A phase I study of oral uracil-tegafur prior to weekly intravenous gemcitabine in patients with advanced pancreatic cancer

BACKGROUND: Gemcitabine is widely accepted as the first-line agent for advanced pancreatic cancer. The antitumor cell activity of gemcitabine is higher when administered after 5-fluorouracil (5-FU) rather than before 5-FU in an in vitro study. The present study was conducted to define the maximum tolerated dose and dose-limiting toxicity associated with an oral fluoropyrimidine prodrug that combines uracil and tegafur (UFT), given prior to weekly intravenous gemcitabine in patients with advanced pancreatic cancer. METHODS: Over a 21-day cycle, gemcitabine was given intravenously over 30 min on days 8 and 15, while UFT was given orally from days 1 to 14. The dose of UFT used was 400 mg per day, given as two doses. The dose of gemcitabine was escalated in a stepwise fashion from 800 (level 1, n = 3) to 900 mg/m2 (level 2, n = 6) and then to 1,000 mg/m2 (level 3, n = 3), such that totally 12 patients received the combination chemotherapy. RESULTS: During the first cycle, grade 3 leukopenia was observed in 2 patients at dose level 1. Only 1 patient treated at dose level 2 experienced dose-limiting toxicity (grade 3 elevated transaminase), including additional patients treated at this dose level. No grade 3/4 toxicities occurred in patients treated at dose level 3. A significant response was observed in 1 out of 12 patients (8.3%). Seven patients (58.3%) had stable disease, while 4 patients (33.3%) showed disease progression. CONCLUSIONS: The combination chemotherapy of oral UFT and gemcitabine was convenient, well tolerated and may benefit patients with advanced pancreatic cancer. Doses recommended for further study of this schedule are gemcitabine 1,000 mg/m2 and UFT 400 mg/day.     

Quantitative T2 mapping of femoral head cartilage in systemic lupus erythematosus patients with noncollapsed osteonecrosis of the femoral head associated with corticosteroid therapy

Purpose:

To evaluate articular cartilage degeneration with transverse relaxation time (T2) mapping in systemic lupus erythematosus (SLE) patients with noncollapsed and asymptomatic osteonecrosis of the femoral head associated with corticosteroids.

Materials and Methods:

T2 mapping with a 1.5‐T magnetic resonance imaging system was prospectively performed for 28 normal hips from 14 healthy volunteers (control group) and 15 hips from 10 SLE patients that met the inclusion criteria of noncollapsed and asymptomatic osteonecrosis of the femoral head (osteonecrosis group). Exclusion criteria were past experience of pain, trauma, infection, or prior hip joint surgery. Distribution of T2 values of the femoral head cartilage were compared between the control group and the osteonecrosis group with respect to acetabular dysplasia by center‐edge angle (CEA).

Results:

T2 values of the femoral head cartilage were significantly higher in the osteonecrosis group than in the control group (34.4 msec vs. 30.8 msec, P = 0.001). Multiple regression analysis revealed that the osteonecrosis group and decreased CEA was significantly associated with high T2 values (T2 value = 34.6 + 3.6 × [osteonecrosis] ? 0.14 × CEA, R² = 0.52, P = 0.003).

Conclusion:

Degeneration of articular cartilage was associated with osteonecrosis of the femoral head in SLE patients and acetabular dysplasia. J. Magn. Reson. Imaging 2011;. © 2011 Wiley Periodicals, Inc.

     

Phase I study of taselisib in Japanese patients with advanced solid tumors or hormone receptor‐positive advanced breast cancer

Taselisib is a potent and selective phosphatidylinositide 3‐kinase (PI3K) inhibitor. The present article reports the first study of taselisib administration in Japanese patients. The aim of this 2‐stage, phase I, multicenter, open‐label, dose‐escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)‐positive locally advanced or recurrent breast cancer (stage 2). In stage 1, oral taselisib tablets 2, 4, and 6 mg/d were given in 28‐day cycles. In stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/d) with i.m. fulvestrant 500 mg. Nine and 6 patients were enrolled in stage 1 and stage 2, respectively. Taselisib was well tolerated. No dose‐limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment‐related adverse events in stage 1 and stage 2, respectively, were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), and stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after dosage; its half‐life was 12.9‐32.0 hours in stage 1 and 16.1‐26.5 hours in stage 2. Two patients achieved partial response (PR), 5 patients had stable disease (SD) and 2 patients had progressive disease (PD) in stage 1, and 1 patient had PR and 3 patients had SD in stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA‐mutated solid tumors or HR‐positive advanced breast cancer.     

Molecular pathology quality control in Southeast Asia: Results of a multiregional quality assurance study from MASTER KEY Asia

Tissue specimen quality assurance is a major issue of precision medicine for rare cancers. However, the laboratory standards and quality of pathological specimens prepared in Asian hospitals remain unknown. To understand the methods in Southeast Asian oncology hospitals and to clarify how pre-analytics affect the quality of formalin-fixed paraffin-embedded (FFPE) specimens, a questionnaire surveying pre-analytical procedures (Part I) was administered, quality assessment of immunohistochemistry (IHC) staining and DNA/RNA extracted from the representative FFPE specimens from each hospital (Part II) was conducted, and the quality of DNA/RNA extracted from FFPE of rare-cancer patients for genomic sequencing (Part III) was examined. Quality measurements for DNA/RNA included ΔΔCt, DV200, and cDNA yield. Six major cancer hospitals from Malaysia, Philippines, and Vietnam participated. One hospital showed unacceptable quality for the DNA/RNA assessment, but improved by revising laboratory procedures. Only 57% (n = 73) of the 128 rare-cancer patients' specimens met both DNA and RNA quality criteria for next-generation sequencing. Median DV200 was 80.7% and 64.3% for qualified and failed RNA, respectively. Median ΔΔCt was 1.25 for qualified and 4.89 for failed DNA. Longer storage period was significantly associated with poor DNA (fail to qualify ratio = 1579:321 days, p < 0.001) and RNA (fail to qualify ratio = 1070:280 days, p < 0.001). After improvement of pre-analytical factors, the qualification rate increased for hospitals A and E from 41.5% to 70.5% and 62.5% to 86%, respectively. This is the first report to elucidate the pre-analytical laboratory procedures of main Southeast Asian oncology hospitals. An external quality assessment program may improve factors associated with tumor FFPE specimen quality.     

The influence of familial factors on the choice of the place of death for terminally ill breast cancer patients: a retrospective single-center study

Background

The social or familial factors influencing the location chosen for end-of-life (EOL) care for terminally ill breast cancer patients are unknown.

Methods

We retrospectively analyzed 195 patients with recurrent or progressive breast cancer who received anticancer treatment at the National Cancer Center Hospital between January 2008 and May 2012. Detailed data concerning the patients’ demographic, familial, and clinical characteristics were collected, and multivariate and Cox logistic regression analyses were performed to evaluate the impact of these characteristics on the place of EOL care and on survival, respectively.

Results

Sixty-eight patients (34.9 %) died in a hospital, 26 patients (13.3 %) at home, and 101 patients (51.8 %) in hospice. Most of the patients having caregivers received EOL care at palliative care facilities (hospice or home) [odds ratio (OR) 2.57; 95 % confidence interval (CI) 1–6.6; p = 0.05]. In contrast, patients with factors suggesting a clinically severe status (performance status ≥2, use of opioids, delirium, and ascites) more often received EOL care in a hospital. Among patients who received EOL care at hospice or home, patients with minor children received EOL care at home (OR 0.08; 95 % CI 0.02–0.38; p = 0.001). Patients with brain metastases chose hospice (OR 12.37; 95 % CI 2.25–68.13; p = 0.004). Furthermore, having a caregiver was associated with prolonged survival (hazard ratio 0.62; 95 % CI 0.39–0.97; p = 0.035).

Conclusion

Familial factors such as having children and caregivers significantly influenced the place of EOL care for terminally ill breast cancer patients.