High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.     

Association of Roadway Proximity with Fasting Plasma Glucose and Metabolic Risk Factors for Cardiovascular Disease in a Cross-Sectional Study of Cardiac Catheterization Patients

Background

The relationship between traffic-related air pollution (TRAP) and risk factors for cardiovascular disease needs to be better understood in order to address the adverse impact of air pollution on human health.

Objective

We examined associations between roadway proximity and traffic exposure zones, as markers of TRAP exposure, and metabolic biomarkers for cardiovascular disease risk in a cohort of patients undergoing cardiac catheterization.

Methods

We performed a cross-sectional study of 2,124 individuals residing in North Carolina (USA). Roadway proximity was assessed via distance to primary and secondary roadways, and we used residence in traffic exposure zones (TEZs) as a proxy for TRAP. Two categories of metabolic outcomes were studied: measures associated with glucose control, and measures associated with lipid metabolism. Statistical models were adjusted for race, sex, smoking, body mass index, and socioeconomic status (SES).

Results

An interquartile-range (990 m) decrease in distance to roadways was associated with higher fasting plasma glucose (β = 2.17 mg/dL; 95% CI: –0.24, 4.59), and the association appeared to be limited to women (β = 5.16 mg/dL; 95% CI: 1.48, 8.84 compared with β = 0.14 mg/dL; 95% CI: –3.04, 3.33 in men). Residence in TEZ 5 (high-speed traffic) and TEZ 6 (stop-and-go traffic), the two traffic zones assumed to have the highest levels of TRAP, was positively associated with high-density lipoprotein cholesterol (HDL-C; β = 8.36; 95% CI: –0.15, 16.9 and β = 5.98; 95% CI: –3.96, 15.9, for TEZ 5 and 6, respectively).

Conclusion

Proxy measures of TRAP exposure were associated with intermediate metabolic traits associated with cardiovascular disease, including fasting plasma glucose and possibly HDL-C.

Citation

Ward-Caviness CK, Kraus WE, Blach C, Haynes CS, Dowdy E, Miranda ML, Devlin RB, Diaz-Sanchez D, Cascio WE, Mukerjee S, Stallings C, Smith LA, Gregory SG, Shah SH, Hauser ER, Neas LM. 2015. Association of roadway proximity with fasting plasma glucose and metabolic risk factors for cardiovascular disease in a cross-sectional study of cardiac catheterization patients. Environ Health Perspect 123:1007–1014; http://dx.doi.org/10.1289/ehp.1306980     

Effects of beta 1-selective and nonselective beta-adrenoceptor blockade during exercise conditioning in healthy adults

The interaction of beta 1-selective (cardioselective) and nonselective beta-adrenoceptor blockade with exercise conditioning was investigated in 30 healthy adult persons. A double-blind protocol was used and the effects of atenolol (100 mg/day), propranolol (80 mg twice daily), and placebo were studied by treadmill testing (Bruce protocol) before and after a 2-month supervised program of dynamic exercise. Exercise tolerance was assessed by time and work performed to exhaustion. Subjects who received propranolol, but not those who received atenolol or placebo, showed an acutely impaired exercise tolerance after drug administration but before training (-8 +/- 4%, p less than 0.05). All 3 groups showed significantly improved exercise capacity following training after drug treatment had been discontinued (atenolol, 22 +/- 6% improvement; propranolol, 13 +/- 6%; placebo, 10 +/- 3%). However, when tested while still receiving medication, subjects who received propranolol failed to show significant improvement in exercise capacity. In contrast, patients who received atenolol and placebo improved significantly. The data indicate that enhancement of maximal work capacity by exercise conditioning can occur despite administration of either beta 1-selective or nonselective beta-adrenoceptor antagonists. However, the fatiguing effects of propranolol that were evident when work performance during propranolol therapy was compared with work performance while not receiving propranolol before the training program persists after training and may limit the net improvement in work capacity induced by exercise conditioning compared with the pretraining state.     

Consensus-recommendations for sirolimus in liver transplantation

Sirolimus is an m-TOR inhibitor without renal side effects and potentially protects against the development of malignancy. Due to a higher incidence of complications in two trials and an official warning in the drug information, the use of Sirolimus in liver transplantation is limited. The participants of this consensus meeting had to analyse and evaluate the literature with respect to the potential role of Sirolimus in liver transplantation. This consensus statement follows the scheme normally employed for the presentation of guidelines including the grading of evidence (1a-5) and the extent of recommendation (A-C). Moreover, the consensus included the experience of the authors with respect to the handling of Sirolimus after liver transplantation.     

Decreased frequency of HLA-B35 in patients with gastric MALT lymphoma

Persistent infection with Helicobacter pylori has been shown to be strongly associated with the development of low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, the prevalence of H. pylori infection exceeds the incidence of MALT lymphoma by far. This discrepancy might at least partially be explained on a genomic basis of the host. To evaluate the association between HLA type and MALT lymphoma, we investigated 46 patients with MALT lymphoma recruited in a prospective multicenter study from October 1998 to March 2001. Over 13,000 voluntary stem cell donors from over 40 German blood banks represented the control group. Exploratory statistical analysis using Fishers exact test showed significantly decreased frequency of HLA-B35 in the MALT lymphoma group compared to the control group. Our data suggest a negative association between HLA-B35 and MALT lymphoma; however, larger studies are necessary to confirm a protective role of this HLA antigen.     

Chronic upper abdominal pain without improvement after using proton pump inhibitors

HISTORY AND CLINICAL FINDINGS: A 57-year-old woman was admitted to our hospital because of relapsing, therapy-resistant pain, predominantly in the upper abdomen. The symptoms began 6 years previously, after a resection of parts of the small intestine for an ileus of unclear cause. Subsequently 11 (!) gastroscopies showed repeatedly gastritis and Helicobacter pylori- negative gastric and/or small intestinal ulcers which were treated with proton pump inhibitors. This led to no significant improvement of the complaints and produced no healing. DIAGNOSTIC FINDINGS AND THERAPY: Gastroscopy showed, at the transition of the gastric fundus to the corpus, an area with multiple, fibrin coated ulcers. Histologically an active, chronic gastric ulcer was seen, with perifocally dense inflammatory infiltration by predominantly eosinophils. In the colon these histological findings, although clearly less pronouncedly, were also seen i.e. an eosinophilic gastroenteropathy. This was initially treated with 60 mg/day prednisone. Under this treatment she became completely symptom-free. After a dose reduction to 5 mg prednisone daily the symptoms occurred again. Thereupon long-term immunosuppressive therapy with 100 mg azathioprine daily was introduced. Regular clinical and endoscopic monitoring showed a complete remission of the ulcers and no complaints after 1.5 years. CONCLUSION: Our case report shows that in patients with uncharacteristic abdominal pain and gastric ulcers, which improve inadequately under the usual medication such as proton pump inhibitors, less common illnesses must be considered. Despite the rarity of eosinophilic gastroenteropathy the exact (histological) diagnosis plays an important role, because a specific therapy with corticosteroids and/or azathioprine can induce improvement of the symptoms.