Roe O.D.,Norwegian University of Science and Technology |
Szulkin A.,Karolinska Institutet |
Anderssen E.,University of Tromso |
Flatberg A.,Norwegian University of Science and Technology |
And 6 more authors.
PLoS ONE | Year: 2012
Background: Pemetrexed, a multi-folate inhibitor combined with a platinum compound is the first-line treatment of malignant mesothelioma, but median survival is still one year. Intrinsic and acquired resistance to pemetrexed is common, but its biological basis is obscure. Here we report for the first time a genome-wide profile of acquired resistance in the tumour from an exceptional case with advanced pleural mesothelioma and almost six years survival after 39 cycles of second-line pemetrexed/carboplatin treatment. Methodology and Principal Findings: Genome-wide analysis with Illumina BeadChip Kit of 25,000 genes was performed on mRNA from pre-treatment and post-resistance biopsies from this individual as well on case and control samples from our previously published study (in total 17 samples). Cell specific expression of proteins encoded by selected genes were analysed by immunohistochemistry. Serial serum levels of CA125, CYFRA21-1 and SMRP levels were examined. TS protein, the main target of pemetrexed was overexpressed. Proteins and genes related to DNA damage response, elongation and telomere extension and repair related directly and indirectly to platinum resistance were overexpressed, as the CHK1 protein and the genes CHEK2, LIG3, POLD1, POLA2, FANCD2, PRPF19, RECQ5 respectively, the last two not previously described in mesothelioma. We observed a down-regulation of leukocyte transendothelial migration and cell adhesion molecules pathways. Silencing of NT5C in two mesothelioma cell lines did not sensitize the cells to Pemetrexed. Proposed resistance markers are TS, KRT7/ CK7, TYMP/ thymidine phosphorylase and down-regulated SPARCL1 and CDKN1B. Moreover, comparison of the primary expression of the sensitive versus a primary resistant case showed multi-fold overexpressed DNA repair, cell cycle, cytokinesis, and spindle formation in the latter. Serum CA125 and SMRP reflected the clinical and radiological course and tumour burden. Conclusions: Genome-wide microarray of mesothelioma pre- and post-resistance biopsies indicated a novel resistance signature to pemetrexed/carboplatin that deserve validation in a larger cohort. © 2012 Røe et al.
Duke P.,Memorial University of Newfoundland |
Godwin M.,Memorial University of Newfoundland |
Ratnam S.,Public Health Laboratories |
Dawson L.,Memorial University of Newfoundland |
And 9 more authors.
BMC Women's Health | Year: 2015
Background: Cervical cancer is highly preventable and treatable if detected early through regular screening. Women in the Canadian province of Newfoundland & Labrador have relatively low rates of cervical cancer screening, with rates of around 40 % between 2007 and 2009. Persistent infection with oncogenic human papillomavirus (HPV) is a necessary cause for the development of cervical cancer, and HPV testing, including self-sampling, has been suggested as an alternative method of cervical cancer screening that may alleviate some barriers to screening. Our objective was to determine whether offering self-collected HPV testing screening increased cervical cancer screening rates in rural communities. Methods: During the 2-year study, three community-based cohorts were assigned to receive either i) a cervical cancer education campaign with the option of HPV testing; ii) an educational campaign alone; iii) or no intervention. Self-collection kits were offered to eligible women at family medicine clinics and community centres, and participants were surveyed to determine their acceptance of the HPV self-collection kit. Paired proportions testing for before-after studies was used to determine differences in screening rates from baseline, and Chi Square analysis of three dimensional 2?×?2?×?2 tables compared the change between communities. Results: Cervical cancer screening increased by 15.2 % (p?0.001) to 67.4 % in the community where self-collection was available, versus a 2.9 % increase (p?=?0.07) in the community that received educational campaigns and 8.5 % in the community with no intervention (p?=?0.193). The difference in change in rates was statistically significant between communities A and B (p?0.001) but not between communities A and C (p?=?0.193). The response rate was low, with only 9.5 % (168/1760) of eligible women opting to self-collect for HPV testing. Of the women who completed self-collection, 15.5 % (26) had not had a Pap smear in the last 3 years, and 88.7 % reported that they were somewhat or very satisfied with self-collection. Conclusions: Offering self-collected HPV testing increased the cervical cancer screening rate in a rural NL community. Women who completed self-collection had generally positive feelings about the experience. Offering HPV self-collection may increase screening compliance, particularly among women who do not present for routine Pap smears. © 2015 Duke et al.
Noguchi S.,Osaka University |
Kim H.J.,Asan Medical Center |
Jesena A.,Cancer Clinic |
Parmar V.,Tata Group |
And 7 more authors.
Breast Cancer | Year: 2015
Background: Monthly goserelin 3.6 mg dosing suppresses estradiol (E2) production and has proven efficacy in pre-menopausal women with estrogen receptor (ER)-positive breast cancer. This non-inferiority study evaluated the efficacy and safety of 3-monthly goserelin 10.8 mg compared with monthly goserelin 3.6 mg. Methods: This was a Phase 3, open-label, multicenter trial. Pre-menopausal women with ER-positive advanced breast cancer were randomized to 3-monthly goserelin 10.8 mg or monthly goserelin 3.6 mg; all patients received concomitant tamoxifen (20 mg daily). The primary endpoint was progression-free survival (PFS) rate at 24 weeks; non-inferiority was to be confirmed if the entire 95 % confidence interval (CI) for the treatment difference was above −17.5 %. Secondary endpoints included objective response rate (ORR), serum E2 levels, safety, and tolerability. Results: In total, 222 patients were randomized (goserelin 10.8 mg, n = 109; goserelin 3.6 mg, n = 113). PFS rate at week 24 was 61.5 % (goserelin 10.8 mg) and 60.2 % (goserelin 3.6 mg); treatment difference (95 % CI) was 1.3 % (−11.4, 13.9), confirming non-inferiority of goserelin 10.8 mg compared with goserelin 3.6 mg. ORR was 23.9 % (goserelin 10.8 mg) and 26.9 % (goserelin 3.6 mg); treatment difference (95 % CI) was −3.0 % (−15.5, 9.7). At week 24, mean serum E2 concentrations were similar in the goserelin 10.8 mg and goserelin 3.6 mg groups (20.3 pg/mL and 24.8 pg/mL, respectively). Conclusion: A regimen of 3-monthly goserelin 10.8 mg demonstrated non-inferiority compared with monthly goserelin 3.6 mg for PFS rate at 24 weeks, with similar pharmacodynamic and safety profiles, in pre-menopausal women with ER-positive breast cancer. © 2015 The Author(s)
Strom H.H.,Helgeland Hospital |
Strom H.H.,University of Tromso |
Bremnes R.M.,University of Tromso |
Sundstrom S.H.,Cancer Clinic |
And 2 more authors.
Clinical Lung Cancer | Year: 2015
Background In a phase III trial of patients with unresectable, locally advanced, stage III non-small-cell lung cancer (NSCLC) with a poor prognosis, palliative concurrent chemoradiotherapy (CRT) provided a significantly better outcome than chemotherapy alone, except among performance status (PS) 2 patients. In the present subgroup analysis, we evaluated the effect on patients aged ≥ 70 years (42% of all included) compared with patients aged < 70 years enrolled in the trial. Patients and Methods All patients received 4 courses of intravenous carboplatin and oral vinorelbine. The experimental arm also received radiotherapy (42 Gy in 15 fractions). The included patients were required to have large tumors (> 8 cm), weight loss (> 10% within the previous 6 months) and/or PS 2. Results The overall survival was increased among the CRT patients in both age groups, but the difference was significant only in patients aged < 70 years (median survival, 14.8 vs. 9.7 months; P =.001; age ≥ 70 years, median survival, 10.2 vs. 9.1 months; P =.09). Patients aged ≥ 70 years experienced better preserved health-related quality of life (QOL) and significantly less hematologic toxicity. The 2- and 3-year survival was significantly increased in both age groups receiving CRT. Conclusion Elderly patients aged ≥ 70 years with unresectable, stage III, locally advanced, NSLCL and a poor prognosis can tolerate CRT with the doses adjusted to age and palliative intent. These results indicate that CRT can provide both survival and QOL benefits in elderly patients, except for those with PS 2 or worse. The male predominance in the ≥ 70-year-age group and the reduced chemotherapy intensity for the patients aged > 75 years might explain the lack of significant survival improvement among those patients aged ≥ 70 years. © 2015 The Authors.
Jain M.M.,Hospital and Research Center |
Gupte S.U.,Cancer Clinic |
Patil S.G.,HCG Bangalore Institute of Oncology |
Pathak A.B.,Cancer Care Clinic |
And 18 more authors.
Breast Cancer Research and Treatment | Year: 2016
Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m2 [n = 64] and 295 mg/m2 [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m2 every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m2, PICN 295 mg/m2, and nab-paclitaxel 260 mg/m2 arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m2, PICN 295 mg/m2, and nab-paclitaxel 260 mg/m2 arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m2 every 3 weeks was effective and well tolerated and showed similar tolerability compared with nab-paclitaxel 260 mg/m2 every 3 weeks. Statistically, significant differences were not observed in the PICN and nab-paclitaxel treatment arms for radiologist-assessed ORR or median PFS. The novel paclitaxel formulation, PICN, offers apart from efficacy, potential safety advantage of decreased use of corticosteroid pretreatment and the absence of the risk of transmission of blood product-borne disease. © 2016 The Author(s)