tbuckley/cabot-search huggingface dataset:
Phase II multicentric uncontrolled national trial assessing the efficacy of nilotinib in the treatment of advanced melanomas with c-KIT mutation or amplification: Results of the pharmacodynamic study.
Authors: Elodie Lesteven, Maxime Battistella, Thomas Jouary, Sophie Dalac, Stephane Dalle, Bernard Guillot, Jean-Philippe Arnault, Marie-Françoise Avril, Christophe Bedane, Guido Bens, Marie- Beylot-Barry, Florent Grange, Nicolas Meyer, Laurent Machet, Philippe Saiag, Nicolas Dumaz, Samia Mourah, Celeste Lebbe
Journal: Journal of Clinical Oncology (2015)

e20062 Background: A recent French national phase II clinical trial (NCT01168050) evaluating nilotinib in KIT mutated advanced melanoma showed an overall response rate of 20% (Lebbe et al, ASCO 2014). We conducted a pharmacodynamic study to evaluate potential biomarkers associated with clinical response and disease control. Methods: 25 patients had tumor specimen available at baseline and tested for c-KIT mutation, amplification and c-KIT expression. Twelve had available follow-up biopsies, 5 with a progressive disease (PD), 8 with a stable disease (SD), 1 with a partial response (PR). Follow-up biopsies were tested for c-KIT secondary mutations, gene copy number variation and expression related to angiogenesis, apoptosis and proliferation. IHC staining was performed on sections at baseline and after treatment for c-KIT, p-ERK, p-AKT and p-MEK. Results: C-KIT expression was confirmed in all patients treated with nilotinib at baseline. The presence of a c-KIT exon 11 or 13 mutations was associated with clinical response. No secondary c-KIT mutations were detected at progression. c-KIT gene copy number revealed an amplification in 5 out of 25 patients prior to treatment without association with response rate. However, 1 SD patient had a decrease in c-KIT amplification after treatment. VEGFR-2 gene copy number whose co-amplification with c-KIT is frequent in other solid cancers was not associated with clinical outcome. pMek and pErk decreased in some SD and PR patients, with no variation of pAKT. Interestingly, using transcriptomic analyses FGF2 overexpression prior to treatment was observed in all PR and SD patients studied. Conclusions: Clinical response is associated with c-KIT exon 11 or 13 mutations, and not with the sole amplification of c-KIT. In this study, we found no mutation associated with primary resistance. Albeit no evident biomarker signature was identified in this pharmacodynamics analysis, further studies are needed to evaluate the predictive value of FGF2 expression for nilotinib response. Clinical trial information: NCT01168050.
Vinflunine in patients with advanced unresectable hepatocellular carcinoma and liver impairment
Authors: F. Saliba, B. Paule, R. Adam, D. Castaing, D. Azoulay, I. Ogier, M. Pinel, V. Cadic, M. Delgado
Journal: Journal of Clinical Oncology (2007)

15023 Background: In patients (pts) with advanced hepatocellular carcinoma (HCC) and liver cirrhosis, systemic chemotherapy has most commonly been associated with a very low response rate and high toxicity leading to death from liver failure. Vinflunine (VFL) is a new microtubule inhibitor of the vinca alkaloid class which has demonstrated clinical activity in several tumour types. Methods: A phase I trial was designed to determine VFL dose adjustments in cancer pts with various degrees of liver dysfunction. A high number of pts with HCC and concomitant liver cirrhosis (Child-Pugh grades A and B) were included in the study (18/30 pts). Therefore, a subgroup analysis was carried out in order to determine the safety profile of VFL in these pts (NCI-CTC version 2.0) and to estimate its anti-tumour activity (WHO criteria). Results: Eighteen pts (15 males) of median age 60.7 [26.4–75.3] years with advanced stage and unresectable HCC were treated with VFL. All these pts were outside Milan criteria and ineligible for liver transplantation. Thirteen pts had been previously treated by chemotherapy. The WHO performance status was 0: 11 pts, 1: 5 pts, 2: 2 pts. They received a median number of 4 cycles [1.0–31.0] of different doses of VFL according to the severity of the underlying liver impairment 320 mg/m 2 (3 pts), or 250 mg/m 2 (6 pts) or 200 mg/m 2 (9 pts). One partial response (PR) was observed while 11 pts (61.1%) had stable disease (SD) yielding a disease control rate (PR + SD) of 66.7%. The median progression free survival was 3.4 months [95% confidence interval (CI): 2.6–6.0]. Haematological toxicity: grades (G) 3 anaemia = 4 pts, G3/4 neutropenia = 11 pts, G3 thrombocytopenia = 7 pts, no febrile neutropenia. Other G3 toxicities included G3 abdominal pain (2 pts), constipation (3 pts), neutropenic infection (1 pt). Six pts experienced G3 (5 pts) or 4 (1 pt) fatigue. Conclusions: Vinflunine can be given safely at 320 mg/m 2 or 250 mg/m 2 or 200 mg/m 2 in pts with unresectable advanced HCC with different degrees of liver impairment. The disease control rate is promising (66.7%). No significant financial relationships to disclose.
Methylation profiling of the DNA repair genes in glioblastoma multiforme and its clinical relevance
Authors: H. Kobayashi, N. Ishii, J. Ikeda, Y. Sawamura, Y. Iwasaki
Journal: Journal of Clinical Oncology (2004)

1572 Background: Alterations of DNA repair protein have been associated with sensitivity to anticancer drugs, and transcriptional repression by promoter hypermethylation is an essential role in the protein inactivation. Recently methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter is an expected predictor not only of responsiveness to chemotherapy but also of prognosis of patient with glioma. The aim of this study was to investigate the methylation profile in DNA repair genes, MGMT, FANCF and hMLH1, of glioblastoma multiforme and correlation between the methylation status and outcome of the patients. Methods: In 40 adult patients with glioblastoma multiforme treated with surgery, irradiation, and/or chemotherapy (ACNU: n=19, cisplatin: n=11), median age at diagnosis was 55 years old, and median overall survival time was 14 months. Promoter hypermethylation of MGMT, hMLH1 and FANCF genes in tumor DNA was examined using the methylation-specific PCR assay and COBRA (combined bisulfite restriction analysis) method. We analyzed relation between methylation status of the MGMT promoter and survival in these patients. Results: The hypermethylation in MGMT, FANCF and hMLH1 promoter were detected 24 of 40 (60%), 1 of 40 (2.5%), and 0 of 40, respectively. Kaplan-Meier analysis and log-rank test revealed no significant difference in overall survival between patient subgroups divided by methylation status of MGMT promoter. Cox proportional hazard regression analysis adjusted for age of onset and extent of surgical resection showed the MGMT promoter hypermethylation had no significant association with overall survival time. Conclusions: In our series, promoter hypermethylation of MGMT was not a predictive factor for outcome, however, more controlled study would be required to validate this result. And it is still suggested epigenetic alteration of MGMT might influence nature of glioblastoma compared with other DNA repair genes. No significant financial relationships to disclose.
Whole genome sequencing of Shigella sonnei through PulseNet Latin America and Caribbean: advancing global surveillance of foodborne illnesses
Authors: K.S. Baker, J. Campos, M. Pichel, A. Della Gaspera, F. Duarte-Martínez, E. Campos-Chacón, H.M. Bolaños-Acuña, C. Guzmán-Verri, A.E. Mather, S. Diaz Velasco, M.L. Zamudio Rojas, J.L. Forbester, T.R. Connor, K.H. Keddy, A.M. Smith, E.A. López de Delgado, G. Angiolillo, N. Cuaical, J. Fernández, C. Aguayo, M. Morales Aguilar, C. Valenzuela, A.J. Morales Medrano, A. Sirok, N. Weiler Gustafson, P.L. Diaz Guevara, L.A. Montaño, E. Perez, N.R. Thomson
Journal: Clinical Microbiology and Infection (2017)

Shigella sonnei is a globally important diarrhoeal pathogen tracked through the surveillance network PulseNet Latin America and Caribbean (PNLA&C), which participates in PulseNet International. PNLA&C laboratories use common molecular techniques to track pathogens causing foodborne illness. We aimed to demonstrate the possibility and advantages of transitioning to whole genome sequencing (WGS) for surveillance within existing networks across a continent where S. sonnei is endemic.We applied WGS to representative archive isolates of S. sonnei (n = 323) from laboratories in nine PNLA&C countries to generate a regional phylogenomic reference for S. sonnei and put this in the global context. We used this reference to contextualise 16 S. sonnei from three Argentinian outbreaks, using locally generated sequence data. Assembled genome sequences were used to predict antimicrobial resistance (AMR) phenotypes and identify AMR determinants.S. sonnei isolates clustered in five Latin American sublineages in the global phylogeny, with many (46%, 149 of 323) belonging to previously undescribed sublineages. Predicted multidrug resistance was common (77%, 249 of 323), and clinically relevant differences in AMR were found among sublineages. The regional overview showed that Argentinian outbreak isolates belonged to distinct sublineages and had different epidemiologic origins.Latin America contains novel genetic diversity of S. sonnei that is relevant on a global scale and commonly exhibits multidrug resistance. Retrospective passive surveillance with WGS has utility for informing treatment, identifying regionally epidemic sublineages and providing a framework for interpretation of prospective, locally sequenced outbreaks.
Estimating health care costs for advanced metastatic bladder cancer patients who are lost to follow-up: Applications of the Kaplan-Meier sampling average (KMSA).
Authors: Binglin Yue, Maria L. Lankford, Pamela Landsman-Blumberg
Journal: Journal of Clinical Oncology (2017)

21 Background: There is an increasing need to evaluate the quality and cost of care within oncology. Estimating health care costs for patients who are lost to follow-up or censored often results in underestimating costs, biasing comparative assessments. This study compared traditional costing approaches with that of KMSA methods for patients treated for metastatic bladder cancer. Methods: Advanced metastatic bladder cancer patients receiving second line chemotherapy were identified from the Truven Health MarketScan Claims Databases (04/2011 to 09/2014). All-cause health care costs represent the total dollars paid to all providers of care regardless of diagnosis and were inflated to 2014 USD. Total, medical, pharmacy, and site-of-care costs from treatment initiation to death, end-of-enrollment, or end-of-study period were compared using the KMSA and traditional methods. In KMSA, the follow-up period is divided into small uniform intervals; total cost in each interval is then multiplied by the individual patient’s survival probability at the beginning of each interval and then summed across the intervals. Results: The censoring rate of patients’ follow-up was 49%. The mean per patient total health care captured by traditional method was only 72% of the total cost estimated by KMSA method or $32,930 less per patient. Overall, underestimates ranged from 28% to 41% with pharmacy, ER, and lab service costs underestimated the largest when using the traditional method. Conclusions: The KMSA produced estimates more reflective of actual patient-level health care costs in this claims-based observational cancer study compared to traditional methods by accounting for the effect of censoring. Researchers should consider KMSA when evaluating and comparing costs of care in the presence of variable follow-up.[Table: see text]
Cellular organization and molecular differentiation model of breast cancer-associated fibroblasts
Authors: Susann Busch, Daniel Andersson, Eva Bom, Claire Walsh, Anders Ståhlberg, Göran Landberg
Journal: Molecular Cancer (2017)

The role of cancer-associated fibroblasts (CAFs) during tumour progression is obscured by the inherently complex, heterotypic nature of fibroblast cells and behaviours in various subtypes of malignancies. Therefore, we sought to identify distinct fibroblast subpopulations at the single-cell level. Using single-cell quantitative PCR as a powerful tool to study heterogeneity and rare cell events, in a high-throughput manner a panel of gene targets are run simultaneously on transcripts isolated from single cells obtained by fluorescence-activated cell sort. Assessment of cells with stem-like characteristics was attained by anchorage-independent, anoikis-resistant culture. Single-cell analysis of fibroblasts and their tumour-activated counterparts demonstrated molecularly distinct cell types defined by differential expression of characteristic mesenchymal and fibroblast activation markers. Identified subpopulations presented overlapping gene expression patterns indicating transitional molecular states during fibroblast differentiation. Using single-cell resolution data we generated a molecular differentiation model which enabled the classification of patient-derived fibroblasts, validating our modelling approach. Remarkably, a subset of fibroblasts displayed expression of pluripotency markers, which was enriched for in non-adherent conditions. Yet the ability to form single-cell derived spheres was generally reduced in CAFs and upon fibroblast activation through TGFβ1 ligand and cancer cell-secreted factors. Hence, our data imply the existence of putative stem/progenitor cells as a physiological feature of undifferentiated fibroblasts. Within this comprehensive study we have identified distinct and intersecting molecular profiles defining fibroblast activation states and propose that underlying cellular heterogeneity, fibroblasts are hierarchically organized. Understanding the molecular make-up of cellular organization and differentiation routes will facilitate the discovery of more specific markers for stromal subtypes and targets for anti-stromal therapies.
Erratum: Depletion of clusterin in renal diseases causing nephrotic syndrome (Kidney International (2202) 62 (184-2194))
Authors: G. M. Ghiggeri, M. Bruschi, G. Candiano, M. P. Rastaldi, F. Scolari, P. Paserini, L. Musante, N. Pertica, G. Garidi, F. Ferrario, F. Perfumo, C. Ponticelli
Journal: Kidney International (2003)
Pretreatment serum uPA and survival in patients with advanced pancreatic cancer
Authors: S. M. Ali, J. H. Marx, K. Leitzel, W. Carney, P. Hamer, R. Linnartz, W. Mietlowski, L. Demers, H. A. Harvey, A. Lipton
Journal: Journal of Clinical Oncology (2004)

4247 Background: Urokinase-type plasminogen activator (uPA) is a serine protease associated with tumor cell migration, angiogenesis, metastasis, and invasion. uPA has been reported to be secreted by tumors, adjacent stromal cells, and fibroblasts, and has been proposed as a prognostic factor in breast, liver, and colon cancers. Methods: This study determined serum uPA levels in a phase III clinical trial of 149 patients with advanced pancreatic cancer. A double-antibody sandwich ELISA (Oncogene Science Diagnostics, Cambridge, MA) was employed to determine the pretreatment serum uPA levels in 149 pancreatic cancer patients enrolled in a randomized, double-blind, placebo-controlled phase III trial. A healthy control group consisting of 47 males and 62 females was used to determine control serum levels of uPA. Results: The results showed that serum uPA levels were significantly higher in female (1.37 ng/mL) compared to male (1.15 ng/mL) healthy control individuals (p = 0.0002). Within the female control group, there was no significant difference in serum uPA levels between premenopausal (1.39 ng/mL, n = 47) and post-menopausal (1.31 ng/mL, n = 15) females (p = 0.39). Cutpoint analysis was performed separately using the mean + 2 SD for female (1.94 ng/mL) and male (1.74 ng/mL) controls. In the pancreatic cancer patients, serum uPA levels were elevated in 23 of 63 (36%) female patients, and 40 of 86 (46%) male patients. In addition, mean serum uPA levels were significantly higher in both female (1.85 ng/mL, p<0.00001) and male (1.96 ng/mL, p<0.00001) pancreatic cancer patients when compared to controls. Patients with elevated serum uPA trended toward a shortened survival (median 127 days) compared to patients with normal serum uPA levels (median 198 days)(p = 0.083). Conclusions: Serum uPA levels are significantly elevated in a proportion of advanced pancreatic cancer patients, and these patients trend toward shortened survival. Serum uPA levels may have potential for selection of patients to be treated with novel uPA small-molecule inhibitors. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp.; Oncogene Science/Bayer HealthCare Oncogene Science/Bayer HealthCare Novartis Pharmaceuticals Corp.
Providing consistent patient education across the continuum of cancer care.
Authors: Becky Hoff, Heidi Tonne
Journal: Journal of Clinical Oncology (2017)

187 Background: The need for consistent patient education across Cancer Care Services was identified while planning for the Fred and Pamela Buffett Cancer Center. Work began in November 2015 to validate if education provided by multiple providers in various settings was consistent and delivered a clear message to patients. A plan was developed to provide consistent education across the care continuum with the goal of enhancing patient experience, improving staff workflow and defining expectations for patient education. Methods: A survey to assess the current state of education was conducted. Participants in the survey included multidisciplinary team members from inpatient and ambulatory care settings. Five questions were asked about education consistency. Comments about the current and future state of education were encouraged. An audit of educational materials was completed and outdated resources eliminated. Results: 456 surveys were sent with 154 surveys completed (34% return rate). Five major themes emerged (documentation, role expectation, resource standardization/availability, handoff between departments and disciplines, and assessment of individual learning needs). The documentation in Electronic Medical Record was inconsistent and unable to easily assess learner progress. Role expectation was poorly defined with no consistent approach to education delivery. Resource standardization/availability had varying availability of education materials and staff unaware of resources. Handoff between departments and disciplines had inconsistent documentation and no established process to identify needs and barriers related to successful handoffs. Assessment of individual learning needs had unknown compliance in completing the Learning Questionnaire. A team was assembled to address the themes. A process map of patient education was created starting at the initial encounter through end of treatment. Staff was educated on their role, available resources, and documentation expectations. Conclusions: Conducting an evaluation of the patient education process allows for identification of improvement opportunities. This reduces patient confusion and increases trust. Patient satisfaction scores related to education have increased. This work enhanced the patient experience and helped prepare for a smooth transition of patient education initiatives into our new cancer center.
Triplet therapy with oxaliplatin, irinotecan, 5-fluorouracil and folinic acid within a combined modality approach in patients with liver metastases from colorectal cancer
Authors: J. De La Cámara, J. Rodriguez, F. Rotellar, A. Viudez, J. García-Foncillas, F. Pardo, I. Gíl-Bazo, A. Chopitea, S. Martín-Algarra
Journal: Journal of Clinical Oncology (2004)

3593 Background: Although surgical resection remains the treatment of choice for liver metastases from colorectal cancer, only a minority of pts are suitable for surgery. Preoperative chemotherapy allows secondary liver resection and subsequent long-term survival in some patients (pts)with unresectable CCR liver metastases Methods: The aim of this study was to evaluate the safety and efficacy of oxaliplatin 120 mg/m2 day 1, CPT-11 150 mg/m2 day 1 and 14, fluorouracil 2600 mg/m2 days 1 and 14 and folinic acid 500 mg/m2 days 1 and 14, every four weeks, in metastasic liver CCR patients either technically unresectable or with known poor prognostic factors for long term survival after surgery. Results: 39 pts (M/F: 30/9), median age 55 (28–77), median ECOG 1 (0–2) were included. Mean number of liver nodes and mean size were 6.7 and 6.1 cm, respectively. 22 pts (56.4%) were initially unresectable while 17 (43.6%) had poor prognostic factors including large tumor size (52.9%), multinodular (23.5%), ill-located (23.5) and/or bilobar metastases (35.3%).Overall response rate to induction chemotherapy was 64%, 3 pts (7.7%) progressed while on-therapy. 23 pts underwent secondary surgery, including hepatectomy (52.2%) and wedge resections (47.8%), with (n=10) or without radiofrequency. An R0 resection was achieved in 84 % of pts, with margins <1cm in 60.9% of them. Pathological complete response rate was 17.4%. After neoadyuvant chemotherapy, 11 out of 22 initially unresectable CCR pts underwent surgery with curative intent, including 9 of then with a R0 resection. After a median follow up of 15 months (4–40), median progression-free survival and overall survival have not been reached. Main grade 3–4 toxicity included anemia (7.7%), leucopenia (13.9%), neutropenia (30.8%), plaquetopenia (5.1%), vomiting (5.1%) and diarrhea (23%) 1 pt died due to postoperative complications. Conclusions: Induction therapy with this triplet regimen achieves a high resectability and pathological complete response rates. No significant financial relationships to disclose.
Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model
Authors: Leah A. Mitchell, Fernando Lopez Espinoza, Daniel Mendoza, Yuki Kato, Akihito Inagaki, Kei Hiraoka, Noriyuki Kasahara, Harry E. Gruber, Douglas J. Jolly, Joan M. Robbins
Journal: Neuro-Oncology (2017)

Toca 511 (vocimagene amiretrorepvec) is a retroviral replicating vector encoding an optimized yeast cytosine deaminase (CD). Tumor-selective expression of CD converts the prodrug, 5-fluorocytosine (5-FC), into the active chemotherapeutic, 5-fluorouracil (5-FU). This therapeutic approach is being tested in a randomized phase II/III trial in recurrent glioblastoma and anaplastic astrocytoma (NCT0241416). The aim of this study was to identify the immune cell subsets contributing to antitumor immune responses following treatment with 5-FC in Toca 511-expressing gliomas in a syngeneic mouse model.Flow cytometry was utilized to monitor and characterize the immune cell infiltrate in subcutaneous Tu-2449 gliomas in B6C3F1 mice treated with Toca 511 and 5-FC.Tumor-bearing animals treated with Toca 511 and 5-FC display alterations in immune cell populations within the tumor that result in antitumor immune protection. Attenuated immune subsets were exclusive to immunosuppressive cells of myeloid origin. Depletion of immunosuppressive cells temporally preceded a second event which included expansion of T cells which were polarized away from Th2 and Th17 in the CD4+ T cell compartment with concomitant expansion of interferon gamma-expressing CD8+ T cells. Immune alterations correlated with clearance of Tu-2449 subcutaneous tumors and T cell-dependent protection from future tumor challenge.Treatment with Toca 511 and 5-FC has a concentrated effect at the site of the tumor which causes direct tumor cell death and alterations in immune cell infiltrate, resulting in a tumor microenvironment that is more permissive to establishment of a T cell mediated antitumor immune response.