bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose escalation of doxorubicin hydrochloride and ifosfamide in previously untreated Ewing sarcoma.
Authors: Memon Muhammad , Raja Madras A. , Ahmad Javed , Pant Rajive , Shaheen Mahmoud , Al-Dayel Fouad
Published: March 2020

e20508

Background: Ewing’s sarcoma is a primary malignant tumour of the bone. Ifosfamide and doxorubicin hydrochloride are two active drugs. Administration of the maximum feasible doses may help achieve the best result. In this study we proposed to use the combination of vincristine, actinomycin D, doxorubicin hydrochloride, ifosfamide (VAAI) for total of 12 cycles. Methods: All eligible patients will receive initially four cycles of VAAI. Doses include: vincristine maximum 2 mg IV doxorubicin hydrochloride 25 mg/m2 IVpush for 3 days ifosfamide 3 Gm/m2 as an intravenous infusion over 2 hours for 3 days. Each cycle will be repeated every 21 days. Patient will then undergo response evaluation, and subjected to surgical resection when posible. If surgery is incomplete, not possible or refused, radical radiation therapy to a dose of 55 Gy was given. Post operatively patient will recice two cycle of adriamycin base chemotherapy and than will continue with actinomycin d to complete 12 cycles. Results: 16 patients were enroll, mean age 19 years range 15-35, male/female 9/7, tumor location pelvis 3 femur 5 tibia 1 humrus 2 foot 2 maxilla 1 radius 1 extra skeletal at thigh 1. After the enrolment of three patients, there was frequent incidence of febrile neutropenia and mucositis, dose of ifofamide was reduce to 2.25 gm/m2 and GCSF was added. Out of 16 patients enrolled, 5 patients withdrew (1 recurrent febrile neutropenia, 2 disease progression, 1 delay of chemotherapy more than 3 weeks and 1 was rediagnosed post 4 cyles and surgert as synovial sarcoma). 9 patients received all 12 cycles of chemotherapy (5 patients needed further dose reduction of ifofamide by 20% as per protocol, and 2 patients received 11 cycles. There was no toxic death. 8 patients had mild to moderate mucositis, nausea and vomiting grade 2 in 4 patients and in 3 grade 3.10 patients underwent surgical resection of tumor and 8 patient received radiation therapy. 8 patient achieve complete remission. Conclusions: This is a unique study that all the patient enrolls were more than 14 years, this combination of chemotherapy was well tolerated, had good feasibility and easily manageable toxicity and can be administered as a outpatient. To the best of our knowledge this is the first study using this chemotherapy as outpatient.
Effect of zeb1 and zeb2 on pancreatic fibrobast-induced epithelial-to-mesenchymal transition (EMT) in pancreatic cancer.
Authors: Visa Laura , Samper Esther , Rickmann Mariana , Postigo Antonio , Sanchez-Tillo Esther , Fernandez-cruz Laureano , Balsells Josep , Maurel Joan , Molero Xavier , Vaquero Eva Cristina
Published: March 2020

e21035

Background: EMT renders neoplastic cancer cells the ability to migrate and to invade distant organs. The hallmark of EMT is the loss of E-cadherin, which is a prerequisite for epithelial tumor cell invasion. In pancreatic cancer, loss of tumor E-cadherin is an independent predictor of poor outcome. Aims: To analyze the effect of pancreatic fibroblasts (PF) on inducing EMT in pancreatic cancer cells and to identify the transcription factors (Snail, Slug, ZEB1, ZEB2) that mediate EMT process. Methods: Human PFs were isolated from human pancreatic specimens obtained from chronic pancreatitis and from unaffected margins of pancreatic adenocarcinoma and serous cistoadenoma. PF were cultured until complete cellular activation, as assessed by expression of α-smooth muscle actin, vimentin and fibronectin. Human pancreatic cancer cells Panc-1 were exposed to PF conditioned medium (PF-CM) and EMT analyzed by cell morphology, migration, and E-cadherin expression (quantitative RT-PCR and immunoblot). Gene expression of Snail, Slug, ZEB1, and ZEB2 was analyzed by quantitative RT-PCR, and their activity modulated by siRNA Results: Conditioned media from all types of activated PFs induced EMT changes in Panc-1 cells, as shown by 1) morphological transition from cobblestone shaped to fibroblast-like cells, 2) stimulation of cell migration, and 3) E-cadherin down–regulation; mRNA expression of Snail transiently increased at 30 min after exposure to PF returning to basal levels afterwards; mRNA levels of ZEB1 were not up-regulated upon exposure to PF-CM. However, ZEB1 protein greatly accumulated after 48h incubation with PF-CM, suggesting that PF prevent ZEB1 degradation in Panc-1 cells. Combined RNA downregulation of ZEB1 and ZEB2, but not of Snail and/or Slug, suppressed E-cadherin repression induced by PF. Conclusions: Activated PFs promote the invasive phenotype of pancreatic cancer cells through ZEB1 and ZEB2 activation.
Interleukin-15 expression in lung cancer.
Authors: Adhami Faisal , Steel Jason C , Morris John Charles
Published: March 2020

e21064

Background: Interleukin-15 (IL-15) is a pro-inflammatory cytokine that stimulates the differentiation and proliferation of T, B, and NK cells. IL-15 is normally tightly bound by its receptor, IL-15Rα. Dendritic cells and monocytes/macrophages primarily express both IL-15 and IL-15-Rα; however, expression has been detected on epithelial cells including those of the lung. In the lung, IL-15 is thought to play a role in the induction of immune responses to infection. Over expression of IL-15 has been shown to induce NK cell activation and cytotoxic T-lymphocyte (CTL) responses leading to tumor regression. Little is known about IL-15 or IL-15Rα expression in lung cancer. Methods: mRNA from 146 primary lung cancers were analyzed by multiplex qPCR for expression of IL-15, IL-15Rα and b-actin (internal control) and compared to expression in normal lung tissue from 45 patients. Of the 146 patients, 50 were stage I (IA=20, IB=30), 49 stage II (IIA=9, IIB=40), 36 stage III (IIIA=18, IIIB=18), and 11 stage IV. Results: Comparing the expression of IL-15 between normal lung and tumor, we found tumors expressed significantly less IL-15 than normal lung (P<0.001). Lung cancers at any given stage, expressed significantly less IL-15 than that seen in normal lung. When comparing stages, stage IV tumors expressed significantly less IL-15 than tumors of stages I (P=0.021), II (P=0.020), or III (P=0.024). There was no difference in expression between stages I, II or III (P>0.05). When examining the expression of IL-15Rα we found no differences between normal lung and tumor. No differences were seen between normal lung and stages I-IIIA; however, significantly less IL-15Rα expression was noted in stages IIIB and IV compared to normal lung. Between stages, stages I and II had significantly more IL-15Rα expression than stage IV tumors. There were no differences between stages I, II and III. Conclusions: Pro-inflammatory cytokines such as IL-15 may be important for the induction of lung immunity. IL-15 expression is down regulated in lung cancers and this down regulation increases with stage. We posit that the down regulation of IL-15 by lung cancers may aid in their evasion of immune responses allowing progression and dissemination of tumor.
Analysis of the mutation rate in lymphocytes derived from patients with cutaneous T-cell neoplasms using the PIG-a gene.
Authors: Doratotaj Behzad , Zamechek Leah B. , Hymes Kenneth B. , Araten David J.
Published: March 2020

e21082

Background: It has been proposed that genomic instability may account for the high number of mutations observed in cancer. Inherited mutations in repair genes might play a role; alternatively, hypermutability may be the result of mutagens, or may be limited to a specific pre-malignant population. Here we have investigated the hypothesis that cutaneous T cell neoplasms might be associated with constitutional hypermutability, using an assay based on the PIG-A gene. A broad spectrum of mutations can inactivate PIG-A, which is X-linked; thus, only one mutation is required to produce the PIG-A-null phenotype, which entails a loss of all GPI-linked membrane proteins (e.g. CD48, CD55, CD59, CD52). Methods: We have isolated peripheral blood lymphocytes from normal donors and patients with cutaneous T cell neoplasms, which are initially stimulated with phytohemagglutinin. After 1 week, cells are stained with an anti-CD59 antibody and sorted to eliminate pre-existing mutants. The collected GPI (+) cells are then counted, returned to culture with IL-2 and IL-15, and re-stimulated with beads bearing anti-CD2, anti-CD3, and anti-CD28. After 3 weeks in culture the cells are re-counted, and the frequency (f) of new mutants arising in vitro is determined by flow cytometry, by staining sequentially with a mixture of mouse antibodies specific for 4 GPI-linked proteins, followed by a secondary PE-conjugate, followed by a FITC conjugated antibody specific for a non-GPI linked protein, e.g., CD4, CD8, or CD45. The number of cell divisions (d) in culture is determined by live cell counts before and after expansion, and the mutation rate (μ) is calculated as μ = f / d. Results: Amongst 15 normal donors (mean age 54), μ in proliferating CD45 + T cells ranged from 10 to 183 x 10-7 mutations per cell division (median 35 x 10-7). Amongst 10 patients with cutaneous T cell neoplasms (mean age 60) μ ranged from 7 to 116 x 10-7 (median 23 x 10-7) in proliferating CD4+ cells, and μ ranged from 10 to 363 x 10-7 (median 26 x 10-7) in proliferating CD8 + cells. Conclusions: We conclude that a constitutional increase in the mutation rate, as detected by this assay, is not a common feature of cutaneous T cell malignancies.
Gene expression combined with gene set enrichment analysis to identify markers of vinorelbine efficacy in breast cancer patients.
Authors: Audet Robert , Shen Changyu , Willis Scooter , Duchnowska Renata , Adamowicz Krzysztof , Zok Jolanta , Rogowski Wojciech , Litwiniuk Maria Malgorzata , Debska Sylwia , Jaworska Magdalena , Foszczynska-Kloda Malgorzata , Kulma-Kreft Monika , Zabkowska Katarzyna , Jassem Jacek , Edgerton Susan , Thor Ann D. , Miller Kathy , Sledge George W. , Leyland-Jones Brian
Published: March 2020

e21099

Background: Vinorelbine (V) induces mitotic arrest and apoptosis but there are limited data on its effect on gene expression in breast cancer clinical setting. Methods: 43 adult female patients with pathologically confirmed breast cancer and locally advanced or metastatic disease were treated with V 25 mg/m2 days 1, 8, 15 of a 28-day cycle. Gene expression was assessed in archival FFPE tissue using the microarray-based DASL assay (cDNA-mediated Annealing, Selection extension and Ligation) and correlated with time-to-progression (TTP). Using a Gene Set Enrichment Analysis (GSEA), groups of genes that share a common molecular function, chromosomal location, or regulation were identified in patients classified as having either a short (S) (n=25) or a long (L) (n=18) time to progression (TTP) divided by the median (72 days). The GSEA software ( http://www.broadinstitute.org/gsea/index.jsp ) was used for the analysis. Results: GSEA focusing on genes grouped according to similar a) molecular function: 16 out of a set of 43 genes involved in histone binding were enriched in group S (p = 0.002), consistent with higher expression in group S of HIST3H2BB and HIST1H3I as well as a nuclear transcription factor promoting their expression. b) transcription factors: 14 out of 47 genes were enriched in group S (p = 0.004) and corresponds to genes with promoter regions that match c-fos serum response element-binding transcription factor that modulates, for example, ABCC1 and ABCB1 (P-gp/MDR1) solute carriers. c) chromosomal location: in group S, genes were enriched on chromosome 11q21 (20 out of 45 genes p = 0.004) and on chromosome 12p12 (14 out of 22 genes p = 0.002). Conclusions: a) the up-regulation of histone binding genes is consonant with recent discovery of high affinity V binding to histones b) the role of P-gp/MDR1 in V transport is well known c) our observations on chromosome 11q21 and12p12 are novel. DASL expression combined with GSEA highlights gene sets that correlate with clinical outcome and may lead to predictive markers of V efficacy. Further confirmatory analysis is needed due to the limitation of small sample size and multiple comparisons.
Expression of prostate-specific membrane antigen (PSMA) in the neovasculature of nonprostate human tumors of epithelial and nonepithelial origin.
Authors: Magargal Wells Wrisley , Qian Dapeng , Olson William C.
Published: March 2020

e21131

Background: PSMA is a transmembrane glycoprotein present not only in prostate cancer epithelial cells but also in the neovasculature of many other solid tumors. This expression profile makes it an attractive target for tumor-specific delivery of chemotherapeutic agents to the neovasculature of non-prostate solid tumors. We generated an antibody-drug conjugate (ADC) comprised of a fully human anti-PSMA monoclonal antibody (mAb), conjugated to monomethylauristatin E, a potent cytotoxic agent. PSMA ADC is currently undergoing Phase I clinical testing in men with advanced prostate cancer. Previously, we reported high level PSMA expression in the neovasculature of carcinomas from kidney, colon, non-small cell lung, breast and liver. Here we extend our study to additional carcinomas as well as tumors of non-epithelial origin. Methods: Expression of PSMA protein was evaluated by immunohistochemical analysis of frozen tissues using biotinylated mAb that specifically recognizes the native dimeric form of PSMA. The semi-quantitative scheme of 0 to 3+ was used to indicate the amount of epitope based on the intensity of the color reaction. The strongest possible staining was scored 3+ while 2+ staining was considered moderate and 1+ was considered weak. Endothelial cells were detected by morphology and staining of selected slides with an anti-CD 34 mAb. Results: Moderate to strong (2+ to 3+) neovasculature staining was seen in over 80% of specimens from, bladder (10/10), ovarian (9/10) and pancreatic (8/10) carcinomas. Moderate to strong neovascular staining was seen in 40-80% of specimens from several non-carcinoma tumors, including glioblastoma (4/5), melanoma (7/10), non-Hodgkins lymphoma (6/10), osteosarcoma (3/7) and myeloma (2/5). Only weak (1+) staining was seen in angiosarcoma (2/3) and no staining was observed in the testicular cancers tested (0/5). Conclusions: Robust neovascular expression of PSMA dimer was observed across all eight non-prostatic carcinomas. Significant neovascular expression was also observed in several non-epithelial tumors. These findings may be relevant to the development of novel anti-neovascular therapies that target PSMA.
Multicenter performance evaluation of the MultiDrugQuant assay kit.
Authors: Krajcsi Peter , Tauber Jakab Katalin , Barath Sandor , Gyimesi Edit , Hevessy Zsuzsanna , Sziraki Kiss Valeria , Szabo Peter , Tokes-Fuzesi Margit , Trucza Eva , Kappelmayer Janos , Marki-Zay Janos
Published: March 2020

e21140

Background: Multidrug resistance is the most frequent type of resistance to anticancer chemotherapy, which usually results from the overexpression of efflux transporters, such as the MDR1, MRP1 and BCRP. Unfortunatelly, neither the genetic polymorphisms nor the mRNA/protein expression levels correlate closely with the functional activity. On the other hand, although the functional methods separately gave promising results, standardization and reproducibility of these tests failed to conform with values required from routine diagnostic methods. MultiDrugQuant (MDQ) kit was developed as an improved functional assay system, which can measure the multidrug resistance activity of the three, clinically most relevant efflux transporters using flow cytometry in living tumor cells. The present study aimed to carry out the laboratory validation and to evaluate the performance of the MDQ-kit. Methods: Validation of the kit was carried out according to the standards of the Clinical Laboratory Standards Institute in three university centres. Mononuclear cells were separated using Ficoll gradient and tested at 2-5×106/ml within 6 hours after specimen collection. Activities of the multidrug transporters were calculated from the difference between the mean fluorescent intensity of cells w/o the specific inhibitors, respectively. Inaccuracy and comparative measurements were carried out using cell lines with low and high activity of the transporters. Results on different flow cytometers were compared using CD45 CD19 or CD3 monoclonal antibodies for gating the population of interest. Results: The assay proved to be specific and robust at various concentrations of the fluorescent dyes (10-100 % of the original) or inhibitors (50-150 % of the original). Both intraassay and interassay reproducibilities were <5 %. Multidrug resistance activity values determined on different flow cytometers were comparable and eligible. Conclusions: The MDQ assay provides quantitative results on the activity of the MDR1, MRP1 and BCRP in the target cells, which might be used to predict the resistance of these cells to particular cytotoxic agents. Recently, the MDQ-kit has been registered for in vitro diagnostic use in the EU.
The Caris registry: Building a biomarker-focused database to advance patient care.
Authors: Sanders Sheri , Schroeder Wendy , Wright Alan , Field Jeff
Published: March 2020

e21152

Background: The medical community is continually searching for the best way to treat cancer. The value and utility of biomarkers in guiding treatment decisions is widely accepted but remains a challenge for the bedside clinician and requires ongoing validation and correlation to clinical outcomes. Caris Life Sciences has a dedicated team of scientists who study volumes of scientific literature, synthesize biomarker research and by way of an evidence-based electronic rules engine, translates the application of the literature to biomarker analysis of tumor tissue (The Target Now Report) in support of biomarker-drug association evidence useful in clinical decision-making. Subsequently, Caris initiated the Caris Registry to capture clinical disease, treatment and outcome data from patients who have a Target Now Report. Methods: The Caris Registry is a web-based data entry platform based on an IRB approved protocol. The eligible subject for the Registry will have a qualified Target Now Report. All clinical data elements are defined and supported by the NCI caBIG standardized data dictionary. Disease history/status, treatments and outcomes are captured at enrollment with Day 1 defined as the date of the Target Now Report and every 9 months for 5 years or death whichever is first. Results: As of January 19, 2012, there are 68 participating centers across the country and 43 centers pending IRB submission. There are 852 Target Now cases enrolled with the following cancer lineage distribution: Breast 209, Ovary 169, Lung 117, Colon 79, Endometrium 33, and other 245. There are 323 completed follow up reports and 175 completed end of study reports capturing vital status and cancer related deaths. Conclusions: Caris has successfully launched a scientifically valid and regulatory compliant Registry and database intended to become a robust library of tumor biomarker results linked to clinical outcomes data. As the library grows, data mining could provide vital information access to researchers, pharmaceutical firms, government, academia and insurers for use in drug development, molecular and biomarker research, economic impact assessments, healthcare policy discussion and most importantly directing personalized cancer treatment.
Detection of discordant HER2 status by FISH in circulating tumor cells and disseminated tumor cells in early-stage breast cancer using a microfluidic-based cell enrichment and extraction platform (OncoCEE).
Authors: Krishnamurthy Savitri , Bischoff Farideh Z. , Mayer Julie Ann , Kuerer Henry Mark , Lodhi Ashutosh , Bhattacharyya Anirban , Hall Carolyn S. , Wong Karina , Pham Tam , Pircher Tony J , Lucci Anthony
Published: March 2020

TPS10631

Background: Evaluation of HER2 in circulating (CTCs) and disseminated (DTC) tumor cells may aid therapy in breast cancer. We report here the discordance in HER2 status in CTCs and DTCs in early stage breast cancer by fluorescence in situ hybridization (FISH) using a microfluidic cell platform (OncoCEE). Methods: Blood (10ml) and BM (1-2ml) from patients with Stage T1 and T2 breast cancer was collected in OncoCEE-Sure collection tubes. Mononuclear cells were recovered using a Percoll density gradient method, incubated with a mixture of 10 primary capture antibodies (Abs), and introduced into streptavidin coated OncoCEE microchannels for tumor cell capture. For blood samples, captured cells were stained with anti cytokeratin (CK) and CD45 Abs for CTC enumeration followed by FISH using probes specific to centromere 17 and HER2. For BM samples, captured cells were subjected to HER2 FISH analysis. The ratio of HER2:CEP17>2.0 in any CK+/ CD45- and CK-/CD45- cell was regarded as positive for HER2. Results: Blood and BM from 68 patients (68 Blood, 54 BM; 54 matched blood and BM) with stage T1N0 (41), T1N1 (6), T2N0 (11), T2N1(2), T2N2 (1), T2N3 (2) with HER2+ (n=7) and HER2- (n=61) breast cancers were studied. The 7 patients with HER2 + primary tumor had HER2+ DTCs in 3/7 (43 %) and HER2 + CTCs in 1/6 (17 %) patients. HER2 + DTCs and HER2 + CTCs occurred in 10/47 (21%) and in 4/57 (7%) patients with HER2- primary breast tumors. The discordance of HER2 status was observed in 14% in CTCs and in 22% in DTCs. Conclusion: 1. The cell enrichment and extraction microfluidic platform (OncoCEE) provides a sensitive approach for evaluation of HER2 in CTCs and DTCs. 2. CTCs and DTCs acquired HER2 gene amplification in 21% and 7% of patients with HER2 negative early stage primary breast cancer. 3. CTCs and DTCs lost HER2 gene amplified status in 57% and 83% of patients with HER2 positive early stage primary breast cancer. 4. The clinical significance of alterations in HER2 status among CTCs and DTCs in early stage breast cancer needs further investigation.
Gemcitabine with nab-paclitaxel in neoadjuvant treatment of pancreatic adenocarcinoma: GAIN-1 study.
Authors: Desai Neelam Vijay , Hughes Steven , Ivey Alison , Hochwald Steven N. , Allegra Carmen Joseph , Trevino Jose Gilberto , Dang Long H. , Behrns Kevin , Lightsey Judith L. , Zlotecki Robert , Liu Chen , Chauhan Shailendra , Zajac-Kaye Maria , Zuluaga Toro Tania , Hou Wei , George Thomas J.
Published: March 2020

TPS4136

Background: Pancreatic adenocarcinoma remains a deadly disease with a dismal prognosis. Only 15% of patients present with resectable disease with 5-year survival only 20% despite adjuvant therapy. Neoadjuvant treatment may improve R0 resection rates, allows more patients curative surgery, is cost effective, and may improve overall survival by incorporating earlier systemic therapy. Methods: This is a prospective single arm open-label phase II trial using gemcitabine (G) and nab-paclitaxel (A) in the neoadjuvant treatment of resectable and borderline-resectable pancreatic cancer. Patients are stratified by risk group as defined by a predictive model published by Bao et al and the NCCN expert consensus statement (Table): low-risk resectable (Group 1) and high-risk resectable or borderline-resectable (Group 2). Group 1 receives 3 cycles of G+A then surgical resection. 1 cycle = G 1000mg/m2 +A 100mg/m2 IV on Days 1, 8, 15 Q28 days. Group 2 receives 2 cycles of G+A followed by 2 weeks of hypofractionated IMRT (50.4Gy in 10 fx) with G 400mg/m2 IV weekly, then surgical resection. The primary endpoints are R0 resection rate and overall response rates. Secondary endpoints are PFS, OS, 30-day post-op mortality, toxicity, QOL and molecular analysis including DPC4 and SPARC levels in tumor and stroma. Enrollment has just begun with a total accrual goal of 60 patients. This platform will allow targeted systemic therapy and tailored treatment stratification to optimize outcomes in curable pancreatic cancer. This study is registered with Clinicaltrials.gov (NCT01470417). [Table: see text]
What is optimal timing of post prostatectomy radiotherapy? Is adjuvant radiotherapy equivalent to early salvage radiotherapy? The “RAVES” phase III randomized clinical trial.
Authors: Pearse Maria , Kneebone Andrew , Duchesne Gillian M. , Fisher Richard , Fraser-Browne Carol , Frydenberg Mark , Haworth Annette , Jose Chakiath , Joseph David John , Lim Tee , Matthews John , Millar Jeremy , Sidhom Mark , Spry Nigel , Tang Colin , Turner Sandra , Williams Scott G. , Wiltshire Kirsty , Woo Henry , Davis Ian D.
Published: March 2020

TPS4690

Background: Three randomised trials have demonstrated a significant benefit of adjuvant post prostatectomy radiotherapy in patients with positive margins, extra capsular extension or seminal vesicle involvement, and it should be regarded as current standard of care. However, adopting this approach will expose nearly half of such patients to unnecessary radiotherapy and potential treatment morbidity. Salvage radiotherapy, if given early, is recognised to be effective. The RAVES trial is designed to compare these two approaches, and was developed in collaboration with the Trans Tasman Radiation Oncology Group (TROG), Australian and New Zealand Urogenital and Prostate Trials Group (ANZUP) and the Urological Society of Australia and New Zealand (USANZ). It aims to test the hypothesis that active surveillance with early salvage radiotherapy is non-inferior to adjuvant radiotherapy with respect to risk of biochemical failure (defined as PSA level ≥ 0.40 ng/mL and rising). Methods: Patients must have at least one of the following risk factors: positive margins, extracapsular extension or seminal vesicle involvement. They must start radiotherapy within 4 months of radical prostatectomy (RP) and have an undetectable PSA (≤ 0.10 ng/ml) prior to randomisation. Patients receiving androgen deprivation or who have an artificial hip are excluded. Eligible patients are randomised to either: Arm 1: Adjuvant RT (64Gy in 32#) commenced within 4 months of RP, or Arm 2: Active surveillance with 3 monthly PSA tests and commencement of early salvage RT (64Gy in 32#) if PSA rises ≥ 0.20 ng/ml. Stratification is by seminal vesicle invasion, Gleason Score, pre-operative PSA, margin positivity (no/yes) and radiotherapy institution. A sample size of 470 patients is required to detect a 10% non-inferiority margin in the 5-year biochemical failure-free rate between the adjuvant and active surveillance arms. As of 31 Jan 2012, 186 patients have been recruited across 26 centres in Australia and New Zealand. A meta analysis with the MRC RADICALS and GETUG-17 trials will be prospectively designed to detect a survival difference between the two approaches.
OPTIMA prelim: Optimal personalized treatment of early breast cancer using multiparameter analysis: Preliminary study.
Authors: Stein Rob , Makris Andreas , Hughes-Davies Luke , Dunn Janet A , Bartlett John M. S. , Donovan Jenny , McCabe Christopher , Cameron David A. , Canney Peter , Earl Helena Margaret , Francis Adele , Morgan Adrienne , Pinder Sarah , Rea Daniel , Poole Christopher John , Hall Peter , Hiller Louise , Stallard Nigel , Higgins Helen B
Published: March 2020

TPS665

Background: “Multi-parameter” prognostic tests such as Oncotype DX are increasingly used to identify women with ER +ve HER2 -ve breast cancer treated with endocrine therapy who are unlikely to benefit meaningfully from adjuvant chemotherapy. The supporting evidence for predictive testing is retrospective and is strongest for women with negative nodes. Randomised trials to validate testing are in progress but more evidence is needed, especially for node positive disease. There is early evidence that other multi-parameter tests which are in development have a predictive utility. Methods: OPTIMA will assess the value of multi-parameter tests in a UK population. OPTIMA prelim, the feasibility phase, will recruit 300 patients from May 2012 (with a 200 patient bridging extension to the main study). Eligible patients will have ER +ve HER2 -ve tumours with involved nodes (pN1-2). Patients will be randomised to the standard arm of both chemotherapy and endocrine therapy, or to the “test-directed treatment” arm in which patients will be assigned either the same chemotherapy and endocrine therapy or endocrine therapy only according to the result of an Oncotype DX test. OPTIMA prelim has 3 objectives. (1) To establish whether randomisation to test-directed treatment is acceptable to patients and clinicians. This will be done through qualitative research with in-depth interviews with OPTIMA researchers and by recording and analysing consultations when the trial is discussed with potential participants. (2) Alternative multi-parameter tests will be evaluated on all patients’ tumours and their performance will be compared to Oncotype DX using statistical and cost-effectiveness analysis to select a candidate test(s) appropriate for NHS use to be evaluated in the main trial. (3) The success of the main trial depends on efficient tumour sample collection and analysis to avoid treatment delays. The obstacles to this will be analysed in detail using a sample tracking database. The main study is an efficacy trial of 2-3 arms with the same design but uses tests selected in OPTIMA prelim. It will compare 5-year relapse free survival of test-directed vs. conventional treatment with a non-inferiority hypothesis.
A multicenter randomized phase III trial of customized chemotherapy versus standard of care for first-line treatment of elderly patients with advanced non-small cell lung cancer (EPIC).
Authors: Simon George R. , Novello Silvia , Vavala Tiziana , Stinchcombe Tom , Gregorc Vanesa , Otterson Gregory Alan , Gitlitz Barbara Jennifer , Langdon Robert M. , Bordoni Rodolfo , Axelrod Rita , Gandara David R. , Scagliotti Giorgio
Published: March 2020

TPS7619

Background: Personalizing therapy based on an individual patient’s molecular profile is a potentially promising approach to optimize efficacy with the available agents. Optimizing efficacy in the elderly is particularly relevant owing to their increased propensity to suffer therapy-induced toxicity. In this proposal we will attempt to demonstrate optimization of therapy in good performance EGFR mutation negative elderly patients by taking in to consideration the histology of the tumor, the ERCC1 (marker of platinum resistance), RRM1 (for gemcitabine resistance) and TS (for pemetrexed resistance) status. Methods: Untreated advanced stage NSCLC patients age >70 years with measurable disease will be enrolled. Patients will be randomized in a 2:1 randomization to experimental arm (A) or standard arm (B). In arm A, treatment with single or dual-agent chemotherapy will be selected based on histology, ERCC1 (E), RRM1(R) and TS (T) expression at the RNA level. The cut off for high (+, therefore resistant) or low (-, therefore sensitive) expression have been previously defined. Patients with squamousNSCLC who are E-R+ will be treated with single agent carboplatin, E+R- with gemcitabine, E-R- with carboplatin and gemcitabine and E+R+ with docetaxel or vinorelbine. In non-squamous NSCLC patients E-T+ will be treated with carboplatin, E+T- withpemetrexed, E-T- with carboplatin and pemetrexed, E+T+R- with gemcitabine and E+T+R+ with docetaxel or vinorelbine. In arm B treatment with single or dual-agent chemotherapy will be at the discretion of the care provider, i.e., standard of care. The primary endpoint of the trial is overall survival (OS). The secondary endpoint is progression-free survival (PFS). The tertiary endpoint is disease response. Treatment will continue to maximum of 6 cycles if tolerated or until disease progression. A sample size of 453 patients will give us 90% power to detect a three-month improvement in median survival (8 to 11 months; corresponding to a HR of 0.73) with the log rank test at a significance level of 5%(1-sided) allowing for a 10% failure rate in gene analyses.
Topotecan-vincristine-doxorubicin in metastatic neuroblastoma with insufficient response to rapid COJEC: Results of a SIOPEN Group study.
Authors: Amoroso Loredana , Valteau-Couanet Dominique , Castel Victoria , Brock Penelope , Pearson Andrew DJ , Ladenstein Ruth Lydia , Garaventa Alberto
Published: March 2020

10016

Background: This study evaluated the activity and toxicity of a topotecan-vincristine-doxorubicin (TVD) combination administered to patients with stage 4 neuroblastoma failing to achieve adequate metastatic remission after induction therapy (rapid COJEC) according to the HR-NBL-1 SIOPEN protocol. Methods: Patients above 1 year of age with stage 4 neuroblastoma, who failed to achieve adequate metastatic remission with rapid COJEC were eligible. Topotecan was administered at 1.5 mg/m²/day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m² and doxorubicin, 45 mg/m². Tumour response was assessed after 2 TVD courses, according to the INSS criteria. Patients achieving CR or VGPR (metastatic CR) or PR (≤ 3 skeletal MIBG spots and cytomorphological CR on 2 bone marrow aspirates) underwent myeloablative therapy (MAT) followed by PBSC rescue. Patients who failed to achieve PR after 2-4 TVD courses, or developed PD were withdrawn from the study and were treated at physicians’ discretion. Results were recorded in the SIOPEN-R-NET database. Results: Sixty-eight patients who did not achieve CR or VPGR after rapid COJEC were enrolled in the study. Responses of 68 assessable patients after 2 TVD courses included 4 CR, 13 VPGR, 26 PR, 7 MR, 14 NR, 2 PD, 2 missing data (major response rate 65 %). Twenty-five patients who achieved CR or VGPR or PR (metastatic CR) received MAT according to protocol. Thirty-three/68 patients are presently alive, no toxic deaths occurred. Toxicity was mostly hematopoietic. Fifty-three patients experienced grade 4 neutropenia, 47 grade 4 thrombocytopenia and 12 grade 4 anemia after the first course. Forty-nine patients developed grade 4 neutropenia, 41 grade 4 thrombocytopenia and 12 grade 4 anemia after the second course. Twenty-six patients required hospitalisation for systemic antibiotic therapy after the first course, and 19 patients after the second. Grade 3-4 stomatitis requiring a liquid diet or TPN was observed in 17 patients after the first cycle and 9 after the second. Conclusions: This TVD combination was active and tolerable in patients with metastatic neuroblastoma after treatment with rapid COJEC. Clinical trial information: 2006-001489-17.
Outcome of risk-adapted therapy for pediatric acute lymphoblastic leukemia in Egypt.
Authors: Sidhom Iman A. , Mokhles Abir , Soliman Sonya , Shaaban Khaled , Salem Sherine , Yassin Dina , Hassanein Hala , Hamdy Nayera , Rashed Waffa , El-Nashar Amr , Magdi Hadeel , Elhaddad Alaa
Published: March 2020

10044

Background: With modern risk directed therapy, >80% of children with acute lymphoblastic leukemia (ALL) in western countries are cured. The 5-year event free survival (EFS) and relapse free survival (RFS) of pediatric ALL patients in Egypt were 65% and 75% respectively in a previous study using an intensive treatment protocol for all patients. Aim: To improve cure rates of Egyptian children with ALL using risk adapted therapy. Methods: From July 2007 to December 2010, 706 patients aged 1-18 years with newly diagnosed ALL were treated at Children Cancer Hospital Egypt with a risk directed ALL protocol adopted from St Jude Total Study XV. Results: B-precursor phenotype was encountered in 75.8% and T-cell in 24.2%. Based on initial presentation and response to therapy measured by minimal residual disease (MRD), 42.6%, 45.8% and 11.6% of the patients were classified as low, intermediate and high risk respectively. The 5-year RFS and EFS were 88.2 ± 1.5% and 76.5 ± 1.7% respectively. Adverse events included 4.4% induction deaths, 2.5% failure to achieve induction remission (1.4% remained refractory), 6.8% deaths in remission, 9.2% relapses (3.1% hematological, 1.8% combined hematological and CNS, 4% isolated CNS, 0.3% isolated testicular), 0.9% abandonment of therapy and one patient had secondary myeloid leukemia. The median follow up for patients alive in CR was 43months (range 24–65). The 5-year RFS of the low, intermediate and high risk groups were 92.2 ± 2.4%, 85.3 ± 2.2% and 82.7 ± 4.8% respectively (p=0.001), while the 5-year EFS were 87.6 ± 2.5%, 78.2 ± 2.5% and 57.9 ± 5.7% respectively (p<0.001). Prognostic factors that had statistically significant unfavorable impact on both EFS and RFS by univariate analysis were age ≥10 years, TLC ≥100x109/L, T-cell phenotype, risk groups, MRD d42 ≥1% and MRD W7 ≥0.1%, while MRD d15 ≥1% had statistically significant unfavorable outcome on EFS only. By multivariate analysis, TLC and MRD W7 had prognostic significance on EFS and RFS, MRD d42 on EFS, while MRD d15 had marginal significance on EFS (p=0.055). Conclusions: Risk adapted therapy was effective in improving ALL survival among patients at our institution compared with previous trials, although the outcome remains lower than that in high income countries.
Association of genetic polymorphisms in the folate pathway with efficacy and toxicity of methotrexate in pediatric osteosarcoma.
Authors: Park Jeong A , Kang Hyoung Jin , Im Ho Joon , Shin Hee Young , Ahn Hyo Seop
Published: March 2020

10051

Background: Osteosarcoma is the most common childhood malignant bone tumor. Methotrexate (MTX), one of the main drugs used for osteosarcoma, is a representative folic acid antagonist. Genetic polymorphisms in folate pathway genes are expected to influence the response and toxicity of high-dose MTX therapy. However, there are scarce data available regarding associations between genetic polymorphisms and pediatric osteosarcoma. This study evaluated the effect of common genetic polymorphisms in the folate metabolic pathway on overall survival, event-free survival and histological response to neoadjuvant chemotherapy including high-dose MTX. In addition, whether these genetic polymorphisms affect the concentrations of MTX and toxicity after high-dose MTX therapy for osteosarcoma was investigated. Methods: Blood and tissue samples from 48 osteosarcoma patients who had completed chemotherapy were obtained, and the following polymorphisms were analyzed; RFC1 80G>A, DHFR 829C>T, MTHFR 677C>T, MTHFR 1298A>C, AMPD1 34C>T, ATIC 347C>G, and ITPA 94C>A. Associations between candidate polymorphisms and survival, histological response (tumor necrosis rate) and MTX level and toxicity after high-dose MTX therapy were analyzed. Results: Event-free survival significantly decreased in DHFR 829 CC homozygote (P=0.045). Variant carriers of MTHFR 677C>T had tendency towards poor histological response (P=0.078). MTX concentration was significantly associated with RFC1 80G>A polymorphism (P=0.027). Liver toxicity after high-dose MTX was associated with ATIC 347C>G (P=0.043) and tended to increase in carriers of MTHFR 677C>T (P=0.069). Severe stomatitis was associated with RFC1 80G>A (P=0.012). Conclusions: This study has demonstrated that several genetic polymorphisms in folate pathway can significantly influence therapeutic response, clinical outcome and MTX level and toxicity after high-dose MTX therapy in osteosarcoma patients. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of patients with osteosarcoma, aiding the development of tailored therapeutic approaches.
Hypoxia, angiogenic markers, and response to neoadjuvant radiotherapy in soft-tissue sarcomas.
Authors: Lewin Jeremy , Khamly Kenneth , Mitchell Catherine , Hicks Rodney J , Toner Guy C. , Ngan Sam , Powell Gerard , Desai Jayesh , Choong Peter , Stacker Steven , Slavin John , Thomas David Morgan
Published: March 2020

10567

Background: Hypoxia is common in soft-tissue sarcomas (STS) and may correlate with radiotherapy (RT) resistance and worse outcomes. We aimed to quantify intratumoral hypoxia with 18-fluoroazamycin arabinoside (FAZA)-PET in resectable STS and correlate this to 18-fluorodeoxyglucose (FDG)-PET, tumour response, angiogenesis biomarkers and patient (pt) outcomes. Methods: This phase II prospective study enrolled pts with resectable STS prior to neoadjuvant RT. Pts underwent FDG-PET and FAZA-PET prior to RT. Circulating and immunohistochemical (IHC) markers of hypoxia and vessel architecture were measured weekly. Response to RT was measured by surgically resected pathologic necrosis (PN), radiological response and relapse-free survival. Results: 23 pts were recruited. 47% (8/17) demonstrated hypoxia on FAZA-PET with a possible association between hypoxia and enhanced metabolic activity on FDG-PET (FDG SUVmax=15.33 with hypoxia; SUVmax=5.86 without hypoxia p=.08). FDG-PET response to RT correlated with PN (good/equivocal FDG-PET response: 59% PN; poor FDG-PET response: 19%PN p=.008). All relapses were distant (n=10) at average follow up of 5 years. Relapse was associated with higher FAZA-PET SUV (1.94 vs 1.28 p=0.02), FDG-PET SUVmax (14.4 vs 6.2 p=0.05), and poorer response to RT (PN 36% vs 66%, p=0.04). Baseline VEGF-C (531±82pg/ml, mean±SEM) were higher than VEGF-A (35±8pg/ml) and VEGF-D (131±17pg/ml), and correlated with protein expression on IHC staining. Hypoxia on FAZA-PET correlated with lower baseline VEGF-A/C (VEGF-C: (292pg/ml vs 688pg/ml p=0.16) and VEGF–A (14pg/ml vs 46pg/ml p=0.13). Low VEGF-C correlated with resistance to RT assessed by FDG-PET. In hypoxic tumors after 1 week of RT, VEGF-A and C levels were significantly increased (VEGF-A 80pg/ml vs 14pg/ml; VEGF-C 541ng/ml vs 292ng/ml). Response to RT correlated with less induction of VEGF-A/C. Relapse was associated with lower baseline VEGF and higher IHC levels of other hypoxic markers (GLUT-1, CA 9). Conclusions: In STS, hypoxia is common, measurable, predicts poorer response to RT and is associated with adverse outcomes. Circulating levels of VEGF-C, the dominant isoform, inversely correlated with hypoxia and is induced by RT.
Association between single nucleotide polymorphism (SNPs) of CYP3A4 and SLC28A3 and clinical outcome in metastatic breast cancer (MBC) patients receiving paclitaxel plus gemcitabine (PG) chemotherapy as first-line treatment.
Authors: Im Seock-Ah , Park Yeon Hee , Lee Soo-Youn , Woo Sook Young , Kim Seonwoo , Chang Won Jin , Choi Moon Ki , Hong Jung Yong , Ok Oh-Nam , Seo Jeong Ju , Ahn Jin Seok , Im Young-Hyuck
Published: March 2020

1088

Background: Paclitaxel and gemcitabine (PG) combination chemotherapy is an effective regimen in metastatic breast cancer (MBC) patients as first-line chemotherapy. The primary purpose of our study was to investigate the association of the single nucleotide polymorphisms (SNPs) and clinical outcome in MBC patients treated with PG chemotherapy. Methods: A total of 324 MBC patients were enrolled in this prospective multicenter trial as the first-line chemotherapy. Eighty five of 324 patients were available for SNP analysis. Germline DNA from peripheral blood (PB) mononuclear cells was extracted. SNPs in 15 genes (27 SNPs) from pathways that may influence cellular sensitivity to paclitaxel and gemcitabine were genotyped from PB sample. Results: Median progression free survival (PFS) and overall survival (OS) of all 324 patients was 8.7 months (95% CI: 7.5-9.6 mo.) and 26.9 months (95% CI: 23.6-30.1 mo.), respectively. Among clinical parameters, young age (p = 0.047, HR 1.03 [95% CI, 1-1.07]), positive hormonal receptor status (p = 0.0004, HR 0.26 [95% CI, 0.12-0.54]), and hepatic metastasis (p = 0.046, HR 2.30 [95% CI, 1.02-5.18]) were identified predictive factors for OS in Cox-regression analysis. SLC28A3 SNP which participates in transcription showed correlation with OS. OS of the patients with CC and CT genotypes in SLC28A3 was significantly longer than the OS of the patients with TT genotype (median OS: 31 vs. 37 vs. 21 months, p = 0.027, HR 2.6 [95% CI, 1.1-6.3]). OS of the patients with TT genotype in CYP3A4 was significantly longer than the OS of the patients with TC genotype (median OS: 37 vs. 19 months, p = 0.021, HR 5.8 [95% CI, 1.3-25.7]). After adjusting hormonal receptor status, age, and hepatic metastasis, prognostic value of SLC28A3 remained significant (HR 2.9, p = 0.047). Other SNPs were not significantly associated with PFS, OS, or toxicities. Conclusions: SLC28A3 SNP can predict with the clinical outcome of MBC patients treated with PG chemotherapy. Further studies for functional mechanism of germline polymorphisms in SLC28A are warranted.
ALDH1-positive cells in primary tumor and axillary lymph node metastases after chemotherapy as a prognostic factor in breast cancer patients.
Authors: Sakakibara Masahiro , Nagashima Takeshi , Sangai Takafumi , Fujimoto Hiroshi , Suzuki Tiberu-Hiroshi , Miyazaki Masaru
Published: March 2020

1097

Background: The cancer stem cell theory that was established for hematopoietic neoplasms has significantly changed the concept of cancer therapy. Aldehyde dehydrogenase 1 (ALDH1)-positive cells show stem-like or progenitor ability, and have been considered as a clinically important diagnostic and therapeutic target in breast cancer patients. However, responsiveness of ALDH1-positive cells to chemotherapy in primary and metastatic lesions remains unclear, along with relationships to prognosis in patients with breast cancer. This study evaluated responsiveness to chemotherapy in the ALDH1-positive cells for primary and metastatic lesions and relationships to prognosis in patients with node-positive breast cancer. Methods: We evaluated 115 breast cancer patients with cytologically confirmed lymph node metastases who had undergone surgery after neoadjuvant chemotherapy (NAC). Using ALDH1 immunohistochemistry of core needle biopsy for the primary tumor and cytology samples for axillary lymph nodes before NAC and pathological samples of each after NAC, we evaluated the clinical significance of ALDH1-positive cell status in primary and metastatic lesions before and after NAC. Results: Presence of ALDH1-positive cancer cells, not ALDH1-negative cancer cells, in primary and metastatic lesions after NAC was associated with worse prognosis. In multivariate analysis, only ALDH1-positive cells in metastatic lesions after NAC correlated with overall survival. Responsiveness of ALDH1-positive cells to chemotherapy differed between primary and metastatic lesions, and ALDH1-positive cells in metastatic lesions after NAC might clinically precede those in the primary lesion. Conclusions: Responsiveness of the ALDH1-positive cells to chemotherapy in primary and metastatic lesions, and the prognostic significance, were clarified in breast cancer patients. ALDH1-positive status might offer a surrogate marker as a new concept in patients with node-positive breast cancer.