Pharmacogenetics of ABCB5, ABCC5 and RLIP76 and doxorubicin pharmacokinetics in Asian breast cancer patients.

This study investigated the impact of ABCB5, ABCC5 and RLIP76 polymorphisms on doxorubicin pharmacokinetics in Asian breast cancer patients (N=62). Direct sequencing was performed to screen for previously identified ABCC5 polymorphisms as well as polymorphisms in the exons and exon-intron boundaries of ABCB5 and RLIP76 genes. Genotype-phenotype correlations were analyzed using Mann-Whitney U-test. The homozygous variant allele at the ABCC5 g.+7161G>A (rs1533682) locus was significantly associated with higher doxorubicin clearance (g.+7161AA vs g.+7161GG, CL/BSA (Lh-1m-2): 30.34 (25.41-33.60) vs 22.46 (15.04-49.4), P=0.04). Homozygosity for the reference allele at the ABCC5 g.-1679T>A locus was associated with significantly higher doxorubicinol exposure (g.-1679TT vs g.-1679TA, AUC0-∞/dose/BSA (hm-5): 15.48 (6.18-67.17) vs 8.88 (3.68-21.71), P=0.0001). No significant influence of the three newly identified ABCB5 polymorphisms (c.2T>C, c.343A>G and c.1573G>A) on doxorubicin pharmacokinetics was observed. No polymorphisms were identified in the RLIP76 gene. These findings suggest that ABCC5 polymorphisms may explain partially the interpatient variability in doxorubicin disposition.

Occurrence, Distribution, and Fate of Organic UV Filters in Coral Communities.

Organic ultraviolet (UV) filters are widely used in personal care products and occur ubiquitously in the aquatic environment. In this study, concentrations of seven commonly used organic UV filters were determined in seawater, sediment and five coral species collected from the eastern Pearl River Estuary of South China Sea. Five compounds, benzophenone-1, -3, and -8 (BP-1, -3, and -8), octocrylene (OC) and octyl dimethyl-p-aminobenzoic acid (ODPABA), were detected in the coral tissues with the highest detection frequencies (>65%) and concentrations (31.8 ± 8.6 and 24.7 ± 10.6 ng/g ww, respectively) found for BP-3 and BP-8. Significantly higher concentrations of BP-3 were observed in coral tissues in the wet season, indicating that higher inputs of sunscreen agents could be attributed to the increased coastal recreational activities. Accumulation of UV filters was only observed in soft coral tissues with bioaccumulation factors (log10-values) ranging from 2.21 to 3.01. The results of a preliminary risk assessment indicated that over 20% of coral samples from the study sites contained BP-3 concentrations exceeding the threshold values for causing larval deformities and mortality in the worst-case scenario. Higher probabilities of negative impacts of BP-3 on coral communities are predicted to occur in wet season.

Decadal stability in coral cover could mask hidden changes on reefs in the East Asian Seas.

Coral reefs in the Central Indo-Pacific region comprise some of the most diverse and yet threatened marine habitats. While reef monitoring has grown throughout the region in recent years, studies of coral reef benthic cover remain limited in spatial and temporal scales. Here, we analysed 24,365 reef surveys performed over 37 years at 1972 sites throughout East Asia by the Global Coral Reef Monitoring Network using Bayesian approaches. Our results show that overall coral cover at surveyed reefs has not declined as suggested in previous studies and compared to reef regions like the Caribbean. Concurrently, macroalgal cover has not increased, with no indications of phase shifts from coral to macroalgal dominance on reefs. Yet, models incorporating socio-economic and environmental variables reveal negative associations of coral cover with coastal urbanisation and sea surface temperature. The diversity of reef assemblages may have mitigated cover declines thus far, but climate change could threaten reef resilience. We recommend prioritisation of regionally coordinated, locally collaborative long-term studies for better contextualisation of monitoring data and analyses, which are essential for achieving reef conservation goals.

Association of common genetic variants with breast cancer risk and clinicopathological characteristics in a Chinese population.

Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations, and thus GWAS-identified single nucleotide polymorphisms (SNPs) in one population may not be of significance in another population. In order to explore the role of breast cancer susceptibility variants in a Chinese population of Southern Chinese descent, we analyzed 22 SNPs for 1,191 breast cancer cases and 1,534 female controls. Associations between the SNPs and clinicopathological features were also investigated. In addition, we evaluated the combined effects of associated SNPs by constructing risk models. Eight SNPs were associated with an elevated breast cancer risk. Rs2046210/6q25.1 increased breast cancer risk via an additive model [per-allele odds ratio (OR) = 1.43, 95 % confidence interval (CI) = 1.26-1.62], and was associated with estrogen receptor (ER)-positive (per-allele OR = 1.39, 95 % CI = 1.20-1.61) and ER-negative (per-allele OR = 1.55, 95 % CI = 1.28-1.89) disease. Rs2046210 was also associated with stage 1, stage 2, and stage 3 disease, with per-allele ORs of 1.38 (1.14-1.68), 1.48 (1.25-1.74), and 1.58 (1.28-1.94), respectively. Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95 % CI) of 1.26 (1.12-1.43) at rs1219648, 1.22 (1.07-1.38) at rs2981582, 1.21 (1.07-1.36) at rs2981579, and 1.18 (1.04-1.35) at rs11200014. Variants of rs7696175/TLR1, TLR6, rs13281615/8q24, and rs16886165/MAP3K1 were also associated with increased breast cancer risk, with per-allele ORs (95 % CI) of 1.16 (1.00-1.34), 1.15 (1.02-1.29), and 1.15 (1.01-1.29), respectively. Five SNPs associated with breast cancer risk predominantly among ER-positive tumors (rs2981582/FGFR2, rs4415084/MRPS30, rs1219648/FGFR2, rs2981579/FGFR2, and rs11200014/FGFR2). Among our Chinese population, the risk of developing breast cancer increased by 90 % for those with a combination of 6 or more risk alleles, compared to patients with ≤3 risk alleles.

Phase I pharmacokinetic study of a weekly liposomal paclitaxel formulation (Genexol-PM) in patients with solid tumors.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD) and the pharmacokinetic profile of Genexol-PM in Asian cancer patients. MATERIALS AND METHODS: Patients (N = 24) refractory to previous chemotherapy received Genexol-PM as an 1-h infusion on a weekly basis for 3 weeks followed by a resting week. The starting dose was 80 mg/m(2) and the maximum administered dose was 200 mg/m(2). RESULTS: The majority of patients had lung, nasopharyngeal and breast cancers and in eleven patients (46%), taxane-based chemotherapy had previously failed. The MTD was defined at 180 mg/m(2). The most common grade 3 non-hematologic adverse events in cycle 1 were fatigue (4%) and neuropathy (4%) occurring mainly at 200 mg/m(2). Five (21%) patients had partial response, nine (38%) had stable disease and seven (29%) had disease progression. Five of 11 previously taxane-refractory patients showed clinical benefit to Genexol-PM. The pharmacokinetics of Genexol-PM displayed dose-proportionality, with both the maximum concentration (C(max)) and the area under the concentration-time curve from zero to infinity (AUC(0-infinity)) increasing by approximately four- and threefold, respectively, as the dose of Genexol-PM was escalated from 80 to 200 mg/m(2). The median total-body clearance of Genexol-PM for all patients was 43.9 l/h. CONCLUSION: The weekly regimen of Genexol-PM was well tolerated and responses were observed in patients with refractory tumors, including patients who had failed taxane-based chemotherapy previously.

Post-colonoscopy colorectal cancers identified by probabilistic and deterministic linkage: results in an Australian prospective cohort.

OBJECTIVE: Post-colonoscopy colorectal cancers (PCCRCs) are recognised as a critical quality indicator. Benchmarking of PCCRC rate has been hampered by the strong influence of different definitions and methodologies. We adopted a rigorous methodology with high-detail individual data to determine PCCRC rates in a prospective cohort representing a single jurisdiction. SETTING: We performed a cohort study of individuals who underwent colonoscopy between 2001 and 2008 at a single centre serving Australian Capital Territory (ACT) and enclaving New South Wales (NSW) region. These individuals were linked to subsequent colorectal cancer (CRC) diagnosis, within 5 years of a negative colonoscopy, through regional cancer registries and hospital records using probabilistic and deterministic record linkage. All cases were verified by pathology review. Predictors of PCCRCs were extracted. PARTICIPANTS: 7818 individuals had a colonoscopy in the cohort. Linkage to cancer registries detected 384 and 98 CRCs for notification dates of 2001-2013 (ACT) and 2001-2010 (NSW). A further 55 CRCs were identified from a search of electronic medical records using International Classification of Diseases-10 diagnosis codes. After verification and exclusions, 385/537 CRCs (58% male) were included. PRIMARY OUTCOME MEASURE: PCCRC rates. RESULTS: There were 15 PCCRCs in our cohort. The PCCRC incidence rate was 0.384/1000 person-years and the 5-year PCCRC risk was estimated as 0.192% (95% CI 0.095 to 0.289). The index colonoscopy prior to PCCRC was more likely to show diverticulosis (p=0.017 for association, OR 3.56, p=0.014) and have poor bowel preparation (p=0.017 for association, OR 4.19, p=0.009). CONCLUSION: In this population-based cohort study, the PCCRC incidence rate was 0.384/1000 person-years and the 5-year PCCRC risk was 0.192%. These data show the 'real world' accuracy of colonoscopy for CRC exclusion.

Development and validation of algorithms for the detection of statin myopathy signals from electronic medical records.

The purpose of this study was to develop and validate sensitive algorithms to detect hospitalized statin-induced myopathy (SIM) cases from electronic medical records (EMRs). We developed four algorithms on a training set of 31,211 patient records from a large tertiary hospital. We determined the performance of these algorithms against manually curated records. The best algorithm used a combination of elevated creatine kinase (>4× the upper limit of normal (ULN)), discharge summary, diagnosis, and absence of statin in discharge medications. This algorithm achieved a positive predictive value of 52-71% and a sensitivity of 72-78% on two validation sets of >30,000 records each. Using this algorithm, the incidence of SIM was estimated at 0.18%. This algorithm captured three times more rhabdomyolysis cases than spontaneous reports (95% vs. 30% of manually curated gold standard cases). Our results show the potential power of utilizing data and text mining of EMRs to enhance pharmacovigilance activities.

Analysis of dose intensity in doxorubicin-containing adjuvant chemotherapy in stage II and III breast carcinoma.

Three hundred thirty-six patients with stage II or stage III breast cancer were treated on an adjuvant protocol containing fluorouracil, doxorubicin, cyclophosphamide, vincristine, and prednisone (FACVP). Depending on the estrogen-receptor (ER) status, the patients were subdivided to receive maintenance chemotherapy with or without tamoxifen. The administered dose intensity of fluorouracil, doxorubicin, and cyclophosphamide (FAC) (mg/m2/wk) relative to the projected dose intensity (based on planned dose) was computed for each patient. The relative dose intensity of the first six cycles of chemotherapy (RDI6) was compared with disease-free survival (DFS). Of the 299 patients who completed at least six cycles of therapy, 83% received dose intensities within 20% of standard intensity (.8 less than or equal to RDI6 less than or equal to 1.2). The group with the highest dose intensity (RDI6 greater than or equal to 1.13) had the longest DFS, though there was not a clear trend of linear association between dose intensity and DFS after adjustment for prognostic factors (P = .16). The patients who received at least standard dose intensity (RDI6 greater than or equal to 1.0) had longer DFS than those whose therapy did not reach standard intensity (RDI6 less than 1.0). This difference was significant in patients with stage III disease (P = .01). The 37 patients who completed fewer than six cycles of chemotherapy had the shortest DFS (5-year DFS of 48% v 65% in the others). This retrospective analysis, in a heterogeneously treated group of patients, did not show the differences in outcome associated with dose intensity as demonstrated in the earlier studies comparing projected dose intensity of various cyclophosphamide, methotrexate-, and fluorouracil (CMF)-containing adjuvant trials. Improved DFS was noted in the stage III patients receiving higher dose intensity. Our failure to demonstrate the differences in stage II patients may be due to the narrow range of dose intensity in this study or to a difference in the dose-response curves depending on the stage of disease.

Acceptance of prophylactic surgery and chemoprevention of cancer in Singapore - a survey.

INTRODUCTION: In addition to surveillance practices, chemoprevention and prophylactic surgery can reduce the risk of cancer in individuals at high risk. Sociocultural factors may have a role to play in such decision making. Little is known regarding the factors that play a role in decision making in Singapore. MATERIALS AND METHODS: One hundred and two individuals at normal risk completed a questionnaire on the concept of chemoprevention and prophylactic surgery. The results were analysed using the convenience sampling method. RESULTS: Participants were mostly Chinese (94.1%). More than 90% of the respondents answered the section on prophylactic surgery and chemoprevention. Thirty-eight individuals (41.3%) would not consider prophylactic surgery, while 42 (45.7%) would not consider prophylactic surgery now but might consider it in the future. Twenty-five individuals (26.9%) would not consider chemoprevention by taking a medication, 57% would not consider it now but might in the future. CONCLUSION: A cross-sectional public view suggests that medical prophylaxis is likely to be more acceptable to the general public compared to surgical prophylaxis.

Fulminant hepatic failure in non-Hodgkin lymphoma patients treated with chemotherapy.

Chemotherapy is the mainstay of therapy for patients with non-Hodgkin lymphoma. Among side-effects associated with the use of chemotherapy, immunosuppression is one which can be potentially fatal. In hepatitis B carriers, immunosuppression permits widespread infection of the hepatocytes and its subsequent withdrawal causes an "immunological rebound" leading to massive necrosis of hepatocytes. 4 patients who died of fulminant hepatitis following chemotherapy are reported. These were patients with positive hepatitis B serology. Caution is advised when treating non-Hodgkin lymphoma in patients from hepatitis B endemic regions.

Genetic susceptibility for breast cancer--risk assessment and counseling.

The incorporation of genetic information into clinical oncology practice is a process in evolution, necessitating consideration of cancer risk assessment, ethical and social implications of testing and efficacy of treatment, and prevention interventions. Although most cancers do have a hereditary component, recognizing individuals who are at unusually high risk is important for planning their surveillance practices and considering options for risk management over a lifetime, and because of implications for their family members. Genetic information has enormous potential to inform and transform cancer risk identification, risk reduction, and treatment practices. In this review, we summarize basic information about breast cancer genetics, examine accumulating data about the prevalence and penetrance of deleterious mutations and management options for BRCA1 and BRCA2 mutation carriers, and discuss some of the counseling issues that may occur as physicians and patients explore this exploding area of oncology. The rapid incorporation of careful genetic testing into oncology practice is an important step toward more precise risk management. Currently, the time necessary for careful discussion of the complex issues raised by genetic testing for inherited breast/ovarian cancer susceptibility may necessitate referral to geneticists or genetic counselors for truly informed consent to be obtained. However, identification of women for whom testing is appropriate and management of cancer risk with women after testing, are critical new functions for oncologists. They are only the beginning of exciting new opportunities in cancer risk and prevention.

Concurrent chemoradiotherapy followed by adjuvant chemotherapy in Asian patients with nasopharyngeal carcinoma: toxicities and preliminary results.

PURPOSE: Nasopharyngeal carcinoma (NPC) is endemic in Singapore. Nearly 60% of the patients diagnosed with NPC will present with locally advanced disease. The North American Intergroup study 0099 reported improved survival outcome in patients with locally advanced NPC who received combined chemoradiotherapy when compared to radiotherapy alone. Hence we explored the feasibility and efficacy of a similar protocol in our patients. METHODS AND MATERIALS: Between June 1996 and December 1997, 57 patients were treated with the following schedule as described. Radical radiotherapy (RT) of 66-70 Gy to the primary and neck with cisplatin (CDDP) 25 mg/m2 on days 1-4 given by infusion over 6-8 hours daily on weeks 1, 4, and 7 of the RT. This is followed by a further 3 cycles of adjuvant chemotherapy starting from week 11 from the first dose of radiation (CDDP 20 mg/m2/d and 5-fluorouracil [5-FU] 1 gm/m2/d on days 1-4 every 28 days). RESULTS: The majority of patients (68%) had Stage IV disease. About 54% of patients received all the intended treatment; 75% received all 3 cycles of CDDP during the RT phase and 63% received all three cycles of adjuvant chemotherapy. The received dose intensity of CDDP and 5-FU of greater than 0.8 was achieved in 58% and 60% of the patients respectively. Two treatment-related deaths due to reactivation of hepatitis B and neutropenic sepsis respectively, were encountered. At median follow-up of 16 months, 14 patients had relapsed, 12 systemically and 2 loco-regionally. CONCLUSION: Due to the acceptable tolerability of such a protocol in our cohort of patients, we have embarked on a Phase III study to confirm the results of the 0099 Intergroup study in the Asian context.

Primary intrathoracic malignant effusion: a descriptive study.

BACKGROUND: Patients who present with malignant pleural/malignant effusion without a definite primary site are not well described in the medical literature. In the course of our clinical practice, we have observed certain traits that are peculiar to patients with such a presentation. We have applied the term primary intrathoracic malignant effusion (PIME) to describe this condition. STUDY OBJECTIVES: Patients must fulfill the following criteria before a diagnosis of PIME can be made: clinical presentation dominated by pleural/pericardial effusion; histologic proof of malignancy obtained from the pleura and/or pericardium; no definite primary site in the lungs or elsewhere from CT scan of the chest, chest radiograph, or physical and endoscopic examination; no history of malignancy; and no history of asbestos exposure. Exposure to environmental tobacco smoke (ETS) among the nonsmokers was examined in a case-control setting. METHODS: We conducted a retrospective search of our database of patients who were referred to the Department of Medical Oncology with a diagnosis of pleural/pericardial effusion from January 1993 to January 2000. RESULTS: Seventy-one of 200 patients from our database met the criteria. A significant majority of the patients were women (65%) and nonsmokers (72%). All patients had adenocarcinoma shown on biopsy. The majority of patients (63%) had disease localized to the intrathoracic serosal surfaces; the rest had distant metastases involving the lung (50%), bone (27%), liver (19%), brain (8%), and skin (4%). Six patients had two or more sites of distant metastases. There was a significant association with ETS exposure when compared to a control group comprised of patients with colonic cancer, matched for sex and age. The median survival was 10 months for patients with disease localized to the pleura/pericardium and 7 months for those with distant metastases. Thirty-eight patients (54%) received chemotherapy. All had platinum-based chemotherapy, except for three patients. The median survival for patients treated or not treated with chemotherapy was 12 months and 5 months, respectively. This difference in survival was statistically significant (p = 0.003). CONCLUSIONS: PIME should be viewed as a distinct entity. Its etiology remains largely unknown, although exposure to environmental tobacco smoke may play a part. Platinum-based chemotherapy may have a positive biological effect on this disease. More studies are required to elucidate the epidemiology, possible etiologic factors, and treatment options for this group of patients.

Primary pulmonary lymphoma--clinical review from a single institution in Singapore.

Primary pulmonary lymphoma is a rare and vexing subset of extranodal non-Hodgkin's lymphoma. We report 11 cases and provide a brief literature review. We also highlight an unusual case of a relapsed peripheral T-cell primary lung lymphoma that underwent apparent spontaneous remission. Eleven cases of primary pulmonary lymphoma treated in our institution were studied for their clinical characteristics, behaviour, response to treatment and clinical outcome. The median duration of follow up was 26 months. The mean age was in the 50s and the presenting symptoms generally respiratory and non-specific. LDH levels did not correlate with either stage or grade of disease. Lower lobe involvement was most common and nodules and mass-like lesions the main radiologic feature. Small lymphocytic lymphoma accounted for the majority of cases and were indolent in behaviour. Good symptom control and radiologic response was achieved with chemotherapy in disseminated low grade lung lymphomas. Combination chemotherapy was effective in the aggressive lymphomas. In conclusion, Small lymphocytic lymphoma of the lung is an indolent disease with a long symptom-free survival even after recurrence. Our series confirms the clinical characteristics of primary pulmonary lymphoma. The role of Ling Zhi in effecting the spontaneous remission in the peripheral T-cell lymphoma is speculative.

Antiviral property and mode of action of a sulphated polysaccharide from Sargassum patens against herpes simplex virus type 2.

A sulphated polysaccharide (SP2) was isolated from the brown alga Sargassum patens. SP2 inhibited the replication of herpes simplex virus type 2 (HSV-2) dose-dependently by 38.5-96.1% of the control level, after incubations with 0.78-12.5 microg/ml of the polysaccharide. SP2 exhibited extracellular virucidal activity only in high concentrations (>/=12.5 microg/ml) but significantly inhibited the virus attachment to its host cells by 45.1%, at concentration as low as 1 microg/ml. All the results from this study suggested that the antiviral mode of action of SP2 could be ascribed to the inhibition of virus adsorption, which is different from that of the current drug of choice acyclovir.

Magnetic resonance imaging of spinal intradural granulocytic sarcoma.

We report the case of a young black male with a spinal intradural granulocytic sarcoma proved by needle aspiration. The tumor was evaluated by myelography, computed tomography, and magnetic resonance imaging (MRI). Other than its rarity, the "dripping candle wax" appearance on MR T1-weighted images and the lack of enhancement with Gd-DTPA makes this case unique. Progressive changes of the tumor following chemo- and radiotherapy were successfully demonstrated by MR.

Enteric MRI contrast agents: comparative study of five potential agents in humans.

We compared the effectiveness of 1 mM Geritol, 12% corn oil emulsion, Kaolin-pectin, single contrast oral barium sulfate, and effervescent granules as enteric magnetic resonance imaging (MRI) contrast agents. Five volunteers were recruited. Each volunteer ingested for examinations, separated by at least one week, either 500 ml of each of the liquid preparations or two packets of the CO2 granules (producing 400 ml of CO2 per packet). Abdominal MR images were then obtained using a 1.5 T Magnetom imager and SE 550/22, SE 2000/45/90 and FISP 40/18/40 degrees pulse sequences. The oil emulsions were best tolerated. Barium sulfate caused the greatest amount of nausea, followed by Geritol and Kaolin-pectin. With FISP 40/18/40 degrees, 60%-80% of the small bowel was well delineated using oil emulsion, Kaolin-pectin, or barium sulfate. We conclude that oil emulsion was by far the best enteric MR contrast agent in our study. Good delineation of the small bowel and pancreas can be achieved using oil emulsion and gradient echo pulse sequences. The lack of side-effects and the excellent taste make it highly acceptable to human subjects.

Paramagnetic oil emulsions as oral magnetic resonance imaging contrast agents.

The combination of a paramagnetic agent with an oil emulsion can uniformly enhance the small bowel. We discovered that the entire small bowel becomes homogeneously brighter than its surroundings when imaged with all commonly utilized pulse sequences. We have tried various combinations of ferric ammonium citrate, ferrous sulfate, gadolinium-DPTA and corn oil, olive oil and peanut oil. All paramagnetic oil emulsions tested were uniformly distributed throughout the small bowel, but the enhancement effect is much stronger with the ferric ammonium citrate and gadolinium-DPTA oil emulsions. We have also developed a mixture of Geritol, corn oil, ice cream and milk, which uniformly coats the small bowel wall, has good enhancement effect, tastes good, and is nutritious. With this dietary contrast, retroperitoneal structures including the pancreas can be well delineated. We conclude that the combination of a paramagnetic agent with an oil emulsion can work as a safe and effective magnetic resonance imaging (MRI) oral contrast agent with high patient acceptance.

MACOP-B in advanced non-Hodgkin's lymphoma.

Between May 1986 and March 1991, 38 patients with previously untreated advanced intermediate and high-grade non-Hodgkin's lymphoma were treated with methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B): 73% of the patients had stages III and IV disease, 55% had "B" symptoms, and 55% had bulky disease (nodal masses > 10 cm). Histologic subtypes included diffuse large-cell and immunoblastic lymphoma. In 96% of patients clinical response was achieved (69% complete response and 27% partial response). Acturial disease-free survival and overall survival were 55% and 60%, respectively, at 2 years. Treatment-related mortality was 16%: 3 patients died from neutropenic sepsis and 3 (hepatitis B carriers) from fulminant hepatitis at the time of steroid withdrawal. The incidence of nonfatal neutropenic fever was 24% and mucocutaneous toxicity was common. The poorer overall results may be attributed to more advanced disease. Caution is advised in the use of MACOP-B among hepatitis B carriers.