A phase II study of thioTEPA in children with recurrent solid tumor malignancies: a Children's Cancer Group study

Summary A Phase II study of thioTEPA was performed by the Children's Cancer Group. ThioTEPA was administered intravenously every three weeks, at a dose of 65 mg/m². Pediatric patients with recurrent sarcomas were targeted, but patients with other tumor diagnoses were also eligible. Toxicity was primarily hematopoietic, with thrombocytopenia being predominant. ThioTEPA did not demonstrate significant activity in the target tumor groups evaluated.     

HLA‐A*24:02 is associated with metronidazole‐induced cutaneous adverse drug reactions in Han Chinese individuals: A pilot case‐control study with both HLA gene and T cell receptor repertoire analysis

Metronidazole, a widely used drug for the treatment of infections with anaerobic and facultative anaerobic bacteria and protozoa, can frequently cause metronidazole‐induced cutaneous adverse reactions (McADRs). The aim of the present study was to investigate the association between human leucocyte antigen (HLA) alleles and McADRs in a Chinese Han population. The frequency of HLA‐B*24:02 carriers among the McADR patients was 73.3%, which was significantly higher than that of the population controls (32.16%, OR = 5.80, 95% CI = [1.80‐18.72], Pc = 0.004) and of the metronidazole‐tolerant patients (26.67%, OR = 7.56, 95% CI = [2.02‐28.35], Pc = 0.004). Molecular docking showed that metronidazole and one of its major metabolites had the potential to bind in the HLA groove and that there was a relatively stable binding state of the HLA‐B*24:02‐metronidazole/the metabolite complex. The CDR3 repertoires of both T cell receptor (TCR)Vα and Vβ of the patients showed a significantly skewed or an oligoclonal distribution. The TCRVβ CDR3 of the patients shared a similar motif, “CASSxxxxxxQxF.” The current study demonstrated that both the HLA‐A*24:02 allele and TCR are involved in the pathogenesis of McADRs.     

Phase I escalation of gemcitabine combined with protracted oral etoposide in gynecologic malignancies: A Gynecologic Oncology Group study

Objective: Although improvementshave been made in the management ofpatients with advanced ovarian cancer,long-term survivors are still uncommon. Gemcitabine and prolonged oral etoposidehave shown reproducible single-agentactivity in patients withplatinum/paclitaxel-resistant ovariancancer. This, combined with preclinicalsynergism, prompted the GynecologicOncology Group to determine the maximumtolerated dose (MTD) of this combination. Methods: Eligible patients hadrecurrent epithelial ovarian cancer,primary papillary peritoneal, or fallopiantube carcinoma. All had received priorplatinum/paclitaxel-based chemotherapy andhad adequate hepatic, renal and bone marrowfunction. Oral etoposide was administeredat 50 mg/m² for ten days, with threeproposed dose levels for gemcitabine ondays 1 and 8: 400, 550 and 700 mg/m². Cycles were to be repeated every 28 days. Three patients were to enter at each doselevel. Results: Patients were enrolled onlyto dose level 1 as this dose exceeded MTD. Of six patients initially enrolled, one wasremoved after three days with fever,ascites and decreased albumin believed notto be treatment related. Five patientswere evaluable for toxicity and response. One of the first three patients developeddose limiting toxicity (DLT) manifested asgrade 4 neutropenia. A second DLT(neutropenic fever and thrombocytopeniaassociated with bleeding) occurred amongthe next three patients; therefore, MTD wasreached at dose level 1. Grade 4toxicities included episodes of neutropenia(4) and thrombocytopenia (3). No objectiveresponse was observed. Conclusions: Oral etoposide andgemcitabine at this dose and schedule wasassociated with substantial toxicity inthis population. Patients who are previously treated withplatinum/paclitaxel-based chemotherapy maybe at particular risk for toxicity.     

Sub-antimicrobial doxycycline for periodontitis reduces hemoglobin A1c in subjects with type 2 diabetes: A pilot study

In vitro and animal studies suggest a possible role for the tetracycline class of drugs in the inhibition of non-enzymatic protein glycation. We conducted a 3-month, randomized placebo-controlled pilot clinical trial of conventional sub-gingival debridement (periodontal therapy), combined with either a three month regimen of sub-antimicrobial-dose doxycycline (SDD), a two week regimen of antimicrobial-dose doxycycline (ADD), or placebo in 45 patients with long-standing type 2 diabetes (mean duration 9 years) and untreated chronic periodontitis. Subjects were taking stable doses of oral hypoglycemic medications and/or insulin. Treatment response was assessed by measuring hemoglobin A1c (HbA1c), plasma glucose, and clinical periodontal disease measures. At one-month and three-month follow-up, clinical measures of periodontitis were decreased in all groups (data to be presented elsewhere). At three months, mean HbA1c levels in the SDD group were reduced 0.9% units from 7.2% units ± 2.2 (±SD), to 6.3% units ± 1.1, which represents a 12.5% improvement. In contrast, there was no significant change in HbA1c in the ADD (7.5% ± 2.0 to 7.8% ± 2.1) or placebo (8.5% ± 2.0 to 8.5% ± 2.6) groups. Mean HbA1c change from baseline was significantly greater in the SDD group compared with the ADD group (p = 0.04) but not placebo (p = 0.22). Moreover, a larger proportion of subjects in the SDD group experienced improvement (p < 0.05) compared to the ADD or placebo groups. Mean plasma glucose levels were not significantly different between or within the groups. The results of this pilot study suggest that the treatment of periodontitis with sub-gingival debridement and 3-months of daily sub-antimicrobial-dose doxycycline may decrease HbA1c in patients with type 2 diabetes taking normally prescribed hypoglycemic agents.     

A pilot study of plasma metabolomic patterns from patients treated with ketamine for bipolar depression: evidence for a response-related difference in mitochondrial networks

Background and Purpose

(R,S)-ketamine produces rapid and significant antidepressant effects in approximately 65% of patients suffering from treatment-resistant bipolar depression (BD). The genetic, pharmacological and biochemical differences between ketamine responders and non-responders have not been identified. The purpose of this study was to employ a metabolomics approach, a global, non-targeted determination of endogenous metabolic patterns, to identify potential markers of ketamine response and non-response.

Experimental Approach

Plasma samples from 22 BD patients were analyzed to produce metabolomic patterns. The patients had received ketamine in a placebo-controlled crossover study and the samples were obtained 230 min post-administration at which time the patients were categorized as responders or non-responders. Matching plasma samples from the placebo arm of the study were also analysed. During the study, the patients were maintained on either lithium or valproate.

Key Results

The metabolomic patterns were significantly different between the patients maintained on lithium and those maintained on valproate, irrespective of response to ketamine. In the patients maintained on lithium, 18 biomarkers were identified. In responders, lysophosphatidylethanolamines (4) and lysophosphatidylcholines (9) were increased relative to non-responders.

Conclusions and Implications

The results indicate that the differences between patients who respond to ketamine and those who do not are due to alterations in the mitochondrial β-oxidation of fatty acids. These differences were not produced by ketamine administration. The data indicate that pretreatment metabolomics screening may be a guide to the prediction of response and a potential approach to the individualization of ketamine therapy.

Linked Articles

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

A phase II pilot study of high-dose 24-hour continuous infusion of 5-FU and leucovorin and low-dose PALA for patients with colorectal cancer: A Southwest Oncology Group study

PURPOSE: The purpose of this phase II multi-institutional study was to define the efficacy and toxicity of infusional 5-FU in combination with PALA and leucovorin in patients with advanced colorectal cancer. PATIENTS AND METHODS: Patients were required to have histologically confirmed colorectal cancer with distant metastases. The treatment regimen consisted of 5-FU 2600 mg/m(2) as a 24-hours continuous infusion given once a week, concurrently with leucovorin (LV) at 500 mg/m(2) as a 24-hour continuous infusion. PALA was administered 24 hours prior to 5-FU/LV at a dose of 250 mg/m(2) iv over 15 minutes weekly. Patients were continued on the assigned treatment regimen until progression of disease, unacceptable toxicity, or the patient declined further therapy. RESULTS: This study accrued 28 patients and all were eligible and evaluable for toxicity. Four patients had inadequate assessment of response and are considered non-responders. There was one complete response and five partial responses for an overall response rate of 6/28 or 21% (95% confidence interval 8-41%). Estimated median survival was 17.4 months (95% confidence interval 13.3-20.5 months). One patient died of a treatment related infection. This patient also had grade 4 diarrhea and vomiting. CONCLUSION: The combination of 5-FU, leucovorin, and PALA in the doses and schedule used here, produces a response rate similar to other modulated schedules of 5-FU with similar survival and toxicity profiles.