Retrospective evaluation of sodium acetate use for urine alkalinization in patients receiving high dose methotrexate.

PURPOSE: Methotrexate is an antifolate agent used in treatment of several malignancies. Many toxicities accompany methotrexate that are minimized with urine alkalinization. Parenteral sodium bicarbonate is the historical standard alkalinizing agent, but use has been limited by intermittent shortages. However, intravenous sodium acetate may be considered as a chemically equivalent alternative. The primary objective of this study is to determine the efficacy of sodium acetate versus sodium bicarbonate for urine alkalinization for high-dose methotrexate (HDMTX). METHODS: This is a retrospective cohort study including adults admitted to Barnes-Jewish Hospital to receive HDMTX for lymphoma, breast cancer with leptomeningial spread, or osteosarcoma. Patients must have received intravenous sodium acetate or sodium bicarbonate alkalinization. RESULTS: Of 192 HDMTX encounters, 154 (sodium bicarbonate, n = 86; sodium acetate, n = 68) were evaluated for efficacy and safety. Safety outcomes were not significantly different between groups except for higher peak methotrexate level in the bicarbonate group (2.9 mcmol/L vs. 1.7 mcmol/L, p = 0.023), and increased incidence of grade 3-4 ALT in the sodium bicarbonate group (23.5% vs. 9%, p = 0.02). Time from alkalinizer initiation to pH ≥7 was significantly shorter with sodium bicarbonate (4 vs. 5.15 h, p = 0.021). Nonetheless, outcomes such as length of stay (4.4 vs. 4 days respectively, p = 0.037) and time to methotrexate clearance (3.6 vs. 3.2 days respectively, p = 0.023) reveal that inpatient time was shorter with sodium acetate overall. CONCLUSION: This retrospective analysis suggests that sodium acetate has similar efficacy and safety to sodium bicarbonate for alkalinization and may be considered as an alternative in future shortage situations.

High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis.

High-dose methotrexate (HDMTX), defined by doses of methotrexate (MTX) ≥ 1 g/m(2), is a widely used regimen known to cause renal toxicity. The reported incidence of renal toxicity in patients with osteosarcoma is 1.8%, but the incidence in hematologic malignancies is not well characterized. In this retrospective study of 649 cycles of HDMTX in 194 patients, renal toxicity occurred in 9.1% of cycles in patients with lymphoma compared to 1.5% in patients with sarcoma. Older age, male sex, decreased baseline creatinine clearance (CrCl) and increased proton pump inhibitor use among the lymphoma population likely contributed to the observed difference. The incidence of renal toxicity was independent of the incidence of delayed MTX elimination, suggesting that kidney function is only one factor involved in MTX clearance. Renal toxicity prolonged the duration of hospitalization but severe renal insufficiency was uncommon. No significant impact on progression-free or overall survival was observed.

Comparative evaluation of single fixed dosing and weight-based dosing of rasburicase for tumor lysis syndrome.

STUDY OBJECTIVE: To evaluate single fixed dosing versus weight-based dosing strategies for rasburicase to determine the minimum dose required to mitigate hyperuricemia in the treatment or prevention of tumor lysis syndrome. DESIGN: Retrospective medical record review SETTING: Academic medical center PATIENTS: A total of 373 patients with a diagnosis of a hematologic malignancy or solid tumor and who received at least one dose of rasburicase over a 6-year period between January 1, 2005, and February 18, 2011; 180 patients received single doses of 3 mg (38 patients), 6 mg (99 patients), or 7.5 mg (43 patients), and 193 patients received weight-based dosing. MEASUREMENTS AND MAIN RESULTS: Tumor lysis syndrome laboratory data were recorded at baseline and monitored up to 72 hours after initial rasburicase administration. Median baseline plasma uric acid levels were 6.85 mg/dl, 8.80 mg/dl, 8.00 mg/dl, and 9.20 mg/dl, respectively, in the 3-mg, 6-mg, 7.5-mg, and weight-based dosing groups. Treatment success was defined as a normalized plasma uric acid level (< 7.5 mg/dl) within 24 hours after receiving rasburicase. The mean weight-based dose was 0.16 mg/kg. Six rasburicase treatment failures occurred; two were in the 3-mg group, one was in the 6-mg group, and three were in the weight-based dosing group. At 24 hours after rasburicase administration, no statistically significant differences in treatment success were noted among groups (92.9% vs 97.6% vs 100.0% vs 98.0% in the 3-mg, 6-mg, 7.5-mg, and weight-based dosing groups, respectively, p=0.1238). CONCLUSION: The efficacy of all single fixed doses and weight-based dosing strategies evaluated in this study appear to be comparable in normalizing plasma uric acid levels within 24 hours of rasburicase administration. Although use of a 3-mg rasburicase dose may be the most cost-effective treatment strategy in managing hyperuricemia secondary to tumor lysis syndrome, the 6-mg dose resulted in lower sustained uric acid levels after rasburicase administration. Further analysis of patient specific factors contributing to the need for repeat rasburicase administration should be conducted in larger, prospective clinical trials.

Mechanism of anemia in Schistosoma mansoni-infected school children in Western Kenya.

A better understanding of the mechanism of anemia associated with Schistosoma mansoni infection might provide useful information on how treatment programs are implemented to minimize schistosomiasis-associated morbidity and maximize treatment impact. We used a cross-sectional study with serum samples from 206 Kenyan school children to determine the mechanisms in S. mansoni-associated anemia. Serum ferritin and soluble transferrin receptor levels were measured by using an enzyme-linked immunosorbent assay. Results suggest that S. mansoni-infected persons are more likely (odds ratio = 3.68, 95% confidence interval = 1.33-10.1) to have levels of serum ferritin (> 100 ng/mL) that are associated with anemia of inflammation (AI) than S. mansoni-uninfected children. Our results suggest that AI is the most common form of anemia in S. mansoni infections. In contrast, the mechanism of anemia in S. mansoni-uninfected children was iron deficiency. Moreover, the prevalence of AI in the study participants demonstrated a significant trend with S. mansoni infection intensity (P < 0.001). Our results are consistent with those observed in S. japonicum-associated anemia.

Eribulin mesylate: a novel halichondrin B analogue for the treatment of metastatic breast cancer.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, and administration of eribulin in patients with metastatic breast cancer are reviewed. SUMMARY: Classical chemotherapeutic agents for breast cancer have dominated treatment regimens even in the era of targeted therapy. Disease progression through these agents is often due to the development of resistance or lack of efficacy with these agents. Recently, a new nontaxane agent, eribulin mesylate, was approved for the treatment of metastatic breast cancer in patients who have received at least two prior chemotherapeutic agents. Eribulin is a member of a new class of synthetic cytotoxic agents derived from the Japanese sea sponge Halichondria okadai. Eribulin differs from other antimicrotubule agents in that it can bind to the microtubule cap and inhibit tubulin polymerization, leading to microtubule arrest. In Phase II clinical trials, eribulin demonstrated activity in extensively pretreated patients who had previously received an anthracycline, taxane, and capecitabine and had shown disease progression within the last six months of treatment. In a pivotal Phase III clinical trial of heavily pre-treated patients, patients who received eribulin versus the physician's treatment of choice showed a significant increase in overall and progression-free survival. Eribulin has a manageable adverse-effect profile, consisting mainly of neutropenia and fatigue. Eribulin has been associated with a low incidence of peripheral neuropathy. CONCLUSION: Eribulin, a novel synthetic antimicrotubule agent that binds to the vinca domain of tubulin and inhibits the polymerization of tubulin, offers a new treatment option for metastatic breast cancer or locally advanced breast cancer.

Schistosomiasis among young children in Usoma, Kenya.

Although schistosomiasis burden is greatest among school-age children (SAC) (6-15 years of age), infection among preschool-age children (PSAC) (1-5 years), may be underestimated in endemic areas. We conducted a cross-sectional study evaluating Schistosoma mansoni infection among children 1-15 years of age in a highly endemic community in Kenya. Diagnostic tests included stool exam (Kato/Katz technique), serum testing for schistosome-specific antibodies, and urine testing for circulating cathodic antigen (CCA). Overall, 268 SAC and 216 PSAC were enrolled; prevalence increased with age, with 14% of 1 year olds and more than 90% of children > 10 years of age infected. Stool exam was more sensitive among SAC than PSAC, but performance was similar after adjusting for infection intensity (based on CCA). Schistosomiasis poses a threat to PSAC in endemic areas, and stool exam may underestimate the prevalence of infection. Control programs in such areas should consider PSAC in addition to SAC.

Evaluation of urine CCA assays for detection of Schistosoma mansoni infection in Western Kenya.

Although accurate assessment of the prevalence of Schistosoma mansoni is important for the design and evaluation of control programs, the most widely used tools for diagnosis are limited by suboptimal sensitivity, slow turn-around-time, or inability to distinguish current from former infections. Recently, two tests that detect circulating cathodic antigen (CCA) in urine of patients with schistosomiasis became commercially available. As part of a larger study on schistosomiasis prevalence in young children, we evaluated the performance and diagnostic accuracy of these tests--the carbon test strip designed for use in the laboratory and the cassette format test intended for field use. In comparison to 6 Kato-Katz exams, the carbon and cassette CCA tests had sensitivities of 88.4% and 94.2% and specificities of 70.9% and 59.4%, respectively. However, because of the known limitations of the Kato-Katz assay, we also utilized latent class analysis (LCA) incorporating the CCA, Kato-Katz, and schistosome-specific antibody results to determine their sensitivities and specificities. The laboratory-based CCA test had a sensitivity of 91.7% and a specificity of 89.4% by LCA while the cassette test had a sensitivity of 96.3% and a specificity of 74.7%. The intensity of the reaction in both urine CCA tests reflected stool egg burden and their performance was not affected by the presence of soil transmitted helminth infections. Our results suggest that urine-based assays for CCA may be valuable in screening for S. mansoni infections.

Summary of presentations from the 46th annual meeting of the American Society of Clinical Oncology (2010): focus on supportive care issues related to lung cancer.

BACKGROUND: Patients with advanced cancer, particularly of the lung, frequently experience deteriorating physical health. Supportive care measures help ensure optimal quality of life during difficult psychologic and social situations. Research in the area of supportive care in patients with cancer should be made a priority. METHODS: This review summarizes the findings from selected supportive care studies presented at the recently concluded 46 annual meeting of the American Society of Clinical Oncology. DISCUSSION: Topics discussed include the use of a single dose of fosaprepitant for prevention of chemotherapy-induced nausea and vomiting, statins to lower the incidence of venous thromboembolic events, fentanyl pectin nasal spray for cancer-related pain, and a closer look at the utilization of complementary and alternative medicine in patients with cancer.

Mycoplasma hominis infection of Trichomonas vaginalis is not associated with metronidazole-resistant trichomoniasis in clinical isolates from the United States.

Trichomonas vaginalis is a protozoan parasite that is the cause of the most common non-viral sexually transmitted disease, trichomoniasis. Metronidazole and tinidazole are the only drugs approved for treatment of T. vaginalis infections in the USA. However, drug resistance exists and some patients are allergic to these medications. Furthermore, the exact mechanism of metronidazole resistance remains undefined and current testing methods require several weeks before results are available. Identification of the mechanism of drug resistance may lead to the development of molecular tools to detect drug resistance, and quicker results for clinical treatment. In a recent study, Chinese T. vaginalis isolates that were polymerase chain reaction (PCR) positive for Mycoplasma hominis DNA demonstrated greater in vitro resistance to metronidazole than isolates with no evidence of M. hominis infection. To evaluate this finding in isolates from a distinct epidemiologic setting, we tested 55 T. vaginalis isolates collected from patients in the USA through the Centers for Disease Control and Prevention metronidazole susceptibility testing service. One half of the isolates demonstrated resistance to metronidazole by an in vitro sensitivity assay. Of the metronidazole-resistant T. vaginalis isolates, 18% were PCR positive for M. hominis, as were 22% of the metronidazole-susceptible T. vaginalis isolates (p = 0.746). We also observed no change in metronidazole sensitivity of two infected T. vaginalis isolates after they were cleared of their M. hominis infection by culturing the isolates in antibiotics. Thus, M. hominis infection of USA T. vaginalis isolates did not correlate with in vitro resistance to metronidazole.

Transcription of the LAT gene is regulated by multiple binding sites for Sp1 and Sp3.

The LAT gene encodes an adaptor molecule that links receptor engagement to critical downstream signaling events. Previously, we identified the proximal promoter for the human LAT gene and found that it contains binding sites for members of the Ets and Runx transcription factor families. In the present study, we show that the promoter also contains 5 GC-rich elements that contribute to promoter activity and that are capable of binding the transcription factors Sp1 and Sp3. Overexpression of either Sp1 or full-length Sp3 was shown to augment LAT promoter activity, while siRNA-mediated knockdown of each transcription factor was demonstrated to have an inhibitory effect. We also discovered a cell-type specific DNase hypersensitive site that maps to the Sp1/Sp3 and adjacent Ets and Runx binding sites. Collectively, these results provide compelling data that implicates Sp1 and Sp3 in the transcriptional regulation of the human LAT gene.