, this would be particularly problematic when the C5 glucose–to–plasma ²H₂O ratio was used to assess gluconeogenesis in groups in whom insulin action, and therefore glucose clearance, differed. The present experiments addressed this question by measuring both plasma C5-to-C2 glucose and the C5 glucose–to–²H₂O ratios in diabetic and nondiabetic subjects before and every hour from 2 h onward during a 5-h hyperinsulinemic-euglycemic clamp.     

Gallbladder Cancer: Defining the Indications for Primary Radical Resection and Radical Re-resection

Background The role of radical resection for gallbladder cancer is an ongoing area of debate. In this review, we present our experience managing gallbladder cancer at a tertiary center by using an aggressive surgical approach for T2 or greater disease, reserving simple cholecystectomy only for T1 lesions. Methods Seventy-six patients with histologically confirmed gallbladder cancer were identified from our cancer registry. Estimated survival distributions were calculated by the Kaplan-Meier method, and comparisons were made by using the log-rank test. The Cox proportional hazards model was used to determine the effect on survival of T stage, nodal status, age, and margins. Results Sixty-four patients were assessable for this study. Simple cholecystectomy was the only procedure performed in 10 T2 and 15 T3 cases. Radical cholecystectomy was performed as the primary procedure in two T2, two T3, and six T4 cases. Radical re-resection was accomplished in seven T2 and two T3 cases. Excluding the T4 group, there was a significant survival advantage (P = .007) for the radical resection group (n = 13; median survival not yet reached) compared with the simple cholecystectomy group (n = 25; median survival, 17 months; 95% confidence interval, 7–27 months). Analysis of the 13 T2 and T3 patients who underwent radical resections revealed that the radical re-resection group (n = 9) had an overall survival similar to that of the primarily resected group (n = 4). All T2N⁺ and T3N⁻ patients are still alive and disease free after 5 years of follow-up, whereas none of the T3N⁺ or T4 patients survived beyond 24 months. Increasing T stage and age (>65 years) were independent predictors of a poor prognosis. Conclusions Radical resection for T2 and T3 disease resulted in a significant survival advantage compared with simple cholecystectomy. Patients who undergo radical re-resection after an incidentally discovered gallbladder cancer experience the same survival benefit as primarily resected patients. Radical resection for T2N⁻, T2N⁺, and T3N0 cases can achieve long-term survival. Conversely, the prognosis for T3N⁺ and T4 patients is poor, and improved outcome for this group will likely depend on the development of multi-institutional neoadjuvant clinical trials that can identify effective systemic regimens. Presented at the 58th Annual Meeting of the Society of Surgical Oncology, Atlanta, Georgia, March 3–6, 2005.     

Nonsteroidal anti-inflammatory drugs and the risk of developing breast cancer in a population-based prospective cohort study in Washington County, MD

The objective of this study was to examine the association between nonsteroidal anti-inflammatory drug (NSAID) use and the development of breast cancer, and to assess whether this association differed by estrogen receptor (ER) subtype. Data were analyzed from 15,651 women participating in CLUE II, a cohort study initiated in 1989 in Washington County, MD. Medication data were collected at baseline in 1989 and in 1996. Incident cases of invasive breast cancer occurring from baseline to March 27, 2006 were identified through linkage of cohort participants with the Washington County Cancer Registry and the Maryland State Cancer Registry. Cox proportional hazards modeling was used to calculate the risk ratios (RR) and 95% confidence intervals (95% CI) for breast cancer associated with medication use. Among women in the CLUE II cohort, 418 invasive breast cancer cases were identified during the follow-up period. The results showed that self-reported use of NSAIDs in both 1989 and in 1996 was associated with a 50% reduction in the risk of developing invasive breast cancer compared with no NSAID use in either 1989 or 1996 (RR = 0.50; 95% CI 0.28, 0.91). The protective association between NSAID use and the risk of developing breast cancer was consistent among ER-positive and ER-negative breast cancers, although only the RR for ER-positive breast cancer was statistically significant. Overall, findings from this study indicate that NSAID use is associated with a decrease in breast cancer risk and that the reduction in risk is similar for ER-positive and ER-negative tumors.