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1.  A Phase I Study of the Safety and Pharmacokinetics of Trabectedin in Combination With Pegylated Liposomal Doxorubicin in Patients With Advanced Malignancies 
To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies.
Patients and Methods
Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m2, and normal cardiac function. A 1-hour PLD (30 mg/m2) infusion was followed immediately by 1 of 6 trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) infused over 3 hours, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable txicity. Plasma samples were obtained to assess PK profiles.
The MTD of trabectedin was 1.1 mg/m2. Drug-related grade 3 and 4 toxicities were neutropenia (31%) and elevated transaminases (31%). Six patients responded (1 CR, 5 partial responses), with an overall response rate of 16.7%, and 14 had stable disease >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared to trabectedin and PLD each given as a single agent.
Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types, and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
PMCID: PMC2598415  PMID: 18497430
trabectedin; ET-743; pegylated liposomal doxorubicin (PLD); sarcomas; ovarian cancer
2.  Associations of Diabetes Mellitus with Site-Specific Cancer Mortality in the Asia-Pacific Region 
Owing to the increasing prevalence of obesity and diabetes in Asia, and the paucity of studies, we examined the influence of raised blood glucose and diabetes on cancer mortality risk.
Thirty-six cohort Asian and Australasian studies provided 367,361 participants (74% from Asia); 6% had diabetes at baseline. Associations between diabetes and site-specific cancer mortality were estimated using time-dependent Cox models, stratified by study and sex, and adjusted for age.
During a median follow-up of 4.0 years, there were 5,992 deaths due to cancer (74% Asian; 41% female). Participants with diabetes had 23% greater risk of mortality from all-cause cancer compared with those without: hazard ratio (HR) 1.23 (95% CI 1.12, 1.35). Diabetes was associated with mortality due to cancer of the liver (HR 1.51, 95% CI 1.19, 1.91), pancreas (HR 1.78, 95% CI 1.20, 2.65), and, less strongly, colorectum (HR 1.32, 95% CI 0.98, 1.78). There was no evidence of sex- or region-specific differences in these associations. The population attributable fractions for cancer mortality due to diabetes were generally higher for Asia compared with non-Asian populations.
Diabetes is associated with increased mortality from selected cancers in Asian and non-Asian populations.
PMCID: PMC4170754  PMID: 20705912
Diabetes Mellitus; Cancer Mortality; Epidemiology; Asia-Pacific
3.  Adult height and cancer mortality: The Asia Pacific Cohort Studies Collaboration 
The observation that taller people experience an increased risk of selected cancers is largely restricted to Caucasian cohorts. These associations may plausibly differ in Asian populations. For the first time, we make direct comparison of the associations between height and a series of malignancies in Australasian (Caucasian) and Asian populations.
Analyses were based on the Asia Pacific Cohort Studies Collaboration of 506, 648 male and female study participants (408,381 Asia, 98267 Australasia) drawn from 38 population-based cohort studies. Cox proportional hazards regression was used to estimate the relationship between height and cancer rates.
A total of 3,272,600 person years of follow-up gave rise to 7497 cancer deaths (5232 in men, 2265 in women). After multiple adjustments and left censoring, taller individuals experienced increased rates of carcinoma of the intestine (men and women); all cancers, liver, lung, breast, ‘other’ malignancies (all women); and prostate and bladder (men). No consistent regional (Asia vs. Australasia) or sex-differences were observed.
In the present study, taller men and women had an elevated risk of selected malignancies. These associations did not differ appreciably between Asian and Caucasian populations.
PMCID: PMC4170779  PMID: 19889610
Asia; body height; stature; cancer; malignancy
4.  High-dose chemotherapy and autologous hematopoietic progenitor cell transplantation for non-Hodgkin’s lymphoma in patients >65 years of age 
Patients and methods
We present a retrospective analysis of 99 consecutive patients with relapsed non-Hodgkin’s lymphomas who were older than 65 years at the time of high-dose chemotherapy and autologous progenitor cell transplantation.
Median age at transplant was 68 years (range 65–82). Thirty-six percent of patients had a hematopoietic cell transplantation comorbidity index of >2 at the time of transplantation. The cumulative nonrelapse mortality was 8% [95% confidence interval (CI) 4–17] at 26 months and the 3-year overall survival (OS) was 61% (95% CI 49–71). On multivariate analysis, disease status at transplant and lactate dehydrogenase (LDH) > normal were significant predictors for OS (P = 0.002). Comorbidity index of >2 did not impact OS but did predict for higher risk of developing grade 3–5 toxicity (P = 0.006). Eight patients developed secondary myelodysplastic syndrome/acute myelogenous leukemia after transplantation (cumulative incidence 16%).
Patients with relapsed lymphomas who are >65 years of age should be considered transplant candidates, particularly if they have chemosensitive disease and normal LDH levels at the time of transplantation. Patients with comorbidity index of >2 can also undergo transplantation with acceptable outcomes but may be at higher risk for developing toxicity.
PMCID: PMC4112363  PMID: 18272911
autologous transplant; elderly; non-Hodgkin’s lymphoma
5.  Phase I study of troxacitabine administered by continuous infusion in subjects with advanced solid malignancies 
Troxacitabine is a novel L-nucleoside analogue. Preclinical studies showed improved activity with infusions of at least 3 days compared with bolus regimens, especially at concentrations >20 ng/ml. This phase I study tested the feasibility of achieving a troxacitabine steady-state concentration of 20 ng/ml for at least 72 h in patients with solid tumors.
Patients and methods
Patients with solid tumors received troxacitabine as a progressively longer infusion on days 1–4 of a 28-day cycle. The initial length of infusion and infusion rate were 48 h and 3 mg/m2/day.
Twenty-one patients were treated at infusion lengths that increased from 48 to 72 h and then 96 h. The infusion rate was decreased from 3 to 1.88 mg/m2/day due to toxicity. Dose-limiting toxicities consisted of grade 4 neutropenia (three) and grade 3 constipation (one). The maximum tolerated dose of continuous infusion troxacitabine in patients with solid tumors is 7.5 mg/m2 administered over 96 h. This dose level resulted in steady-state drug concentration of at least 20 ng/ml for 72 h.
Administration of troxacitabine by continuous infusion achieved the prospectively defined target plasma concentration. Pharmacokinetics (PK) modeling coupled with real-time PK assessment was an efficient approach to conduct hypothesis-driven phase I trials.
PMCID: PMC3557502  PMID: 18245131
continuous infusion; PK modeling; troxacitabine
6.  Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy 
Low tumour expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) have been linked with improved outcome for colorectal cancer (CRC) patients treated with 5-fluorouracil (5-FU). It is unclear whether this occurs because such tumours have better prognosis or they are more sensitive to 5-FU treatment.
Patients and methods
Associations between TS, DPD and TP levels, determined by tissue microarrays and immunohistochemistry, and survival was evaluated in 945 CRC patients according to treatment status.
Low TS and DPD expression associated with worse prognosis in stage II [hazard ratio (HR) = 1.69, 95% confidence interval (CI) (1.09–2.63) and HR = 1.92 (95% CI 1.23–2.94), respectively] and stage III CRC patients treated by surgery alone [HR = 1.39 (95% CI 0.92–2.13) and HR = 1.49 (95% CI 1.02–2.17), respectively]. Low TS, DPD and TP associated with trends for better outcome in stage III patients treated with 5-FU [HR = 0.81 (95% CI 0.49–1.33), HR = 0.70 (95% CI 0.42–1.15) and HR = 0.66 (95% CI 0.39–1.12), respectively].
Low TS and DPD expression are prognostic for worse outcome in CRC patients treated by surgery alone, whereas low TS, DPD and TP expression are prognostic for better outcome in patients treated with 5-FU chemotherapy. These results provide indirect evidence that low TS, DPD and TP protein expression are predictive of good response to 5-FU chemotherapy.
PMCID: PMC2931808  PMID: 18245778
colorectal cancer; fluorouracil; predictive; prognostic; thymidylate synthase

Results 1-9 (9)